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SIRPα Antagonists

Humanized IgG monoclonal antibodies

BI 765063 and BI 770371: SIRPα antagonists

Our signal-regulatory protein alpha (SIRPα) program includes 2 monoclonal antibodies.1 BI 765063* is an IgG4Pro mAb that recognizes only the V1 variant of SIRPα, while BI 770371* is an IgG1 mAb that recognizes both the V1 and V2 variants of SIRPα.1 By blocking the interaction between SIRPα and cluster of differentiation 47 (CD47), SIRPα antagonism 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* and BI 770371* are currently undergoing investigation as monotherapy and in combination with ezabenlimab* (BI 754091), a programmed cell death protein-1 (PD-1) inhibitor, and with further compounds in Phase I trials involving patients with solid tumors as well as those with advanced squamous cell cancer of the head and neck (HNSCC), hepatocellular carcinoma (HCC), non-small cell lung carcinoma (NSCLC), or melanoma.3-7 

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

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.8 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.2,8

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.2,9 The SIRPα/CD47 axis is a critical regulator of myeloid cell activation and serves as a myeloid-specific immune checkpoint.9

About SIRPα antagonists

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.1,8 Our SIRPα antagonists block the interaction of SIRPα with CD47, thereby restoring the immune functions of myeloid cells in the tumor microenvironment.1 

SIRPα antagonist mechanism of action1,8-10

SIRPα-antagonist-mechanism-of-action

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

Watch the SIRPα antagonist mechanism of action animation

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.8,9

Clinical development

BI 765063 and BI 770371 are currently undergoing investigation as monotherapy and in combination with ezabenlimab (BI 754091), a programmed cell death protein-1 (PD-1) inhibitor, and with further compounds, in Phase I trials involving patients with solid tumors as well as those with advanced squamous cell cancer of the head and neck (HNSCC), hepatocellular carcinoma (HCC), non-small cell lung carcinoma (NSCLC), or melanoma.3-7 Initial results have shown that BI 765063 acts as an immunomodulator of the tumor microenvironment—consistent with preclinical findings and its mechanism of action.11

SIRPα antagonist clinical trials

Trial numberPhaseTreatmentPatient populationStatus

NCT03990233 (1443-0001)4,11

I

BI 765063 ± ezabenlimab (PD-1 inhibitor)

Advanced solid tumors that have a SIRPα polymorphism, including at least one V1 allele

Completed recruitment

NCT05249426 (1443-0002)6

I

BI 765063 ± ezabenlimab (PD-1 inhibitor) alone or with BI 836880, chemotherapy, or cetuximab

Recurrent/metastatic HNSCC or HCC

Completed recruitment

NCT05068102 (1443-0003)5

I

BI 765063 or BI 770371 in combination with ezabenlimab (PD-1 inhibitor)

Advanced HNSCC, NSCLC, or melanoma

Recruiting

NCT05327946 (1501-0001)7

I

BI 770371 ± ezabenlimab (PD-1 inhibitor)

Advanced solid tumors 

Recruiting 

HCC, hepatocellular carcinoma; HNSCC, head and neck squamous cell carcinoma; NSCLC, non-small cell lung carcinoma; SIRPα, signal regulatory protein α. 

You may also be interested in...

  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. https://ose-immuno.com/wp-content/uploads/2019/06/EN_190617_BI-765063_FirstPatientDosed.pdf Press release. (Accessed: February 2024).

  4. ClinicalTrials.gov. NCT03990233. https://clinicaltrials.gov/study/NCT03990233 (Accessed: February 2024).

  5. ClinicalTrials.gov. NCT05068102. https://clinicaltrials.gov/study/study/NCT05068102 (Accessed: February 2024).

  6. ClinicalTrials.gov. NCT05327946. https://clinicaltrials.gov/study/NCT05249426 (Accessed: March2024). 

  7. ClinicalTrials.gov. NCT05249426. https://clinicaltrials.gov/study/NCT05327946 (Accessed: February 2024).

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

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

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

  11. Champiat S, et al. AACR 2022. Poster 1993.

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