Novel Oncology Target Claudin 6 Makes its Case in Solid Tumors
26 Jun 2023
ImmunotherapyASCOCell TherapyAACRClinical Study
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Source: FierceBiotech
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Harnessing the Power Within
The evolving understanding of the underlying biology of cancer continues to advance, enabling the development of further improvements in new therapies. One area of particular interest is immunotherapy, the concept of awakening a patient’s own immune system to attack cancer cells. A fundamental challenge to this approach is that the immunotherapy needs to lock in on a target that is selectively expressed on cancer cells, otherwise the patient’s immune system may attack normal, otherwise healthy tissues and organs leading to debilitating side effects. While the pharmaceutical industry has made great strides in developing new strategies to activate the patient’s immune system better and more safely, there is a dearth of suitable targets expressed by cancer cells to direct the immune system response.
An Attractive Oncology Target
There is growing interest in applying immunotherapy modalities, particularly T-cell activating therapies, including bispecific antibodies and chimeric antigen receptor (CAR) T-cell therapies (CAR-T), to solid tumors. However, identifying appropriate tumor-specific targets that avoid adverse effects in healthy tissue has been challenging.
Claudin 6 (CLDN6) is a protein selectively expressed in cancer cells and functions as cellular glue, helping the cancer cells attach to one another. CLDN6 is prognostic, meaning the more CLDN6 that is found on the cancer cell, the worse the prognosis is for the cancer patient. This may be attributed to CLDN6 enhancing cell attachment, enabling the cancer cells to form an impenetrable ball-like structure. CLDN6 is enriched in a wide range of cancers – most notably non-small cell lung (NSCLC), testicular, and ovarian.
Overcoming the CLDN6 Selectivity Challenge
Despite being an attractive target, therapeutic monoclonal antibodies targeting CLDN6 are difficult to discover due to an abundance of closely related Claudin (CLDN) proteins and an absolute need for high specificity. There are over two dozen human CLDN proteins, and most are broadly expressed and highly conserved. For example, the extracellular region of CLDN6 closely resembles the widely expressed CLDN9, differing by only three amino acids.
Unlike CLDN6, these closely related CLDN proteins are expressed in normal healthy tissue, making selectivity for CLDN6 critical. The few CLDN6 assets already in clinical development have demonstrated significant binding to other CLDN family members, which may be associated with loss of hearing, liver enzyme elevations, and nausea.
Clinical Validation
First-in-human CLDN6 data presented at the American Society for Clinical Oncology 2023 Annual Meeting for BioNTech’s BNT211, a CAR-T cell therapy targeting CLDN6, provides strong support for CLDN6 as a potentially clinically relevant immunotherapy target for cancers that express high levels of CLDN6, most notably ovarian and testicular cancer. Despite these promising clinical findings, there is ample room for new entrants to improve upon both efficacy and safety, particularly in cancers such as NSCLC where CLDN6 expression is more heterogeneous. Emerging T cell engager assets, including from Context Therapeutics ($CNTX), highlight additional CLDN6-targeted products that could enhance the treatment of CLDN6-positive tumorsCLDN6-positive tumors.
An Ideal CLDN6-targeted Therapy
With an evolving understanding of the CLDN6 selectivity challenge and the enthusiasm for novel immunotherapy treatments, scientists and clinicians have been searching for ways to discover and develop better CLDN6-directed therapies.
Context Therapeutics’ lead candidate, CTIM-76, is a CLDN6 x CD3 bispecific antibody that incorporates a highly selective CLDN6 binding arm and a CD3 binding single-chain Fv domain in an Immunoglobulin G format with a silenced Fc that is designed to be functionally monovalent to avoid aberrant T-cell activation and to enhance the safety profile. Preclinical research has demonstrated that CTIM-76 is potent with specific lysis of CLDN6-positive cancerCLDN6-positive cancer cells over normal cells and can activate cytotoxic T cells without concomitant activation of free cytokines – critical determinants of immunotherapy safety and activity. In addition, these preclinical studies suggest the potential for convenient dosing with low immunogenicity risk and scalable manufacturing to address the significant number of patients who are potentially eligible for CTIM-76 therapy.
A Hopeful Future
This year in the U.S. alone an estimated 62,500 patients will be diagnosed with invasive cancer that expresses CLDN6. While recent clinical progress has been made in targeting CLDN6, there remains an unmet need for a potent immunotherapy that is both well tolerated and convenient to administer for patients. Such a drug would be able to potentially treat the spectrum of cancers that express CLDN6.
CTIM-76 is among the potential therapies that may transform the treatment of patients with CLDN6-positive cancers.
To learn more about Context Therapeutics’ science and approach to targeting CLDN6-positive cancers, visit www.contexttherapeutics.com.
This article may contain forward-looking statements, which are subject to a number of risks; you are cautioned to refer to the cautionary statements on forward-looking statements that appear in Context Therapeutics’ filings with the SEC.
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