HMPL-A251

**HMPL-A251** is a first-in-class PI3K/AKT/mTOR (PAM)-HER2 antibody-targeted therapy conjugate (ATTC) developed by HUTCHMED using their proprietary ATTC platform. It consists of a humanized anti-HER2 IgG1 antibody conjugated via a cleavable hydrophilic linker to a highly selective and potent PI3K/PIKK inhibitor payload (HM-5041609). The conjugate binds to HER2 on tumor cells, undergoes internalization and lysosomal trafficking, releases the payload to inhibit PAM and PIKK signaling pathways, inducing apoptosis with synergistic effects and bystander killing on neighboring HER2-low or null cells. Preclinical data demonstrate superior antitumor efficacy and tolerability compared to naked antibody/payload combinations and benchmarks like trastuzumab deruxtecan (T-DXd) in HER2-positive and HER2-low models with or without PAM alterations, addressing resistance in HER2-overexpressing cancers associated with poor prognosis.[1][2][5][11]