1. Academic Validation
  2. An antibody-drug conjugate targeting a GSTA glycosite-signature epitope of MUC1 expressed by non-small cell lung cancer

An antibody-drug conjugate targeting a GSTA glycosite-signature epitope of MUC1 expressed by non-small cell lung cancer

  • Cancer Med. 2020 Dec;9(24):9529-9540. doi: 10.1002/cam4.3554.
Deng Pan 1 2 Yubo Tang 3 Jiao Tong 1 Chengmei Xie 1 Jiaxi Chen 1 Chunchao Feng 1 Patrick Hwu 4 Wei Huang 3 Dapeng Zhou 1 2
Affiliations

Affiliations

  • 1 Tongji University School of Medicine, Shanghai, China.
  • 2 Shanghai Pudong New Area Mental Health Center affiliated with Tongji University School of Medicine, Shanghai, China.
  • 3 CAS Key Laboratory of Receptor Research, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
  • 4 Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Abstract

Antibodies targeting aberrantly glycosylated proteins are ineffective in treating Cancer. Antibody-drug conjugates have emerged as effective alternatives, facilitating tumor-specific Drug Delivery. Previous studies have assessed the aberrantly glycosylated tandem repeat region of MUC1 glycoprotein as three site-specific glycosylated neoantigen peptide motifs (PDTR, GSTA, and GVTS) for binding with a monoclonal antibody. This study aimed to develop an antibody-drug conjugate for Cancer treatment based on monoclonal Antibodies against the aforementioned three neoantigen peptide motifs. Internalization of monoclonal Antibodies was assessed via immunofluorescence staining and colocalization with lysosomal markers in live cells. Antibody positivity in tumor and peritumoral tissue samples was assessed via immunohistochemistry. The efficacy of anti-MUC1 ADCs was evaluated using various Cancer cell lines and a mouse tumor xenograft model. An anti-MUC1 ADC was synthesized by conjugating GSTA neoantigen-specific 16A with monomethyl Auristatin E (MMAE), which displayed potent antitumoral efficacy with an IC50 ranging 0.2-49.4 nM toward various Cancer cells. In vivo, 16A-MMAE inhibited tumor growth in a dose-dependent manner in a mouse xenograft model established using the NCI-H838 NSCLC cell line, at a minimum effective dose of 1 mg/kg. At 3 mg/kg, 16A-MMAE did not cause significant toxicity in a transgenic mouse expressing human MUC1. The high antitumoral efficacy of 16A-MMAE suggests that aberrant glycosylated MUC1 neoantigen is a potential target for the development of ADCs for treating various cancers. Personalized therapy may be achieved through such glycosite-specific ADCs.

Keywords

MUC1; aberrant glycosylation; antibody-drug conjugate; glycosite; neoantigen.

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