Relationship between the intratumor pharmacokinetics and antitumor effect of the payload eribulin in the novel antibody–drug conjugate MORAb-202

Background: Antibody–drug conjugates have the potential to improve antitumor activity through specific targeting of tumor cells, using antibodies attached to a cytotoxic payload, compared with the payload alone. Material and methods: MORAb-202 (farletuzumab ecteribulin) is an antibody–drug conjugate composed of the humanized antifolate receptor-alpha (FRα) monoclonal antibody, farletuzumab, conjugated to eribulin by a cathepsin B-cleavable linker. In this preclinical study, we investigated the relationship between the antitumor effect and the intratumor pharmacokinetics of the potent cytotoxic microtubule inhibitor payload, eribulin, as part of MORAb-202, compared with eribulin alone, using FRα+ and FRα− human cancer models. Results: MORAb-202 treatment showed a statistically significant antitumor effect in the tumor xenograft model with high-FRα expression, even at doses that did not indicate an antitumor effect in the equivalent eribulin- or antibody-treated groups (P < 0.05). In the xenograft models with high-FRα expression, the maximum concentration of intratumor eribulin was 10-fold higher with MORAb-202 treatment, when dosed at equivalent eribulin levels, than with eribulin treatment alone. Also in the xenograft models with high-FRα-expression, with eribulin treatment, the maximum concentration was reached within 12 hours after administration and was below the detection limit at 72 hours, while with MORAb-202 treatment, the concentration was almost saturated 24 hours after administration and remained so until 144 hours after administration. Conclusions: MORAb-202 notably increased intratumor accumulation and sustained tumor-release of eribulin (payload) compared with dosed eribulin alone. Thus, MORAb-202 is expected to have a more-potent antitumor effect compared with eribulin alone. Conflict of interest: Corporate-sponsored Research: Eisai Inc. - Shigehiro Koganemaru Other Substantive Relationships: Employees of Eisai Inc. - Keiji Furuuchi and Toshimitsu Uenaka