ASCO 2023 Spotlight: Claudin 6 Anticipated To Shine

The escalating battle between Claudin 6 (CLDN6) immunotherapies from Amgen, BioNTech and Context Therapeutics CNTX, and CLDN6 antibody-drug-conjugates (ADC) from Daiichi-Sankyo and TORL BioTherapeutics will be a highlight of the upcoming 2023 American Society of Clinical Oncology Annual Meeting (ASCO 2023), taking place on June 2-6, 2023, in Chicago, IL.

At ASCO 2023, BioNTech and TORL will present Phase 1 clinical trial data on CLDN6-targeted programs, including BNT142, BNT211, and TORL-1-23. This will be the first major clinical data set presented on the emerging target CLDN6 and, if positive, could position CLDN6 as one of the most-promising cancer drug targets in recent years.

CLDN6 – a promising drug target for oncology drug developers

CLDN6 is selectively expressed in cancer cells and functions as cellular Velcro, helping the cancer cells attach to one another. The more CLDN6 that is found on the cancer cell, the worse prognosis for the 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 cancer (NSCLC), testicular, and ovarian.

The development of CLDN6-targeted therapies is challenged by the genetic overlap between CLDN6 and closely related Claudins, including CLDN3, CLDN4, and CLDN9. Unlike CLDN6, these closely related proteins are expressed in normal healthy tissue, making selectivity for CLDN6 critical.

CLDN6 drug development is nascent, with the first substantial clinical data to be presented at ASCO 2023. Multiple therapeutic strategies against the target are being pursued, including bispecific antibody and cell therapy immunotherapies, and ADCs.

A still unknown quantity is Context Therapeutic’s CTIM-76, a CLDN6 x CD3 bispecific antibody, said to be the most selective CLDN6 binder of the bunch.     

Preclinical data presented at the 2023 American Association for Cancer Research (AACR) Annual Meeting highlighted CTIM-76’s unique attributes, including the potent killing of CLDN6-expressing cells, developability, and manufacturability.

BioNTech will present multiple updates from its CLDN portfolio, most notably an update from their CLDN-6-targeting CAR-T cell therapy, BNT211, in combination with CLDN6- encoding mRNA vaccine (CARVac) in solid tumors (poster #2518).

The company first communicated results at the 2022 AACR Annual Meeting. In that data, the addition of CARVac, an mRNA vaccine expressing CLDN6 antigen, stimulated BNT211 proliferation, but not to the extent that the company saw with mice, and the overall response rate was 43% with the most positive results in testicular cancer.

At the 2022 European Society for Medical Oncology Congress, BioNTech presented follow-up data with additional patients with testicular cancer which demonstrated stronger response durability in testicular cancer with six of 11 patients ongoing in study >30 weeks, including one complete response and one partial response. At ASCO 2023, it will be informative to learn whether BNT211 can generate durable clinical responses in larger indications like ovarian cancer or NSCLC.

Additionally, any update regarding safety issues, including how BioNTech addresses transaminase and lipase-related toxicities, which are potentially connected to off-target binding to CLDN3 and CLDN4, sister proteins to CLDN6 that are enriched in healthy liver and pancreatic cells, respectively. 

BioNTech will also provide a trial-in-progress update for BNT142 (mRNA vaccine encoding a CD3 x CLDN-6 bispecific, poster abstract TPS2669). Given that mRNA vaccines accumulate in the liver, any reported CLDN3-related liver toxicities would be of importance. If BNT142 exhibits a relatively clean safety profile, then the CLDN6 field would benefit from greater investor confidence in the ability to treat for extended periods of time with a modest risk of dose-limiting toxicities.

TORL Biotherapeutics will present the first clinical data from its CLDN6 ADC TORL-1-23. In April, TORL announced a $158 million financing to support the development of its pipeline. At ASCO 2023, TORL-1-23 trial-in-progress clinical data will be presented and may show if the ADC can generate responses on par with BNT211, particularly in testicular and ovarian cancer.  In vitro and in vivo preclinical data suggest that TORL-1-23 may exert much of its activity through ADCC-mediated immune response as opposed to direct ADC-mediated cell death. Clinical data presented will hopefully provide greater insight into immune cell recruitment versus bystander-mediated cell killing.

Additionally, it will be important to learn more about any toxicity TORL-1-23 exhibits including bone marrow toxicity, sepsis, and severe motor neuropathy, which would be consistent with other ADCs that utilize monomethyl auristatin E (MMAE) as their toxin.

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