ASCO 2023 – Claudin 6 Makes A Splash In Ovarian Cancer

This year’s 2023 American Society of Clinical Oncology Annual Meeting (ASCO 2023) provided a surprising amount of clinical data relevant to biopharma investors.

The meeting, normally a hotspot of late-stage clinical research, featured several prominent early clinical trials evaluating novel therapies targeting Claudin 6 (CLDN6). At ASCO, BioNTech BNTX and TORL Biotherapeutics presented phase 1 dose escalation trial data on their respective CLDN6-targeted programs, BNT211 and TORL-1-23. This was the first major clinical data presented on the emerging target CLDN6. If the positive data presented at the conference holds up in later stage trials, CLDN6 may be well positioned to establish itself as one of the most-promising cancer drug targets in recent years.

CLDN6 is 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 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.

Development of CLDN6-targeted therapies is challenged by 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.

During a June 3rd session devoted to experimental therapeutics, ASCO participants were treated to a first clinical look from ongoing phase 1 dose escalation trials evaluating CLDN6-targeted therapies.  

TORL Presented Its First Clinical Data From Its CLDN6 Antibody-Drug Conjugate (ADC) TORL-1-23

TORL-1-23 is a CLDN6-ADC with a protease labile linker licensed from WuXi Biologics conjugated to monomethyl auristatin E (MMAE) toxin with four MMAE per antibody. Given the fact that TORL-1-23 incorporates a relatively unstable linker and CLDN6 is believed to not internalize, the mechanism of action of TORL-1-23 is currently unknown and may be a combination of ADCC-mediated recruitment of natural killer cells and bystander effect. Data presented at ASCO points to TORL-1-23 being highly active, particularly in late-line ovarian cancer, with a toxicity profile (alopecia, anemia, lymphocytopenia, neuropathy) consistent with other MMAE ADCs. Even at low doses, TORL-1-23 was active with a 28% overall response rate (ORR) across the phase 1 dose escalation trial evaluating doses ranging from 0.2 mg/kg to 2.4 mg/kg. Of particular interest is that the ADC demonstrated a 75% ORR (3/4 patients) in late-line ovarian cancer at a dose of 2.4 mg/kg. Given the robust clinical activity and generally manageable toxicity of TORL-1-23, the trial has been amended to add a Cohort 9 (3 mg/kg) and Cohort 10 (4 mg/kg), with six patients having already been enrolled in Cohort 9. In the future, it will be important to learn whether TORL-1-23 can maintain its impressive response rates across a larger clinical population and in tumor types such as NSCLC where CLDN6 expression is often heterogeneous and/or less intense than in ovarian or testicular cancer. Also, TORL did not disclose which patients continue to be on treatment, so durability of effect remains an open question. Further, MMAE toxicity, particularly neuropathy, tends to accumulate over time, so it will be informative to learn if toxicity is correlated with duration of treatment and if the presentation of toxicities accelerates at the higher doses in Cohorts 9 and 10.

BioNTech Presented Multiple Updates From Its CLDN Portfolio – Notably An Update From Its CLDN6-Targeting CAR-T, BNT211 In Combination With CLDN6- Encoding mRNA Vaccine (CarVac) In Solid Tumors

In data presented at the American Association of Cancer Research (AACR) Annual Meeting 2022, the addition of CarVac, a mRNA vaccine expressing CLDN6 antigen, stimulated T cell expansion (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 ASCO 2023, BioNTech followed up its previous positive results in testicular cancer with a deeper look into the potential of BNT211 across a wider range of CLDN6+ tumors and evaluated a new automated CAR-T manufacturing process. At the second dose level (1x108 CAR-T cells), the company saw a 75% ORR overall (6/8 patients) and an 80% ORR (4/5 patients) in late-line ovarian cancer patients. The data presented also hints at the potential for CarVac to enhance T cell persistence, but a more complete analysis of data is required to determine CarVac influence on T cells. The overall safety picture for BNT211 is consistent with data presented at AACR 2022 and the European Society of Medical Oncology Congress 2023, wherein BNT211 side effects are generally associated with lymphodepletion and cytokine release syndrome, which continue to be low grade and adequately managed with anti-IL6 antibodies. BNT211 treatment also resulted in liver enzyme elevations, which are potentially connected to off-target binding to CLDN3, a sister protein to CLDN6 that is enriched in liver cells, or BNT211 accumulation and subsequent cytokine release in the liver. 

In addition to clinical data for BNT211, BioNTech provided a poster with a trial-in-progress update for BNT142, an mRNA vaccine encoding a CD3 x CLDN-6 bispecific, which is in phase 1 dose escalation clinical trials. Limited information was provided in the poster; however, BioNTech noted that 20 trial sites are now open, and dosing is ongoing in Cohort 3 of the ongoing phase 1 dose escalation trial.

ASCO 2023 did not disappoint. First-in-human data for TORL-1-23 and BNT142 provide strong support for CLDN6 as a potentially clinically relevant target in testicular and ovarian cancer. A data follow-up for BNT211 underscored that point. However, despite these promising clinical findings, there is ample room for new entrants to improve upon both efficacy and safety. Emerging T cell engager assets from Context Therapeutics CNTX and Amgen AMGN highlight additional CLDN6-targeted products that could enhance the treatment of CLDN6-positive tumors.

*Analysis based on current understanding of publicly available information compiled as of June 5, 2023

Featured photo by Louis Reed on Unsplash.

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