Dataset Information

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

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 ?3 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.

SUBMITTER: Panchamoorthy G

PROVIDER: S-EPMC6124453 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Panchamoorthy Govind G Jin Caining C Raina Deepak D Bharti Ajit A Yamamoto Masaaki M Adeebge Dennis D Zhao Qing Q Bronson Roderick R Jiang Shirley S Li Linjing L Suzuki Yozo Y Tagde Ashujit A Ghoroghchian P Peter PP Wong Kwok-Kin KK Kharbanda Surender S Kufe Donald D

JCI insight 20180621 12

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 ...[more]

PMID: 29925694

Similar Datasets

Project description:Endoglin (EDG) is a cell surface protein with an important role in the establishment of neo-angiogenesis and vasculogenic mimicry. EDG is part of the transforming growth factor-β (TGF-β) family, acting as an important co-receptor. EDG is shed from the cell surface into the extracellular compartment by matrix metalloproteinase 14 (MMP14), in its soluble form (sEDG). Both transmembrane and soluble forms of EDG exert important signaling functions in the development of new blood vessels and tumour progression. To better understand the role of EDG in Ewing sarcoma (ES), a deadly neoplasm of late childhood and adolescence, we test the efficacy of OMTX703, an endoglin-targeting antibody-drug conjugate in ES8 xenograft. Having determined an optimal dose for OMTX703, an additional experiment was conducted to assess the mechanism(s) of OMTX703 action and its potential mechanism(s) of resistance following a 2-week exposure to OMTX703 at 0, 10, 30, and 60 mg/kg; 246 proteins were assessed by reverse-phase protein array (RPPA). Analysis of variance (ANOVA), Pearson’s correlation as distance metric and Ward’s linkage as the clustering method using a false discovery rate (FDR) of 0.01, identified 60 proteins that discriminated between treatment groups (Matrix#1-Normalized Values). To investigate the proteomic changes associated with the heightened clinical activity of the 60 mg/kg dose, a secondary analysis was performed, which grouped the 10 mg/kg OMTX703 samples and the 10 mg/kg OMTX003 ones with the placebo-treated samples (Matrix#2-Normalized Values). Using a FDR of 0.0001, an absolute log2 fold change of 1.5, Pearson’s correlation as distance metric and Ward’s linkage as the clustering method, 22 proteins were discriminately identified between the 3 treatment groups (Matrix#2-Normalized Values). Notably, a protein regulator of altered metabolism (RPS6) was exclusively upregulated following OMTX703 (60mg/kg), and a second metabolism biomarker (LDHA) was down-expressed in the 30 and 60 mg/kg-treated groups. Conversely, BRD4 was one of about a dozen proteins that were preferentially down-regulated in samples treated only by 60 mg/kg.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets