#1Innovation Series June 29, 2022 2022 BIONTECH#2This slide presentation includes forward-looking statements This presentation contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, as amended, including, but not limited to, statements concerning: the future commercial demand and medical need for initial or booster doses of a COVID-19 vaccine; competition from other COVID-19 vaccines or related to our other product candidates, including those with different mechanisms of action and different manufacturing and distribution constraints, on the basis of, among other things, efficacy, cost, convenience of storage and distribution, breadth of approved use, side-effect profile and durability of immune response; the rate and degree of market acceptance of our COVID-19 vaccine and, if approved, our investigational medicines; the initiation, timing, progress, and results of our research and development programs and our current and future preclinical studies and clinical trials, including statements regarding the timing of initiation and completion of studies or trials and related preparatory work, the period during which the results of the trials will become available and our research and development programs; the timing of and our ability to obtain and maintain regulatory approval for our product candidates; our collaboration with Pfizer to develop and market a COVID-19 vaccine (including a potential booster dose of BNT 162b2 and/or a potential booster dose of a variation of BNT162b2 having a modified mRNA sequence); the ability of BNT162b2 to prevent COVID-19 caused by emerging virus variants; our ability to identify research opportunities and discover and develop investigational medicines; the ability and willingness of our third-party collaborators to continue research and development activities relating to our development candidates and investigational medicines; the impact of the COVID-19 pandemic on our development programs, supply chain, collaborators and financial performance; unforeseen safety issues and claims for personal injury or death arising from the use of our COVID-19 vaccine and other products and product candidates developed or manufactured by us; our ability to progress our Malaria, Tuberculosis and HIV programs, including timing for selecting clinical candidates for these programs and the commencement of a clinical trial, as well as any data readouts; the nature and duration of support from the World Health Organization, the European Commission and other organizations with establishing infrastructure; the development of sustainable vaccine production and supply solutions on the African continent and the nature and feasibility of these solutions; our estimates of research and development revenues, commercial revenues, cost of sales, research and development expenses, sales and marketing expenses, general and administrative expenses, capital expenditures, income taxes, shares outstanding; our ability and that of our collaborators to commercialize and market our product candidates, if approved, including our COVID-19 vaccine; our ability to manage our development and expansion; regulatory developments in the United States and foreign countries; our ability to effectively scale our production capabilities and manufacture our products, including our target COVID-19 vaccine production levels, and our product candidates; and other factors not known to us at this time. In some cases, forward-looking statements can be identified by terminology such as "will," "may," "should," "expects," "intends,” “plans,” “aims," "anticipates," "believes," "estimates," "predicts," "potential," "continue," or the negative of these terms or other comparable terminology, although not all forward-looking statements contain these words. The forward- looking statements in this presentation are neither promises nor guarantees, and you should not place undue reliance on these forward-looking statements because they involve known and unknown risks, uncertainties, and other factors, many of which are beyond BioNTech's control and which could cause actual results to differ materially from those expressed or implied by these forward-looking statements. You should review the risks and uncertainties described under the heading "Risk Factors" in this presentation for the three months ended March 31, 2022 and in subsequent filings made by BioNTech with the SEC, which are available on the SEC's website at https://www.sec.gov/. Except as required by law, BioNTech disclaims any intention or responsibility for updating or revising any forward-looking statements contained in this presentation in the event of new information, future developments or otherwise. These forward-looking statements are based on BioNTech's current expectations and speak only as of the date hereof. BIONTECH 2#3Safety information COMIRNATYⓇ (the Pfizer-BioNTech COVID-19 vaccine) has been granted conditional marketing authorization (CMA) by the European Commission to prevent coronavirus disease 2019 (COVID-19) in people from 5 years of age. The vaccine is administered as a 2-dose series, 3 weeks apart. In addition, the CMA has been expanded to include a booster dose (third dose) at least 6 months after the second dose in individuals 18 years of age and older. For immunocompromised individuals, the third dose may be given at least 28 days after the second dose. The European Medicines Agency's (EMA's) human medicines committee (CHMP) has completed its rigorous evaluation of COMIRNATY®, concluding by consensus that sufficiently robust data on the quality, safety and efficacy of the vaccine are now available. IMPORTANT SAFETY INFORMATION: Events of anaphylaxis have been reported. Appropriate medical treatment and supervision should always be readily available in case of an anaphylactic reaction following the administration of the vaccine. Very rare cases of myocarditis and pericarditis have been observed following vaccination with Comirnaty. These cases have primarily occurred within 14 days following vaccination, more often after the second vaccination, and more often in younger men. Available data suggest that the course of myocarditis and pericarditis following vaccination is not different from myocarditis or pericarditis in general. Anxiety-related reactions, including vasovagal reactions (syncope), hyperventilation or stress-related reactions (e.g. dizziness, palpitations, increases in heart rate, alterations in blood pressure, tingling sensations and sweating) may occur in association with the vaccination process itself. Stress-related reactions are temporary and resolve on their own. Individuals should be advised to bring symptoms to the attention of the vaccination provider for evaluation. It is important that precautions are in place to avoid injury from fainting. The efficacy, safety and immunogenicity of the vaccine has not been assessed in immunocompromised individuals, including those receiving immunosuppressant therapy. The efficacy of COMIRNATY® may be lower in immunosuppressed individuals. As with any vaccine, vaccination with COMIRNATY® may not protect all vaccine recipients. Individuals may not be fully protected until 7 days after their second dose of vaccine. In clinical studies, adverse reactions in participants 16 years of age and older were injection site pain (> 80%), fatigue (> 60%), headache (>50%), myalgia and chills (> 30%), arthralgia (> 20%), pyrexia and injection site swelling (> 10%) and were usually mild or moderate in intensity and resolved within a few days after vaccination. A slightly lower frequency of reactogenicity events was associated with greater age. The overall safety profile of COMIRNATY® in participants 5 to 15 years of age was similar to that seen in participants 16 years of age and older. The most frequent adverse reactions in children 5 to 11 years of age were injection site pain (>80%), fatigue (>50%), headache (>30%), injection site redness and swelling (>20%), myalgia and chills (>10%). The most frequent adverse reactions in clinical trial participants 12 to 15 years of age were injection site pain (> 90%), fatigue and headache (> 70%), myalgia and chills (> 40%), arthralgia and pyrexia (> 20%). There is limited experience with use of COMIRNATY® in pregnant women. Administration of COMIRNATY® in pregnancy should only be considered when the potential benefits outweigh any potential risks for the mother and fetus. It is unknown whether COMIRNATY® is excreted in human milk. Interactions with other medicinal products or concomitant administration of COMIRNATY® with other vaccines has not been studied. For complete information on the safety of COMIRNATY® always make reference to the approved Summary of Product Characteristics and Package Leaflet available in all the languages of the European Union on the EMA website. ● ● ● ● ● ● . The black equilateral triangle ▼ denotes that additional monitoring is required to capture any adverse reactions. This will allow quick identification of new safety information. Individuals can help by reporting any side effects they may get. Side effects can be reported to EudraVigilance or directly to BioNTech using email [email protected], telephone +49 6131 9084 0, or via the website www.biontech.de Pfizer BIONTECH 3#4Safety information AUTHORIZED USE IN THE U.S. COMIRNATYⓇ (COVID-19 Vaccine, mRNA) is an FDA-approved COVID-19 vaccine for active immunization to prevent coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in individuals 16 years of age and older. It is also authorized under EUA to provide a 3-dose primary series to individuals 6 months through 4 years of age, 2-dose primary series to individuals 5 years of age and older, a third primary series dose to individuals 5 years of age and older who have been determined to have certain kinds of immunocompromise, a single booster dose to individuals 12 years of age and older who have completed a primary series with Pfizer-BioNTech COVID-19 Vaccine or COMIRNATYⓇ, a single booster dose to individuals 18 years of age and older who have completed primary vaccination with a different authorized COVID-19 vaccine, a second booster dose to individuals 50 years of age and older who have received a first booster dose of any authorized COVID-19 vaccine; and a second booster dose to individuals 12 years of age and older who have been determined to have certain kinds of immunocompromise and who have received a first booster dose of any authorized COVID-19 vaccine. The booster schedule is based on the labeling information of the vaccine used for the primary series. IMPORTANT SAFETY INFORMATION Individuals should not get the vaccine if they: had a severe allergic reaction after a previous dose of this vaccine had a severe allergic reaction to any ingredient of this vaccine Individuals should tell the vaccination provider about all of their medical conditions, including if they: have any allergies have had myocarditis (inflammation of the heart muscle) or pericarditis (inflammation of the lining outside the heart) have a fever have a bleeding disorder or are on a blood thinner are immunocompromised or are on a medicine that affects the immune system are pregnant, plan to become pregnant, or are breastfeeding have received another COVID-19 vaccine have ever fainted in association with an injection The vaccine may not protect everyone. Side effects reported with the vaccine include: There is a remote chance that the vaccine could cause a severe allergic reaction O A severe allergic reaction would usually occur within a few minutes to 1 hour after getting a dose of the vaccine. For this reason, vaccination providers may ask individuals to stay at the place where they received the vaccine for monitoring after vaccination O Signs of a severe allergic reaction can include difficulty breathing, swelling of the face and throat, a fast heartbeat, a bad rash all over the body, dizziness, and weakness If an individual experiences a severe allergic reaction, they should call 9-1-1 or go to the nearest hospital Myocarditis (inflammation of the heart muscle) and pericarditis (inflammation of the lining outside the heart) have occurred in some people who have received the vaccine, more commonly in males under 40 years of age than among females and older males. In most of these people, symptoms began within a few days following receipt of the second dose of the vaccine. The chance of having this occur is very low. Individuals should seek medical attention right away if they have any of the following symptoms after receiving the vaccine: O chest pain O shortness of breath feelings of having a fast-beating, fluttering, or pounding heart Additional side effects that have been reported with the vaccine include: ● severe allergic reactions; non-severe allergic reactions such as injection site pain; tiredness; headache; muscle pain; chills; joint pain; fever; injection site swelling; injection site redness; nausea; feeling unwell; swollen lymph nodes (lymphadenopathy); decreased appetite; diarrhea; vomiting; arm pain; and fainting in association with injection of the vaccine These may not be all the possible side effects of the vaccine. Serious and unexpected side effects may occur. The possible side effects of the vaccine are still being studied in clinical trials. Call the vaccination provider or healthcare provider about bothersome side effects or side effects that do not go away Data on administration of this vaccine at the same time as other vaccines have not yet been submitted to FDA. Individuals considering receiving this vaccine with other vaccines should discuss their options with their healthcare provider. Patients should always ask their healthcare providers for medical advice about adverse events. Individuals are encouraged to report negative side effects of vaccines to the US Food and Drug Administration (FDA) and the Centers for Disease Control and Prevention (CDC). Visit https://www.vaers.hhs.gov or call 1-800-822-7967. In addition, side effects can be reported to Pfizer Inc. at www.pfizersafety reporting. com or by calling 1-800-438-1985. Pfizer BIONTECH 4#5Agenda Ugur's welcome The BioNTech approach to innovation Target discovery and characterization Multi-platform innovation engine Digital & AI/ML Manufacturing and automation New frontiers in infectious diseases Q&A Coffee break An introduction to the oncology pipeline mRNA cancer vaccines Protein therapeutics Extending cell therapy to solid tumors RiboCytokines Closing remarks Q&A Meeting close Innovation Series 42022 BIONTECH#6BIONTECH Ugur's welcome#7The human immune system plays a central role in >80% of human diseases Hundreds of billion cells Impacts the function of every organ system in the body Ability to kill targeted cells or pathogens with high precision Potential for long-term memory Cell types T-cell Macrophage B-cell NK cell Dendritic cell Function Cell migration Removal of diseased cells Healing Cell-cell communication Diseases Cancer Infectious diseases Autoimmune diseases Cardiovascular disease Neurodegenerative diseases Inflammatory diseases BIONTECH 7#8The tools we have developed for cancer will enable us to treat many diseases mRNA vaccines and therapeutics Small molecule immunomodulators Cell and gene therapies Protein therapeutics BIONTECH 8#9Taking mRNA from vision to reality BNT162b2 BioNTech COVID-19 Va on vial contains 5 doses a cular use. Contains no pre der Emergency Use Autho EFORE USE. hours after dilution wher to 25°C (35 to 77°F). and time COMIRNATYⓇ COVID-19 mRNA Vaccine First ever approved mRNA therapy¹ Fastest pharma product development and launch 3.4 bn doses administered ² 2 bn to low- and middle-income countries³ > 1 bn individuals vaccinated² > 175 countries / regions reached Millions of cases of severe illness or death likely averted4 Trillions of dollars of global economic impact5 1 Authorized or approved for emergency use or temporary use or granted marketing authorization in over 100 countries and regions worldwide, April 2022; 2 As of end April 2022; 3 By end of 2022; 4 Eric C. Schneider et al., The U.S. COVID-19 Vaccination Program at One Year: How Many Deaths and Hospitalizations Were Averted? (Commonwealth Fund, December 2021). European Centre for Disease Prevention and Control; 5. https://www.statista.com/topics/6139/covid-19-impact-on-the-global-economy/ 2Pfizer Pfizer BIONTECH 9#10Strong momentum built on two decades of innovation 2014 Mid 1990s Start of mRNA vaccine research by founders 2008 BioNTech founding By Ugur Sahin, Özlem Türeci, and Christoph Huber in Mainz, Germany 2005 First mRNA patents Published 2006 in Blood Individualized mRNA cancer vaccine first-in-human trial 2013 Off-the-shelf mRNA vaccine first-in-human trial Published 2017 in Nature 2015 Nanoparticle mRNA vaccine first in-human trial Published 2016 in Nature 2017 Individualized mRNA vaccine reduces metastatic relapse rate in melanoma patients published in Nature ¹ IVAC trial with extension of relapse. free survival 2016 Pre-clinical proof-of-concept of RNA-lipoplex treatment 2020 2021 2022 Project Lightspeed COVID-19 vaccine Improved initiated full FDA approval2 Small molecule immuno-modulator first-in-human trial CARVac pre-clinical proof-of-concept published in Science. 2019 NASDAQ Initial Public Offering Bispecifics first-in-human trial³ 7 clinical programs MS, multiple sclerosis. 1 iNeST collaboration with Genentech; 2 Global co-development co-commercial agreement with Pfizer; ³ GEN1046 collaboration with Genmab. RiboCytokine first-in-human trial MS vaccine pre- clinical proof-of- concept published in Science COVID-19 vaccine formulation launch Cell therapy first-in-human trial Variant-adapted COVID-19 vaccine submission RiboMab first-in-human trial for BNT211 PRIME designation Adjuvant pancreatic data presented at ASCO annual meeting 17 clinical programs BIONTECH 10#11BioNTech today مربع ČC Discovery powerhouse >1,000 research and development professionals IP portfolio with >200 patent families >300 publications including >100 in leading peer reviewed journals Diversified pipeline across 4 drug classes 21 clinical trials 17 product candidates in clinical development World-class partners Pfizer, Genentech, Genmab, Regeneron, Fosun, Sanofi, Crescendo, Medigene, InstaDeep, TRON, BMGF, UPenn and multiple not-for-profit organizations ဝဂ္ဂီ -O Global organization on 3 continents >3,300 employees >60 nationalities Presence in Europe, United States and Asia Diversified GMP manufacturing infrastructure 2 state-of-the-art cGMP cell therapy sites Global commercial scale mRNA production Initial commercial team in Germany Strong shareholder base, fortress balance sheet >€18bn in cash equivalents and trade receivables as end of Q1 22 BIONTECH 11#12Advancing toward our long-term vision 1 marketed vaccine Market leader in COVID-19 vaccines 16 programs in 21 clinical trials 5 randomized Phase 2 trials Oncology 1 Phase 1 program 10+ preclinical programs Infectious diseases Next-gen or variant adapted COVID-19 vaccines Multiple product launches in next 3-5 years 5-10 IND submissions per year Maintain and deepen COVID-19 vaccine leadership Approved products across various disease areas Driving transformation today Mid-term goals Long-term vision By 2030, we aim to be a multi-product global biotechnology leader, aspiring to address the world's most pressing health challenges with pioneering, disruptive technologies delivered at scale BIONTECH 12#13The BioNTech approach to innovation BIONTECH {Photo: V2osk, unsplash کیا کرو اور#14Focused on five innovation pillars Deep understanding of the immune system a Multi-platform innovation engine Target discovery and characterization 0000 || Digital & AI/ML Manufacturing and automation D F D 1 BIONTECH A 14#15www Davamax mRNA mRNA involved essentially in all biological processes Gene Transcription Translation Protein R2 BE RE CAC HOLA 2001 SMH Immune system The immune system - body-wide control of physiological and pathological mechanisms BIONTECH 15#16Understanding and exploiting immunological mechanisms APC Naive T cell CD40 MHC TCR 2 4-1BB Moch 3 T cell 5 Pro-inflammatory cytokines Tumor cells 4 PD-1 PD-L1 2 Treg 5 Antibodies Healthy cells 1 B cell Pathogens 1 2 3 4 5 mRNA-encoded infectious disease vaccines mRNA-encoded cancer vaccines Shared antigens Individualized antigens Immune system CAR-, TCR-, and non- engineered cell therapies Shared antigens Individualized antigens Next-generation immunomodulators Dual agonist CPI + agonist mRNA-encoded effector molecules Antibodies Cytokines BIONTECH 16#17Focused on five innovation pillars Deep understanding of the immune system Multi-platform innovation engine Target discovery and characterization ☺ Digital & AI/ML Target discovery Manufacturing and automation BIONTECH 17#18Target discovery Mutation-based cancer heterogeneity: The root cause of cancer therapy failure sooth Individual patients XX DNA mutation Healthy cell XXX Mutations Mutations Mutations $% 5-20 years Up to 10,000 mutations Cancer Cells Genetically diverse & adaptable BIONTECH 18#19Mutations from cancer tissues are druggable and 15-20% of mutations are immunogenic when exploited as vaccine targets Exploiting the Mutanome for Tumor Vaccination John C. Castle¹, Sebastian Kreiter¹, Jan Diekmann¹, Martin Löwer¹, Niels van de Roemer¹,2, Jos de Graaf¹, Abderraouf Selmi¹, Mustafa Diken¹, Sebastian Boegel¹2, Claudia Paret¹, Michael Koslowski¹, Andreas N. Kuhn ¹,3, Cedrik M. Britten2,3, Christoph Huber¹,3, Özlem Türeci, and Ugur Sahin ¹,2,3 C57BL/6 (DNA) Castle JC, et al. Cancer Res 2012; 72:1081-1091. Mutation discovery B16F10 DNA and RNA Immunogenicity testing DNA and RNA sequencing Cancer Research шипники Validated mutations Sequence analysis Normal Tumor Mutation identification Immunize with peptide containing mutation Mutation validation ELISPOT mutated and wild type Target discovery BIONTECH 19#20Exploiting the mutanome for personalized mRNA vaccination mRNA delivers genetic information to APCs 5 Cap 5'UTR mRNA Nanoparticle Formulation Vaccine mRNA IIIAAAA 3'UTR Poly(A) tail viral antigen ↑ In vitro Synthesis Antigen-coding sequence AAAA O DNA template RNA Protection from Degradation by extracellular RNAses Uptake by endocytosis Cytoplasmic translocation Ribosome Intracellular mRNA decay RNases Vormehr et al., Curr Opin Immunol 39:14-22 (2016). Immune response Translation Protein Vaccine antigen Outer space Cytoplasm Protein release Protein Uptake of exogenous protein MHC class I epitope processing MHC class! Endoplasmic reticulum MHC class epitope processing MHC classi ECCE Golgi MHC class II Presentation of protein-derived epitopes μμ MHC class II Proteasome Mutations are prevalent across different cancer indications Expressed nsSNVs 10000- 1000- 100- 10- kin Lung (smoker) Bladder Esophagus Colorectal (MSI-H) Stomach Head and neck Cervix B-cell lymphoma . Lung (non-smoker) . Liver Glioblastoma Kidney (papillary) Kidney (clear cell) Colorectal (MSI-L/MSS) Uterus (carcinosarcoma) Pancreas ||||||| Breast Target discovery Prostate Ovarian Adrenocortical Thyroid BIONTECH 20#21Acquisition of the patient's tissue and blood samples 1 2 3 Individual patient samples (blood and tissue) NORMAL GGGAAACTTTTTCC TUMOR GGGAAACGTTTTCC Mapping of mutations Neoantigen prediction 4 On-demand tailored RNA manufacturing 5 H& Individualized immunotherapy Target discovery BIONTECH 21#22Identification of the patient's cancer mutations 2 3 Individual patient samples (blood and tissue) Normal 1 Cancer NORMAL GGGAAACTTTTTCC TUMOR GGGAAACGTTTTCC Mapping of mutations Sequencer Neoantigen prediction DNA DNA RNA On-demand tailored RNA manufacturing TAU 4 Mutation 5 H& Individualized immunotherapy Target discovery Cancer mutanome BIONTECH 22#23Computerized prediction of mutations 3 #001 #002 #003 #... #267 Individual patient samples (blood and tissue) Gene 1 KIF21B Computer predicted mutation list Key PIK3CA R115L IMPA2 R202P KRAS G12D Kreiter et. al. Nature 2015 Mut NORMAL GGGAAACTTTTTCC TUMOR 2 GGGAAACGTTTTCC Mapping of mutations Chrom Score 3 18 12 P188S 1 3,45 0,2 0,3 0.45 Neoantigen prediction 4 On-demand tailored RNA manufacturing 8 2 5 MMMM H& Individualized immunotherapy Target discovery Verification by Expert Review BIONTECH 23#24Individualized vaccine manufacturing 1 Individual patient samples (blood and tissue) NORMAL GGGAAACTTTTTCC TUMOR 2 GGGAAACGTTTTCC Mapping of mutations Mutation 1 Vaccine Backbone Kreiter, Vormehr et al, Nature 2015; Kranz, Diken et. al. Nature 2016. 3 Neoantigen prediction Mutation 2 Mutation N Linker Linker messenger RNA Vaccine 4 On-demand tailored RNA manufacturing Linker Mutation N+1 5 L& Individualized immunotherapy mu Vaccine Backbone Target discovery BIONTECH 24#25How do different types of neoantigens induce T-cell responses and kill tumors? NATURE REVIEWS | DRUG DISCOVERY Identification of neoantigens for individualized therapeutic cancer vaccines Franziska Lang', Barbara Schrörs', Martin Löwer¹, Özlem Türeci² and Ugur Sahin 2,3 T cell count Tumour growth ICB therapy Neoantigen vaccine ផ្ទុ Evolution of neoantigen-specific T cell responses Tumour onset Restrained neoantigen-specific T cells Ignored neoantigen-specific T cells Cross-reactive guarding neoantigen-specific T cells Lang F, et al. Nature Rev Drug Discov 2022; 21:261-282. Level of neoantigen presentation Threshold for effective priming of naive T cells Threshold for effective activation of memory T cells Guarding Restrained Ignored neoantigens neoantigens neoantigens Characteristic feature Guarding neoantigens Supreme neoantigens with strong antigenicity that drive early priming and rapid expansion of neoantigen- specific cytotoxic T cells Neoantigen cross-recognized by preformed memory T cells induced by heterologous immunity Restrained neoantigens Neoantigens that are immunogenic in the immunotherapy-naive host and induce PD1+ memory T cells that proliferate and expand under ICB Ignored neoantigens Neoantigens that do not induce a relevant immune response in the tumor-bearing host but are able to drive tumor immunity once memory effector T cells are induced by vaccination Target discovery Estimated frequency Extremely rare <2% of all mutations <2% of all mutations 15-25% of all mutations BIONTECH 25#26Absolute frequency of genes selected for iNeST¹ vaccination across BioNTech trials 2 iNeST selection frequency [absolute] 150 140 50 40 30- 20 10- 0 28 7 6 5 1,400+ patients screened 4 1 Collaboration with Genentech 2 GO39733, GO40558, BNT122-01, ML41081. 3 28 different cancer indications ~ 1,700 tumor samples processed 2 >12.500 neoantigens selected The long tail of individual targets Genes grouped by iNeST selection frequency [absolute] P - 420+ 1 patients treated Target discovery BIONTECH 26#27Focused on five innovation pillars Deep understanding of the immune system Multi-platform innovation engine Target discovery and characterization E D Digital & AI/ML D 111 D Multi-platform engine Manufacturing and automation BIONTECH 27#28Multi-platform strategy Technology-agnostic innovation engine ● ● ● ● ● mRNA vaccines Individualized cancer vaccines (iNeST) Off-the-shelf cancer vaccines (FixVac) Antigen-specific tolerance vaccines Prophylactic infectious disease vaccines CAR T cells Individualized TCR therapies Polyspecific T-cell therapies • In vivo engineered cell therapies Cell & gene therapies BIONTECH • Against highly selective cancer cell surface antigens for high precision Targeted antibodies Selective TLR 7 antagonism ● Small molecule immunomodulators Next-generation immunomodulators Targeting immune checkpoint molecules Multiple product classes with unique combination potential Multi-platform engine Engineered bispecific antibodies Engineered mechanisms of action ● D 111 D mRNA-encoded cytokines (RiboCytokines) mRNA-encoded antibodies (RiboMabs) mRNA-encoded lysins (RiboLysins) Ribologicals BIONTECH 28#29mRNA technology Broad mRNA toolkit built out of deep immunological expertise Multiple mRNA formats Backbone-optimized uridine mRNA (URNA) Cap UTR Antigen Backbone-optimized nucleoside-modified mRNA (modRNA) ש Cap UTR Antigen UTR Cap ww UTR A30-L-A70 Self-amplifying mRNA (saRNA) VUTR Replicase SGP Antigen VUTR A30-L-A70 A30-L-A70 UTR Replicase Trans-amplifying mRNA (taRNA) Cap Cap VUTR Antigen VUTR A30-L-A70 Cap VUTR Cap VUTR A30-L-A70 Antigen Antigen VUTR VUTR A30-L-A70 UTR A30-L-A70 NUM + H Delivery formulations ршит пшит ашит пшит VIININ VAN VIN IN VIN NUM NUM Lipoplex (LPX) Lipid nanoparticles (LNP) Polyplexes Flexible delivery routes Local, intratum oral, tissue-specific, or systemic D 111 D Multi-platform engine More than a decade of mRNA research has led to potency increase of >10,000× and improved persistence BIONTECH 29#30mRNA technology Each mRNA format is optimized for specific applications Targeted application Multiple mRNA formats Backbone-optimized uridine mRNA (URNA) Cap UTR Antigen Cap UTR Backbone-optimized nucleoside-modified mRNA (modRNA) ש UTR ψ ψψ UTR Antigen A30-L-A70 A30-L-A70 Self-amplifying mRNA (saRNA) Cap VUTR Replicase SGP Antigen VUTR A30-L-A70 Cap UTR Replicase Cap VUTR Antigen Cap VUTR Antigen Cap VUTR Antigen Trans-amplifying mRNA (taRNA) UTR A30-L-A70 VUTR A30-L-A70 VUTR A30-L-A70 VUTR A30-L-A70 Potent T cell response Repeat administration Potent B cell response Non-immunogenic vector Sustained expression High potency at low dose Sustained expression High potency at low dose Ability to co-develop multiple antigens B cell וש WAN APC TCR וש MHC Antibodies Y T cell Cytokines. Antigens 1 Antigens 2 Antigens 3 حال 80% og so 0808 Platforms Infectious disease vaccines mRNA-encoded antibodies mRNA-encoded cytokines D 111 D Shared antigen mRNA vaccines Individualized neoantigen mRNA vaccines Infectious disease vaccines Multi-platform engine BIONTECH 30#31mRNA technology I saRNA could induce higher and extended in vitro and in vivo expression compared to mRNA in vitro expression Increased expression mock Internal data. mRNA (C2C12 cells, equim olar RNA transfer) saRNA in vivo expression Total Flux [p/s] 1.5x107. 1.0x107- 5.0x106. 3x105. 2x106- 1x106- 0 6h Cap Backbone-optimized nucleoside-modified RNA (modRNA) W UTR W ψ ψψ Antigen UTR A30-L-A70 D 111 D 1 2 3 6 10 13 time after i.m. application [days] Multi-platform engine *Self-amp RNA mRNA saRNA showed potential as a vaccine modality with much lower doses Comparable immunogenicity with approximately 100-fold lower doses of saRNA compared to mRNA BIONTECH 31#32mRNA technology | Trans-amplifying RNA could potentially be a vaccine strategy to induce potent immunity Trans-amplifying mRNA structure Cap UTR Replicase VUTR Antigen Cap Cap VUTR Antigen Cap VUTR Antigen Cap VUTR Antigen Trans-amplifying mRNA mechanism Positive-sense replicase Replicase (non-self amplifying) Transgene UTR A30-L-A70 VUTR A30-L-A70 VUTR A30-L-A70 VUTR A30-L-A70 VUTR A30-L-A70 Internal data. Positive-sense transgene no RNA Cytoplasm HET-ARINA mRNA wwwwwwwww HEL-WINA G24+ EFPA GFP Negative-sense transgene taRNA HER-ENTRAMenin. OPPA Enhanced translation by ribosomes Vaccine antigen (enhanced immunogenicity) mRNA (transgene) Immunogenicity model taRNA: SFV Formulation: PBS Route: i.d. VNT-titer/50μl prime Day 1 1000 100 10 1 boost Day 21 O buffer 20 µg mRNA O O O 6.25 +* Day 55 titer O Multi-platform engine D 111 D Virus neutralisation 018 1.25 0.25 trans-replicon (x µg) + 20 µg replicase Comparable immunogenicity with approximately 400-fold lower doses of taRNA compared to mRNA ၅၀၀ 0.05 BIONTECH 32#33mRNA technology Multi-platform engine We are exploring taRNA and saRNA in multiple infectious disease programs Disease type SARS-COV-2 Influenza A virus HIV Ebola virus Lassa virus Marburg virus CCHFV Nipahvirus MERS-CoV uRNA uRNA mRNA modality modRNA modRNA CCHFV, Crimean-Congo hemorrhagic fever orthonairovirus; MERS-CoV, Middle East Respiratory syndrome-related coronavirus; modRNA backbone-optimized nucleoside-modified RNA; saRNA, self-amplifying mRNA; taRNA, trans-amplifying mRNA; URNA; backbone optimized uridine RNA. Internal data. saRNA saRNA saRNA saRNA saRNA saRNA saRNA saRNA ta RNA ta RNA ta RNA D 1 1 ta RNA ta RNA ta RNA BIONTECH 33#34Delivery formulations A diversified and rationally designed delivery platform for mRNA medicine Lipoplex (LPX): mRNA embedded between lipid bilayers to form a sandwich like complex Target: Lymphoid-resident dendritic cells in lymphoid compartments body-wide (spleen, lymph nodes, bone marrow) Therapeutic applications: ● Therapeutic cancer vaccines: Fix Vac, iNeST 1 Grabbe S, et al. Nanomedicine 2016; 11:2723-2734; 2 Kranz LM, et al. Nature 2016; 534:396-401. Schematic depiction of lipid bilayers¹ Schematic depiction of RNA-lipoplex screening process ¹ DOT MA/DOPE RNA condensing Lungs Liver Spleen RNA (LP) Fluid Rigid formation protocols Biological testing + Variation of cationic lipid-to-nucleotide ratio Multi-platform engine Liposome screening Bioluminescence imaging of BALB/c mice (n=3) after IV injection of Luc-LPX at various charge ratios² (+):(-) 5:1 (+):(-) 3:1 (+):(-) 1.7:2 (+):(-) 1.3:2 (+):(-) 1:5 Size D 1 Charge Ligands PEG 2.7 x 106 2.0 x 105 2.0 x 105 X ī 1.2 × 10² Spleen Liver Lungs BIONTECH 34#35Delivery formulations A diversified and rationally designed delivery platform for mRNA medicine Exploring novel delivery formulation through a high-throughput screening platform to: Optimize stability Improve potency Maintain immune quiescence/reduce immunogenicity Seek PEG alternatives: reduce impact of anti-PEG antibodies to improve pharmacokinetics Seek alternative routes of administration Polysarcosine-functionalized LNPs exhibited comparable but more durable in vivo expression profile to pegylated LNPs LNP, liquid nanoparticles; PEG, Polyethylene glycol. Nogueira SS, et al. ACS Appl Nano Mater 2020; 3:10634-10645. Plasma EPO [pg/ml] 1x107 1×106. 1×105. 1x104 1×103 1x102 1×101. PSAR-LNP structure PolySarcosine PEG- DMG DODMA DSPC Cholesterol RNA HO 24 48 0 3 6 Time post intravenous injection [h] -PBS pSar23-DPL14 →PEG-DMG-DPL14 *** D 1 Multi-platform engine LNP BIONTECH 35#36Focused on five innovation pillars Deep understanding of the immune system Multi-platform innovation engine Target discovery and characterization || Digital & AI/ML Digital & AI/ML Manufacturing and automation BIONTECH 36#37BioNTech's Al & ML applications 1) Neoantigen prediction 2 COVID-19 variants monitoring and prediction Digital & AI/ML BIONTECH 37#381 Neoantigen prediction AI & ML drive individualized cancer medicine iNeST¹ Individualized mRNA cancer vaccine Neoantigens NEO-STIM Individualized T-cell therapy Neoantigens Individualized TCR T cells Mix of shared and neoantigens 1 Partnered with Genentech. Powered by data and cutting-edge Al & ML technologies Expression Individual 3 gééén Neoantigen prediction patient samples (blood and tissue) MHC binding NORMAL Bioinformatic algorithms 2 GGGAAACTTTTTCC TUMOR GGGAAACGTTTTCC Mapping of mutations Target selection: Al and machine learning Digital & AI/ML On-demand tailored Individualized RNA manufacturing immunotherapy GOOD BINDING 5 INTERMEDIATE BINDING NO BINDING Predicted MHC Class I or Class II binding BIONTECH 38#391 Neoantigen prediction How do we identify, predict, and characterize neoantigens? a CD4+ T cells CD4+ T cell Mutated DNA DC Activation CD8+ T cell MOOMOO Recognition of cancer-associated mutations by cytotoxic T cells¹ Tumor-draining lymph node Tumor Biology relevant for immunogenicity Tumour cell Mutated peptide/ neo-epitope Uptake Cross presentation CTL b Stability Amount Neo-epitope # HLA-I TCR Tumor CD8+ T cell Localization Expression Clonality Processing MHC binding/stability TCR binding Tolerance Biology relevant for tumor cell recognition ● ● ● ● ● Digital & AI/ML Type of the mutation (SNV, INDEL, Fusion..)2 Clonality of the mutation (clonal, subclonal) 3,4 Mutation position (anchor, non-anchor, TCR accessibility) 5-7 Mutated transcript expression level8,⁹ Similarity to foreign antigens/lack of self-similarity² Peptide/HLA binding strength (affinity, off-rate)² 1 Türeci Ö, et al. Nat Biomed Eng 2018; 2:566-569; 2 Sahin U. AACR Annual Meeting 2022; Oral presentation; 3 McGranahan N, et al. Science 2016; 351:1463-1469; 4 Gejman RS, et al. eLife 2018; 7:e41090; 5 Duan F, et al. J Exp Med 2014; 211:2231-2248; 6 Balachandran VP, et al. Nature 2017; 551:512-516; 7 Yadav M, et al. Nature 2014; 515:572-576; 8 Kreiter S, et al. Nature 2015; 520:692-696; 9 Abelin JG, et al. Immunity 2017; 46:315-326. BIONTECH 39#401 Neoantigen prediction Individualized targets: Not all neoantigens are created equal Neoantigen selection process -Tumor HLA typing Unique patient WES ↓ XX Germline Somatic mutation ID Expression on malignant tissue. Epitope prediction Yadav M, et al. Nature 2014; 515:572-576. Quantifying mutant epitope characteristics to rank immunogenicity Will the mutant peptide be presented on the antigen-presenting cell surface? Will T cells recognize the mutant peptide? Candidate tumor neoantigen(s) 28,439 4,285 1,290 170 7 2 3 Digital & AI/ML Is the mutation expressed in the tumor, but not in normal tissues? Is the mutation clonal? Exome variations Exome coding variations Transcript coding variations Predicted neo-epitopes Spectra-identified neo-epitopes Predicted immunogenic neo-epitopes Validated immunogenic neo-epitopes Target selection ranked list Target rank #1 Target rank #2 Target rank #20 BIONTECH 40#411 Neoantigen prediction Digital & AI/ML Genomic and ligandomic expertise drive our individualized-target database Neoantigen Gene Mutation Length Transcript MHC I MHC II rank (aa) VAF score score 1 27 16.05 0.1 2 27 1.44 0.04 3 26 2.07 0.28 20 Internal data. SNF8 SEMA7A DUS4L V 183M G340S S305P Characterization of neoantigen peptide Types of mutation and clonality of mutations 2.16 8.6 8.54 Peptide-MHC binding affinity/quality Mutated transcription expression level Coverage VAF Coverage in in tumor in tumor normal tissue 155 0.33 113 0.44 213 0.48 Similarity/richness across tumors 119 120 150 VAF in normal tissue 0.00 0.01 0.00 Lack of expression in healthy tissues BIONTECH 41#421 Neoantigen prediction New Al-based immune response model may improve accuracy of prediction Trained to enable an integrated view of immune response features i.e. Biochemical features Physical (structure-based) features Eluted ligand (also predicted by NetMHCpan) Transcript expression ● ● Al-based immune response model incorporates new features ● Predicted immunogenicity of 3980 targets compared to NetMHCpan EL model EL, eluted ligand; ROC, receiver-operator-characteristics. Lang M, et al. CIMT Annual Congress 2022; Poster presentation 21. ROC curve for the Al-based immune response model and NetMHCpan 4.1 EL-based evaluation True positive rate 1.0 0.8 0.6 0.4 0.2 0.0 0.0 0.2 Immune Response Model NetMHCpan 4.1 EL 0.4 0.6 False positive rate New features significantly improved immune response prediction across data from >100 publicly available resources vs NetMHCpan EL Digital & AI/ML 0.8 1.0 InstaDeep™ BIONTECH 42#432 COVID-19 variants monitoring and prediction Reduction in time to detect new variants of concern by ~2 months SARS-CoV-2 virus www Structural modeling Spike protein ACE2 SHEE Epitope alteration score Detection and neutralization by antibodies ACE2 binding Score Spike protein binding to ACE2 receptor EWS score Immune escape score Pareto score Infectivity score Machine learning modeling Semantic change ¹ Artificial intelligence collaboration of BioNTech and InstaDeep. EWS, emergency warning system. Beguir K, et al. bioRxiv 2021; doi: 10.1101/2021.12.24.474095. Distance to wild-type in embedding space Log-likelihood Sum of predicted probabilities over the residues Metadata (sequences + experimental data) Language model Growth rate Cumulative sum of variant cases over time (in log scale) Beta (B.1.351) 10k 1000 100 10 1 10k 1000 100 10 1 100 10 1 Jul 2020 Jan 2021 Jul 2021 Digital & AI/ML Epsilon (B.1.427, B.1.429) Jul 2020 Jan 2021 Jul 2021 Jul 2020 Early computational detection¹ of high-risk SARS-CoV-2 variants supports rapid COVID-19 vaccine adaptation to combat new threats, saving months in response time Theta (P.3) Jan 2021 Jul 2021 Flagging by EWS WHO designation InstaDeep™ BIONTECH 43#442 COVID-19 variants monitoring and prediction Digital & AI/ML Predicted scores for immune escape and fitness prior correlate with in vitro data Wuhan RBD NTD RBD Beta (B.1.351) NTD RBD Omicron (BA.1) NTD Side view A n A Beguir K, et al. bioRxiv 2021; doi: 10.1101/2021.12.24.474095. Top view Distinct epitopes Evaded epitopes 336 300- 200 100 1 336 300- 200 100 PVNT50 Reduction PVNT50 Reduction 00% B0% 40% 0% 0% 80% 60% 40% 20% 0% B.1.1.290 WT 0 8.1.1.298 WT B.1.429 D B.1.258 9.1429 B.1.817.1 8.1.17 B.1.617.1 B.1.517 B.1.817.2 C.SP AV1 8.1.1.7+E484K C.37 8.1258 8.1.517 C.37 Epitope Alteration Score 50 B.1.351" 81.526 B.1.160 B.1.526 P.1 A.VOLV2 50 B.1.351 B.1.162 8.1.1.7 B.1.351 Immune Escape Score 81.351 0.11740084K 8.16172 B.1.351 BA.1 BA2-> AY.1 C.37 BA.2 B.1.351 AVOI.V2 BA.1 100 100 1 DVNT50 Reduction Dissociation Constant, KD (nM) 16 80% 40% 20% 1.00-8 8.0e-9 6.00-9 4.00-9 2.00-9 0.010 8.1.1.299 WT B.1429 8.1.617.1 0 0 P.1 K417N 1452R 0 C.37 B.1.100 8.1.351" 8.1.528 K417N/L452R/T478K 8.1.517 B.1.258 8.14172 Semantic Change Score V367F 5477N "L452R/T478K L4520/F4909 50 WT N501Y 81.351 81174E484K BA:10 K417T/E484K/N501Y E484K BA.16 GA2 ACE2 Binding Score AY.1 AVOLV2 E4840 TATSK 00 B.1.301 B.1.1.7 C.37 N439K L452R/E4840 K417N/E484K/N501Y S477N/E484K Y453F ● 100 E484K/N501Y 100 InstaDeep™ BIONTECH 44#45Digital & AI/ML (2) COVID-19 variants monitoring and prediction EWS report: June 24, 2022 1.0 0.8 8 0.0 Mutations commonly found in lineage not commonly found in lineage Mutations NTD Region (14-303) RBD Region (319-541) T191¹ L24-7 P25-16 P26-16 A27S¹ Y38H A67V¹ H69-4 V70-5 T951¹ E96D G142 G142D¹ V143-16 Y144-5 Y145-8 F157S L176F D178N N211-18 L2121¹ V213F V213G¹ R214S ins214EPE L242- A243-5 L244-¹0 W258R F329C 1332F T333K L335F C336G C336Y P337S G339D¹ E340D E340K²¹ F342L R346K¹ R346T2¹ S371F¹ S371L¹ S373P¹ $375F¹ T376A¹ P384L V395L D405N¹ B4085 K417N¹ K417T N440K¹ G4465¹ L452M L455F4 L455S L455W F456L14 K458M S477N¹ T478K¹ E484A¹ E484V Q493R¹ G4965¹ Q498R¹ N501Y¹ Y505H¹ Antibody Escape H5190 A520T K537R BA. 1. > < BA.1.1 > BA.1.1 3 BA.1.1 BA.1.1 BA.1.1 Σ BA.1.1 ΣΙΣ ! Σ Σ BA.1.1 BA.1.1 BA.3.1 BA.1 BA.1.1 3 3 3 > 3 3 3 Risk 3 ΣΙΣΙΣΙΣ BA.1.1.1 BA.2.13 BA.1.1 ΣΙΣ > Z 3 Σ ΣΙΣ BA.1.1 BA.1.13.1 BA.1.1 3 3 3 3 BA.1.1 ΙΣΙΣ 45 BIONTECH#46Focused on five innovation pillars Deep understanding of the immune system Multi-platform innovation engine Target discovery and characterization 0000 ✡ Digital & AI/ML Manufacturing and automation Manufacturing and automation BIONTECH 46#47BIONTECH Manufacturing and automation#48Diversified manufacturing expertise across four distinct capabilities. Bulk mRNA • End-to-end mRNA production capabilities ● Combined >100,000 square ft across 2 facilities Total capacity of >1 billion doses (COVID-19 vaccine) Flexibility to support broad range of mRNA therapies ● ● ● ● ● Marburg, Germany New site, Singapore (planned for 2023) Modular mRNA / BioNTainer End-to-end mRNA production units with capacity of up to 50 million doses/year To initially support sustainable production of COVID-19 vaccines and Pandemic Preparedness offerings Rwanda (under construction) New sites, Senegal, South Africa (planned) BioNTech Manufacturing Infrastructure >1,000 employees at 4 sites ● ● Manufacturing and automation Individualized mRNA Semi-automated bespoke manufacturing capability to produce just-in-time mRNA vaccines >1,000 CGMP iNeST batches produced since 2018 Mainz, Germany (clinical) New commercial site, Mainz (under construction) Cell therapy Two clinical-scale facilities with combined ~80,000 sq. ft Deep expertise in gamma retroviral vectors and CAR- T and TCR cell therapies IMFS, Idar-Oberstein, Germany | Gaithersburg, MD, USA BIONTECH 48#49Expanding global manufacturing footprint BIONTECH Gaithersburg Clinical-scale cell therapy -50 employees >45,000 square ft 930 As of June 2022. Marburg Commercial-scale mRNA ~750 employees >100,000 square ft Mainz Commercial-scale mRNA Individualized mRNA -200 employees -5,500 square ft Idar-Oberstein Clinical-scale cell therapy ~220 employees -30,000 square ft Senegal, Rwanda, & South Africa (planned for 2023) Modular mRNA BioNTainer 8 BONTAINER ⠀ Manufacturing and automation Construction and GMP licensure of new Mainz facility for iNeST 191 extiln Singapore (planned for 2023) Commercial-scale mRNA BIONTECH 49#50Scaling up mRNA manufacturing 1 g - 350 g in early 2020 in late 2020 Marburg bulk mRNA batch size 10 in 2011 Batch-size and capacity expansion through Annual clinical patient batch capacity 1,000 10,000 > in 2022 Planned capacity digitalization and automation 1.4 kg in 2022 Manufacturing and automation BIONTECH 50#51Scaling up mRNA batch numbers: Marburg BIONTECH Manufacturing and automation Acquired from Novartis in 2020 for less than EUR 100M >100,000 square ft and 8 retrofitted production suites Retrofitted to produce mRNA vaccine within 6 months of acquisition >1.5 billion doses of COVID-19 vaccine produced since Q2 2021 BioN Tainer development hub BIONTECH 51#52Manufacturing and automation iNeST manufacturing innovation: Cycle-time reduction with automated process 3 4 5 A BAROD A ET 17 1 Individual patient samples (blood and tissue) NORMAL 2 GGGAAACTTTTTCC TUMOR GGGAAACG TTTTCC Weeks Mapping of mutations Neoantigen prediction On-demand tailored RNA manufacturing Manual process (until 2016) 6 1Σ2 Σ3 Σ4 Σ 5 Needle to needle: >3 months Weeks >1 Σ2 Σ34 5 7 Targeting delivery: <5 weeks Individualized immunotherapy Semi-automated process (from 2017) 6 8 8 9 9 10 11 12 13 10 11 12 13 BIONTECH 52#53We are investing in global cGMP cell therapy infrastructures IMFS, Idar-Oberstein, Germany (fully owned) 37712 Advantages of an automated approach 24/7 operational model Reduction of steps and time Reduction of complexity Increased efficiency Manufacturing and automation BioNTech, Gaithersburg, MD, US (long-term lease) 930 Reproducibility of manufacturing process Unlocks capacity Faster turnaround time per patient. Advanced planning algorithms BIONTECH 53#54BioN Tainer: A platform for localized and sustainable mRNA production The challenge Establishing GMP production of mRNA is complex and requires overcoming challenges at many levels. The solution Manufacturing and automation Turnkey package that includes modular production units, GMP-compliant setup and personnel training BIONTAINER EcMac- BIONTECH 54#55BioNTainers: What is next in 2022 Finalize the planning and initial assets for the new facility in the African Union Broke ground for first BioN Tainer manufacturing facility in Rwanda First BioN Tainer expected to be shipped (YE 2022) Regulatory framework in alignment with international and local standards Evaluation of additional use cases and products for BioN Tainers worldwide Manufacturing and automation BIONTAINER by BIONTECH BIONTECH 55#56Deep understanding of the immune system Focused on five innovation pillars to enable a new era of synthetic medicine a Multi-platform innovation engine Target discovery and characterization 0000 || Digital & AI/ML D F Manufacturing and automation D 5 BIONTECH 56#57Manufacturing and automation Focused on five innovation pillars to enable a new era of synthetic medicine A Digital & AI/ML Deep understanding of the immune system SYNTHETIC MEDICINE II 0000 Target discovery and characterization D F Multi-platform innovation engine D 5 BIONTECH 57#58Multi-platform innovation engine Expanding the therapeutic universe through platform extension and novel combinations TCR therapy Individualized TCR therapy Four drug classes Platforms Combination of platforms CAR-T Solid tumor CAR T cells Cell & gene therapies Individualized neoantigen T-cell therapy Off-the-shelf mRNA cancer vaccines Fix Vac CARVac mRNA-vaccine amplified CAR T cells mRNA-encoded humabodies (Crescendo) Individualized mRNA cancer vaccines iNeST mRNA technology RiboMabs mRNA-encoded multi-specific antibodies Ribolysins Precision antibacterials (Phagomed) Infectious diseases vaccines Prophylactic Therapeutic RiboCytokines mRNA-encoded cytokines Protein therapeutics Small molecules Targeted cancer therapies Next-gen immunomodulators Bispecific antibodies Selective TLR-7 agonism D F D 1 BIONTECH A 58#59Nos Klausner BIONTECH New frontiers in infectious diseases#60Building on COVID-19 vaccine leadership to address global challenges Advancing a broad toolkit of mRNA vaccines, Ribologicals, Ribolysins Diverse pipeline of next-generation COVID-19 vaccines Delivering breakthroughs against infectious diseases with high need Ability to precisely address diverse and difficult-to-target pathogens New vaccine launches and clinical trial starts expected in 2H 2022 NUM INUT BIONTECH YOUR 60#61Medical burden from infectious diseases is a growing global challenge Insufficient protection against wide variety of pathogens -20% of deaths worldwide caused by infectious diseases with >10 million deaths in 20191 Our solutions (IND mRNA vaccines RiboMabs 图 NA Future pandemic threats >600,000 undiscovered viruses thought to be transmissible from mammal/avian hosts to humans² Rapid pandemic preparedness capability Antimicrobial resistance Top 10 global public health threats include antibacterial resistance with >1 million deaths annually³ FOR RiboLysins 1 World Health Organization; 2022. https://cdn.who.int/media/docs/default-source/gho-documents/world-health-statistic-reports/world health statistics_2022.pdf?sfvrsn=6fbb4d17_3 (accessed May 26, 2022); 2 IPBES; 2020. https://ipbes.net/sites/default/files/2020-12/IPBES % 20Workshop%20on%20Biodiversity%20and%20Pandemics%20Report_0.pdf (accessed June 08, 2022); 3 World Health Organization; 2021. https://www.who.int/news-room/fact-sheets/detail/antimicrobial-resistance (accessed June 08, 2022). NUM INUT BIONTECH YOUR 61#62COVID-19 vaccine validates our mRNA technology and paves the way for future mRNA products H 10 months development time 3.4 billion 1+ billion doses administered as of April 2022 vaccinated persons safety database COMIRNATY NUM FOR mRNA for ID Pfizer BIONTECH 62#63Shingles Potential first-in-class mRNA-based shingles vaccine with blockbuster potential FIH Phase 1 trial 2H 2022 BioNTech and Pfizer global mRNA collaboration programs in infectious diseases FIH, first-in-human. COVID-19 COMIRNATY: globally leading franchise Variant-adapted vaccine launch planned for 2H 2022 BIONTECH + Pfizer Influenza Single-dose quadrivalent mRNA vaccine Phase 1 data update expected in 2022 NUM Building on a track record of rapid clinical development and successful global commercialization of infectious disease vaccines mRNA for ID FOR Pfizer Pfizer BIONTECH 63#64Well prepared for the next phase of COVID-19 pandemic ~3.4 billion doses delivered to >175 of countries and regions 1 FDA EUA granted for pediatric use (6 months to <5 years old) Key drivers 2 Prepared for launch of variant-adapted vaccine in 2H 2022 3 First pandemic response for governments contract signed As of March 2022 1 Approved as a 2-dose series for prevention of COVID-19 in individuals 16 years of age and older; 2-dose series under Emergency Use Authorization for individuals 5-15 years old, and 3-dose series under Emergency Use Authorization for children 6 months through 4 years of age; 2 The vaccine is indicated for active immunization to prevent COVID-19 caused by SARS-CoV-2 virus, in individuals 5 years of age and older. CAR Pandemic prep. Pfizer BIONTECH 64#651 FDA EUA granted for pediatric use Low-dose vaccination safely confers high protection Three doses of BNT16b2 likely to confer high degree of protection against Omicron BA.1 Vaccine efficacy against BA.1 (%) 100 75 50 25 0 21.8 Phase 2/3 Children aged 6 months to <5 years Post dose 2 Post dose 3 80.3 6 months to <5 years 4.2 75.5 6 months to <2 years 32.9 82.3 2 years to <5 years R 2:1 year_age_groups_and_sex,_EU-27,_1_January_1999_and_2019_(%25_share_of_total_population)_BYIE 20.png AE, adverse event; AESI, AE of special interest; MIS-C, multisystem inflammatory syndrome in children. BNT162b2n=3,013 3 µg; 3 doses Placebo n=1,513 Safety profile comparable to placebo Reactogenicity mostly mild to moderate and short lived Systemic reactions comparable to placebo, after any dose AEs reflect reactogenicity/common childhood illnesses 1 Or facial paralysis/paresis. 2 Available at: https://www.census.gov/dataviz/visualizations/034/ and https://ec.europa.eu/eurostat/statistics -explained/index.php?title=File:Population structure_by_five- Similar frequency of AESIs between BNT162b2 vs placebo • FDA-defined AESI main categories: potential angioedema and hypersensitivity (mainly urticarias and rashes) CDC-defined AESIS: No vaccine-related anaphylaxis, myocarditis/pericarditis, Bell's palsy,¹ or MIS-C [DAN Pandemic prep. CAR Pfizer BIONTECH Pfizer 65#662 Variant-adapted vaccines Next-generation vaccine approaches aim to provide durable variant protection 17 COMIRNATY IN Omicron-adapted Kil ¿ Mono-/Multi-valent Clinical data presented at VRBPAC meeting June 2022 Variant adapted and next-generation vaccine approaches Rolling submissions initiated in US and EU KM T-cell enhancing K Pan-coronavirus NUA Expected to enter the clinic in 2H 2022 CAR Pandemic prep. Pfizer BIONTECH 66#672 Variant-adapted vaccines | Omicron BA.1 GMR consistent with simple superiority criterion for Omicron-modified vaccines (>55y participants) Participants WITHOUT evidence of infection up to 1 month after the study vaccination Assay SARS-CoV-2 neutralization assay - Omicron BA.1 - NT50 (titer) Vaccine groups BNT162b2 30 µg BNT162b2 OMI 30 μg BNT162b2 OMI 60 μµg n 163 169 174 178 GMT (95% CI) 1M post-dose 455.8 (365.9, 567.6) 1014.5 (825.6, 1246.7) 1435.2 (1208.1, 1704.8) 175 711.0 (588.3, 859.2) 900.1 (726.3, 1115.6) Vaccine group / BNT162b2 30 μg GMR (95% CI) 2.23 (1.65, 3.00) 3.15 (2.38, 4.16) Bivalent OMI 30 μg ¹ Bivalent OMI 60 µg ² GMR superiority criterion: the lower bound of 95% confidence interval for GMR is >1.0 1 Multiple hypotheses are to be evaluated in sequential order for alpha control. Declaration of OMI 30 µg simple superiority pending outcome of additional hypotheses. Note: Omicron BA.1 NT50 measured using validated 384-well assay. Internal data. 1.56 (1.17, 2.08) 1.97 (1.45, 2.68) Met superiority (Y/N)¹ Y Y Y Y NUA Pandemic prep. CAR Pfizer BIONTECH Pfizer 67#682 Variant-adapted vaccines | Omicron BA.1 GMR consistent with super superiority criterion for monovalent Omicron-modified vaccine (>55y participants) Participants WITHOUT evidence of infection up to 1 month after the study vaccination Assay SARS-CoV-2 neutralization assay - Omicron BA.1 - NT50 (titer) Vaccine groups BNT162b2 30 µg BNT162b2 OMI 30 μg BNT162b2 OMI 60 μµg n 163 169 174 178 GMT (95% CI) 1M post-dose 455.8 (365.9, 567.6) 1014.5 (825.6, 1246.7) 1435.2 (1208.1, 1704.8) 175 711.0 (588.3, 859.2) 900.1 (726.3, 1115.6) 1 Multiple hypotheses are to be evaluated in sequential order for alpha control. Declaration of super superiority pending outcome of additional hypotheses. Note: Omicron BA.1 NT50 measured using validated 384-well assay. Internal data. Vaccine group / BNT162b2 30 µg GMR (95% CI) 2.23 (1.65, 3.00) Bivalent OMI 30 μg ¹ Bivalent OMI 60 µg ² GMR superiority criterion: the lower bound of 95% confidence interval for GMR is >1.5 3.15 (2.38, 4.16) 1.56 (1.17, 2.08) 1.97 (1.45, 2.68) Met superiority (Y/N)¹ Y Y Y DIN Y Pandemic prep. CAR Pfizer BIONTECH Pfizer 68#692 Variant-adapted vaccines | Omicron BA.1 sero response rate exceeds non inferiority criterion for Omicron-containing vaccines (>55y participants) Participants WITHOUT evidence of infection up to 1 month after the study vaccination Assay SARS-CoV-2 neutralization assay - Omicron BA.1 - NT50 (titer) Vaccine groups BNT162b2 30 µg BNT162b2 OMI 30 µg BNT162b2 OMI 60 µg 1 Bivalent OMI 30 µg ¹ Bivalent OMI 60 µg² N 149 163 166 169 162 n (%) 85 (57.0) 125 (76.7) 143 (86.1) 121 (71.6) 110 (67.9) (95% CI) 1M post-dose (48.7, 65.1) (69.4, 82.9) (79.9, 91.0) (64.2, 78.3) (60.1, 75.0) % (95% CI) Seroresponse difference in % Vaccine group - BNT162b2 30 μµg Met non-inferiority (Y/N)¹ 19.6 (9.3, 29.7) 29.1 (19.4, 38.5) 14.6 (4.0, 24.9) 10.9 (0.1, 21.4) Y Y Y NUA Y Pandemic prep. CAR Non-inferiority criterion: the lower bound of 95% confidence interval for interval for the percentage difference is >-5 1 Multiple hypotheses are to be evaluated in sequential order for alpha control. Declaration of OMI 30 ug non inferiority pending outcome of additional hypotheses. Note: Omicron BA.1 NT50 measured using validated 384-well assay. Internal data. Pfizer BIONTECH 69#702 Variant-adapted vaccines I GMTs in participants without evidence of infection up to 1 month after study vaccination: Immunogenicity subset NT50 (titer) GMT 10,000 1,000 100 Internal data. 10 GMFR BNT162b2 (30 g) 74.3 455.8 I Prevax 1 MPD 5.8 BNT162b2 (60 g) 103.3 727.3 Prevax 1 MPD 6.9 BNT162b2 OMI BNT162b2 OMI (30 g) (60 g) 73.9 1014.5 I Prevax 1 MPD 13.5 70.5 1435.2 I Prevax 1 MPD 19.6 Bivalent (30 g) 77.2 711 Prevax 1 MPD 9.1 Bivalent (60 g) 81.6 900.1 Prevax 1 MPD 10.9 NUA CAR Pandemic prep. Pfizer BIONTECH Pfizer 70#712 Variant-adapted vaccines I Reactogenicity profile of variant vaccines overall similar to prototype BNT162b2 vaccine Participants aged 18-55 years Monovalent Omicron-modified vaccine (30 µg) showed a similar local reaction and systemic event profile as the prototype vaccine (30 µg) Internal data. Participants aged >55 years Monovalent and bivalent Omicron-modified vaccines (30 µg) showed a similar local reaction and systemic event profile as the prototype vaccine NUA 60 µg dose level: Mild to moderate injection site pain, fatigue and muscle pain were more common compared to 30 µg Pandemic prep. CAR Pfizer BIONTECH 71#722 Variant-adapted vaccines Omicron-containing modified-variant vaccine summary Neutralizing responses for Omicron-containing vaccines are consistent with regulatory criteria: Simple superiority for GMR and non-inferiority for sero response (monovalent and bivalent vaccines) "Super" superiority for GMR (monovalent vaccines) ● Internal data. Reactogenicity profile of variant vaccines overall similar to prototype BNT162b2 vaccine [DAN Pandemic prep. CAR Pfizer BIONTECH 72#732 Variant-adapted vaccines I SARS-CoV-2 epidemiology changes quickly: Vaccine updates need to adapt with the pace of the virus Variant vaccine update pathway Clinical (current) ~8 months Pre-clinical/CMC (proposed) ~3 months Proportion of Strains 100 75 50 25 0 Delta Omicron BA.1 Omicron BA.2 Omicron BA.2.12.1 Omicron BA.4 Omicron BA.5 GISAID Initiative database: https://www.gisaid.org/ (accessed June 20, 2022). Dec 2021 Feb 2022 Omicron Wave Circulating Strains Apr 2022 Sampling Date USA Jun 2022 NUA CAR Pandemic prep. Pfizer BIONTECH 73#742 Variant-adapted vaccines Omicron has more sublineages than all other variants combined Larger clades in GISAID were named in context of marker variants relative to WIV04-reference: s CR7821,128144C includes N58-L845 LC241.C3037 A23403,08782,011091,025563,626144,728144.628882 (W/VD4- reference) V G110911025144T includes NSP6-L37F+NS3-4251V G C2411,C30377 423405G 5-D6146 GK C2417,C30377 A23403G,C22995A includes 5 0614G-ST478K GH C2411 C30371,A23403G GISS563T includes 5-06340 N53 Q57H GV C2437 C30371,A234036 C22227T includes S-06140 +5-AZ22V GR C2417C30371 A23403G G28882A includes 5-06140-N-G204R GRY C241T C10371,21765 21770de21991-21995ddl A210631 A234030,G28882A includes del S-V70del S-Y144del S-N501Y+S-D5140+N-02018 GRA: C243T.C30371,A234035,628882A includes 5-0614G+N62048 (at (ezt & of the following amino acid changes S-V143del S-V145del,S N211del, ins214PES 03390,5-537115-5477NS-T4785-8484A,S-QASES-C4,575475525 P681HS-P68115-N764K5-0796Y-NS50K,S-Q954HS-N90965-1981) GRA Omicron Neighbor-Joining tree with fasttree visualized in ete3. L Clade references and Pango lineages OVAS A BUTC-00200035482070-44-28 OBCH/C GISAID Initiative database: https://www.gisaid.org/ (accessed June 22, 2022). 471022003, 43452020-02 #£111208C-Irgand 2010042003- Or Au 811720 CW-16--23 AC 821 2022 202-11- SKELETON 2013-04-2 ANC-2020-15-30 LEBLOW-4/2402104208-0-31 LEA 202010-05-14 GH Beta GR GRY Gamma Alpha Blue: Asia 20-12-2 S GV GK Delta Green: new from Oceania Magenta: new from Americas Red: new from Europe Yellow: new from Afrien Grey: from previous updates Sampled genome tree derived from all outbreak sequences 2022-06-21 Notable changes 10,424,471 full genomes (+85,020) (excluding low coverage, out of 11,433,557 entries) S clade [#RBDx] 16,478 [6,334] (+1 [+1]) L clade (#RBDx] 5,977 [144] (+9 [+0]) V clade [#RBDx] 6,687 [41] (+1 [+0]) G clade [#RBDx] 288,883 [120,306] (+178 [+20]) GR clade [#RBDx] 475,918 [247,819] (+165 [+86]) GRY clade [#RBDx) 1,031,623 [113,225] (+65 [+4]) GH clade [#RBDx] 508,442 [233,686] (+230 [+23]) GV clade [#RBDx] 171,815 (9,712] (+6 [+5]) GK clade [#RBDx] 4,051,491 [637,802] (+2,353 [+430)) GRA clade 3,823,229 (+81,980) Other clade [#RBDx] 43,919 [30,263] (+32 [+5)) We gratefully acknowledge the Authors from Originating and Submitting laboratories of sequence data on which the analysis is based. GISAID by BII/GIS, A STAR Singapore Omicron mutanome continues to rapidly expand Pandemic prep. Omicron sublineages continue to show increased immune escape properties [DAN Omicron sublineages have become mutationally distinct CAR Pfizer BIONTECH 74#752 Variant-adapted vaccines BA.2.12.1 and BA.4/5 are now increasing in prevalence Proportion of Strains 100 75 DOM Aug 2021 Oct 2021 Sampling Date 50 25 0 Feb 2021 Apr 2021 USA circulating strains trend Jun 2021 GISAID Initiative database: https://www.gisaid.org/ (accessed May 31, 2022). Dec 2021 Feb 2022 Apr 2022 Jun 2022 Alpha Beta Delta Gamma Omicron BA.1 Omicron BA.2 Omicron BA.2.12.1 Omicron BA.4 Omicron BA.5 [DAN Pandemic prep. CAR Pfizer BIONTECH 75#762 Variant-adapted vaccines Omicron BA.4/5 RBD and NTD sequences are distinct from BA.1 and BA.2 F486V BA.4/5 additional mutations L452R RBD top view R408S S477N T478K K417N D405N Y505H T376A G4905 S375F Tuekprakhon A, et al. bioRxiv 2022; doi.org/10.1101/2022.05.21.492554. Q493R N501Y E484A Q498R S373P N440K G446S S371L/F R346K X N343 glycan X ACE2 footprint Common to BA.1, BA.1.1, BA.2 & BA.3 BA.1, BA.1.1 & BA.3 (except 496) BA.1.1 only BA.2 only (D405N Also in BA.3) S371L: BA.1, BA.1.1 S371F: BA.2, BA.3 not in BA.4/5 not in BA.3 A67V,A69-70,T951,G142D,A143-145,N2111,A212, A67V,A69-70,T951,G142D,A143-145,N2111,A212, G142D, BA.1 BA.1.1 BA.2 T191,424-26,A27S, BA.3 BA.4/5 T191,A24-26,A27S, A67V,A69-70,T951,G142D, A143-145,N2111,A212 A69-70, G142D, $371L,S373P,S375F, BA.1 G339D, BA.1.1 G339D,R346K,S371L,S373P,S375F, BA.2 G339D, BA.3 G339D, BA.4/5 G339D, BA.1 BA.1.1 BA.2 BA.3 BA.4/5 L452R,S477N,T478K, E484A,F486V, S477N,T478K,E484A, S477N,T478K,E484A, S477N,T478K,E484A, S477N,T478K,E484A, S371F,S373P,S375F,T376A,D405N, R408S,K417N, N440K S371F,S373P,S375F, D405N, K417N,N440K, G446S S371F,S373P,S375F,T376A, D405N, R408S,K417N, N440K, V213G Q493R, Q493R, V213G Q493R,G496S,Q498R, N501Y,Y505H K417N,N440K,G446S K417N,N440K, G446S Q493R,G496S,Q498R,N501Y,Y505H D614G,H655Y,N679K,P681H,N746K,D796Y, D614G,H655Y,N679K,P681H,N764K, D796Y, Q498R,N501Y,Y505H Q498R,N501Y,Y505H Q498R, N501Y,Y505H Omicron BA.4 and BA.5 contain additional mutations in the RBD, in particular the reversion mutation R493Q, together with mutations L452R and F486V BA.1 T547K,D614G,H655Y,N679K,P681H,N764K,D796Y,N856K,Q954H,N969K,L981F BA.1.1 T547K, D614G,H655Y,N679K,P681H,N764K,D796Y,N856K,Q954H,N969K, L981F BA.2 D614G,H655Y,N679K, P681H,N764K,D796Y, BA.3 BA.4/5 ins214EPE ins214EPE Q954H,N969K Q954H,N969K Q954H,N969K NUA Pandemic prep. NTD RBD CAR Pfizer Pfizer BIONTECH 76#772 Variant-adapted vaccines | Omicron-containing modified variant vaccines as 4th dose elicit improved Omicron neutralization response FFRNT 50 10,000 1,000 100 10 Participants WITHOUT evidence of infection up to 1 month after first study vaccination >55 years old participants, 30 and 60 µg dose 501.1 78.4 OMI 30 µg n=17 FFRNT, fluorescent foci reduction neutralization test; LOD, limit of detection. Internal data. BA.1 822.0 145.3 OMI 60 µg n=18 771.3 226.3 Bivalent 30 μµg n=13 BA.4/BA.5 response lower than that of BA.1 BA.4/5 678.1 137.2 Bivalent 60 µg n=18 2 LATNI [DAN Pandemic prep. LOD CAR Pfizer BIONTECH 77#78Omicron BA.4/5 Monovalent and Bivalent Boosters in Mice Substantially Increase Omicron Neutralization Responses to all Omicron Variants Including BA.4/5 and Reference Strain PVN 50 titer (Serum Dilution-¹) 105 104 103 10² 101 TTTT - Compared to Monovalent OMI BA.1, BA.4/5 neutralizing titers increase by 11.3 fold [mono BA.4/5] or ~4.8 fold (bivalent BA.4/5) 4150 Wuhan 018 3490 1131 617 436 BA.1 BA.2 BA. BA.4/5 2.12.1 9870 4150 5869 4935 4935 Wuhan BA.1 BA.2 BA. BA.4/5 2.12.1 OMI BA.1 OMI BA.4/5 N=8 mice Balb/c mice. Mice preim munized with 2 doses of BNT162b2; boosters given at day 104 Pseudovirus neutralization assay; LOD, Limit of Detection 4H W LOD 5869 2075 2691 3200 2075 GMT Wuhan BA.1 BA.2 BA. BA.4/5 2.12.1 BNT162b2 + OMI BA.4/5 BU-875#792 Variant-adapted vaccines | Omicron BA.4/5 variant-adapted vaccines increase Omicron sub-lineages/Wuhan ref. pVN 50 titer ratio in balb/c mice ● ● Ratio of variant/ Wuhan ref. pVN 50 titer Internal data. 0.1- Wuhan N=8 Balb/c mice per group Pre-immunized with 2-doses of 1 µg Booster administered on day 104 ( BA.1 BA.2 Cross-neutralization analysis BA.2.12.1 BA.4/BA.5 T162b2 on day 0 and day 21 Geometric mean ratio BNT162b2 Omi BA.4/5 b2+ Omi BA.4/5 Omi BA.1 Omi BA.2 0.21 0.09 0.10 0.08 0.42 0.59 0.50 0.50 0.35 0.46 0.55 0.35 Omi BA.2.12.1 Omi BA.4/BA.5 NUA CAR Pandemic prep. Pfizer BIONTECH 79#802 Variant-adapted vaccines A science-driven preparedness strategy ● ● Extensive clinical experience with multiple other variant-adapted vaccines Consistent safety and immunogenicity profiles Robust manufacturing process Requires minimal changes to introduce updated antigen sequence for new variant/sublineage As of today, safety profile of COMIRNATY is well characterized Extensive post-marketing exposure and close monitoring No identification of new important safety issues in pediatric populations as well as with booster schemes Discussions with regulators are ongoing to define most appropriate pathways to leverage current experience and ensure that variant-adapted vaccines can be made available in the future to timely address newly emerging variants / sublineages [DAN CAR Pandemic prep. Pfizer Pfizer BIONTECH 80#813 Pandemic preparedness An integrated, multi-faceted model for future pandemic preparedness Ur Field-based testing A Laboratory testing PREPAREDNESS II Risk prediction (Al driven) M Manufacturing Planning for deployment IN Response H LATNI NUA CAR Pandemic prep. Our goal: Enable end-to-end manufacturing and delivery of our vaccines world-wide, whilst ensuring quality of production Pandemic preparedness contract with German Federal Ministry of Health in April 2022 For the next five years: reserve and maintain manufacturing capabilities to produce at least 80 million mRNA-based vaccine doses per year BIONTECH 81#82Malaria, tuberculosis, and HIV remain endemic Malaria ~229 million cases in 2020 across the WHO Africa Region 601,000 deaths in 2020 in the WHO African Region (80% in children <5 years) Tuberculosis 10 million cases globally in 2020 1.5 million deaths globally in 2020 HIV, human immunodeficiency virus; WHO, World Health Organization. World Health Organization fact sheets. https://www.who.int/news-room/fact-sheets (accessed June 09, 2022). HIV [DAN Pandemic prep. 37.7 million living with HIV (of whom 2/3 in the WHO Africa Region) 680,000 deaths globally from HIV-related causes in 2020 CAR BIONTECH 82#83BioNTainer: Building an mRNA manufacturing network to address infectious diseases in Africa and beyond BIONTAINER by BIONTECH Indicative manufacturing network Potential partners for fill & finish BIONTAINER by BIONTECH I - ■ H ■ M M ■ 1 - The BioNTainer solution aims to ensure: Acceleration of knowledge and technology transfer Rapid set-up of new mRNA manufacturing nodes for licensed mRNA vaccines Pandemic preparedness & other use cases Sustainability through maintenance and updating Partner contribution: SE (GMP Utilities Access to talent Regulatory framework Operation permit 66 / Logistics & supply [DAN Pandemic prep. Fill & finish capacity CAR BIONTECH 83#84Urgent need for next-generation precision antibacterials Prevent up to 10 million deaths from antimicrobial resistance by 20501 Oni TITI MM 1:1 3: Improve standard-of-care for >150 million people suffering from chronic and severe bacterial infections¹ KN KNA KN Safeguard modern medicine via effective antibacterials 1,2 ¹ Antimicrobial Resistance Collaborators. Lancet 2022; 399:629-655; 2 O'Neill J. Wellcome Collection. Attribution 2014; Available at: https://wellcomecollection.org/works/rdpck35v (accessed June 06, 2022). Antibacterials FOR BIONTECH 84#85Synthetic (endo)lysins - A potentially ideal class of precision antibacterials Used by phages to degrade bacterial cell wall Gram- positive Gram- negative Bacteriophage Endolysin Bacterial killing Modular domain architecture Outer-membrane penetrating peptide High diversity in architectures and combinations Enzymatically active domain AF Cell-wall binding domain Enzymatically active domain Highly potent No resistance Biofilm active Laser focus Safe ● ● ● Highly bactericidal Minimum inhibitory concentration (MIC) often <1 µg/ml Active on antibiotics-resistant bacteria Resistance formation hardly possible Lyse cell-wall irrespective of metabolic state Penetrate biofilm matrix Do not harm beneficial bacteria Suitable where microbiome has to be preserved Mammals have no peptidoglycan Very safe, no off-target effects (Endo)lysins could be developed against virtually any type of bacteria Antibacterials 1 Fischetti VA. Int J Med Microbiol 2010; 300:357-362; 2 Vázquez R, et al. J Virol 2021; 95:e0032121; 3 Fowler VG, et al. J Clin Invest 2020; 130:3750-3760. ~D BIONTECH 85#86Diverse and modular domain architecture allows flexibility in engineering Enzymatically active domain EADS hydrolyze peptidoglycan Different classes of EAD cleave 5 different chemical bonds in peptidoglycan There are 28++ classes of EADs with low sequence similarity Endolysins can have ≥1 EADs Alphafold homology model of PM-477 Cell-wall binding domain CBDs bind specific features on bacterial cell wall CBDS mediate genus or species specificity (but EADs also contribute to specificity) 15+ different classes of CBDs known Outer-membrane penetrating peptide (OMP) Engineered endolysins can combine modules of multiple classes High sequence diversity and option space, even within one class CBD, Cell-wall binding domain; EAD, enzymatically active domain. 1 Oliveira H, et al. J Virol 2013; 87:4558-4570; 2 Vázquez R, et al. J Virol 2021; 95:e0032121; 3 Gutiérrez D & Briers Y. Curr Opin Biotechnol 2021; 68:15-22. Enzymatically active domain To be active on Gram negative bacteria (outer-cell membrane), many but not all endolysins require outer-membrane penetrating peptides Antibacterials FOR BIONTECH 86#87Endolysins are highly potent and allow laser-focused microbiome modulation Pathogenic bacteria¹ G. swidsinskii CFU/ml Method: Bacteria grown in vitro and then treated with single dose of PM-477 for 5 hours. Suspension plated and CFU evaluated quantitatively on a log₁0 scale 10⁹. 108. 107- 106- 105. 104- 103. 102. G. vaginalis > 100,000x reduction Untreated Treated G. leopoldii Untreated Treated PM-477 0.03-1 Untreated Treated 40 µg/ml LOD CFU/ml 10⁹ 108. 107- 106- 105. 104- 103- 102, MIC, minimum inhibitory concentration 1 Landlinger C, et al. Pathogens 2021; 10:54; 2 Landlinger C, et al. Antimicrob Agents Chemother 2022; 66:e0231921. L. crispatus ooo Beneficial bacteria Untreated Treated L. L. L. gasseri jensenii rhamnosus مهم Untreated Treated معم MIC range (µg/ml) for Gardnerella (>20 strains tested)² Clindamycin <0.06-1 Untreated Treated Untreated Metronidazole 8 to 128 (R) Treated 256 μg/ml LOD PM-477 with low MIC (0.1-1 µg/ml) for Gardnerella Lactobacilli grow in the presence of high doses of PM-477 (MIC >256 µg/ml) Antibacterials -60% of strains resistant to metronidazole (MDZ) FOR BIONTECH 87#88Expanding opportunities in infectious diseases: 4 first-in-human mRNA vaccine trial starts expected in 2022 Platform Product candidate BNT162b21 Omicron ¹ Omicron + BNT162b21 BNT161² Preclinical unnamed program² BNT163 (prophylactic)³ HeTVac (therapeutic)³ BNT1644 mRNA vaccines BNT165 Unnamed program 4 Ribolysins Unnamed program Indication (targets) COVID-19 COVID-19 COVID-19 Influenza Shingles HSV2 HSV2 Tuberculosis Malaria HIV Precision antibacterials Next milestone Data updates in 2022 Data updates in 2022 Data updates in 2022 Data updates in 2022 First-in-human trial to start in 2H 2022 First-in-human trial to start in 2H 2022 First-in-human trial to start in 2H 2022 First-in-human trial to start in 2H 2022 1 Global co-development co-commercial agreement with Pfizer; 2 Global rights licensed to Pfizer; 3 University of Pennsylvania collaboration; 4 Collaboration with Bill & Melinda Gates Foundation. BioNTech holds worldwide distribution rights except developing countries where BMGF holds distribution rights. NUM INUM BIONTECH YOUR 88#89● Q & A BIONTECH#90TIME FOR A 15-min BREAK! BIONTECH#91BIONTECH Oncology pipeline#92Understanding and exploiting immunological mechanisms APC Naive T cell CD40 MHC TCR 1 T cell 4-1BB Hochf 4 2 Pro-inflammatory cytokines 00MMUO Tumor cells PD-1 PD-L1 -Co MJCH 3 1 Treg y 4 & Antibodies B cell 1 2 3 4 mRNA-encoded cancer vaccines Shared antigens Individual antigens CAR-, TCR-, and non- engineered cell therapies Shared antigens Individual antigens Next-generation immunomodulators Dual agonist CPI + agonist mRNA-encoded effector molecules Antibodies Cytokines BIONTECH 92#93Oncology pipeline: Significant progress and expansion in 2022 Drug class Platform mRNA Cell therapies Antibodies Fix Vac iNeST RiboMabs RiboCytokines CAR T cells + CARVac Neoantigen-based T cells TCR engineered T cells Next-gen checkpoint immunomodulators Product candidate Indication (targets) Adjuvant pancreatic ductal adenocarcinoma ¹ Intratum oral immunotherapy SAR441000 (BNT131)³ Solid tumors (IL-12sc, IL 15-sushi, GM-CSF, IFNa) BNT141 Multiple solid tumors (CLDN 18.2) BNT142 BNT 151 BNT152, BNT153 BNT211 BNT212 BNT221 (NEO-PTC-01) To be selected Multiple solid tumors (CD3×CLDN6) Multiple solid tumors (optimized IL-2) Multiple solid tumors (IL-7, IL-2) Multiple solid tumors (CLDN6) Pancreatic, other cancers (CLDN18.2) Multiple solid tumors GEN1046 (BNT311)4 GEN1042 (BNT312)4 BNT321 (MVT-5873) BNT411 Targeted cancer antibodies Toll-like receptor binding BNT111 BNT112 BNT113 BNT 1151 BNT 116 Autogene cevum eran (BNT122)² Advanced and R/R melanoma Prostate cancer HPV16+ head and neck cancer Ovarian cancer NSCLC 1L melanoma Adjuvant colorectal cancer Solid tumors All tumors Metastatic NSCLC (PD-L1x4-1BB) Multiple solid tumors (PD-L1×4-1BB) Multiple solid tumors (CD40×4-1BB) Pancreatic cancer (sLea) Solid tumors (TLR7) SMIM SMIM, small molecule immunomodulators. 1 Investigator-initiated Phase 1 trial; 2 Collaboration with Genentech; 3 Collaboration with Sanofi; 4 Collaboration with Genmab. Pre-clinical Phase 1 Phase 2 Phase 3 IMAJU Milestones FPD June 2021 FPD, July 2021 Start Phase 1/2 Data H2 2022 FPD, Dec 2021 Follow-up trial FPD Jan 2022 Start Phase 1/2 Ph 2 planned 2023 FPD, Dec 2021 BIONTECH 93#94Unique combination potential across platforms Selected examples in the clinic LYTNI mRNA cancer vaccines Y Approved anti-PD-1/PD-L1 Vaccine-induced T-cell response expansion through PD1 blockade Several Phase 1 and Phase 2 trials ongoing for both FixVac and iNeST platforms in combination with anti-PD1 LAIN) LATIN mRNA cancer vaccines mRNA-encoded cytokines Vaccine-induced T-cell response amplification through RiboCytokines BNT151, BNT 153: IL-2 RiboCytokines in preclinical studies INLAT Engineered cell therapies mRNA cancer vaccines Autologous CAR T-cell therapy vaccine-amplified T-cell response BNT211: Ongoing Phase 1 trial across multiple tumors BIONTECH 94#95BIONTECH mRNA cancer vaccines#96mRNA vaccines for enabling potent multi-targeting of cancers IV injection of RNA-LPX 2 decatopes Delivery of RNA-LPX to dendritic cells in lymphoid compartments Spleen Dendritic cell CD8 T cell CD4 T cell RNA-LPX Dendritic cell Innate immune stimulation Endosome Polypeptide mRNA TLR 7/8 MHCI Proteasome NF-KB Endoplasmic TAP. reticulum Endo-lysosomes Antigen presentation MHCII TCR Co-stimulatory molecules Pro-inflammatory cytokines CD80 CD28 MHCI TCR Kranz LM, et al. Nature 2016; 534:396-401; Lopez J, et al. AACR Annual Meeting 2020; Oral presentation CT301. * Collaboration with Genentech. CD40 CD40L CD8 T cell stimulation Cytokine help CD4 T cell stimulation Backbone optimized uridine mRNA (URNA) Cap UTR Antigen Neo- antigens Individualized therapy iNeST* individualized Neoantigen-Specific immunoTherapy UTR NUM mRNA cancer vaccines A30-L-A70 Multiple shared antigens Off-the-shelf therapy Fix Vac Fixed Antigen Vaccine 6668 手 BIONTECH 96#97iNeST I Autogene cevumeran (BNT122) Driving continuous iNeST innovation with data 1 Individual patient samples (blood and tissue) Driven by data Constant improvement as more data are generated and analyzed iNeST is being developed in collaboration with Genentech. NORMAL 2 GGGAAACTTTTTCC TUMOR GGGAAACGTTTTCC Mapping of mutations 3 Neoantigen prediction Selection algorithms Al and ML optimization Continuous platform evolution 4 On-demand tailored RNA manufacturing 5 Individualized immunotherapy NUM mRNA cancer vaccines Just-in-time manufacturing Dedicated mRNA GMP production facilities Targeting delivery of <5 weeks BIONTECH 97#98iNeST I Autogene cevumeran (BNT122) Phase 1 as monotherapy and in combination with atezolizumab ● ● ● Evaluation of BNT122 safety & feasibility with/without Tecentriq in> 10 indications Data from Phase 1 trial in heavily pre-treated, PD-L1 low patients across multiple tumor types Demonstrated ability to elicit significant T cell responses of both effector and memory phenotype as monotherapy and in combination (multiple patients with > 5% T cell response per neoepitope) Treatment-related adverse events were primarily transient systemic reactions, manifesting as low-grade CRS, IRR or flu-like symptoms Initial signals of clinical activity observed as single agent and in combination with Atezo Blood and tumor biopsy collection 5 Cap analog Sequencing 5' UTR SEC RNA backbone Bioinformatics Neoantigen Prediction NEOANTIGENS 2-3-4-5 RNA-lipoplex manufacturing Innate Immune Stimulation Intrinsic TLR7/8 agonist Cold storage and distribution 3' UTR MITDAAAA RNA backbone Intravenous administration Single-stranded mRNA Antigen Expression Up to 20 neoantigens (2 decatopes) BNT122 induces CD8+ T cells in CPI-sensitive and CPI-insensitive tumor types PE Multimer Patient with Prostate Cancer Treated With RO7198457 (38 µg) C2D1 C3D1 1.95% 2.49% Baseline 0.03% 97.79% BV605 Multimer CCR7 95.69% T TIME TIET CD45RO 95.88% JA TIET PD-1+ Cells Phenotype of MHC Multimer-Positive Cells Effector Memory Phenotype Tam T₁ 87.7% PD-1 PD-1+ CD8 T cells 99.6% CD8 C4D1 4.7% 193.89% TE PYTING TING T CPI, checkpoint inhibitor; PR, partial response; PD, progressive disease; SD, stable disease. 1. Sahin U, et al. Nature 2017; 547:222-226; BNT121 was a precursor to BNT122 and the iNeST collaboration with Genentech. 2. Lopez J, et al. AACR Annual Meeting 2020; Oral presentation CT301; 3. Braiteh F, et al. AACR Annual Meeting 2020; Poster presentation CT169; 4. Collaboration with Genentech. Frequency of TCRs (log,0) in Baseline Tumor BNT122 induces CD8+ T cell Infiltrates in tumors -1.8- -2- -2.2 -24- -2.6 -3.2 -34- -3.6- -3.8- XODOO C O O NUM Content OOO O mRNA cancer vaccines 0 RO7198457-specific TCRs Other TCRs RO7198457-specific TCRs are present only in post-treatment tumor. ●00000 COD -36-34-32 -3 -28-26-24-22 -2 -18-16-4 Frequency of TCRs (log 10) in Post-Treatment Tumor BIONTECH 98#99iNeST I Autogene cevumeran (BNT122) Neoantigen vaccines are well suited for the early-line setting Normal DNA U 1000000000 00000000000 Tumor DNA Adjuvant Residual cancer cells may remain - emphasis on recurrence free survival Tumor mass Tumor resistance mechanisms Immune system health iNeST is being developed in collaboration with Genentech. Early line (adjuvant/first line) Low tumor burden Not fully established. Functional T cell responses inducible. ● 1L metastatic ● Rapidly growing but often still in early phase of metastases ● O Three trials ongoing in early lines: Advanced melanoma (Phase 2) Adjuvant colorectal cancer (Phase 2) Adjuvant pancreatic ductal adenocarcinoma (Phase 1) NUM Late-line metastatic mRNA cancer vaccines Bulky tumors with multiple organs involved Late line (refractory) Large bulky tumors Multiple resistance mechanisms. Higher rate of dysfunctional immune cells. BIONTECH 99#100iNeST I Autogene cevumeran (BNT122) Phase 2 open-label, randomized trial in 1L advanced melanoma Ⓒ Advanced metastatic or unresectable melanoma Previously untreated Key endpoints Safety run-in (n=6-12) Pembrolizumab 1 cycle Primary: PFS Secondary: ORR Efficacy: OS, DOR, ORR post crossover Safety Quality of life BNT122 + pembrolizumab R 1:2 Pembrolizumab 200 mg q3w, ≤24 months Pembrolizumab (1 cycle) 200 mg q3w Cross-over allowed after confirmed PD CPI, checkpoint inhibitor; DoR, duration of response; ORR, overall response rate; OS, overall survival; PD, progressive disease; PFS, progression-free survival. Clinical Trials.gov: NCT03815058. Status n=131 enrolled (active, not recruiting) Success may unlock 1L use of iNeST in CPI-sensitive advanced cancers for combination therapy Collaboration with Genentech NUM mRNA cancer vaccines BNT122 + pembrolizumab ≤24 months total BIONTECH 100#101High medical need in the adjuvant treatment of Stage II (high risk)/Stage III colorectal cancer Stage II (high risk) High medical need in the adjuvant treatment of Stage II (high risk)/Stage III colorectal cancer Colorectal cancer is second deadliest cancer worldwide¹, 5-year OS in regional disease is 71% ² SoC in Stage II (high risk) and Stage III CRC after removal of the primary tumor and adjuvant chemotherapy is watchful waiting ctDNA is a marker for minimal residual disease and thus can identify patients at high risk of disease recurrence ³ 3,4 In ctDNA-positive, Stage 2 (high risk) and Stage 3 CRC post adjuvant chemotherapy, duration of disease-free survival is 6 months 5 and Stage III Surgery colorectal cancer CT scan Adjuvant chemo given to all patients CRC, colorectal cancer; ctDNA, circulating tumor DNA; ; OS, overall survival; SoC, standard of care., 1 WHO factsheet on cancer. 2018; 2 Seer database; 3 Fan G, et al. PLoS One 2017; 12: e0171991; 4 Loupakis F, et al. JCO Precis Oncol 2021; 5:PO.21.00101; 5 Reinert T, et al. JAMA Oncology, 2019; 5:1124-1131. No residual disease Microscopic residual disease NUM 50% Cured by surgery alone mRNA cancer vaccines 20% Cured by chemo on top of surgery 30% Recur despite surgery + chemo BIONTECH 101#102Patients with surgically-resected. stage II (high-risk) or stage III CRC iNeST | Autogene cevumeran (BNT122) Phase 2 randomized trial vs watchful waiting in adjuvant colorectal cancer Adjuvant SoC chemotherapy for 12-24 weeks Screening 2 neoantigen selection for vaccine manufacture Screening 1 ctDNA status (post-operative) Biomarker: BNT122 irrespective of ctDNA status (n=15) Key endpoints Primary: Disease-free survival (DFS) Efficacy: RFS, TTR, TTF, OS Change in ctDNA status. iNeST manufacturing ≤20 neo-epitopes CRC, colorectal cancer; ctDNA, circulating tumor DNA; OS, overall survival; q1/2/6w, every 1/2/6 weeks; R, randomize; RFS, relapse-free survival; SoC, standard of care; TTF, time to treatment failure; TTR, time to response. Clinical Trials.gov: NCT04486378. S M Screening 3 final eligibility (ctDNA-positive) Exploratory: BNT122 recurrent disease at Screening 3 (n≤20) R 1:1 NUM mRNA cancer vaccines n=166 BNT122 15 doses: 6xq1w, 2xq2w, 7xq6w Observational watchful waiting Status First patient dosed (randomized cohort): December 2021 Collaboration with Genentech BIONTECH 102#103iNeST | Autogene cevumeran (BNT122) Phase 1 trial of adjuvant BNT122 in pancreatic ductal adenocarcinoma Surgically resectable PDAC No borderline resectable No locally advanced or metastatic No neoadjuvant therapy ● Week 0 ● Surgery High unmet need in PDAC PDAC: anticipated to be the 2nd leading cause of cancer-related death in the US by 2030 ● Week 6 Atezolizumab 1 dose Surgery offers the only chance of cure 5-year survival rates after resection alone: ~10% • 69-75% relapse within 2 years after adjuvant therapy Immunotherapy resistant: Low mutation burden presumed few mutation-derived neoantigens Custom manufacture of BNT122; up to 20 neo-antigenes from tumor sample Weeks 9-17 BNT122 8 priming doses Key endpoints mFOLFIRINOX, modified FOLFIRINOX; PDAC, pancreatic ductal adenocarcinoma; q2w, every 2 weeks. Balachandran VP, et al. ASCO Annual Meeting 2022; Poster presentation 2516; Clinical Trials.gov: NCT04161755. Weeks 21-43 m FOLFIRINOX 12 q2w cycles Primary: Safety Immunogenicity Feasibility 18-month recurrence-free survival (RFS) Week 46 NUM BNT122 1 booster dose mRNA cancer vaccines →Follow-up Status Target accrual n=20 Investigator-initiated single-center study Collaboration with Genentech MSKCC-sponsored study BIONTECH 103#104Immunogenicity iNeST | Autogene cevumeran (BNT122): Substantial and durable T cell expansion observed in immune responders after BNT122 treatment 50% 50% (n=8) (n=8) Immune responder Immune non-responder Responder positive assay 1 and 2 Non-responders (n=8) Responders (n=8) iNeST is being developed in collaboration with Genentech. Balachandran VP, et al. ASCO Annual Meeting 2022; Poster presentation 2516. % of all blood T cells Assay 1: T-cell clonal expansion by TCRVB sequencing Responders (n=8) 100- 10- 0 (0.0) 0 (0.0) 0.1- 0.01- 0.001- Median % of all blood T cells (95% CI) Pre-vaccine Post-vaccine ▪▪▪▪▪▪▪▪▪▪▪▪▪ 20 40 60 80 100 Weeks after surgery 0 (0.0) 2.9 (0.2-10.4) P value 0.001 0 NUM Non-responders (n=8) mRNA cancer vaccines 20 40 60 80 100 BIONTECH 104#105iNeST | Autogene cevumeran (BNT122) Functional T cells confirmed by ELISPOT in immune responders Number of neoantigens in autogene cevumeran 20- 15- 10- 0 Assay 2: T cell specificity to autogene cevumeran neoantigens by IFNY ELISPOT Responders (n=8) iNeST is being developed in collaboration with Genentech. Balachandran VP, et al. ASCO Annual Meeting 2022; Poster presentation 2516. Non-responders (n=8) Immunogenic Non-immunogenic No data IFNy spots x 10° cells 1000 100 10 0 Responders (n=8) NUM 20 40 60 80 Weeks after surgery *Patient treated in non-protocol-specified sequence mRNA cancer vaccines 100 BIONTECH 105#106100 iNeST | Autogene cevumeran (BNT122) Immune response correlates with delayed recurrence in adjuvant PDAC RFS from resection (n=16) RFS (%) 50- No. at risk Responder Non-responder 00 00 0 6 8 Median RFS: Not reached 8 Median RFS: 13.7 months 8 6 12 18 24 Time (months) iNeST is being developed in collaboration with Genentech. Balachandran VP, et al. ASCO Annual Meeting 2022; Poster presentation 2516. 7 5 62 2 20 30 00 ● ● Responder positive assay 1 and 2 Median follow-up: 18 months HR=0.08 (95% CI 0.01-0.40); p=0.003 = A follow-up randomization trial is being developed NUM mRNA cancer vaccines BIONTECH 106#107Fix Vac Leveraging shared tumor-associated antigens for cancer treatment 5' Vaccine backbone with shared antigens THI ANTIGEN CASSETTE Backbone-optimized uridine mRNA (URNA) + Multi-antigen approach tailored to each indication Melanoma NY-ESO-1 Tyrosinase MAGE-A3 TPTE AAAA Poly(A) tail BNT111 encodes 4 tumor-associated antigens covering >90% of patients with cutaneous melanoma + HPV-E6 Lipoplex HPV-E7 T RNA-LPX formulation (IV) HPV16+ HNSCC HNSCC, head and neck squamous-cell carcinoma; HPV, human papilloma virus; NSCLC, non-small-cell lung cancer. TALL Th T BNT113 encodes 2 oncoproteins exclusively expressed in pre-malignant and malignant tissue || Prostate cancer KLK2 KLK3 ACPP HOXB13 NKX3-1 Fix Vac BNT112 encodes 5 related antigens specific to prostate cancer NUM 6666 Fixed vaccine combination against shared tumor-associated antigens mRNA cancer vaccines NSCLC Antigen 1 Antigen 2 Antigen 3. Antigen 4 Antigen 5 Antigen 6 BNT116 encodes 6 different NSCLC tumor-associated antigens AAAA AAAA AAAA AAAA AAAA AAAA BIONTECH 107#108Melanoma remains the deadliest skin cancer¹,2 Treatment options needed to address CPI failure in advanced melanoma Incidence + 50% Annual cases have increased by nearly 50% to over 287,0001.2 Deaths + 20% WHO predicts by 2025, number of deaths will increase by 20% ³ CPI R/R patients ~ 55% patients refractory to or relapse on CPI treatment, leaving them with limited treatment options4 ● Ⓡ NUM mRNA cancer vaccines Significant opportunity to improve on standard of care 5-year survival for metastatic melanoma still only 29.8% 5 Frontline immunotherapy with CPI induces durable responses in max. 45-50% of patients but with relatively short PFS4 CPI resistant/refractory patients that fail to respond to CPI or relapse after CPI have an especially poor prognosis with survival as short as 6 months depending on risk factors CPI, checkpoint inhibitor; DoR, duration of response; mPFS, median progression free survival; ORR, overall response rate; R/R, refractory/resistant; WHO, World Health Organization. 1 Available at: https://www.melanomauk.org.uk/2020-melanoma-skin-cancer-report; 2 Global Cancer Observatory - 2018 data from 'Cancer Today'; 3 Global Cancer Observatory - projected 2025 data from 'Cancer Tomorrow'; 4 Larkin J. et al. N Engl J Med 2019; 381:1535-1546; 5 Available at: https://seer.cancer.gov/statfacts/html/melan.html (accessed August 06, 2021. Advanced CPI R/R melanoma is a high medical need population with highly unfavorable prognosis BIONTECH 108#109Fix Vac IBNT111 Durable responses in a Phase 1/2 trial in advanced CPI-experienced melanoma Article An RNA vaccine drives immunity in checkpoint-inhibitor-treated melanoma https://doi.org/10.1038/s41586-020-2537-9 Ugur Sahin¹2,3,4, Petra Oehm', Evelyna Derhovanessian, Robert A. Jabulowsky'. Change from baseline in target lesion (%) 150 100- 50- 0 -50- nature -100 0 -BNT111 BNT111+ anti-PD1 200 400 600 Days after first vaccination PD PR 800 Lipo-MERIT trial Phase 1 trial data in CPI-experienced patients in monotherapy and in combination with anti-PD1 Data cut-off: July 29, 2019. ¹ Patients evaluable for efficacy; 2 One patient had a metabolic complete response with SD as best response, according to irRECIST1.1. CPI, checkpoint inhibitor; ORR, overall response rate; PR, partial response; SD, stable disease; TAA, tumor-associated antigen. Sahin U, et al. Nature 2020; 585:107-112. Analysis of patient subset with evaluable disease: All patients showed TAA-specific T-cell responses (post-IVS ELISpot) >75% of patients showed strong immune responses against 21 TAA (ex vivo EliSpot) Durable ORR¹ in CPI-experienced patients BNT111 (n=25): 3 PRs and 8 SDs² BNT111+ anti-PD1 (n=17): 6 PRs and 2 SDs (ORR=35%) Highest ORR=50% in 5/10 patients treated with 100 µg of BNT111 + anti-PD 1 ● Day Right lung Right lung middle lobe upper lobe -113 Pembrolizumab -71 NUM -14 mRNA cancer vaccines Vaccination 84 BIUNTECH 109#110Fix Vac | BNT111 - Long duration of clinical responses observed for patients receiving BNT111 monotherapy and combination with CPIs ¹ Growth kinetics of Target lesions Change from baseline in target lesion (%) 80 60 40 20 0 -20 -40 -60 -80 -100 -100 0 100 200 300 400 500 600 800 700 Days since first vaccination 900 1000 1100 Data cut-off: May 24, 2021. 1 One patient in the BNT111 monotherapy group who achieved a CR is not shown as only non-measurable target lesions were present (which later disappeared). CPI, checkpoint inhibitor; CR, complete response O 1200 1300 1400 Maximal Dose 14,4 29 50 75 100 Shape by: Treatment MONOTHERAPY CPI NUM BRAF/MEK mRNA cancer vaccines BIONTECH 110#111Fix Vac | BNT111 - Tumor shrinkage observed in patients receiving BNT111 monotherapy or combination with a PD-1 inhibitor 1,2 Best change from baseline in target lesion Best change from baseline in target lesion (%) 100 80 60 40 20 0 -20 -40 -60 -80 -100 CPI નજી MONOTHERAPY MONOTHERAPY MONOTHERAPY CPI Adv dar MONOTHERAPY MONOTHERAPY MONOTHERAPY MONOTHERAPY MONOTHERAPY CPI dy CPL CPT MONOTHERAPY MONOTHERAPY RAPY CPI CPI MONOTHERAPY MONOTHERAPY CPI de MONOTHERAPY MONOTHERAPY in CPI O CPI NALE CPI MONOTHERAPY CPI The O MONOTHERAPY MONOTHERAPY O O CPI CPI o CPI S CPI ADV O Adv MONOTHERAPY MONOTHERAPY CPI 199 MONOTHERAPY ** CPL CPT * * * * CPL CFI CPI on BRAF/MEK MONOTHERAPY MONOTHERAPY CPI * MONOTHERAPY * * de CPT CPL * CPI OFI CPI CPI Maximal dose given [µg] 14,4 29 50 75 100 Best overall response * PR o SD/irSD Data cut-off: May 24, 2021. 1 One patient had an 83.2% decrease of target lesion from baseline but experienced a new target lesion and had SD as the best overall response. Patient B4-31 had several new lesions despite a reduction in the target lesions; 2 One patient in the BNT111 monotherapy group who achieved a CR is not shown as only non-measurable target lesions were present (which later disappeared). CPI, checkpoint inhibitor; irRECIST, immune-related response evaluation criteria in solid tumors; SD, stable disease. LUTIN mRNA cancer vaccines BIONTECH 111#112Proportion of patients (%) Fix Vac I BNT111 Strong immunogenicity and promising clinical activity in Phase 1 Lipo-MERIT Comparable CD4+ and CD8+ T-cell responses was shown between ED and NED patients Proportion of patients (%) 100 80- 8 60 40 20 100 80- 60- 40- 20- Any antigen ED NED 0 14 9 9 19 Any antigen ED NED Ex vivo ELISpot (ED, n=22; NED, n=28) CD4* or CD8+ cell responses (including bulk PMBCs) NY-ESO-1 Tyrosinase MAGE-A3 6 ED 7 14 NED ED 1 1 3 17 NY-ESO-1 NED ED 6 19 ED NED 6 25 3 Post-IVS ELISpot (ED, n=9; NED, n=6) CD4* or CD8+ cell responses Tyrosinase NED 3 ED 3 16 NED 19 ED MAGE-A3 NED ED 2 18 TPTE ED 4 4 NED 23 TPTE NED 2 Ex vivo responses ED: 64% (n=14) NED: 68% (n=19) 3 T-cell response against 21 TAA observed in all patients ● Data cut-off: May 24, 2021. ED, evidence of disease; IVS, in vitro stimulation; NED, no evidence of disease; NR, not reached; TAA; tumor associated antigen. Loquai C, et al. SITC Annual Meeting 2021; Poster presentation 549. IIIC IIIB IV IIIB IIIC IIIB IIIC IV IIIC IIIB IIIC IV IV IIIB IV IV IIIC IV IIIB I|IC IIIC IV IV IV IIIB 言 IIIC IV IV IIIC IV IIIC IIIC IIIB **** Preliminary disease-free survival in patients with no evidence of disease at trial inclusion 0 100 200 300 400 500 600 700 NUM 800 900 mRNA cancer vaccines Treatment start Treatment completed Disease Progression Disease control ongoing Disease control ongoing in study phase, no LTFU info available 1000 1100 1200 1300 1400 Trial day In NED patients: 34.8 month median DFS (95% CI: 7.0-NR) after a median follow-up of 40.7 months (95% CI: 35.3-42.7) BIONTECH 112#113Ⓒ Fix Vac | BNT111 Phase 2 randomized trial ± cemiplimab in patients with anti-PD1-R/R melanoma Unresectable Stage III or IV melanoma Relapsed/Refractory to anti-PD1 Key endpoints Primary: Combination arm: ORR Efficacy: ORR, DOR, DCR, TTR, PFS, OS Safety, including immune-related AEs Quality of life R 2:1:1 T BNT111 + cemiplimab Up to 24 months - n=90 BNT111 Up to 24 months - n=45 Cemiplimab Up to 24 months - n=45 Upon disease progression Status First patient dosed: June 2021 n=180 Global trial (Australia, Germany, Italy, Poland, Spain, UK, US) Collaboration with Regeneron DCR, disease control rate; DoR, duration of response; ORR, overall response rate; OS, overall survival; PFS, progression free survival; R/R, relapsed/refractory; TTR, time to response. Clinical Trials.gov: NCT04526899. NUM mRNA cancer vaccines BNT111 + cemiplimab US FDA Fast Track Designation and Orphan Drug Designation Success measures ORR=30% BIONTECH 113#114mRNA cancer vaccines near-term milestones Platform Product candidate iNeST Neoantigen mRNA vaccine Fix Vac Fixed- combination mRNA vaccine Autogene cevumeran (BNT122) + pembrolizumab¹ Autogene cevumeran (BNT122) ± atezolizumab ¹,2 BNT111 ± anti-PD 1 BNT111 cemiplimab BNT112 ± cemiplimab BNT113 BNT1152 Indication (targets) Phase 2 fully recruited; data update H2 2022 Autogene cevumeran (BNT122)1 Adjuvant colorectal cancer Phase 2 ongoing (FPD, December 2021) Autogene cevumeran (BNT122) Phase 1 fully recruited ± atezolizumab¹ pembrolizumab 1L melanoma Solid tumors Adjuvant PDAC Advanced melanoma R/R melanoma Next milestone Prostate cancer HPV16+ head and neck cancer Ovarian cancer NUM mRNA cancer vaccines Follow-up randomized trial being developed Phase 1 ongoing Phase 2 ongoing (FPD, June 2021) - US FDA Fast Track Designation and Orphan Drug Designation FPD, first patient dosed; HNSCC, head-and-neck squamous-cell carcinoma; NSCLC, non-small-cell lung cancer; PDAC, pancreatic ductal adenocarcinoma; R/R, relapsed/refractory. 1 BNT122, Collaboration with Genentech; 2 Investigator-initiated study. Enrolment ongoing for Part 2 Phase 2 with registrational potential ongoing (FPD, July 2021) Phase 1 ongoing BIONTECH 114#115Protein therapeutics BIONTECH#116BNT311 Combining checkpoint blockade and conditional T cell co-stimulation Dual targeted 4-1BB co-stimulation that is conditional on PD-L1 binding GEN1046 (BNT311) Conditional 4-1BB agonist activity BNT311 binding affinity: KD PD-L1: 0.16 nmol/L, 4-1BB: 0.15 nmol/L 4-1BB-expressing cell (eg, T cell) 4-1BB GEN1046 PD-1 Checkpoint blockade PD-L1 PD-L1-expressing cell (eg, tumor cell) PD-1/PD-L1 blockade (fold increase) 8 + N 0 GEN1046 → Anti-PD-L1 mAb Atezolizumab analogue Isotype ctrl * BNT311 (Gen1046) is partnered with Genmab based on 50/50 sharing of costs and profits. 1 Muik A, et al. Cancer Discov 2022; 12:1248-1345. TITIE 0.001 0.01 0.1 1 10 Antibody concentration (µg/mL) 100 Enhanced NK cell activity Novel mechanism that enhances T- and NK-cell function Enhanced recruitment of immune cells NK coll Reactivation of exhausted T cells Tumor Tumor lysin Activated T cell PD-1 Flictivated PD-1 high cell GEN1046 Blood vessel Tumor 4-1BB Infiltrating immune cells PD-L1 Blood vesse Activated T cell Tumor Jysis Y Dendred Tumor-draining lymph node Differentiation Granzyme Perforin Semen T cell Enhanced effector T-cell activity Activated T cell Proliferation Enhanced T-cell activation Cytokines Protein therapeutics Activate T cell Chemokines T-cell proliferation and differentiation Conditional bi-specific molecule for two preclinically validated targets: PD-L1: receptor-ligand expressed on tumor cells to inhibits the proliferation of PD1-positive cells, and participates in the immune evasion 4-1BB: costimulatory tumor necrosis factor expressed on T cells and NK-cells. Activating the 4-1BB pathway enhances T cell proliferation, T cell effector functions, and prevents T cell death BIONTECH 116#117Metastatic or unresectable solid tumors Patients who are not candidates for standard therapy BNT311 First-in-human Phase 1/2 trial in heavily pretreated advanced solid tumors Key endpoints Phase 1 Dose escalation (N=61) BNT311/GEN1046* IV flat dose Q3W until PD or unacceptable toxicity Primary: MTD, RP2D Safety, pharmacokinetics, immunogenicity Expansion dose 100 mg Q3W — - 14 Status Pharmacodynamics and potential predictive biomarkers Antitumor activity (RECIST v1.1) * BNT311 (Gen1046) is partnered with Genmab based on 50/50 sharing of costs and profits. CC, cervical cancer; EC, endometrial cancer; HNSCC, head and neck squamous-cell cancer; MTD, maximum tolerated dose; NSCLC, non-small-cell lung cancer, PD, progressive disease; RP2D, recommended Phase 2 dose; TNBC, triple-negative breast cancer; UC, urothelial cancer. NCT03917381. ● ● Phase 2a Dose expansion (≤40 per cohort) PD-(L)1-inhibitor pretreated cohorts. Cervical C Endometrial HNSCC Recruiting 11 expansion cohorts Collaboration with Genmab Y ● Protein therapeutics ● NSCLC TNBC UrethelialC BIONTECH 117#118BNT311: Initial results in dose escalation show a manageable safety profile with most AEs being Grade 1 or 2 ALT increased AST increased Anemia Asthenia Fatigue Hypothyroidism Back pain Decreased appetite Malignant neoplasm Nausea TEAES occurring in ≥10% of patients 10 20 Dose escalation cohort TEAE's occuring in ≥10% of patients Any TRAE TRAES in ≥10% patients, by preferred term ALT increased AST increased Hypothyroidism Fatigue 30 T 40 All grades, n (%) 43 (70.5) 14 (23.0) 13 (21.3) 11 (18.0) 8 (13.1) 50 Grade 1 Grade 2 Grade 3 Grade 4+ Grade 23, n (%) 17 (27.9) 5 (8.2) 2 (3.3) 1 (1.6) 1 (1.6) 100 Data cut-off: August 31, 2020. DLT, dose-limiting toxicity; MTD, maximum tolerated dose; TEAE, treatment-emergent adverse event; TRAE, treatment-related adverse event. Garralda E, et al. SITC Annual Meeting 2020; Poster presentation 412. Protein therapeutics Treatment-related transaminase elevations occurred in 26.2% (Grade 23: 9.8%) and decreased with corticosteroid administration No treatment-related bilirubin increases or Grade 4 transaminase elevations 6 patients had DLTs: Grade 4 febrile neutropenia (n=2), Grade 3 nephritis (n=1), Grade 3 ALT increase (n=1), Grade 3 AST/ALT increase (n=1), Grade 3 transaminases increase (n=1) All six patients recovered without sequelae MTD was not reached BIONTECH 118#119BNT311 Anti-tumor activity (Phase 1 dose escalation part) 75 50 25 0 -25 -50 -75 IL T 1 PD PD PD PD PD PD PD mg mg mg 400 mg 11200 mg 50 mg 25 mg 25 140 80 PD 140 mg PD 200 mg PD PD SD SD SD 200 mg 1800 mg 200 mg 500 N N Best percent change from baseline in tumor size 140 mg 400 mg 140 mg 80 mg 140 mg 800 mg 800 mg 200 mg 80 mg 400 mg 50 mg 400 mg 80 mg 25 mg 140 mg 100 mg 200 mg 80 mg 1200 mg 800 mg 100 mg 1200 mg 80 mg 1200 mg 100 mg 400 mg -NE-SD-SD--SD-SD SD SD SD SD SD SD SD SD SD SD SD SD SD SD SD SD SD SD SD PD SD SD SD SD SD SD SD PD PD SD SD SD NEa PR uPRbuPRD PR Dose level Data cut-off: September 29, 2020. Post-baseline scans were not conducted for five patients. A Minimum duration of response (5 weeks) per RECIST v1.1 not reached. B PR was not confirmed on a subsequent scan. 400 mg 800 mg 50 mg 50 mg 80 mg 200 mg 400 mg 400 mg Disease control achieved in 65.6% (40/61) of patients at a median of 3 months follow-up 4 early partial responses in TNBC (1), ovarian cancer (1), and CPI pre-treated NSCLC (2) patients Protein therapeutics NE, non-evaluable; NSCLC, non-small cell lung cancer; PD, progressive disease; PD-(L)1, programmed death (ligand) 1; PR, partial response; SD, stable disease; SoD, sum of diameters; uPR, unconfirmed partial response. Garralda E, et al. SITC Annual Meeting 2020; Poster presentation 412. Colorectal cancer NSCLC Ovarian cancer Pancreatic cancer Other cancer Prior PD-(L)1 800 mg 50 mg 400 mg 800 mg 200 mg 800 mg 80 mg 80 mg 200 mg 100 mg BIONTECH 119#12012 evaluable patients in the NSCLC expansion cohort, of which two experienced PR; one uPR; four SD BNT311 Clinical activity in patients with CPI-experienced relapsed/refractory NSCLC Best change from baseline in tumor size in NSCLC with prior PD(L)-1 (n=12) Best relative change in SoD from baseline (%) 50 25. PD -25 -50 -75 -100 Response to prior CPI: --PD-PD-PD SD SD SD SD NE UPR* PR PR PR PR PD PD PR PR PD PD ΝΑ SD PD NE Change in SoD from baseline (%) 50 25 0 -25 -50 -75 -100 Target lesion SoD change from baseline in NSCLC with prior PD (L)-1 (n=12) 3 Data cut-off: October 12, 2020. *PR was not confirmed by a subsequent scan. Patients all had 21 post-baseline tumor assessment (scheduled every 6 weeks) and thus could be assessed for clinical benefit; 6 of 12 patients are still on treatment. NA, not available, NE, non-evaluable; PD, progressive disease; PR, partial response; SD, stable disease; SoD, sum of diameters; uPR, unconfirmed partial response. Garralda E, et al. SITC Annual Meeting 2020; Poster presentation 412. 9 6 Study week Y PD SD PR uPR 12 PD SD PR ΝΑ Protein therapeutics 15 BIONTECH 120#121BNT311 Objective responses observed more frequently in PD-L1+ patients Best relative change in sum of diameters from baseline, % 40 20 -20 -60 Clinical activity by tumor PD-L1 status in CPI-experienced patients with NSCLC (n=25)¹ PD-L1+ PD-L1- 11 Tumor reduction in 7/11 with PD-L1+ tumors 1 Among patients with evaluable baseline tumors. Fisher exact test odds ration for PD-L1+ vs PD-L1- tumors OR=0.11. Data cut-off: September 21, 2021. Ponce Aix S, et al. SITC Annual Meeting 2021; Poster presentation 516. Y Protein therapeutics Preliminary findings in CPI-experienced patients with advanced NSCLC support enrichment based on tumoral PD-L1 status (TPS ≥1%) A similar trend was observed in patients with UC, TNBC, and HNSCC BIONTECH 121#122Combination of PD-L1x4-1BB bispecific with PD-1 blockade improves activity in preclinical models Median tumor volume per treatment group (n=10)¹ Median tumor volume, mm³ 2500 2000 1500 1000 50 14 21 Time, d 28 35 PBS Anti-mPD-1 (10 mg/kg) bs anti-mPD-L1xm4-1BB (5 mg/kg) bs anti-mPD-L1xm4-1BB (5 mg/kg) + anti-mPD-1 (10 mg/kg) ▼ Treatment Mice with tumor volume <500 mm³, % 100 80 60 40 20 0- Survival² 14 21 Time, d PBS Anti-mPD-1 (10 mg/kg) bs anti-mPD-L1xm4-1BB (5 mg/kg) bs anti-mPD-L1xm4-1BB (5 mg/kg) + anti-mPD-1 (10 mg/kg) ▼ Treatment 28 35 Complete tumor regression in 7/10 mice and significant enhancement of survival 1 Growth curves were discontinued when <50% of the animals within a treatment group remained alive or at day 35; 2 Defined as the percentage of mice with tumor volumes <500 mm³. Mantel-Cox analysis on day 45: PBS vs anti-m PD-1: p=0.012, PBS vs anti-m PD-L1xm4-1BB: p<0.001, PBS vs anti-m PD-L1xm4-1BB+ anti-m PD-1: p<0.001, anti-m PD-1 vs anti-m PD-L1xm4-1BB: p=0.5; anti-m PD-1 vs anti-m PD-L1xm4-1BB+ anti-m PD-1: p=0.001; anti-m PD-L1xm4-1BB vs anti-m PD-L1xm4-1BB+ anti-m PD-1: p<0.001. Ponce Aix S, et al. SITC Annual Meeting 2021; Poster presentation 516. Protein therapeutics 42 BIONTECH 122#123● BNT311 Open-label, randomized Phase 2 trial in CPl-experienced PD-L1+ R/R NSCLC Stage IV metastatic R/R NSCLC (2L+) PD-L1 TPS ≥1% Prior treatment with an anti-PD-(L)1 Significant unmet need in R/R NSCLC ~1.8 million lung cancer deaths worldwide annually² NSCLC is most common type (~85%)³ 5-year survival only 4% for advanced or metastatic NSCLC4 CPI therapy fails in majority of NSCLC patients due to evolution of resistance Poor prognosis for CPI R/R NSCLC Estimated PFS <6 months and OS <1 year New strategies needed to overcome resistance and maximize efficacy 1:1:1 R N-130 A: BNT311 monotherapy B: BNT311+ pembrolizumab (every 21 days)¹ C: BNT311+ pembrolizumab (every 42 days)¹ Key endpoints 6 Primary: Overall response rate Efficacy: Duration of response, time to response, PFS, OS survival Safety and laboratory abnormalities 123 Y Status 6 Partnered with Genmab; 50:50 profit/loss collaboration. CPI, check point inhibitor; NSCLC, non-small-cell lung cancer; OS, overall survival; PFS, progression-free survival; R/R, refractory/relapsed; TPS, tumor proportion score; SoC, standard of care. 1 Following Safety run-in; 2 Bray F, et al. CA Cancer J Clin 2018; 68:394-424; 3 ASCO Cancer.Net® 2022. Available at: https://www.cancer.net/cancer-types/lung-cancer-non-small-cell/statistics (accessed June 28, 2022); 4 Siegel RL, et al. CA Cancer J Clin 2018; 68:7-30; 5 Qu J, et al. 2021; 13; 6 Clinical Trials.gov: NCT05117242. Protein therapeutics Recruiting First patient dosed in December 2021 Collaboration with Genmab BIONTECH 123#124BNT312 Bispecific antibody designed to strengthen T cell and APC synapse Inert Fc, double conditional, dual CD40×4-1BB agonist D GEN1042 (BNT312) 4-1BB-expressing cell (eg, T cell) BNT311 binding affinity: KD CD40 1.0 nmol/L, 4-1 BB: 0.17 nmol/L Conditional 4-1BB agonist activity 4-1BB GEN1042 CD40 Conditional CD40 agonist activity CD40-expressing APC (eg, dendritic cell) APC maturation, Conditional CD40-stimulation of APC and conditional 4-1BB mediated stimulation of T cells T cell T cell Enhanced natural killer (NK) cell activity Expression of costimulatory molecules e.g. HLA-DR, CD86 Production of stimulatory cytokines GEN1042 Activated dendritic CD86/HLA-DR Tumor draining lymph node 4-1BB Tumor lysis CD40 Tumor 00 Granzyme Perforin Granzymes, perforins Activated coll Blood vessel Proliferation Activated T cell Differentiation Memory T cell Cytokines TCR-MHC receptors Tumor lysis Enhanced effector T cell activity Cytokines Y T cell proliferation and differentiation CD28/CD80 receptors Protein therapeutics "Double-conditional" "dual-agonist" molecule for two preclinically validated targets: CD40: stimulatory receptor primarily expressed on APCs. Engagement of CD40 leads to activation and maturation of APC s 4-1BB: costimulatory tumor necrosis factor expressed on T-cells and NK-cells. Activating the 4-1BB pathway enhances T cell proliferation, T cell effector functions, and prevents T cell death Inert Fc to avoid unwanted immune cells crosslinking BNT312 (Gen1042) is partnered with Genmab based on 50/50 sharing of costs and profits; ¹ Muik A, et al. J Immunother Cancer 2022;0:e004322. doi:10.1136/jitc-2021-004322. BIONTECH 124#125BNT312 Double-conditional dual-agonist molecule In the absence of CD40+ cells, BNT312 does not exhibit any 4-1BB activation Relative luminescence units 1x106- 8×1054 6x105- 4x105- 2x105- without 4-1BB* K562 cells CD40 reporter assay 0 TTT 0.0001 0.001 0.01 0.1 T T T T 1 Antibody concentration (µg/mL) 10 DuoBody-CD40x4-1BB recombinant CD40L 4x105. 3x105. 2x105- 1×105- with 4-1BB K562 cells 0 0.0001 0.001 0.01 0.1 ▬▬▬▬▬▬▬▬ 1 Antibody concentration (µg/mL) bsAb-CD40xctrl bsAb-ctrlx4-1BB Isotype ctrl BNT312 (Gen1042) is partnered with Genmab based on 50/50 sharing of costs and profits. Muik A, et al. J Immuno Ther Cancer 2022; 10:e004322. 10 Fold increase in luminescence In the absence of 4-1BB+ cells, BNT312¹ does not exhibit any CD40 activation 2.0₁ 1.5- 1.0- 0.5- 4-1BB reporter assay without CD40* K562 cells 1 0.001 0.01 0.1 Antibody concentration (µg/mL) 10 DuoBody-CD40x4-1BB Recombinant 4-1BBL 2.01 1.5- 1.0- 0.5- Protein therapeutics with CD40 K562 cells bsAb-CD40xctrl bsAb-ctrlx4-1BB T 0.0001 0.001 0.01 0.1 Antibody concentration (µg/mL) 1 BIONTECH 125#126BNT312 strengthens crosslinking between T cells and APCs DAPI LEAT Phalloidin Z-projection on the y Z-projection on the x Single Z plane of iDC cocultured with preactivated CD8+ T cells in the presence of Alexa Fluor 647-conjugated DuoBody-CD40.4-1BB (magenta) and LFA-1 (green) antibodies, on the x and y axes the z-stack of the same picture with the relative zoom in. Nuclei were counterstained with Hoechst (blue) BNT312 (Gen1042) is partnered with Genmab based on 50/50 sharing of costs and profits. Muik A, et al. J Immuno Ther Cancer 2022; 10:e004322. Strengthened crosslinking 10 μm Hoechst bsAb-ctris (CD40+ 4-1BB) LFA-1 Hoechst Protein therapeutics DuoBody-CD40x4-1BB 10 μm Representative fluorescent images of cocultures in the presence of DuoBody-CD40.4-1BB or control antibodies. White dashed line = interface between DC and T cell LFA-1 BIONTECH 126#127BNT312 showed higher ability to promote DC maturation vs either monoclonal antibody or their combination % HLA-DR+/CD86+ of total DC population 60 40 20 0 11 0.001 0.0001 0.1 0.0001 0.001 0.1 ll Antibody concentration (µg/mL) BNT312 (Gen1042) is partnered with Genmab based on 50/50 sharing of costs and profits. The dotted line shows the percentage of HLA-DR+ CD86+ DCs in DC-T-cell cultures in the absence of treatment. Muik A, et al. J Immuno Ther Cancer 2022; 10:e004322. L 0.0001 0.001 0.1 Isotype ctrl bsAb-CD40* ctrl bsAb-ctrlx 4-1BB Protein therapeutics bsAb-CD40x ctrl + bsAb-ctrlx 4-1 BB Fc inert mitazalim ab analog Fc inert urelumab analog DuoBody-CD40×4-1BB BIONTECH 127#128BNT312: Favorable safety profile across a wide dose range; 100 mg selected for dose expansion phase Treatment-emergent adverse events in ≥10% (N=50) Fatigue Nausea Dyspnea Decreased appetite Pyrexia Arthralgia Constipation Headache Anemia Diarrhea Pruritis Transaminase elevation Vomiting Cough Flushing Urinary tract infection 0 10 T 20 30 Patients, % Data cut-off: August 27, 2021. Partnered with Genmab; 50:50 profit/loss collaboration. CRS, cytokine release syndrome; DLT, dose-limiting toxicity; MTD, maximum tolerated dose. Johnson M, et al. SITC Annual Meeting 2021; Oral presentation 493. T 40 50 60 Protein therapeutics MTD not reached 1 DLT (Grade 4 transaminase elevation at 200 mg) resolved with corticosteroids No drug-related Grade 23 thrombocytopenia or CRS No treatment-related deaths BIONTECH 128#129Y Protein therapeutics BNT312: Clinical modulation of peripheral biomarkers supports its function in a wide range of solid tumors Fold change ● 120 100 80 60 40 20 0 T C1D1, pre C1D1, 2 h C1D1, 6 h Doses 230 mg effectively induce proinflammatory cytokine release IFN-Y C1D2 C1D3 F C1D8 Min = 25; Max = 28 C1D15 C2D1, pre Fold change 20 15 10 5 0 C1D1, pre O C1D1, 2 h O C1D1, 6 h TARC C1D2 C1D3 C1D8 o Min = 21; Max = 24 C1D15 C2D1, pre Higher doses more effectively induced IFN-y and TARC, indicating T cell activation and DC/APC activation, respectively (≥30 mg dose vs <30 mg dose) % Ki67+ CD8+ T cells ● 15 10 C1D1, pre C1D2 Doses 230 mg effectively induce cytotoxic T-cell proliferation CD8+ T cells C1D3 C1D8 O Min = 24; Max = 27 C1D15 C2D1, pre Data cut-off: August 27, 2021. Partnered with Genmab; 50:50 profit/loss collaboration. Mean fold changes of cytokine concentrations and % of CD8+ T cells ± standard error of the mean (SEM) are displayed for high- and low-dose cohorts during the first cycle. Minimum and maximum numbers of patients with available data (n) at any given point are displayed. APC, antigen-presenting cell; DC, dendritic cell; TARC, thymus- and activation-regulated chemokine. Johnson M, et al. SITC Annual Meeting 2021; Oral presentation 493. Effector memory CD8+ T cells % Percent Ki67+ Effector Memory CD8+ T cells 60 50 40 C1D1, pre C1D2-0 C1D3 o C1D8- o Min = 24; Max = 27 C1D15 Higher doses more effectively Ki67 (proliferation induced marker) in CD8+ T cells (≥30 mg dose vs <30 mg dose) C2D1, pre BIONTECH 129#130Near-term milestones for protein therapeutics Platform Product candidate BNT311 (PD-L1×4-1BB)¹ Next-gen immunomodulators BNT311 ± pembrolizumab 1 BNT312 (CD40×4-1BB)¹ ± anti PD1 ± chemotherapy FPD, first patient dosed; NSCLC, non-small-cell lung cancer; R/R, relapsed/refractory. 1 (GEN1046 and GEN10542), partnered with Genmab; 50:50 profit/loss collaboration.. Indication Multiple advanced solid tumors PD1+ R/R NSCLC Multiple advanced solid tumors Protein therapeutics Next milestone Phase 1/2 trial: 8 expansion cohorts completed 2 cohorts enrolment ongoing, 1 cohort enrolment to be started Phase 2 ongoing (FPD, December 2021) Phase 2b trial combination expansion cohorts. enrolling BIONTECH 130#131BIONTECH Extending cell therapy to solid tumors#132Developing 3 autologous cell therapy platforms and addressing novel targets Chimeric antigen receptor (CAR)¹ aCLDN6 scFv CD8 hinge 4-1BB CD32 CARVac Autologous engineered cell therapy to address extra-cellular targets RNA-LPX vaccine Lead program: BNT211 CARVac targeting CLDN6 Reinhard K, et al. Science 2020; 367:446-453 NEO-STIM Individualized ex-vivo T-cell therapy targeting neoantigens Lead program: BNT221 across multiple solid tumors ● ● T-cell receptor (TCR) B εδ Ty Engineered cell therapy to address both intra- and extra-cellular targets Individualized TCR-T in development Cell therapies Programs: KRAS, PRAME TCRs BIONTECH 132#133BNT211: Phase 1/2 trial evaluating next-generation CAR T targeting claudin-6 with CARVac in solid tumors CAR T-cell therapy + CARVac RNA vaccine to amplify CAR T cells in vivo Claudin-6 not present in healthy tissues 2nd generation CAR directed against CLDN6, a cancer specific carcino-embryonic antigen CLDN6 is expressed in multiple solid cancers with high medical need CARVac drives in vivo expansion, persistence and efficacy of CAR T Intracellular Extracellular aC LDN6 scFv CD8 hinge 4-1BB CD32 ● Relapsed/Refractory advanced solid tumors CLDN6-positive: ≥50% of tumor cells CLDN6-high [II/II||+] CLDN6, claudin 6; E15, embryonic day 15; EL, extracellular loop; PO, at birth. Reinhard K, et al. Science 2020; 367:446-453. Phase 1 - Dose escalation Monotherapy CLDN6 CAR T cells (3 DLs) Expressed in various cancers Combination CLDN6 CAR T cells (3 DLs) + CLDN6-encoding CARVac Ovarian Phase 2 trial planned for 2023 EMA PRIME designation in testicular cancer RP2D Testicular Lung F Cell therapies Phase 2 - Dose expansion Testicular cancer Ovarian cancer Endometrial cancer Lung cancer Gastric cancer Tumors not otherwise specified BIONTECH 133#134BNT211 16 heavily pre-treated patients assessed in the trial Patient characteristics Median age, years (range) Gender (male/female), n/n Cancer type, n Testicular Ovarian Endometrial Fallopian tube Sarcoma Gastric Median CLDN6 II/III+ cells, % (range) Median prior treatment lines (range) Data cut-off: March 10, 2022. CLDN6, claudin 6; DL, dose level. Haanen J, et al. AACR Annual Meeting 2022; Oral presentation CT002. Monotherapy DL1 (n=3) 33 (25-68) 2/1 1 1 0 0 1 0 60 (60-80) 4 (3-5) Combination DL1 (n=3) 41 (27-56) 3/0 3 O O O OW 0 0 0 0 0 90 (90-95) 4 (3-4) Monotherapy DL2 (n=6) 56 (35-66) 3/3 2 1 1 1 0 1 82.5 (50-90) 5 (2-7) Combination DL2 (n=4) 44 (23-61) 2/2 22000 0 95 (75-100) 5 (3-7) Cell therapies Total (n=16) 46 (23-68) 10/6 8 4 1 1 1 1 85 (50-100) 4 (2-7) BIONTECH 134#135BNT211 was well tolerated at the dose levels evaluated Monotherapy DL1 (n=3) 284 (111-348) N/A Monotherapy DL1 (n=3) Monotherapy DL2 (n=6) 157 (99-241) N/A Monotherapy DL2 (n=6) Treatment schedule Median of follow-up, days (range) Median CARVac injections, n (range) ● Safety, n DLTS Patients with Grade 23 AEs AES Grade 23 suspected to be related to BNT211 Patients with CRS Patients with ICANS Deaths Disease progression SAE 0 3 0 0 1 0 Combination DL1 (n=3) 38 (29-156) 2 (1-6) Combination DL1 (n=3) 0 3 8 1 1 2 0 1 5 11 4 0 2 0 Combination DL2 (n=4) 93 (52-127) 4 (3-5) Combination DL2 (n=4) Data cut-off: March 10, 2022. AE, adverse event; CAR, chimeric antigen receptor; CARVac, CAR T cell-amplifying RNA vaccine; CRS, cytokine release syndrome; DL, dose level; DLT, dose-limiting toxicity; HLH, hemophagocytic lymphohistiocytosis; ICANS, immune effector cell-associated neurotoxicity syndrome; SAE, serious AE. Haanen J, et al. AACR Annual Meeting 2022; Oral presentation CT002. 1 4 22 3 0 0 0 Total (n=16) 127 (2-348) N/A Total (n=16) 2 15 45 8 1 Cell therapies 5 0 ● 2 DLTs observed: prolonged pancytopenia after lymphodepletion (monotherapy DL2) and HLH (combination DL2, before start of CARVac) All CRS were Grade 1 or 2; reported in 70% of patients at DL2 and manageable by administration of tocilizumab (if needed) BIONTECH 135#136BNT211 An ORR 43% and DCR of 86% (6 PR, 5 SD+, 1 SD) were achieved at 6 weeks Mono DL1 Combo DL1 Mono DL2 Pat#1 Pat#2 Pat#3 Pat#1 Pat#2 Pat#3 Pat#1 Pat#2 Pat#3 Pat#4 Pat#5 Pat#6 Pat#1 Pat#2 Combo Pat#3 DL2 Pat#4 Pat#5 Pat#6 Pat#1 (50% lymphodepletion) ACT CR PR SD + SD PD Redosing Mono Combo * EOT Testicular Cell therapies Ovarian Others Non-evaluable Not included 6 weeks 12 weeks 18 weeks 24 weeks 30 weeks 36 weeks 42 weeks 48 weeks In testicular cancer at DL2 (n=5, incl. reduced LD): Best overall response rate-80%, DCR 100% (1 CR, 3 PR, 1 SD+) Data cut-off: March 10, 2022; first assessment, 6 weeks post infusion. ACT, adoptive cell transfer; CR, complete response; DCR, disease control rate; EoT, end of trial (due to PD); PD, progressive disease; PR, partial response; SD (+), stable disease (with shrinkage of target lesions). Haanen J, et al. AACR Annual Meeting 2022; Oral presentation CT002. BIONTECH 136#137BNT211 Clinical benefit seen in patients with testicular cancer receiving DL2 Change in target sum [%] 60 40- 20- 0- -20- -40- -60- Hi -100- Testicular -80- Ovarian Others Best response Change in target sum [%] Data cut-off: March 10, 2022. CR, complete response; DL, dose level; PR, partial response. Haanen J, et al. AACR Annual Meeting 2022; Oral presentation CT002. Durability of responses (testicular cancer) 60 40 20 0 -20- -40- -60- -80- -100- 0 10 20 Weeks 30 One patient with initial PR showed deepening of responses over time, resulting in CR Monotherapy DL1 Combination DL1 Combination DL2 Cell therapies 40 50 BIONTECH 137#138BNT211 Responses in two patients with testicular cancer Patient 1 61-year-old male Diagnosed 2008 (DL2: 1×108) Patient 2 56-year-old male Diagnosed 2020 (DL1: 1x107 + CARVac) Baseline 6 weeks post infusion 12 weeks post infusion 000 OOO Data cut-off: March 10, 2022. AFP, alpha-fetoprotein; CAR, chimeric antigen receptor; CARVac, CAR T cell-amplifying RNA vaccine; CLDN6, claudin 6; CR, complete response; d, day; DL, dose level. Haanen J, et al. AACR Annual Meeting 2022; Oral presentation CT002. ● ● ● ● ● ● Cell therapies Post 12-week scan No new lesions detected Tumor marker (AFP) at normal level Ongoing CR After initial response, new lesions detected On-treatment biopsy showed positivity for CLDN6 Re-dosed on d197 BIONTECH 138#139BNT221: NEO-STIM is an individualized neoantigen-targeted strategy that addresses the limitations of tumor-infiltrating lymphocyte therapies Targets each patient's multiple tumor neoantigens¹ Tumor Sample/Sequencing ● RÉCON ARMATIES Bioinformatics A jos +0° Personalized Immunogen Synthesis (Peptide or RNA) Leukapheresis 888 Culture Reagents APCs & T cells T cell Epitopes Prime NEO.com STIM Activate Specific Cell Subsets From a Patient's Apheresis Product Expand BNT221 Product Multi-target: reduced risk for antigen escape T cells are induced from peripheral blood with no gene engineering or viral vectors: reduced toxicity Broad clinical opportunity across solid tumors ¹ Velez D, et al. SITC Annual Meeting 2021, Poster presentation 201; 2 Lenkala D, et al. SITC Annual Meeting 2020, Poster presentation 153. IFNY* and/or CD107a+ (of CD8+ pMHC*) BNT221 cells specifically recognize autologous tumor² 15 10 0 Cytokine response T BNT221 ** BNT221 + autologous tumor Cell therapies BIONTECH 139#140BNT221 Phase 1 trial in patients with PD-1-refractory metastatic melanoma Unresectable or metastatic melanoma Progression on anti-PD-1 Received anti CTLA-4 Key endpoints Cohort A Dose escalation (3x3) Safety Clinical activity (ORR, response durability) Immune monitoring Cell viability Velez D, et al. SITC Annual Meeting 2021, Poster presentation 201; Clinical Trials.gov: NCT04625205. Selected dose -- H Unresectable or metastatic melanoma Stable or asymptomatic progression on anti-PD-1 ± anti CTLA-4 Status Recruiting Up to 20 patients will be treated in the dose-expansion Cohort B Cell therapies Cohort B Dose expansion BIONTECH 140#141TCR discovery platform for tumor- and patient-specific therapies Establish TCR platform in solid tumors • Technologic iterations. • Combination with other assets ● (e.g. RiboCytokines) Acquisitions: PRAME-TCR and PD1-41BB switch (Medigene, Feb 2022) TCR, T-cell receptor. • TCR warehouse: multiple TCRs to target one or more antigens ● Broad patient coverage ● Library-like approach adding new targets and HLA alleles Collaboration with Medigene R&D Individualized treatment • On-demand identification of neoepitopes, timely manufacturing of customized T cells Cell therapies Acquisition: Neoantigen TCR platform (KITE, Jul 2021) BIONTECH 141#142BIONTECH RiboCytokines#143RiboCytokines Designed to overcome limitations of recombinant cytokine therapy Systemic delivery ● • Backbone optimized and nucleoside-modified mRNA encoding cytokine fused to human albumin Liver-targeting LNP formulation with intravenous delivery Encoded cytokines translated in body cells and secreted Designed for optimized safety, tolerability and dosing Prolonged serum half-life High bioavailability Lower and less frequent dosing Lower toxicity ● ● ● , lipid nanoparticle; PK, pharmacokinetic; IL-2, Interleukin-2; IL7, Interleukin-7; UTR, untranslated region RiboCytokine® is a registered trademark of BioNTech. Lipid nanoparticle (LNP) Cap 30 BOB SPO Lipids Serum concentration 5' UTR RiboCytokine RNA Cytokine-Albumin NUM PK profile TH Time RiboCytokines Recombinant cytokine RiboCytokine 3' UTR AAA BIONTECH 143#144BNT151 Stimulates CD8+ and NK cells, without extensively triggering Treg cells BNT151 design ● ● IL-2RB human IL-2 (hlL2) IL-2Ra IL-2Ry high affinity Regulatory T cells medium affinity Effector T cells BNT151 BNT151 medium affinity Regulatory T cells • Increased binding to IL-2RB ● attraction = repulsion Weakened binding to IL-2Ra Designed to stimulate naïve and effector T cells with low to no expression of IL-2Ra (CD25 low/neg) without extensively triggering immunosuppressive regulatory T cells Vormehr M, et al. SITC Annual Meeting 2019; Poster presentation 626. high affinity Effector T cells B BNT151 mediates increase of effector CD8+ to Treg ratio A Tetramer* CD8* cells per ul blood 15- 10- 0 α-PD-L1: BNT151. 254 CD8+ T cells 20- 15- Adpgk specific CD8+ T cells ns + Control **** + z BNT151 **** 15-1 10- NK cells Control **** BNT 151 1.6- 1.5- 1.4- 1.3- 1.2- 1.1- 1.0- Tregs ns P Control BNT151 NUMM B CD8* to Treg ratio 20- Control BNT151 RiboCytokines BIONTECH 144#145● ● BNT152 + BNT153 Increase CD8 proliferation and reduce Treg fraction BNT152 (IL-7) is anticipated to potentiate the anti-tumor activity of BNT153 (IL-2) by: Reduction/normalization of the BNT153-mediated increase in the Treg fraction among CD4+ T cells Support of T cell lymphopoiesis and survival of memory T cells ● BNT152 Stimulates recently activated anti-tumor T cells and regulatory T cells BNT153 mRNA encoding IL-7 Sensitizes T cells to IL2 & increases CD8+ and CD4+ T cell expansion and survival Controls fraction of immunsuppressive Treg among CD4+ T cells that are stimulated by IL-2 CD8+ T cell expansion of BNT152+153 mainly driven by BNT152 Cells per μl blood 10000 7500- 5000- 2500- 0 CD8+ T cells Control **** BNT152 ns **** H+.. BNT153 BNT152+153 Percent Treg of CD4 BNT152 normalizes the Treg fraction elevated by BNT153 25- 20- 15- Treg frequency Control ns BNT152 **** ns NUM BNT153 BNT152+153 RiboCytokines BIONTECH 145#146BNT152 + BNT153 Combining with mRNA vaccine Per cent survival 100- 75- 50- 25- 0 BNT152 boosts therapeutic anti-tumor activity of BNT153 in combination with an RNA vaccine in the CT26 model 20 40 60 80 Days after tumor inoculation 100 Kranz LM, et al. SITC Annual Meeting 2019; Poster presentation 620. gp70 vaccine gp70 vaccine + BNT153 **** gp70 vaccine + BNT152 ns gp70 vaccine + BNT 153 + BNT152 **** BNT152 + BNT153 preferentially expands vaccine-induced CD8+ T cells Fold increase of CD8+ T cells 100,000 10,000 1,000 100 10 CD8+ T cells 7 days after 2nd treatment 1 vac: irr BNT 153: + mlL7: + Non-E7-specific E7-specific J₁J E7 E7 + **** + E7 ++ NUM + RiboCytokines BIONTECH 146#147BALB/C BNT152 + BNT153 Therapeutic efficacy of BNT152 + BNT153 in combination with RNA vaccination 0 CT26 s.c. ▲ Treatment 10 17 24 31 100 + HA 0 C57BL/6 H CT26: "hot tumor" model Therapeutic efficacy of IL-2 and IL-7 RiboCytokines ± RNA vaccination in a "hot tumor" model¹ Vaccine + BNT152+153 CR 10/11 TC-1 s.c. 12 17 24 + + A 31 73 HA ▲ Treatment ▲ Immunophenotyping (blood) 2048 1024- 512 TC-1: "cold tumor" model Tumor size (mm³) NEBEH NEB42 Tumorsize (mm³) ▬▬▬▬▬▬▬▬ 256 128 64- 32 16 8 Vaccine CR 0/11 2048 1024 0 25 100 0 25 50 75 50 75 100 Days after tumor inoculation Days after tumor inoculation 512- 256 128 64 32 16 Vaccine BNT152 BNT152+153 CR 0/15 CR 2/11 8 4 2 0 25 50 75 Days after tumor inoculation Therapeutic efficacy of IL-2 + IL-7 depends on RNA vaccination in an advanced "cold tumor" model² Vaccine + BNT152 Vaccine + BNT153 CR 0/15 CR 7/11 25 50 75 100 0 25 50 75 100 0 Days after tumor inoculation Days after tumor inoculation Vaccine + BNT153 CR: 0/15 100 0 25 50 75 100 0 25 50 75 100 Days after tumor inoculation Days after tumor inoculation Per cent survival 1 Kranz LM, et al. SITC Annual Meeting 2019; Poster presentation 620; 2 Kranz LM, et al. CIMT Annual Meeting 2021; ePresentation. 100⠀⠀⠀ 0 25 50 75 100 Days after tumor inoculation 75- 50- 25 Vaccine + BNT152+153 CR 7/15 MKU 0 100- 75- 50- 25- 0 25 75 50 Days after tumor inoculation 0 25 50 75 Days after tumor inoculation **** ns 100 NUMM 100 Vaccine * RiboCytokines + ++ + + + Vaccine + Vaccine antigen: gp70 + + + BNT153 + + + + + BNT152 BNT153 BNT152 Vaccine antigen: E7 BIONTECH 147#148BNT151 Therapeutic activity of BNT151 in combination with T cell vaccination Substantial improvement of the therapeutic efficacy of RNA-LPX vaccination by BNT151 Day 0 8 + ↑ ↑ Treatment ↑Immunophenotyping (blood) B16F10 s.c. tumor Vaccine target: TRP1 (differentiation antigen containing a CD8 T-cell epitope) Tumor size (mm³) C57BL/6 128- 64- 15 22 29 100 + + 11 ↑ ↑ 2048 0/11 CR 1024- 512- 256 32 16 8 4 2 0 Vaccine alone 20 40 60 Days after tumor inoculation 80 Per cent of CD8+ T cells TRP1 specific CD8+ T cells 40 30 0 Vaccine: + h|L2: BNT151: **** ns + Vaccine + hIL-2 7/11 CR 0 20 40 60 Days after tumor inoculation 80 CD8+ to Treg ratio 40 0 Vaccine: hlL2: BNT151: 10- CD8+ to Treg ratio On + **** ns 11/11: CR Median tumor size (mm³) 1750 1500- 1250- 1000- 750- 500 250- Vaccine + BNT151 1 Kranz LM, et al. SITC Annual Meeting 2019; Poster presentation 620; 2 Kranz LM, et al. CIMT Annual Meeting 2021; ePresentation. Vormehr M, et al. SITC Annual Meeting 2019; Poster presentation 626. 0 20 40 60 Days after tumor inoculation 80 0 0 25 50 Days after tumor inoculation 75 NUM RiboCytokines Control TRP1 vaccine + Control Control + hlL2 - Control + BNT151 *** →TRP1 vaccine + hlL2 **** TRP1 vaccine + BNT151 **** Days of treatment *** ** BIONTECH 148#149BNT151 mediates CAR T cell expansion in non-tumor bearing mice # CAR Ts = Total flus [p/s] 108 107 Data on file. Tuto Comparable in vivo expansion of CAR T cells in CLDN6-LPX or BNT151 treated mice 5 Days post ACT 10 CAR T dose 2x106 2x106 2x106 2x107 Treatment + CLDN6-LPX + BNT 151 + CLDN6-LPX + BNT151 + ctrl-LPX + crtl-LNP Treatment Time point of analysis Day 1 (Baseline) 1° treatment - Day 1 Day 4 Day 7 2° treatment Day 7 Day 9 Day 10 CLDN6-CAR-BBz-Luc-GFP positive T cells 2x106 2x107 CLDN6-LPX CLDN6-LPX BNT151 BNT 151 NUM C6-LPX+ BNT151 Ctr-LPX + ctrl-LNP C6-LPX+ BNT151 Ctr-LPX + ctrl-LNP Splenocytes isolated for ex vivo cytotox assay BNT151 treatment leads to initial similar CAR T cell expansion in vivo compared to CLDN6-LPX treatment BNT151-mediated CAR T expansion peaks at day 3/4 after treatment, followed by contraction phase at day 7 CLDN6-LPX + BNT151 improves CAR T cell expansion RiboCytokines 10.0 8.0 6.0 x105 4.0 2.0 Radiance (p/sec/cm²/sr) Color Scale Min = 2.00e5 Max 1.00e6 BIONTECH 149#150Long-term in vivo expansion and anti-tumor activity of CAR T cells in combination with vaccine and BNT151 CAR T-cell expansion and persistence in NSG mice after repetitive treatment cycles x fold expansion (day1 as baseline) 100 10- 0.1-T 0 100 10- 0.1 1°2°3° Internal data. CLDN6-LPX 60 Days post ACT CLDN6-LPX + BNT151 0 4° 20 40 20 5° 40 60 Days post ACT 80 100 80 H 100 x-fold expansion (day1 as baseline) 100 10- 0.1- 100- 40 60 Days post ACT Ctrl-LPX+ ctrl-LNP 10- 0.1 Treatment 0 BNT151 0 20 20 80 100 40 60 Days post ACT 80 100 ● 700- 600- 500- 400- 300- 200- 100- Anti-tumor activity of Prodigy-generated human CAR T cells in OV90 tumor-bearing NSG mice 0 Tumor volume 5 10 15 20 25 Days post ACT -0 --0-- CLDN6 CAR-T NUM NTD RiboCytokines + CLDN6-LPX +BNT151 + CLDN6-LPX + BNT151 + ctrl-LPX + ctrl-LNP + CLDN6-LPX +BNT151 CAR-specific stimulation with CLDN6-LPX leads to persistence >90 days BNT151 stimulates repetitively (CAR) T cells. Combination of CLDN6-LPX and BNT151 superior in stimulating initial expansion and persistence CLDN6-LPX, BNT151 expand subtherapeutic CAR T cells in xenograft models and result in therapeutic activity BIONTECH 150#151BNT 151, BNT152 + BNT153 Two Phase 1/2 FIH trials of mRNA-encoded cytokines in solid tumors ● Ⓒ Multiple solid tumors Metastatic unresectable solid tumors Key endpoints Safety and tolerability Antitumor activity Part 1 Monotherapy dose escalation BNT151 Monotherapy dose escalation Group A: BNT153 Group B: BNT152 3 Status MTD / RP2D MTD or MAD OBD and/or MTD Dose-escalation ongoing Total number of patients dosed: 26 Part 2 Combination therapy BNT 152 + BNT153 BNT151 combination Expansion cohorts in HNSCC, HCC, RCC, NSCLC, TNBC Pharmacokinetics and pharmacodynamics FIH, first-in-human, HCC, hepatocellular carcinoma; HNSCC, head and neck squamous-cell cancer; MAD, maximum-administered dose; MTD, maximum tolerated dose; NSCLC, non-small-cell lung cancer; OBD, optimal biological dose; RCC, renal cell carcinoma; RP2D, recommended Phase 2 dose; SoC, standard of care; TNBC, triple-negative breast cancer. Clinical Trials.gov: NCT04455620. NUM RiboCytokines BIONTECH 151#152BIONTECH Closing remarks#153Advancing toward our long-term vision 1 marketed vaccine Market leader in COVID-19 vaccines 16 programs in 21 clinical trials 5 randomized Phase 2 trials Oncology 1 Phase 1 program 10+ preclinical programs Infectious diseases Next-gen or variant adapted COVID-19 vaccines Multiple product launches in next 3-5 years 5-10 IND submissions per year Maintain and deepen COVID-19 vaccine leadership Approved products across various disease areas Driving transformation today Mid-term goals Long-term vision By 2030, we aim to be a multi-product global biotechnology leader, aspiring to address the world's most pressing health challenges with pioneering, disruptive technologies delivered at scale BIONTECH 153#154● Q & A BIONTECH#155THANK YOU BIONTECH#156BIONTECH