TY - JOUR AU - Panchamoorthy, Govind AU - Jin, Caining AU - Raina, Deepak AU - Bharti, Ajit AU - Yamamoto, Masaaki AU - Adeebge, Dennis AU - Zhao, Qing AU - Bronson, Roderick AU - Jiang, Shirley AU - Li, Linjing AU - Suzuki, Yozo AU - Tagde, Ashujit AU - Ghoroghchian, P. Peter AU - Wong, Kwok-Kin AU - Kharbanda, Surender AU - Kufe, Donald T1 - Targeting the human MUC1-C oncoprotein with an antibody-drug conjugate PY - 2018/06/21/ AB - 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. JF - JCI Insight JA - JCI Insight SN - 2379-3708 DO - 10.1172/jci.insight.99880 VL - 3 IS - 12 UR - https://doi.org/10.1172/jci.insight.99880 PB - The American Society for Clinical Investigation ER -