In a statement released earlier today, Eisai and Bristol-Myers Squibb confirm that the two companies have entered into an exclusive global strategic collaboration agreement for the co-development and co-commercialization of MORAb-202.

MORAb-202 is Eisai’s first antibody-drug conjugate.  The investigational drug binds Eisai’s in-house developed humanized anti-human-folate receptor alpha (FRα) antibody farletuzumab (previously known as MORAb-003) via reduced interchain disulfide bonds to maleimido-PEG2-valine-citrulline-p-aminobenzylcarbamyl-eribulin at a drug-to-antibody ratio (DAR) of 4.1.[1]

The microtubule-targeting agent eribulin mesylate (Halaven®; Eisai Inc), the payload in MORab-202, is the first in the halichondrin class of microtubule dynamics inhibitors with a novel mechanism of action. Structurally eribulin is a simplified and synthetically produced version of the macrocyclic polyether halichondrin B, a natural product isolated from the marine sponge Halichondria okadai, and functions by inhibiting the growth phase of microtubule dynamics which prevents cell division. [2]

MORAb-202 targets the folate receptor α (FRα, known as FOLR1), a glycosylphosphatidylinositol-anchored membrane protein, which is an attractive target for antibody-drug conjugates because it is largely absent from normal tissues but is overexpressed in malignant tumors of epithelial origin, including ovarian, lung, and breast cancer. [3] Eribulin payload in MORAb-202 displays a unique mechanism of suppressing microtubule growth without shortening the microtubule, but rather by sequestering tubulin into nonfunctional aggregates, resulting in irreversible G2-M arrest and apoptosis. [4] Furthermore, in addition to the observed anti-mitotic effect of eribulin, the agent has been shown to inhibit cell migration, decrease circulating vascular endothelial growth factor, and promote mesenchymal-epithelial transition in tumor phenotypes

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Linker selection and mechanism of action
In the development of antibody-drug conjugates, linker chemistry plays a crucial role in binding the cytotoxic drug to the antibody. MORAb-202 is characterized by a lysosomal protease-sensitive cleavable linker. Lysosomal protease, like cathepsin, is more highly expressed in tumor cells than in normal cells.[3]

After selectively binding to folate receptor α and being transported into the target FRα-positive cancer cells through receptor-mediated endocytosis, the linker is enzymatically cleaved and as a result of lysosomal protease cleavage, releases the cytotoxic payload. The unleashed payload eradicates the FRα-positive-expressing cell and then penetrates surrounding tissues, killing other cancer cells in what is known as the bystander killing effect, with antitumor activity on the FRα-negative cancer cells surrounding the FRa-positive cancer cells.[3]

Preclinical studies
In preclinical studies, 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 microtubule-targeting payloads, including Monomethyl Auristatin E (MMAE), Monomethyl Auristatin F (MMAF), and the reducible maytansine linker-payload sulfo-SPDB-DM4.  Furthermore, in preclinical studies, 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.[1]

Advanced chemistry
“MORAb-202 combines Eisai’s in-house discovered antibody and payload using the company’s advanced chemistry capabilities,” said Haruo Naito, Chief Executive Officer at Eisai. “It is characterized by its payload of eribulin, which is a product of our modern synthetic organic chemistry that has already made contributions to patients with breast cancer and soft tissue sarcoma. Our collaboration with Bristol Myers Squibb will accelerate the development of MORAb-202 with the goal of bringing a potentially impactful treatment option to patients globally.”

The investigational agent is a potential best-in-class FRα ADC with a favorable pharmacology profile and demonstrated single-agent activity in patients with advanced solid tumors. Eisai is currently investigating MORAb-202 in FRα-positive solid tumors, including endometrial, ovarian, lung, and breast cancers, in two studies: a Phase 1 clinical study in Japan and a Phase 1/2 clinical study in the United States. The companies are planning to move into the registrational stage of development for this asset as early as next year.

“This global collaboration with Eisai is an important strategic fit for Bristol Myers Squibb as it extends our leading position in oncology with a differentiated asset that complements our broad solid tumor portfolio and leverages our deep internal development expertise,” noted Giovanni Caforio, M.D., board chair and chief executive officer, Bristol Myers Squibb.

“We look forward to collaborating with Eisai as we work to bring this potential treatment option to patients in need as soon as possible,” Caforio added.

Under the agreement, Eisai and Bristol Myers Squibb will jointly develop and commercialize MORAb-202 with Eisai remaining responsible for the manufacturing and supply of the drug globally.

Under the financial terms of the agreement, Bristol Myers Squibb will pay US $650 million U.S. dollars to Eisai including US $200 million U.S. dollars as payment toward Eisai’s research and development expenses. Eisai is also entitled to receive up to US $2.45 billion U.S. dollars in potential future development, regulatory, and commercial milestones. Furthermore, the parties will share profits, research, and development, and commercialization costs in the collaboration territories and Bristol Myers Squibb will pay Eisai a royalty on sales outside of the collaboration territories.

Clinical trials
A Study to Evaluate the Safety, Tolerability, and Efficacy of MORAb-202, a Folate Receptor Alpha (FRα)-Targeting Antibody-drug Conjugate (ADC) in Participants With Selected Tumor Types – NCT04300556
A Study of MORAb-202 in Participants With Solid Tumors – NCT03386942

Highlights of prescribing information
Eribulin mesylate (Halaven®; Eisai Inc.)[Prescribing Information]

[1] Cheng X, Li J, Tanaka K, Majumder U, Milinichik AZ, Verdi AC, Maddage CJ, Rybinski KA, Fernando S, Fernando D, Kuc M, Furuuchi K, Fang F, Uenaka T, Grasso L, Albone EF. MORAb-202, an Antibody-Drug Conjugate Utilizing Humanized Anti-human FRα Farletuzumab and the Microtubule-targeting Agent Eribulin, has Potent Antitumor Activity. Mol Cancer Ther. 2018 Dec;17(12):2665-2675. doi: 10.1158/1535-7163.MCT-17-1215. Epub 2018 Sep 27. PMID: 30262588.
[2] Bai RL, Paull KD, Herald CL, Malspeis L, Pettit GR, Hamel E. Halichondrin B and homohalichondrin B, marine natural products binding in the vinca domain of tubulin. Discovery of tubulin-based mechanism of action by analysis of differential cytotoxicity data. J Biol Chem. 1991 Aug 25;266(24):15882-9. PMID: 1874739.
[3] Matsunaga Y, Yamaoka T, Ohba M, Miura S, Masuda H, Sangai T, Takimoto M, Nakamura S, Tsurutani J. Novel Anti-FOLR1 Antibody-Drug Conjugate MORAb-202 in Breast Cancer and Non-Small Cell Lung Cancer Cells. Antibodies (Basel). 2021 Feb 1;10(1):6. doi: 10.3390/antib10010006. PMID: 33535554; PMCID: PMC7930947.
[4] Kuznetsov G, Towle MJ, Cheng H, Kawamura T, TenDyke K, Liu D, Kishi Y, Yu MJ, Littlefield BA. Induction of morphological and biochemical apoptosis following prolonged mitotic blockage by halichondrin B macrocyclic ketone analog E7389. Cancer Res. 2004 Aug 15;64(16):5760-6. doi: 10.1158/0008-5472.CAN-04-1169. PMID: 15313917.

Featured image/photo courtesy: © 2016 – 2021 Fotolia/Adobe Used with permission.

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