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Targeting the human MUC1-C oncoprotein with an antibody-drug conjugate
Govind Panchamoorthy, … , Surender Kharbanda, Donald Kufe
Govind Panchamoorthy, … , Surender Kharbanda, Donald Kufe
Published June 21, 2018
Citation Information: JCI Insight. 2018;3(12):e99880. https://doi.org/10.1172/jci.insight.99880.
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Resource and Technical Advance Oncology Therapeutics

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

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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.

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 Ghoroghchian, Kwok-Kin Wong, Surender Kharbanda, Donald Kufe

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Figure 1

mAb 3D1 binds to MUC1-C/ED at the α3 helix.

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mAb 3D1 binds to MUC1-C/ED at the α3 helix.
(A) mAb 3D1 binding to the M...
(A) mAb 3D1 binding to the MUC1 p62/p58 heterodimer was determined by surface plasmon resonance (SPR). Listed below are the indicated parameters of the binding analysis. (B) Binding of mAb 3D1 by ELISA to the (a) WT MUC1 p62/p58 heterodimer, (b) p62 (LGL→AGA) and p58 (LTL→ATA) mutant proteins that do not form the p62/p58 junction, and (c) WT p62 alone. mAb CD1, which reacts with the MUC1-C cytoplasmic domain, was used as a control. The results are expressed as percentage of control binding as compared with that obtained with the WT protein (>3.0 OD units). (C) The aa sequences of the 58-aa human MUC1-C, cynomolgus monkey, and mouse Muc1-C extracellular domains. The α3 and α4 helices are highlighted. (D) Binding of mAb 3D1 by ELISA to WT p58 and the D19E or D19E/V20A/T22A mutant proteins. mAb CD1 was used as a control. The results are expressed as percentage control binding as compared with that obtained with the WT protein (>3.0 OD units). (E) Localization of the mAb 3D1 epitope to the α3 helix, as shown by NMR spectroscopy of the p62/p58 heterodimer (adapted from Macao et al., ref. 10).

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