HUTCHMED (China) Limited has presented preclinical data for its investigational drug candidate HMPL-A251 at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, which took place from October 22 to 26, 2025, in Boston, USA. This innovative therapy is a first-in-class Antibody-Targeted Therapy Conjugate (ATTC) designed to target the PI3K/AKT/mTOR (PAM)-HER2 pathway.
HMPL-A251 features a highly selective and potent PI3K/PIKK inhibitor payload that is linked to a humanized anti-HER2 IgG1 antibody through a cleavable linker. HER2 is a significant therapeutic target, as its overexpression is linked to several cancer types and often correlates with poor patient outcomes. The PAM signaling pathway, which is activated by HER2, plays a crucial role in resistance to HER2-targeted therapies when altered.
This ATTC is developed to harness the synergy between HER2 targeting and PAM pathway inhibition, addressing the shortcomings of existing toxin-based antibody-drug conjugates (ADCs) and standalone PAM inhibitors. In vitro studies have demonstrated that the PI3K/PIKK inhibitor payload possesses high potency, selectivity, and extensive anti-tumor activity across a diverse array of 130 tumor cell lines.
Upon binding to HER2-positive cells, HMPL-A251 undergoes rapid internalization, leading to lysosomal trafficking and payload release, which subsequently inhibits PAM and PIKK signaling, triggering apoptosis in tumor cells. The compound exhibited HER2-dependent anti-tumor effects in vitro, effectively inhibiting growth in HER2-positive cells, even in the presence of PAM pathway alterations. Furthermore, it showed a bystander effect on HER2-null cells when co-cultured with HER2-positive cells.
In contrast to traditional toxin-based ADCs, which often cause significant toxicity due to their cytotoxic payloads, ATTCs are engineered for tumor-specific delivery of pathway-modulating payloads, thereby enhancing safety for prolonged use and allowing potential frontline combinations with chemotherapy. In vivo evaluations indicate that HMPL-A251 provided superior anti-tumor efficacy and tolerability compared to administering the naked antibody and payload together.
A single intravenous administration of HMPL-A251 resulted in tumor regression across various models, including both HER2-positive and HER2-low models, with or without PAM alterations. The efficacy of HMPL-A251 was closely associated with the concentration of the payload and the level of target inhibition within tumor tissues. Notably, when compared with T-DXd (trastuzumab deruxtecan, a HER2-directed ADC), HMPL-A251 demonstrated comparable or even superior efficacy at similar doses across most tested models.
Importantly, the anticipated payload-related toxicities are expected to be minimal, as the plasma exposure of the free payload is significantly lower than that of HMPL-251, maintaining a mass ratio of less than 1:500,000.
“We are thrilled to present the progress of HMPL-A251, the inaugural candidate from our ATTC platform,” stated Dr. Michael Shi, Head of R&D and Chief Medical Officer of HUTCHMED. “This therapy signifies a substantial advancement in overcoming the limitations associated with toxin-based ADCs and the narrow therapeutic window of systemic PAM inhibitors. By integrating selective PI3K/PIKK inhibition with targeted HER2 therapy, HMPL-A251 achieves significant anti-tumor effects while preserving a favorable safety profile.”
HUTCHMED plans to commence global clinical trials for HMPL-A251 towards the end of 2025, with additional Investigational New Drug (IND) filings for other ATTC candidates anticipated in 2026.
About the ATTC platform
The Antibody-Targeted Therapy Conjugate platform from HUTCHMED embodies a next-generation strategy in precision oncology. This approach combines monoclonal antibodies with proprietary small-molecule inhibitor payloads to deliver dual mechanisms of action. Unlike conventional cytotoxin-based ADCs, ATTCs integrate targeted therapies to produce synergistic anti-tumor effects and sustained responses in preclinical settings, exceeding the efficacy and safety of standalone antibody or small-molecule inhibitor components.
With over two decades of expertise in targeted therapies, this platform facilitates the development of drug candidates for various cancer types. By utilizing antibody-guided delivery and specific payload release at tumor sites, ATTCs enhance tumor accessibility while minimizing off-target toxicity. This novel approach addresses the challenges faced by traditional small-molecule inhibitors, ensuring safer long-term applications and promoting combinations with chemotherapy and immunotherapy, thereby unlocking potential for early-line treatments.
About HUTCHMED
HUTCHMED is a pioneering biopharmaceutical company at the commercial stage, dedicated to discovering, developing, and commercializing targeted therapies and immunotherapies for cancer and immunological diseases. Since its inception, the company has focused on advancing drug candidates from in-house discovery to global patients, with its first three medicines available in China and the initial product also receiving approval in international markets, including the United States, Europe, and Japan.
For more information, please visit: www.hutch-med.com or follow us on LinkedIn.
This press release contains forward-looking statements as defined by the “safe harbor” provisions of the US Private Securities Litigation Reform Act of 1995. These statements reflect HUTCHMED”s current expectations regarding future events, including therapeutic potential, clinical development, and regulatory approvals. Risks and uncertainties may impact the actual outcomes, and investors are advised to consider these factors.
For investor inquiries, please contact: +852 2121 8200 or [email protected].
For media inquiries, please reach out to FTI Consulting at +44 20 3727 1030 or [email protected].
