CDH17: A Target for Diverse Solid Tumor Therapies—Will It Lead to Significant Breakthroughs in Cancer Treatment?

In March 2022, a study published in Nature Cancer highlighted Cadherin 17 (CDH17) as an ideal target for chimeric antigen receptor (CAR) T-cell therapy in gastrointestinal tumors (including gastric cancer, pancreatic cancer, and colorectal cancer) and neuroendocrine tumors (NETs). CDH17 swiftly gained attention across major news platforms, providing fresh insights into tumor-associated antigens and the development of safe immunotherapies for solid tumors. Now, after two years, let’s explore the current landscape of immune therapies targeting the CDH17 pathway. But first, let’s delve into the fundamental aspects of CDH17.

1. The structure of CDH17

Cadherin-17 (CDH17), also known as liver-intestine cadherin (LI-cadherin) or human peptide transporter-1 (HPT-1), is a structurally unique member within the cadherin superfamily. Cadherins constitute a superfamily of cell adhesion molecules that rely on Ca2+ and belong to the type I transmembrane protein family. They are all single-pass transmembrane proteins, with their N-terminus located extracellularly. The extracellular domain of cadherins typically consists of multiple repeats, each composed of approximately 110 amino acid modules, collectively referred to as the cadherin extracellular domain (EC). Within this domain, several cadherin-specific motifs are present. Classical cadherins, such as E-cadherin (CDH1), N-cadherin (CDH2), and P-cadherin (CDH3), contain five EC domains in their extracellular region. Their intracellular domain consists of 150-160 amino acids and remains highly conserved.

Unlike classical cadherins, CDH17 belongs to the 7D-cadherin family. It consists of three parts, including seven extracellular EC repeat domains, a single transmembrane domain and a short cytoplasmic tail. CDH17’s EC1 and EC2 domains originate from EC5 repeats. Notably, CDH17 contains an RGD motif within its EC6 domain, crucial for interactions with α2β1 integrin and activation of integrin signaling pathways in cancer cells. Another significant difference between CDH17 and classical cadherins lies in the extremely short cytoplasmic domain of CDH17 (20 amino acids), contrasting with the highly conserved cytoplasmic regions (150 amino acids) found in classical cadherins or other cadherin subfamilies. Importantly, CDH17 lacks a recognizable binding site for β-catenin, which is essential for interactions with catenins and cytoskeletal components [3] [4].

Figure 1. The structure of Classical cadherins and cadherin-17

The classical cadherin-catenin complex regulates cell adhesion by interacting with intracellular catenins. Although the cytoplasmic domain of CDH17 is short, it also plays a crucial role in cell adhesion processes. Research suggests that the extracellular portion of CDH17 may independently regulate cell adhesion functions. Unlike other cadherins, CDH17 does not seem to act through binding with catenins during cell adhesion; instead, it may directly adhere to cell scaffolding. However, the precise mechanisms of its action remain unclear and require further investigation.

2. CDH17 Distribution and Clinical Significance

CDH17, initially discovered in rat liver and intestines, is also referred to as liver-intestine cadherin. In humans, CDH17’s distribution is primarily limited to the duodenum, jejunum, ileum, colon, and certain pancreatic ducts. It is rarely detected in healthy adult liver, kidney, and heart tissues [5]. Within intestinal epithelium, CDH17 predominantly localizes to lateral and basolateral membranes. Interestingly, CDH17 is aberrantly expressed on the surface of tumor cells, similar to Claudin18.2 and other specific targets. Research findings indicate that CDH17 exhibits varying degrees of expression in gastric cancer, colorectal cancer, bile duct cancer, pancreatic cancer, and hepatocellular carcinoma. Moreover, high CDH17 expression correlates with shorter survival and disease progression in gastric and colorectal cancer patients. CDH17’s differential expression profile makes it an attractive target for novel drug candidates, especially those with enhanced effector function, such as antibody-drug conjugates (ADCs), T cell- and NK cell-redirecting antibodies, and chimeric antigen receptor (CAR) T cells.

3. CDH17 Mechanisms in Tumors

While the precise mechanisms underlying CDH17’s role in cancer remain elusive, several research studies have shed light on its potential functions.

In hepatocellular carcinoma (HCC), John Luk and colleagues observed upregulated expression of CDH17 adhesion molecules. In mouse models, CDH17 could transform pre-cancerous liver progenitor cells into liver cancer. Silencing CDH17 using siRNA inhibited both in vitro and in vivo proliferation of primary and highly metastatic HCC cell lines. The antitumor mechanism involves Wnt signaling pathway inactivation, leading to β-catenin relocalization within the cytoplasm. This process is accompanied by reduced cyclin D1 expression and increased retinoblastoma susceptibility [6]. Subsequently, Felix H. Shek’s experiments confirmed SPINK1 as a downstream effector of the CDH17/β-catenin signaling axis in HCC [7].

In gastric cancer (GC), Karl-F. Becke and colleagues identified abnormal CDH17 splicing variants, particularly those with exon 8 or exon 9 deletions, as dominant [8]. Jin Wang and team validated that the downregulation of CDH17 not only suppressed proliferation, adhesion, and invasion capabilities of MKN-45 gastric cancer cells but also induced cell cycle arrest. Additionally, the NFκB signaling pathway was inactivated, resulting in decreased downstream proteins such as VEGF-C and MMP-9. Silencing CDH17 significantly inhibited in vivo tumor growth and was associated with the absence of lymph node metastasis in CDH17-deficient mice [9].

In colon cancer, CDH17 has been shown to interact with α2β1 integrin. It plays a critical role in regulating cell adhesion and proliferation through α2β1 integrin activity. Furthermore, CDH17 promotes the acquisition of liver metastasis by colorectal cancer cells. In summary, CDH17’s multifaceted roles in different cancers underscore its potential as a therapeutic target, warranting further investigation.

4. Clinical Research Progress on CDH17 Targeted Therapy

Currently, drugs targeting CDH17 are mostly in the early clinical or preclinical development stages, but there is a wide variety of drug types, including monoclonal antibodies, bispecific antibodies, CAR-T cell therapy, and antibody-drug conjugates (ADCs).

4.1 CDH17 Monoclonal Antibody

PA-0661, developed by Protein Alternative (ProAlt), is a monoclonal antibody targeting the calcium-dependent cell adhesion molecule CDH17-RGD. It has been selected by ProAlt as the first development candidate for the treatment of advanced metastatic colorectal cancer (mCRC). The antibody was successfully humanized by the end of 2018. In vitro and in vivo experiments have demonstrated that PA-0661 significantly inhibits the activation of CDH17-RGD-mediated β1 integrin, subsequently suppressing cell adhesion, migration, and proliferation. As a result, treatment with PA-0661 delays cancer metastasis progression in all treated animals and prevents metastatic formation in 50% of treated individuals. Currently, this drug remains in the preclinical stage, undergoing humanization and proof-of-concept confirmation.

4.2 CDH17 Bispecific Antibody

BI905711, developed by Boehringer Ingelheim, is a bispecific, tetravalent therapeutic antibody that simultaneously targets tumor necrosis factor-related apoptosis-inducing ligand receptor 2 (TRAILR2) and CDH17. By crosslinking TRAILR2 and CDH17, BI905711 induces CDH17-dependent TRAILR2 clustering, leading to selective apoptosis activation in tumor cells co-expressing TRAILR2 and CDH17.

Figure 2. The mechanism of BI905711

Preclinical experiments have demonstrated that BI 905711 exhibits nearly 1000-fold increased potency compared to the first-generation TRAILR2 agonist, lexatumumab. In vitro studies have shown that BI 905711 induces apoptosis in CDH17-positive tumor cells and effectively inhibits tumor growth in xenograft models of colorectal cancer (CRC) without observed hepatotoxicity. On September 10, 2020, Boehringer Ingelheim announced that BI 905711 had entered its first-in-human clinical trial for patients with advanced gastrointestinal (GI) cancers (ClinicalTrials.gov Identifier: NCT04137289). This Phase I/II study aims to evaluate the safety, maximum tolerated dose (MTD), pharmacokinetics (PK), pharmacodynamics, and preliminary efficacy of BI 905711 in patients with refractory GI malignancies. Although the clinical trial status is currently listed as completed, specific results have not yet been disclosed.

ARB202 is a humanized IgG4 bispecific antibody targeting CDH17 and CD3, constructed by Arbele using the TriAx technology. Its unique differential binding affinity to CDH17 and CD3 confers high specificity and cytotoxicity, while also avoiding off-target overactivation of T cells. Preclinical data shows that ARB202 can effectively enhance the interaction between T cells and CDH17-expressing cancer cells. In August 2022, Arbele announced the initiation of clinical trials for ARB202 (NCT05411133) in patients with advanced gastrointestinal cancers. This phase I clinical study is a continuous, multicenter, open-label, dose-escalation trial designed to determine the tolerability and/or dosing of ARB202. The study is currently in the recruitment phase. Arbele presented early safety data for its first CDH17xCD3 bispecific T cell-engaging antibody, ARB202, at the 2023 ASCO breakthrough meeting.

In addition to ARB202, Arbele has two other CDH17-targeted drugs in preclinical stages: ARB204 and ARB011. ARB204 is a bispecific antibody targeting both CDH17 and PD-1, while ARB011 is a CDH17-targeted CAR-NK therapy.

4.3 CDH17 CAR-T

CHM 2101 (CDH17 CAR-T) is a third-generation CDH17 CAR-T therapy developed by Chimeric Therapeutics, incorporating CD28 and 4-1BB co-stimulatory domains. In October 2023, CHM 2101 received FDA IND approval, positioning it to become the first CDH17 CAR-T cell therapy to enter clinical trials. The approval for this clinical trial is based on preclinical research published in the prestigious scientific journal “Nature Cancer” in March 2022 by leading immunotherapy scientist Dr. Xianxin Hua and his team at the Abramson Family Cancer Research Institute at the University of Pennsylvania. These experiments demonstrated that CHM 2101 could eradicate tumors formed in seven cancer models without toxicity to normal tissues. With FDA IND approval secured, Chimeric Therapeutics will initiate a phase 1/2 multicenter clinical trial (NCT06055439) for CHM 2101 in patients with advanced colorectal cancer, gastric cancer, and neuroendocrine tumors. Patient enrollment for this study is scheduled to begin in 2024.

4.4 CDH17 ADC

TORL-3-600, developed by TORL BioTherapeutics, is a novel CDH17-targeted antibody-drug conjugate (ADC) formed by conjugating a fully humanized CDH17 mAb with MMAE via a cleavable linker. Binding of TORL-3-600 to CDH17 on the cell surface induces internalization of the protein-ADC complex and trafficking to lysosomes, leading to the release of the MMAE payload. Preclinical studies have demonstrated that TORL-3-600 induces significant regression and inhibition of tumor growth in CDH17-positive human colorectal cancer models, with sustained responses lasting up to nine weeks after cessation of treatment. Additionally, each dose tested in this study exhibited good tolerability in mice, with no observed dose-limiting toxicities. Currently, TORL-3-600 is undergoing phase I clinical testing (NCT05948826).

5. DIMA Biotech: Advancing CDH17 Biotherapy Development

DIMA Biotech is a biotechnology company dedicated to preclinical research and development of products and services for potential drug targets. DIMA now offers a full range of products and services related to the CDH17 target. Our products include active proteins, reference antibodies, and flow cytometry-validated monoclonal antibodies. Our services cover a variety of species-specific antibody customization, antibody humanization, and affinity maturation services.

In addition, to expedite the development of CDH17 biologics, DIMA has prepared a single B-cell seed library for the CDH17 target. With our B cell library, lead antibody molecules can be obtained in as little as 28 days, allowing customers to conduct further functional evaluation and validation. Currently, we have screened 41 lead molecules for CDH17, with 36 verified for cross-reactivity with human and monkey proteins. For some molecules, we are also conducting ADC internalization activity and cytotoxicity validation. For specific data, please feel free to inquire.

• CDH17 Protein and Antibody

• Progress on CDH17 Lead mAb Molecules

Reference:
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