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Updated: Mar 22, 2026
Analyzing Tumor and Tissue Distribution of Target Antigen Specific Therapeutic Antibody
Published on: May 16, 2020
SIRPα-Antibody Fusion Proteins Selectively Bind and Eliminate Dual Antigen-Expressing Tumor Cells
Emily C Piccione1, Silvia Juarez1, Serena Tseng1
1Division of Hematology, Department of Medicine, Cancer Institute, and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, California.
Purpose:
CD47 is highly expressed on a variety of tumor cells. The interaction of CD47 with signal regulatory protein alpha (SIRPα), a protein on phagocytic cells, transmits a "don't eat me" signal that negatively regulates phagocytosis. CD47-SIRPα antagonists enable phagocytosis by disrupting the inhibitory signal and can synergize with Fc-mediated pro-phagocytic signals for potent elimination of tumor cells. A potential limitation of therapeutic CD47-SIRPα antagonists is that expression of CD47 on normal cells may create sites of toxicity or an "antigen sink." To overcome these limitations and address selective tumor targeting, we developed SIRPabodies to improve the therapeutic benefits of CD47-SIRPα blockade specifically toward tumor.
Experimental Design:
SIRPabodies were generated by grafting the wild-type SIRPα either to the N-terminus or to the C-terminus of the heavy chain of rituximab. Selective tumor binding was tested using CFSE-labeled human primary CLL cells in the presence of 20-fold excess of human RBCs. NSG mice were transplanted with Raji-luciferase cells and were assigned to controls versus SIRPabody treatment. Cynomolgus nonhuman primates were administered a single intravenous infusion of SIRPabody at 3, 10, or 30 mg/kg.
Results:
SIRPabodies selectively bound to dual antigen-expressing tumor cells in the presence of a large antigen sink. SIRPabody reduced tumor burden and extended survival in mouse xenograft lymphoma models. SIRPabody caused no significant toxicity in nonhuman primates.
Conclusions:
These findings establish SIRPabodies as a promising approach to deliver the therapeutic benefit of CD47-SIRPα blockade specifically toward tumor cells. SIRPabodies may be applied to additional cancer types by grafting SIRPα onto other tumor-specific therapeutic antibodies. Clin Cancer Res; 22(20); 5109-19. ©2016 AACR.
Insights
SIRPabodies selectively target tumor cells by blocking the CD47-SIRPα "don't eat me" signal, reducing tumor burden and extending survival without toxicity in primates.
Area of Science:
- Oncology
- Immunology
- Biotechnology
Background:
- CD47 on tumor cells interacts with SIRPα on phagocytes, inhibiting phagocytosis via a
- don't eat me
- signal.
- CD47-SIRPα antagonists can enhance anti-tumor immunity but face toxicity and antigen sink limitations due to normal cell expression.
Purpose of the Study:
- To develop SIRPabodies for targeted CD47-SIRPα blockade, overcoming limitations of traditional antagonists.
- To improve selective tumor targeting and therapeutic efficacy of CD47-SIRPα pathway inhibition.
Main Methods:
- SIRPabodies were engineered by fusing SIRPα to rituximab.
- Selective tumor binding was assessed using chronic lymphocytic leukemia (CLL) cells and red blood cells (RBCs).
- Efficacy and toxicity were evaluated in mouse lymphoma xenograft models and nonhuman primates.
Main Results:
- SIRPabodies demonstrated selective binding to tumor cells, even with a large antigen sink.
- Treatment with SIRPabodies reduced tumor burden and prolonged survival in mouse models.
- No significant toxicity was observed in nonhuman primates treated with SIRPabodies.
Conclusions:
- SIRPabodies represent a promising strategy for tumor-specific CD47-SIRPα blockade.
- This approach can be extended to other cancer types by conjugating SIRPα to different tumor-targeting antibodies.
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