C, OVCAR-3 transplanted into the mammary fat pad: dosing at days 1, 8, and 15. 3A5 conjugates are significantly more efficacious than the corresponding 11D10 conjugates across both comparisons (P < 0.01).

B, Kaplan-Meier plot of survival of mice symbols as in (A ). Note the sustained elimination of tumors in the two 3A5 groups but not in other groups. A, tumor burden plotted as relative bioluminescence at day 0 (immediately before first dose), day 28 (1 wk after final dose), and day 63 (6 wks after final dose). Irrelevant control Ab-VC-MMAE conjugate was dosed at an equivalent drug exposure. All conjugates were dosed at 56 Ag/kg drug, corresponding to 2.8 mg/kg 3A5-VCMMAE, 2.3 mg/kg 3A5-MC-MMAF, 2.6 mg/kg 11D10-VC-MMAE, and 2.5 mg/kg 11D10-MC-MMAF. Animals were dosed once weekly for four total doses after tumors were established and bioluminescence values were stabilized: dosing on days 0, 7, 14, and 21. In vivo efficacy of armed anti-MUC16 antibodies against OVCAR-3/ luc mouse xenografts. 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. Additionally, the presence of circulating CA125 in a rat model did not exacerbate the toxicity of 3A5 drug conjugates.

Importantly, drug conjugates of 3A5 were well tolerated in primates at levels in excess of therapeutic doses. 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.

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. 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).

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