Claudin 6: A target opportunity to develop effector-enhanced drug modalities

Claudin 6 (CLDN6) is a compelling tumor antigen. The tetraspan membrane protein is a member of the claudin family of tight junction proteins. CLDN6 is an oncofetal tight junction molecule that is expressed during embryonic and fetal development, transcriptionally silenced in adult tissues, and re-expressed on the surface of several epithelial cancers. The transmembrane protein CLDN6 is virtually absent from any normal tissue, whereas it is aberrantly and frequently expressed in various cancers of high medical need.

Despite being an attractive target due to its exceptionally cancer cell selective expression, therapeutic monoclonal antibodies targeting CLDN6 are difficult to discover due to an abundance of closely related family members and an absolute need for high specificity. Many proteins in the claudin family have high sequence identity. Most similar to CLDN6 is CLDN9, and the two proteins differ at only three of 76 residues in their extracellular loops, creating a challenge for the development of highly selective CLDN6 antibodies.

This report describes and analyzes as of May 2022

• The scientific rationale for CLDN6-targeted therapies based on target characteristics and its differential expression profile;
• Preclinical proof-of-concept of CLDN6-targeted different drug modalities;
• Clinical experience with CLDN6-targeted therapies;
• Clinical indications suitable for development of CLDN6-targeted therapies and their patient populations;
• The competitive landscape of CLDN6-targeted drug modalities in development;
• Specific profiles of CLDN6-targeted drug modalities; and
• Profiles of companies active in the development of anti-CLDN6 therapy candidates.

Effector-enhanced antibodies and cells such as antibody-drug conjugates, chimeric antigen receptor (CAR) T-cells, and bispecific antibodies redirecting T-cells or specifically activating T-cells will be enabled by and benefit from the cancer selective expression profile and the high target selectivity to avoid on-target, off-tumor toxicity.

Despite the technical challenge, novel cellular and humoral CLDN6-targeted drug modalities have emerged and the first product candidates entered clinical development. The facts that preliminary clinical experience shows high anti-tumor activity of the first drug candidate and that the competitive field still is limited, make claudin 6 an exceptionally attractive target for drug discovery and development.