Cadherin 17: A target opportunity to develop effector-enhanced drug modalities

Cadherins are a family of glycoproteins responsible for calcium ion–dependent cell adhesion. There are more than 100 types of cadherins in humans, and many of them are not only responsible for cell adhesion but also involved in tumorigenesis. Cadherin 17 (CDH17), also known as human liver intestine–cadherin (LI-cadherin), or intestinal human peptide transporter-1 (HPT-1), is a non-classical cadherin composed of an ectodomain consisting of seven extracellular cadherin (EC) repeats, a single transmembrane domain, and a short cytoplasmic domain.

CDH17 is a highly specific marker of gastrointestinal epithelium; most gastrointestinal adenocarcinomas are CDH17-positive with strong membranous staining. However, healthy tissue colonic mucosa and duodenal mucosa also are positive for CDH17 which prevented consideration of CDH17 as an ideal tumor associated antigen for development of CDH17-targeted therapies.

It was only very recently, that investigators discovered that CDH17 is masked in healthy tissue and is not attacked by large molecules or cells. Thus, CDH17 represents a class of previously unappreciated tumor-associated antigens that is ‘masked’ in healthy tissues from attack by CAR T cells for developing safer cancer immunotherapy.

This report describes and analyzes as of May 2022

• The scientific rationale for CDH17-targeted therapies based on target characteristics and its differential expression profile;
• Preclinical proof-of-concept of CDH17-targeted different drug modalities;
• Clinical indications suitable for development of CDH17-targeted therapies and their patient populations;
• The competitive landscape of CDH17-targeted drug modalities in development;
• Specific profiles of CDH17-targeted drug modalities; and
• Profiles of companies active in the development of anti-CDH17 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 to avoid on-target, off-tumor toxicity.

CDH17 provides a great opportunity for drug discovery and development as the competitive landscape still is very favorable for new entrants, but the first molecules have entered clinical development.