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Mol Cancer Ther. 2018 Dec;17(12):2665-2675. doi: 10.1158/1535-7163.MCT-17-1215. Epub 2018 Sep 27.

MORAb-202, an Antibody-Drug Conjugate Utilizing Humanized Anti-human FRα Farletuzumab and the Microtubule-targeting Agent Eribulin, has Potent Antitumor Activity.

Author information

1
Department of Biochemistry Discovery, Oncology Biologics Laboratories, Oncology Business Group, Eisai Inc, Exton, Pennsylvania.
2
Department of Translational Chemistry, Eisai AiM Institute, Eisai Inc., Andover, Massachusetts.
3
Department of Chemistry Research, Eisai Co. Ltd., Tsukuba-Shi, Ibaraki, Japan.
4
Department of Discovery Chemistry, Eisai AiM Institute, Eisai Inc., Andover, Massachusetts.
5
Department of Preclinical Development, Oncology Biologics Laboratories, Oncology Business Group, Eisai Inc, Exton, Pennsylvania.
6
Department of Bioanalytical Development, Oncology Biologics Laboratories, Oncology Business Group, Eisai Inc, Exton, Pennsylvania.
7
Department of Discovery Research, Morphotek Inc., Exton, Pennsylvania.
8
Department of Biochemistry Discovery, Oncology Biologics Laboratories, Oncology Business Group, Eisai Inc, Exton, Pennsylvania. ealbone@morphotek.com.

Abstract

Microtubule-targeting agents (MTA) have been investigated for many years as payloads for antibody-drug conjugates (ADC). In many cases, these ADCs have shown limited benefits due to lack of efficacy or significant toxicity, which has spurred continued investigation into novel MTA payloads for next-generation ADCs. In this study, we have developed ADCs using the MTA eribulin, a derivative of the macrocyclic polyether natural product halichondrin B, as a payload. Eribulin ADCs demonstrated in vitro potency and specificity using various linkers and two different conjugation approaches. MORAb-202 is an investigational agent that consists of the humanized anti-human folate receptor alpha (FRA) antibody farletuzumab conjugated via reduced interchain disulfide bonds to maleimido-PEG2-valine-citrulline-p-aminobenzylcarbamyl-eribulin at a drug-to-antibody ratio of 4.0. MORAb-202 displayed preferable biophysical properties and broad potency across a number of FRA-positive tumor cell lines as well as demonstrated improved specificity in vitro compared with farletuzumab conjugated with a number of other MTA payloads, including MMAE, MMAF, and the reducible maytansine linker-payload sulfo-SPDB-DM4. A single-dose administration of MORAb-202 in FRA-positive human tumor cell line xenograft and patient-derived tumor xenograft models elicited a robust and durable antitumor response. These data support further investigation of MORAb-202 as a potential new treatment modality for FRA-positive cancers, using the novel MTA eribulin as a payload.

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