Reshaping the HIV treatment and prevention landscape
The power of functional genomics: combining
Blenrep with a gamma secretase inhibitor (GSI)
Functional Genomics identified
GSI combo potential
BCMA expression CRISPR screen
BCMA-high
anti-BCMA
antibody
FACS Sort
BCMA-low
sgRNA
library
CRISPRI MM cells
sgRNA library cells
CRISPRA MM cells
P value
4.0
3.0
y-secretase
BCMA.
subunits
2.0
1.0
-6
-4
-2
0
2
4
6
Decrease
BCMA cell surface
expression
Increase
Source: Blood Adv (2020) 4 (13): 2899-2911. Kampmann, et al
Count
LOW
HIGH
BCMA expression
Deep sequencing to
determine
sgRNA frequency
-
-
Blenrep + GSI combo should
enable lower dose
gsk
Nirogacestat
秀秀
y-secretase
Belamaf
BCMA
RLU
Cytotoxicity Assay
2.5×107.
2×10%
1.5×107
1x107-
5x10%-
0
0.0001 0.001 0.01
0.1
Blenrep (UG/ML)
1
10
Blenrep
Blenrep/nirogacestat 025uM
-IGG-MMAF
IgG-MMAF/nirogacestat .025uM
Belamaf + nirogacestat a novel
GSI under investigation in DREAMM-5
with an initial 0.95mg/kg dose
Preliminary data expected by end 2021
Source: Eastman et al., Blood (2019) 134 (Supplement_1): 4401.
dreaMM 5
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