SIRP alpha antagonist (BI 765063)

SIRP alpha antagonist (BI 765063)

SIRPα 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 tumor microenvironment.1,2

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

Role of SIRPα

Myeloid cells are an important immune cell type in many solid tumors and their presence in a tumor 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 tumor microenvironment by inhibiting phagocytosis of tumor 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 tumor microenvironment.1

Owing to its mechanism of action, BI 765063 may have particular clinical potential in solid tumors 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 tumor models have demonstrated the clinical benefit of SIRPα antagonist monotherapy, but suggest that clinical outcomes may be enhanced through combination therapy with an adaptive PD-1 immune checkpoint inhibitor, or with a co-stimulatory 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 ezabenlimab (BI 754091) in a Phase I trial involving patients with solid tumors.3,4 

SIRPα antagonist (BI 765063) clinical trials

SIRPα, signal regulatory protein α.
Trial number Phase Treatment Patient population Status

NCT039902334 (1443.1)

I

BI 765063 (monotherapy and in combination with ezabenlimab [BI 754091])

Patients with advanced solid tumors that have a SIRPα polymorphism, including at least one V1 allele

Recruiting

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References

1

Boehringer Ingelheim. Data on file.

2

Barclay AN, et al. Nat Rev Immunol 2006;6(6):457–64

3

Boehringer Ingelheim and OSE Immunotherapeutics. Press release. https://ose-immuno.com/wp-content/uploads/2019/06/EN_190617_BI-765063_FirstPatientDosed.pdf (Accessed: February 2021).

4

ClinicalTrials.gov. NCT03990233. https://clinicaltrials.gov/ct2/show/NCT03990233 (Accessed: February 2021).

5

Gauttier V, et al. Cancer Res 2018;78(13 Suppl.): Abstract 1684.

6

Weiskopf K. Eur J Cancer 2017;76:100–9.

7

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.

 

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Page last updated: March 2021