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SIRP alpha antagonist (BI 765063)

BI 765063: a SIRPα antagonist

BI 765063* is a first-in-class myeloid checkpoint inhibitor.1 By blocking the interaction between myeloid cell surface molecule signal-regulatory protein alpha (SIRPα) and cluster of differentiation 47 (CD47), SIRPα inhibits suppression of the innate immune system and restores the immune functions of myeloid cells in the tumour microenvironment.1,2

Clinical trials (monotherapy and combination therapy): BI 765063 is currently undergoing investigation as a monotherapy and in combination with anti-programmed cell death protein-1 (PD-1) immune checkpoint inhibitor (ICI; BI 754091) in a Phase I trial involving patients with solid tumours.3,4

Role of SIRPα

Myeloid cells are an important immune cell type in many solid tumours and their presence in a tumour is often associated with poor prognosis.4 Members of the SIRP family are mainly expressed on the surface of myeloid cells and contribute to the complex interaction between membrane proteins and leukocytes that regulate the body’s innate immune response.2,5

SIRPα is an inhibitory member of the SIRP family that binds to the receptor CD47. CD47 is highly expressed in many different types of cancer and transduces inhibitory signals through SIRPα on macrophages and other myeloid cells.2,6 The SIRPα/CD47 axis is a critical regulator of myeloid cell activation and serves as a myeloid-specific immune checkpoint.6

About BI 765063

Mechanism of action

The interaction of SIRPα with CD47 contributes to immune-suppression in the tumour microenvironment by inhibiting phagocytosis of tumour cells, downregulation of antigen-presenting cells and maintenance of myeloid-derived suppressor cells.1,5 BI 765063 blocks the interaction of SIRPα with CD47, thereby restoring the immune functions of myeloid cells in the tumour microenvironment.1

Owing to its mechanism of action, BI 765063 may have particular clinical potential in solid tumours with higher myeloid cell infiltration (e.g. non-small cell lung cancer, colorectal cancer).7

SIRPα antagonist mechanism of action1,5,6

SIRPα antagonist mechanism of action

SIRPα, signal-regulatory protein alpha; CD47, cluster of differentiation.

Combination therapy

Preclinical studies in murine tumour models have demonstrated the clinical benefit of SIRPα antagonist monotherapy, but suggest clinical outcomes may be enhanced through combination therapy with an adaptive PD-1 ICI, or with a costimulatory agent (such as anti-4-1BB monoclonal antibody), to provide dual activation of innate and acquired immunity.5,6

Clinical development

BI 765063 is currently undergoing investigation as a monotherapy and in combination with PD-1 blockade (BI 754091) in a Phase I trial involving patients with solid tumours.3,4

Solid tumours4

Clinical trial of a SIRPα antagonist in patients with solid tumours

AEs, adverse events; AESI, AEs of special interest (AESIs); AUC, area under the curve; Cmax, maximum (or peak) serum concentration; DLT, dose-limiting toxicities (DLTs); irAEs, immune related AEs; MDT, maximum tolerated dose; ORR, objective response rate (ORR); RO, receptor occupancy; SAEs, serious AEs; SIRPα, signal regulatory protein α.

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Boehringer Ingelheim. Data on file.


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Cotechini T, et al. Cancer J. 2015;21:343–50.

*This is an investigational compound and has not been approved. Its safety and efficacy have not been established.

© 2019 Boehringer Ingelheim International GmbH. All rights reserved.

Page last updated: December 2019