Abstract 193P
Background
Claudin 1 (CLDN1) is a protein confined within the normal epithelial tight junctions of different tissues. Upon malignant transformation, CLDN1 is overxpressed and epitopes become exposed outside the tight junctions (non-Junctional CLDN1). ALE.C04 is a highly specific humanized monoclonal antibody that recognizes a unique CLDN1 exposed epitope in different solid tumors.
Methods
More than 1200 paraffin embedded tumor biopsies from 12 different indications have been stained by Immunohistochemistry (IHC) for both CLDN1 and CD3 (T cell marker). Different tumor mouse models have been used to assess the anti-tumor activity of ALE.C04 as single agent and/or in combination with either check-point inhibitors (CPIs) /or chemotherapy.
Results
Herein we show that non-Junctional CLDN1 (NJ-CLDN1) is frequently overexpressed in solid tumors. Notably, CLDN1 expression on tumor cells positively correlates with the localization of T-cells into a fibrotic tissue environment. T cell exclusion is one the mechanisms described to hinder the efficacy of Checkpoint inhibitors (CPIs). On this line, the overexpression of Cldn1 in Hepa1-6 mouse liver tumor cells promoted T cell exclusion and resistance to anti-PD1 treatment. Importantly, ALE.C04 restored both T-cell infiltration and anti-PD1 efficacy in Hepa1-6 Cldn1+ tumors. Mechanistically, NJ-CLDN1 interacts with different component involved in extracellular matrix remodeling, thus establishing a physical barrier that exclude immune cells from the tumor nest. ALE.C04 has a direct antifibrotic effect that perturbs the interface between CDLN1+ tumor cells and the stroma, thus restoring im mune cell infiltration. The rationale for developing a CDLN1-based Oncology platform will be also presented.
Conclusions
We have shown that NJ-CLDN1 is overexpressed in different solid tumor, drives T -cell exclusion and resistance to CPIs. Importantly, ALE.C04 restored T cell infiltration and CPI efficacy in a mouse model for liver tumor . Based on our pre-clinical data, rationale and safety profile, we plan a phase 1b study with ALE.C04 in combination with CPIs in solid tumors.
Clinical trial identification
INT: 1011.
Legal entity responsible for the study
Alentis Therapeutics AG.
Funding
Alentis Therapeutics AG.
Disclosure
A. Toso: Financial Interests, Personal, Stocks/Shares: Alentis Therapeutic AG. G. Teixiera: Financial Interests, Personal, Stocks/Shares: Alentis Therapeutics. T. Zimmermann: Financial Interests, Personal, Stocks/Shares: Alentis Therapeutics AG. D. Schmitter: Financial Interests, Personal, Stocks/Shares: Alentis Therapeutics AG. M. Meyer: Financial Interests, Personal, Stocks/Shares: Alentis Therapeutics AG. T. Baumert: Financial Interests, Personal and Institutional, Member of the Board of Directors: Alentis Therapeutic AG. R. Iacone: Financial Interests, Personal, Stocks/Shares, CEO: Alentis Therapeutics AG. All other authors have declared no conflicts of interest.