Therapeutic potential of an anti-CD79b antibody-drug conjugate, anti-CD79b-vc-MMAE, for the treatment of non-Hodgkin lymphoma.
Here we describe the generation of an antibody-drug conjugate (ADC) consisting of a humanized anti-CD79b antibody that is conjugated to monomethylauristatin E (MMAE) through engineered cysteines (THIOMABs) by a protease cleavable linker. By using flow cytometry, we detected the surface expression of CD79b in almost all non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia patients, suggesting that anti-CD79b-vcMMAE could be widely used in these malignancies. By using NHL cell lines to simulate a patient population we discovered that a minimal cell-surface expression level of CD79b was required for in vitro activity. Within the subpopulation of cell lines above this minimal threshold, we found that sensitivity to free MMAE, mutation of cancer genes, and cell doubling time were poorly correlated with in vitro activity; however, the expression level of BCL-XL was correlated with reduced sensitivity to anti-CD79b-vcMMAE. This observation was supported by in vivo data showing that a Bcl-2 family inhibitor, ABT-263, strikingly enhanced the activity of anti-CD79b-vcMMAE. Furthermore, anti-CD79b-vcMMAE was significantly more effective than a standard-of-care regimen, R-CHOP (ie, rituximab with a single intravenous injection of 30 mg/kg cyclophosphamide, 2.475 mg/kg doxorubicin, 0.375 mg/kg vincristine, and oral dosing of 0.15 mg/kg prednisone once a day for 5 days), in 3 xenograft models of NHL. Together, these data suggest that anti-CD79b-vcMMAE could be broadly efficacious for the treatment of NHL.
Dornan
David
D
Genentech Inc, South San Francisco, CA 94080, USA.
Bennett
Fiona
F
Chen
Yvonne
Y
Dennis
Mark
M
Eaton
Dan
D
Elkins
Kristi
K
French
Dorothy
D
Go
Mary Ann T
MA
Jack
Andrew
A
Junutula
Jagath R
JR
Koeppen
Hartmut
H
Lau
Jeffrey
J
McBride
Jacqueline
J
Rawstron
Andy
A
Shi
Xiaoyan
X
Yu
Nancy
N
Yu
Shang-Fan
SF
Yue
Peng
P
Zheng
Bing
B
Ebens
Allen
A
Polson
Andrew G
AG
D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use; D051925:CD79 Antigens / Q000276:immunology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005260:Female; D006801:Humans; D018796:Immunoconjugates / Q000627:therapeutic use; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008813:Mice, Inbred ICR; D016513:Mice, SCID; D009842:Oligopeptides / Q000737:chemistry / Q000627:therapeutic use*; D016896:Treatment Outcome; D047368:Tumor Burden; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D000888:Antibodies, Anti-Idiotypic; D000970:Antineoplastic Agents; D051925:CD79 Antigens; D018796:Immunoconjugates; D009842:Oligopeptides; C495575:monomethyl auristatin E