Armed antibodies targeting the mucin repeats of the ovarian cancer antigen, MUC16, are highly efficacious in animal tumor models.
MUC16 is a well-validated cell surface marker for serous adenocarcinomas of the ovary and other gynecologic malignancies that is distinguished by highly repetitive sequences ("mucin repeats") in the extracellular domain (ECD). We produced and compared two monoclonal antibodies: one (11D10) recognizing a unique, nonrepeating epitope in the ECD and another (3A5) that recognizes the repeats and binds multiple sites on each MUC16 protein. 3A5 conjugated to cytotoxic drugs exhibited superior toxicity against tumor cells in vitro and in tumor xenograft models compared with antibody-drug conjugates of 11D10. Importantly, drug conjugates of 3A5 were well tolerated in primates at levels in excess of therapeutic doses. Additionally, the presence of circulating CA125 in a rat model did not exacerbate the toxicity of 3A5 drug conjugates. We conclude that targeting the repeat MUC16 domains, thereby increasing cell-associated levels of drug-conjugated antibody, provides superior efficacy in vitro and in vivo without compromising safety.
Chen
Youjun
Y
Department of Cancer Pathways and Targets, Genentech, Inc., South San Francisco, California 94080, USA.
Clark
Suzanna
S
Wong
Terence
T
Chen
Yongmei
Y
Chen
Yvonne
Y
Dennis
Mark S
MS
Luis
Elizabeth
E
Zhong
Fiona
F
Bheddah
Sheila
S
Koeppen
Hartmut
H
Gogineni
Alvin
A
Ross
Sarajane
S
Polakis
Paul
P
Mallet
William
W
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000494:pharmacology*; D001666:Binding Sites, Antibody; D018394:CA-125 Antigen / Q000276:immunology*; D005260:Female; D006801:Humans; D008565:Membrane Proteins / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008813:Mice, Inbred ICR; D016513:Mice, SCID; D010051:Ovarian Neoplasms / Q000276:immunology* / Q000628:therapy*; D051381:Rats; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D018394:CA-125 Antigen; C451759:MUC16 protein, human; D008565:Membrane Proteins