Human Epidermal Growth Factor Receptor 2, Natural Killer Group 2 Member D, Fc Gamma Receptor IIIa, and Programmed Cell Death Protein 1 (HER2-NKG2D-CD16A-PD-1)

This target profile describes a multi-specific therapeutic approach that simultaneously addresses the Human Epidermal Growth Factor Receptor 2 (HER2; UniProt P04626), the activating receptors NKG2D (KLRK1; UniProt P26718) and CD16A (FCGR3A; UniProt P08637) on Natural Killer (NK) cells, and the Programmed Cell Death Protein 1 (PD-1; UniProt Q15116) checkpoint. HER2 is a member of the ErbB family of receptor tyrosine kinases and is a well-validated oncogenic driver in breast, gastric, and lung cancers (PubMed: 28115447). NKG2D and CD16A are potent activating receptors on NK cells; their co-engagement by multi-specific antibodies, such as Tri-specific NK cell Engagers (TriNKETs) like DF1001, facilitates the formation of an immunological synapse between the NK cell and the HER2-positive tumor cell, leading to targeted cytotoxicity (Dragonfly Therapeutics, 2023). PD-1 is an inhibitory receptor that, when bound by its ligands, suppresses T-cell and NK-cell activity, allowing for tumor immune evasion. By combining HER2-directed NK cell engagement with PD-1 blockade (e.g., using pembrolizumab), this strategy aims to maximize the recruitment and activation of the innate immune system while preventing the adaptive immune resistance typically mediated by the PD-1/PD-L1 pathway (ClinicalTrials.gov: NCT03548220). This combination is currently being explored in clinical trials to improve outcomes for patients with HER2-expressing solid tumors who are refractory to standard-of-care therapies.

Other names

HER2-NKG2D-CD16A-PD-1 complexDF1001 and PD-1 combinationHER2-targeting TriNKET and PD-1 checkpoint blockadeERBB2-KLRK1-FCGR3A-PDCD1 axis

Simultaneous engagement of NK cell activating receptors (NKG2D and CD16A) and the tumor antigen HER2 to induce antibody-dependent cellular cytotoxicity (ADCC) and NK-cell mediated lysis, combined with the blockade of the PD-1/PD-L1 inhibitory axis to prevent immune exhaustion and enhance anti-tumor durability.