Anti-HER2 Antibody-PI3K/PIKK Inhibitor Conjugate HMPL-A251

**Semantic type:** Pharmacologic Substance

**Definition:** An antibody-targeted therapy conjugate (ATTC) composed of a humanized immunoglobulin G1 (IgG1) monoclonal antibody directed against the receptor tyrosine kinase human epidermal growth factor receptor 2 (EGFR2; HER2; ErbB2) conjugated, via a hydrophilic cleavable linker, to a phosphatidylinositol 3-kinase (PI3K)/PI3K-related kinase (PIKK) inhibitor, with potential antineoplastic activity. Upon administration of anti-HER2 antibody-PI3K/PIKK inhibitor conjugate HMPL-A251, the anti-HER2 antibody moiety targets and binds to HER2 expressed on tumor cells. Upon binding, internalization, and linker cleavage, the PI3K/PIKK inhibitor is released, and inhibits PI3K/PIKK in the PI3K/Akt (protein kinase B)/mammalian target of rapamycin (mTOR) pathway. This results in both apoptosis and growth inhibition in HER2-expressing tumor cells. In addition, HMPL-A251 induces bystander killing of HER2-negative tumor cells. HER2, a receptor tyrosine kinase overexpressed on a variety of tumor cell types, plays an important role in tumor cell proliferation and tumor vascularization. Dysregulation of the PI3K/Akt/mTOR pathway is often found in solid tumors and results in the promotion of tumor cell growth, survival, and resistance to chemo- and radio-therapy.

**Synonyms:** - HER2-directed ATTC HMPL-A251 - HER2-directed Antibody-targeted Therapy Conjugate HMPL-A251 - HMPL A251 - HMPL-A251 - HMPLA251