Yale spinout shows how targeting cancer cells' acidic environment might enhance immunotherapy

Antibody-drug conjugates such as AstraZeneca and Daiichi Sankyo’s Enhertu have shown unparalleled efficacy in certain biomarker-driven tumor types. But those therapies are not as effective at attacking cancer cells that lack the antigen they are designed to target. Yale University spinout Cybrexa Therapeutics is reporting promising early evidence indicating it may have a solution to that shortcoming.

Cybrexa has developed a peptide-drug conjugate (PDC) which, instead of aiming for a specific antigen, targets the acidic environment of cancer cells to deliver a toxic payload. The drug, coded CBX-12, improved the efficacy of immune checkpoint inhibitors in mice with colorectal cancer, Cybrexa unveiled at the AACR-NCI-EORTC virtual International Conference on Molecular Targets and Cancer Therapeutics.

Cybrexa advanced CBX-12 into a phase 1/2 study in May. The phase 1 portion of the trial will examine the safety and tolerability of the PDC at different dosing schedules in patients with solid tumors to determine the best dose for phase 2 testing.

“This is a pan-tumor tumor targeting platform technology,” Vishwas Paralkar, Ph.D., Cybrexa's chief scientific officer, told Fierce Biotech Research in an email. “For CBX-12 the initial indications we aim to pursue are HER2-[overexpressing] ovarian and small cell lung cancer.”

Antibody-drug conjugates link antibodies specific to surface antigens on cancer cells with a toxic payload. Instead of antibodies, CBX-12 uses a peptide called pHLIP, which was developed by scientists at Yale University and the University of Rhode Island. The peptide targets the acidic environment, which is unique to tumor tissues.

Cybrexa’s propriety alphalex technology allows the peptide to form a corkscrewlike helix when it comes in contact with acidic, or low pH, conditions. It then penetrates the cancer cell membrane and releases a potent cytotoxic agent; in CBX-12’s case, that anti-cancer warhead is a compound called exatecan.

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“The novelty of CBX-12 is that it targets acidity, which is a universal feature of all tumors,” study author Sophia Gayle, Ph.D., an associate director of biology at Cybrexa, explained in a statement. “We are, therefore, able to deliver a potent anti-cancer therapeutic selectively to cancer cells in a much broader patient population, as opposed to antibody-drug conjugates that are restricted primarily to patients whose tumors express high levels of a target antigen.”

The company recently showed in different animal models that CBX-12 can selectively kill off tumors without the need to target specific cancer antigens. Because CBX-12 doesn’t seem to suppress bone marrow activity in a phenomenon called myelosuppression, the researchers figured the PDC could be paired with checkpoint inhibitors, immune-boosting drugs that have established themselves as new standard treatment across multiple tumor types.

For the new study, scientists at Cybrexa combined CBX-12 with PD-1 and CTLA4 inhibitors in mouse models of colorectal cancer. Mice that got the combo showed significantly slower tumor growth, complete tumor regressions and improved survival compared with mice treated with checkpoint inhibitors alone. Adding CBX-12 to a PD-1 inhibitor delayed tumor growth by four times and by 10 times when combined with a CTLA4 inhibitor, according to the team.

Rodents that experienced complete tumor regressions showed long-term immunological memory, so, when they were re-challenged with new tumors, the cancer didn't grow.

The results suggest CBX-12 could potentially be combined with checkpoint inhibitors to help patients whose tumors don’t respond to immunotherapies alone, Cybrexa argues.

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Cybrexa was co-founded by Yale scientists Ranjit Bindra, M.D., Ph.D., and Peter Glazer, M.D., Ph.D., in 2016. The New Haven, Connecticut-based company recently raised $25 million in a series B backed by HighCape Capital and Elm Street Ventures to move development of CBX-12 forward.

The company had been working on another drug, CBX-11, which leveraged its alphalex technology to deliver Clovis Oncology’s PARP inhibitor Rubraca. But after seeing encouraging CBX-12 monotherapy data in preclinical studies, “along with the evolving clinical data from both Enhertu and [Gilead Sciences'] Trodelvy demonstrating activity in a wider patient population,” Cybrexa has decided to prioritize the development of CBX-12, Paralkar said. Learnings from CBX-12's phase 1 trial will guide the development of the rest of Cybrexa's portfolio, including CBX-11, he added.

The company has said it will explore CBX-12’s potential alongside other therapeutics such as checkpoint inhibitors and PARP inhibitors.