MORAb-202, Eisai’s first antibody-drug conjugate, targets FRα-positive solid tumors. The investigational agent is composed of the company’s in-house developed anticancer agent farletuzumab, a humanized IgG1 monoclonal antibody that binds to the folate receptor alpha (FRα), and Eisai’s in-house developed anticancer agent eribulin (Halaven®), using an enzyme cleavable linker.

MORAb-202 targets the folate receptor α (FRα also known as FOLR1), a glycosylphosphatidylinositol-anchored membrane protein. This 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.

The eribulin payload is in the halichondrin class of microtubule dynamics inhibitors with a novel mechanism of action. Structurally, eribulin is a simplified and synthetically produced version of 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.

MORAb-202 is has a cleavable linker, which is lysosomal protease-sensitive.

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The investigational drug is currently included in a Phase 1 clinical study in Japan and a Phase 1/2 clinical study in the United States, respectively, for MORAb-202.

Mechanism of action
After MORAb-202 enters the target FRα-positive cancer cells, the linker is enzymatically cleaved, releasing eribulin from the antibody leading to its antitumor activity. Furthermore, in non-clinical studies, MORAb-202 demonstrated a bystander effect, with antitumor activity on the FRα-negative cancer cells surrounding the FRa-positive cancer cells.

Solid tumors
In a recent article published in Antibodies, is an international, peer-reviewed, open-access journal on immunoglobulins, Yuki Matsunaga, MD, and colleagues from the Department of Breast Surgical Oncology, School of Medicine, Showa University, Japan writes about a study, supported in part by Eisai, investigating the effects of novel anti-FOLR1 antibody-eribulin conjugate MORAb-202 in breast cancer and non-small cell lung cancer (NSCLC) cell lines.

The team evaluated FRα expression, cell proliferation, bystander killing effects, and apoptosis in seven breast cancer and nine NSCLC cell lines treated with MORAb-202. They assessed tumor growth and FRα expression in orthotopic xenograft mouse models after a single intravenous administration of MORAb-202 (5 mg/kg).

The results showed that MORAb-202 was associated with inhibited cell proliferation, with specific selectivity toward FRα-expressing breast cancer cell lines.

The eribulin payload of MORAb-202, was unleashed in the cells, diffused into intercellular spaces, and then killed the non-FRα-expressing cells in co-culture systems. In orthotopic xenograft mouse models, FRα-expressing tumors and non-FRα-expressing tumors were suppressed upon MORAb-202 administration.

Based on these results, Matsunaga and colleagues believe that MORAb-202 has potential antitumor effects in breast cancer.

A must-read article.

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] 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. [Pubmed][Article]

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