HUTCHMED Highlights HMPL-A251 Data Presented at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics

— First investigational drug candidate using the HUTCHMED ATTC technology platform to create potent targeted therapy payloads while mitigating related toxicities —— Unique, highly potent PI3K/PIKK inhibitor payload optimized to exploit antibody-conjugate advantages, with directed delivery and low plasma exposure of free payload — — Preclinical data shows robust antitumor activity with synergistic and bystander killing effects —HONG KONG and SHANGHAI and FLORHAM PARK, N.J., Oct. 23, 2025 (GLOBE NEWSWIRE) -- HUTCHMED (China) Limited ("HUTCHMED") (Nasdaq/AIM:​HCM; HKEX:​13) today announces preclinical data for HMPL-A251 at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, held October 22–26, 2025, in Boston, USA. HMPL-A251 is a first-in-class PI3K/AKT/mTOR ("PAM")-HER2 Antibody-Targeted Therapy Conjugate ("ATTC") comprising of a highly selective and potent PI3K/PIKK inhibitor payload linked to a humanized anti-HER2 IgG1 antibody, via a cleavable linker.HER2 is a well-established therapeutic target. HER2 overexpression is found in a variety of cancer types and often associated with poor prognosis. As a key downstream signaling pathway of HER2, the PAM pathway contributes significantly to the resistance against HER2-targeting treatments when altered. HMPL-A251 is innovatively designed to leverage the synergy between HER2 targeting and PAM pathway inhibition to address limitations of traditional toxin-based antibody-drug conjugates ("ADCs") and standalone PAM inhibitors.In vitro, the PI3K/PIKK inhibitor payload exhibited high potency, selectivity, and broad anti-tumor activity across a panel of 130 tumor cell lines. By conjugating this potent payload with an anti-HER2 antibody via a hydrophilic linker, the ATTC compound HMPL-A251, upon binding to the HER2-positive target cells, undergoes rapid internalization, lysosomal trafficking, payload release, and inhibition of PAM and PIKK signaling, inducing tumor cell apoptosis. HMPL-A251 demonstrated HER2-dependent antitumor activity in vitro, potently inhibiting HER2-positive tumor cell growth regardless of PAM pathway alterations, with moderately reduced activity in HER2-low, PAM-altered cell lines. HMPL-A251 also demonstrated a bystander effect on HER2-null cells when co-cultured with HER2-positive cells.Unlike toxin-based ADCs, which often face challenges with toxicity related to their cytotoxic payloads, ATTCs are designed to prioritize tumor-specific delivery of a pathway-modulating payload, enhancing safety for long-term use and enabling potential frontline combinations with chemotherapy. In vivo, HMPL-A251 demonstrated superior anti-tumor efficacy and tolerability as compared to the naked antibody and payload administered together. A single intravenous dose of HMPL-A251 induced tumor regression across multiple models including HER2-positive and HER2-low models with or without PAM alteration. Efficacy correlated strongly with payload concentration and target inhibition in tumor ...Full story available on Benzinga.com