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

• DOI: 10.1172/jci.insight.99880
• Publication Date: 2018-06-20T15:01:31Z
• Authors: Govind Panchamoorthy; Caining Jin; Deepak Raina; Ajit Bharti; Masaaki Yamamoto; Dennis Adeebge; Qing Zhao; Roderick Bronson; Shirley Jiang; Linjing Li; Yozo Suzuki; Ashujit Tagde; P. Peter Ghoroghc...; Kwok-Kin Wong; Surender Kharbanda; Donald Kufe
• Keywords: MUC1; Internalization; Antibody-drug conjugate; Conjugate

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