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Figure S4 from Preclinical Efficacy of the Antibody–Drug Conjugate CLDN6–23-ADC for the Treatment of CLDN6-Positive Solid Tumors

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posted on 2023-04-11, 13:00 authored by Martina S.J. McDermott, Neil A. O'Brien, Benjamin Hoffstrom, KeWei Gong, Ming Lu, Jun Zhang, Tong Luo, Min Liang, Weiping Jia, Jenny J. Hong, Kevin Chau, Simon Davenport, Bin Xie, Michael F. Press, Richard Panayiotou, Abram Handly-Santana, Joan S. Brugge, Leonard Presta, John Glaspy, Dennis J. Slamon

Supplemental Figure S4: Binding of CLDN6-23-ADC (5 μg/ml) in artificial cell lines overexpressing CLDN3, CLDN4, CLDN6 or CLDN9 by flow cytometry.

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ARTICLE ABSTRACT

Claudin-6 (CLDN6) is expressed at elevated levels in multiple human cancers including ovarian and endometrial malignancies, with little or no detectable expression in normal adult tissue. This expression profile makes CLDN6 an ideal target for development of a potential therapeutic antibody–drug conjugate (ADC). This study describes the generation and preclinical characterization of CLDN6–23-ADC, an ADC consisting of a humanized anti-CLDN6 monoclonal antibody coupled to monomethyl auristatin E (MMAE) via a cleavable linker. A fully humanized anti-CLDN6 antibody was conjugated to MMAE resulting in the potential therapeutic ADC, CLDN6–23-ADC. The antitumor efficacy of CLDN6–23-ADC was assessed for antitumor efficacy in CLDN6-positive (CLDN6+) and -negative (CLDN6−) xenografts and patient-derived xenograft (PDX) models of human cancers. CLDN6–23-ADC selectively binds to CLDN6, versus other CLDN family members, inhibits the proliferation of CLDN6+ cancer cells in vitro, and is rapidly internalized in CLDN6+ cells. Robust tumor regressions were observed in multiple CLDN6+ xenograft models and tumor inhibition led to markedly enhanced survival of CLDN6+ PDX tumors following treatment with CLDN6–23-ADC. IHC assessment of cancer tissue microarrays demonstrate elevated levels of CLDN6 in 29% of ovarian epithelial carcinomas. Approximately 45% of high-grade serous ovarian carcinomas and 11% of endometrial carcinomas are positive for the target. We report the development of a novel ADC, CLDN6–23-ADC, that selectively targets CLDN6, a potential onco-fetal-antigen which is highly expressed in ovarian and endometrial cancers. CLDN6–23-ADC exhibits robust tumor regressions in mouse models of human ovarian and endometrial cancers and is currently undergoing phase I study.

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