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A human antibody specific for SIRPα reprograms macrophages and promotes antibody mediated anti-cancer activity
Keifer G Kurtz1,2, Irina Lebedeva3, Stephanie A Pierre1,4
1Molecular Pharmacology Program, Sloan Kettering Institute, New York, United States of America.
Abstract:
Several T cell immune checkpoint blockade therapies have shown initial successes in multiple cancers. However, significant issues remain, including tumor relapse, severe toxicities, and a lack of efficacy in most patients. SIRPα, commonly known as the "do not eat me signal", is a monocyte checkpoint cell surface protein. Agents that block the interaction of CD47 with SIRPα have recently shown clinical success in combination with monoclonal antibody therapy to potentiate macrophage phagocytosis of tumors. However, significant toxicities and logistical issues are associated with CD47-targeted agents due to the expression of CD47 on all human cells. In contrast, SIRPα has expression limited to myelomonocytic cells, meaning highly specific SIRPα blocking agents might reduce these toxicities and avoid the target antigen sink. Herein, we generated a high affinity and highly specific SIRPα-targeting monoclonal antibody, F05, that has enhanced SIRPα binding and reduced SIRPβ and SIRPγ binding capacity when compared to other available SIRPα antibodies. Furthermore, we show F05 reprograms immunosuppressive macrophages toward a phagocytic profile in vitro. F05 demonstrated efficacy in solid tumor animal models, providing a rationale for further development of the antibody.
Insights
A novel antibody targeting SIRPα (Signal Regulatory Protein Alpha) shows promise for cancer therapy. This specific SIRPα blockade may reduce toxicities associated with current treatments, offering a new avenue for improving cancer immunotherapy efficacy.
Area of Science:
- Immunology
- Oncology
- Drug Development
Background:
- T cell immune checkpoint inhibitors show promise but face challenges like tumor relapse and toxicity.
- CD47-SIRPα blockade enhances anti-tumor immunity but causes significant toxicities due to CD47's broad expression.
- SIRPα's restricted expression on myeloid cells offers a potential for more targeted therapies.
Purpose of the Study:
- To develop a highly specific SIRPα-targeting monoclonal antibody with improved binding characteristics.
- To evaluate the efficacy of the novel antibody in reprogramming macrophages and treating solid tumors.
Main Methods:
- Generation of a high-affinity, highly specific SIRPα monoclonal antibody (F05).
- Assessment of F05 binding to SIRPα, SIRPβ, and SIRPγ.
- In vitro evaluation of F05's ability to reprogram immunosuppressive macrophages.
- In vivo testing of F05 efficacy in solid tumor animal models.
Main Results:
- F05 exhibits enhanced binding to SIRPα with reduced binding to SIRPβ and SIRPγ compared to existing antibodies.
- F05 effectively reprograms immunosuppressive macrophages to a phagocytic phenotype in vitro.
- F05 demonstrates significant efficacy in preclinical solid tumor models.
Conclusions:
- F05 represents a promising therapeutic candidate for cancer immunotherapy due to its specificity and efficacy.
- Targeting SIRPα with agents like F05 may offer a safer and more effective approach compared to CD47 blockade.
- Further development of F05 is warranted for its potential clinical application in cancer treatment.
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