Our SIRPα antagonist BI 770371 with or without the PD-1 inhibitor ezabenlimab (BI 754091)* is in a Phase I, dose-escalation and -expansion trial in patients with advanced solid tumors.^2,3 BI 770371 is also being investigated in a Phase Ib trial in combination with pembrolizumab (a PD-1 inhibitor) with or without cetuximab (an epidermal growth factor receptor inhibitor) in patients with metastatic or recurrent HNSCC.⁴

SIRPα antagonist clinical trials

SIRPα antagonist mechanism of action

Disruption of the SIRPα/CD47 axis may restore the immune functions of myeloid cells in the tumor microenvironment by increasing the phagocytosis of cancer cells. This enhanced phagocytosis facilitates increased antigen uptake and presentation that promote T-cell activation and T-cell migration. Thereby, SIRPα inhibition may lead to sustained anti-tumor T cell responses by linking both the innate and adaptive immune systems.^5,6

SIRPα antagonist mechanism of action⁷

Combination therapy

Preclinical studies in mouse tumor models have demonstrated the benefit of SIRPα antagonist monotherapy. Moreover, additional studies indicate that immune function may be enhanced through combination therapy with a PD-1 inhibitor, which would facilitate dual activation of innate and acquired immunity.^6,8

SIRPα is a negative regulatory protein expressed on the surface of macrophages and other myeloid immune cells.⁵ The interaction between SIRPα and CD47 serves as a myeloid-specific immune checkpoint, inhibiting activation of macrophages and migration of other myeloid cells such as monocytes, polymorphonuclear cells, and dendritic cells.^6,9

CD47 is a ubiquitous cell-surface protein that is highly expressed on some cancer cells, acting as a “don’t-eat-me” signal.^5,10 BI 770371 is designed to target the SIRPα receptor on the surface of myeloid cells, blocking the interaction between SIRPα and CD47.¹

*This is an investigational compound and has not been approved. Its safety and efficacy have not been established. 
CD47, cluster of differentiation 47; HNSCC, head and neck squamous cell carcinoma; PD-1, programmed cell death protein-1; SIRPα, signal regulatory protein alpha.