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JCI Insight. 2018 Jun 21;3(12). pii: 99880. doi: 10.1172/jci.insight.99880. [Epub ahead of print]

Targeting the human MUC1-C oncoprotein with an antibody-drug conjugate.

Author information

1
Genus Oncology, Boston, Massachusetts, USA.
2
Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
3
Departments of Medicine and Pathology, Boston University School of Medicine, Boston, Massachusetts, USA.
4
Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical Center, New York, New York, USA.
5
Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, USA.

Abstract

Mucin 1 (MUC1) is a heterodimeric protein that is aberrantly overexpressed on the surface of diverse human carcinomas and is an attractive target for the development of mAb-based therapeutics. However, attempts at targeting the shed MUC1 N-terminal subunit have been unsuccessful. We report here the generation of mAb 3D1 against the nonshed oncogenic MUC1 C-terminal (MUC1-C) subunit. We show that mAb 3D1 binds with low nM affinity to the MUC1-C extracellular domain at the restricted α3 helix. mAb 3D1 reactivity is selective for MUC1-C-expressing human cancer cell lines and primary cancer cells. Internalization of mAb 3D1 into cancer cells further supported the conjugation of mAb 3D1 to monomethyl auristatin E (MMAE). The mAb 3D1-MMAE antibody-drug conjugate (ADC) (a) kills MUC1-C-positive cells in vitro, (b) is nontoxic in MUC1-transgenic (MUC1.Tg) mice, and (c) is active against human HCC827 lung tumor xenografts. Humanized mAb (humAb) 3D1 conjugated to MMAE also exhibited antitumor activity in (a) MUC1.Tg mice harboring syngeneic MC-38/MUC1 tumors, (b) nude mice bearing human ZR-75-1 breast tumors, and (c) NCG mice engrafted with a patient-derived triple-negative breast cancer. These findings and the absence of associated toxicities support clinical development of humAb 3D1-MMAE ADCs as a therapeutic for the many cancers with MUC1-C overexpression.

KEYWORDS:

Breast cancer; Cancer immunotherapy; Lung cancer; Oncology; Therapeutics

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