PI3K conjugates enter the clinic

Hutchmed, already known to have entered one of oncology R&D’s hottest spaces, antibody-drug conjugates, with HMPL-A251, has revealed this anti-HER2 project's unusual feature: it uses a PI3K/PIKK inhibitor as its payload. The molecule is based on what Hutchmed calls its antibody-targeted therapy conjugate (ATTC) platform, and marks the first clinical-stage asset to emerge from that technology. The approach aims to combine monoclonal antibodies with small-molecule inhibitor payloads. Preclinical data presented at the recent Triple meeting suggested HMPL-A251 could rival well-established ADCs; the company claimed superior or comparable efficacy to Enhertu, AstraZeneca and Daiichi’s blockbuster HER2 ADC, across multiple tumour models. Importantly, Hutchmed is signalling that HMPL-A251 is only the beginning. The company has said that two additional ATTC candidates, with undisclosed targets, are expected to enter the clinic over the next year, with HMPL-A580 slated for the first half of 2026 and HMPL-A830 following in the second half. Hutchmed is not the only company developing conjugates with PI3K inhibitor payloads. At AACR, Accutar Biotechnology unveiled preclinical data for a degrader-based antibody conjugate that uses its proprietary PI3Kα degrader, AC4847. The programme remains in IND-enabling studies.