Claudin 6, Cadherin 17, ROR1 and GPRC5D-Targeted Therapies: Target Expression Profile, Safety & Efficacy of Drug Modalities, Pipeline Review, and Competitive Landscape Analysis

This report bundle includes four reports about novel cancer targets which have in common a compelling target expression profile with a low risk of on-target/off-tumor toxicity. As such, drug modalities with enhanced effector function, e.g. antibody-drug conjugates, T cell- and NK-cell redirecting antibodies and chimeric antigen receptor (CAR) T-cells, can be employed for generation and development of novel drug candidates.

Furthermore, preclinical and preliminary clinical study results indicate a high probability of efficacy and low safety risk. And, the competitive pipeline for each target has not yet advanced too far and allows new entrants into the race good chances for success.

These four targets are covered by the reports:

• Claudin-6;
• Cadherin-17;
• ROR1; and

The reports describe and analyze the target expression profile, provide preclinical and clinical efficacy and safety data; describe potential indications and the respective paptient population, assess the competitive landscape; provide specific profiles of drug candidates in R&D and specific profiles of industry stakeholders.

The reports were prepared in May and June of 2022. The bundle of four reports is available with a 30% discount on list prices.

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.

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 uman 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.

ROR1-Targeted Therapy: Target Expression Profile, Safety & Efficacy of Drug Modalities, Pipeline Review, and Competitive Landscape Analysis

This report evaluates Receptor tyrosine kinase-like Orphan Receptor 1 (ROR1) from an industry perspective for its suitability as a tumor-specific target for cancer therapy based on its expression profile and preclinical and clinical safety and efficacy data of the various drug modalities employed for discovery and development of ROR1-targeted therapy candidates.

The report has identified the players in the field and presents a competitive landscape analysis of stakeholders and a pipeline review based on the specific profiles of drug candidates and companies active in the field. The report includes information about business transaction in the field, such as acquisitions, partnerships & collaborations and licensing deals. Furthermore, the financial background and situation of the key players is described.

Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is a type I transmembrane protein that is physiologically expressed in early embryogenesis and plays a critical role in organogenesis. Expression of ROR1 attenuates rapidly after embryonic development, becoming virtually undetectable on post-partem tissues, with the exception of a few B cell precursors. In contrast, ROR1 is expressed on a variety of cancers, particularly those that are less differentiated, and is associated with early relapse after therapy or metastasis.

Because of its tumor-specific expression and potential functional significance, ROR1 has become of interest as a target for various drug modalities, especially with enhanced effector function. The most advanced molecules is currently being evaluated in potentially registrational phase II/III studies, but the majority of programs are in late preclinical and early clinical development, thus still offering opportunities for improvements.

This report is based information retrieved from proprietary database, clinical trial registries, abstracts, presentations and posters from scientific meetings as well as full publications, from company websites, press releases, SEC filings, investor and R&D presentations. The report was prepared in May/June of 2022 and was released on June 16, 2022.

What will you find in the report:

• The scientific rationale for ROR1-targeted therapies based on target characteristics and its differential expression profile;
• Preclinical safety of ROR1-targeted therapy candidates;
• Clinical experience and proof-of-concept with ROR1-targeted drug modalities;
• Clinical indications suitable for development of ROR1-targeted therapies and their patient populations;
• The competitive landscape of ROR1-targeted drug modalities in development;
• Specific profiles of ROR1-targeted drug modalities; and
• Profiles of companies active in the development of anti-ROR1 therapy candidates.

GPRC5D-Targeted Therapy: Target Expression Profile, Safety & Efficacy of Drug Modalities, Pipeline Review, and Competitive Landscape Analysis

This report evaluates G-protein-coupled receptor family C group 5 member D (GPRC5D) from an industry perspective for its suitability as a tumor-specific target for cancer therapy based on its expression profile and preclinical and clinical safety and efficacy data of the various drug modalities employed for discovery and development of GPRC5D-targeted therapy candidates.

The report has identified the players in the field and presents a competitive landscape analysis of stakeholders and a pipeline review based on the specific profiles of drug candidates and companies active in the field. The report includes information about business transactions in the field, such as acquisitions, partnerships & collaborations and licensing deals. Furthermore, the financial background and situation of the key players is described.

GPRC5D is a type C seven-pass transmembrane protein. The endogenous ligands and signaling mechanism, and thereby, its physiological function and its role in cancer remain unknown. GPRC5D is expressed on malignant bone marrow plasma cells, whereas normal tissue expression is limited to skin (hair follicles and eccrine glands) and the testis (seminiferous tubules). The restricted GPRC5D expression profile indicates that the potential for undesired on target/off tumor effects is small. GPRC5D expression on CD138 cells is independent of B-cell maturation antigen (BCMA) expression and showed a membranous pattern.

Treatment of multiple myeloma with BCMA-targeted drug modalities induces high overall response rates. However, relapse occurs commonly. A reservoir of multiple myeloma cells lacking sufficient BCMA surface expression (antigen escape) may be implicated in relapse. Thus, targeting BCMA may be an efficient therapeutic strategy for BCMA treatment- refractory or -relapsed multiple myeloma patients to address BCMA escape and potentially confer cure.

This report is based information retrieved from proprietary database, clinical trial registries, abstracts, presentations and posters from scientific meetings as well as full publications, from company websites, press releases, SEC filings, investor and R&D presentations. The report was prepared in June of 2022 and was released on July 1, 2022.

What will you find in the report:

• The scientific rationale for GPRC5D-targeted therapies based on target characteristics and its differential expression profile;
• Preclinical efficacy and safety of GPRC5D-targeted therapy candidates;
• Clinical efficacy and safety of GPRC5D-targeted drug modalities;
• Patient population for GPRC5D-targeted therapies;
• The competitive landscape of GPRC5D-targeted drug modalities in R&D;
• Specific profiles of GPRC5D-targeted drug modalities; and
• Profiles of companies active in the development of anti-GPRC5D therapy candidates.