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Novel Anti-FOLR1 Antibody-Drug Conjugate MORAb-202 in Breast Cancer and Non-Small Cell Lung Cancer Cells.

ABSTRACT: Antibody-drug conjugates (ADCs), which are currently being developed, may become promising cancer therapeutics. Folate receptor ? (FOLR1), a glycosylphosphatidylinositol-anchored membrane protein, is an attractive target of ADCs, as it is largely absent from normal tissues but is overexpressed in malignant tumors of epithelial origin, including ovarian, lung, and breast cancer. In this study, we tested the effects of novel anti-FOLR1 antibody-eribulin conjugate MORAb-202 in breast cancer and non-small cell lung cancer (NSCLC) cell lines. FOLR1 expression, cell proliferation, bystander killing effects, and apoptosis were evaluated in seven breast cancer and nine NSCLC cell lines treated with MORAb-202. Tumor growth and FOLR1 expression were assessed in T47D and MCF7 orthotopic xenograft mouse models after a single intravenous administration of MORAb-202 (5 mg/kg). MORAb-202 was associated with inhibited cell proliferation, with specific selectivity toward FOLR1-expressing breast cancer cell lines. Eribulin, the payload of MORAb-202, was unleashed in HCC1954 cells, diffused into intercellular spaces, and then killed the non-FOLR1-expressing MCF7 cells in co-culture systems. In orthotopic xenograft mouse models, FOLR1-expressing T47D tumors and non-FOLR1-expressing MCF7 tumors were suppressed upon MORAb-202 administration. The novel anti-FOLR1 antibody-eribulin conjugate MORAb-202 has potential antitumor effects in breast cancer.

SUBMITTER: Matsunaga Y

PROVIDER: S-EPMC7930947 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Novel Anti-FOLR1 Antibody-Drug Conjugate MORAb-202 in Breast Cancer and Non-Small Cell Lung Cancer Cells.

Matsunaga Yuki Y Yamaoka Toshimitsu T Ohba Motoi M Miura Sakiko S Masuda Hiroko H Sangai Takafumi T Takimoto Masafumi M Nakamura Seigo S Tsurutani Junji J

Antibodies (Basel, Switzerland) 20210201 1

Antibody-drug conjugates (ADCs), which are currently being developed, may become promising cancer therapeutics. Folate receptor α (FOLR1), a glycosylphosphatidylinositol-anchored membrane protein, is an attractive target of ADCs, as it is largely absent from normal tissues but is overexpressed in malignant tumors of epithelial origin, including ovarian, lung, and breast cancer. In this study, we tested the effects of novel anti-FOLR1 antibody-eribulin conjugate MORAb-202 in breast cancer and non ...[more]

PMID: 33535554

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Project description:As hematopoietic progenitors supply a large number of blood cells, therapeutic strategies targeting hematopoietic progenitors are potentially beneficial to eliminate unwanted blood cells, such as leukemic cells and immune cells causing diseases. However, due to their pluripotency, targeting those cells may impair the production of multiple cell lineages, leading to serious side effects such as anemia and increased susceptibility to infection. To minimize those side effects, it is important to identify monopotent progenitors that give rise to a particular cell lineage. Monocytes and monocyte-derived macrophages play important roles in the development of inflammatory diseases and tumors. Recently, we identified human monocyte-restricted progenitors, namely, common monocyte progenitors and pre-monocytes, both of which express high levels of CD64, a well-known monocyte marker. Here, we introduce a dimeric pyrrolobenzodiazepine (dPBD)-conjugated anti-CD64 antibody (anti-CD64-dPBD) that selectively induces the apoptosis of proliferating human monocyte-restricted progenitors but not non-proliferating mature monocytes. Treatment with anti-CD64-dPBD did not affect other types of hematopoietic cells including hematopoietic stem and progenitor cells, neutrophils, lymphocytes and platelets, suggesting that its off-target effects are negligible. In line with these findings, treatment with anti-CD64-dPBD directly killed proliferating monocytic leukemia cells and prevented monocytic leukemia cell generation from bone marrow progenitors of chronic myelomonocytic leukemia patients in a patient-derived xenograft model. Furthermore, by depleting the source of monocytes, treatment with anti-CD64-dPBD ultimately eliminated tumor-associated macrophages and significantly reduced tumor size in humanized mice bearing solid tumors. Given the selective action of anti-CD64-dPBD on proliferating monocyte progenitors and monocytic leukemia cells, it should be a promising tool to target cancers and other monocyte-related inflammatory disorders with minimal side effects on other cell lineages.

Dataset Information

Novel Anti-FOLR1 Antibody-Drug Conjugate MORAb-202 in Breast Cancer and Non-Small Cell Lung Cancer Cells.

Publications

Novel Anti-FOLR1 Antibody-Drug Conjugate MORAb-202 in Breast Cancer and Non-Small Cell Lung Cancer Cells.

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