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Published on: November 12, 2019
A bispecific antibody targeting CD47 and CD20 selectively binds and eliminates dual antigen expressing lymphoma cells
Emily C Piccione1, Silvia Juarez, Jie Liu
1a Department of Medicine; Division of Hematology, Cancer Institute; and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University , Stanford , CA , USA.
Abstract:
Agents that block the anti-phagocytic signal CD47 can synergize with pro-phagocytic anti-tumor antigen antibodies to potently eliminate tumors. While CD47 is overexpressed on cancer cells, its expression in many normal tissues may create an 'antigen sink' that could minimize the therapeutic efficacy of CD47 blocking agents. Here, we report development of bispecific antibodies (BsAbs) that co-target CD47 and CD20, a therapeutic target for non-Hodgkin lymphoma (NHL), that have reduced affinity for CD47 relative to the parental antibody, but retain strong binding to CD20. These characteristics facilitate selective binding of BsAbs to tumor cells, leading to phagocytosis. Treatment of human NHL-engrafted mice with BsAbs reduced lymphoma burden and extended survival while recapitulating the synergistic efficacy of anti-CD47 and anti-CD20 combination therapy. These findings serve as proof of principle for BsAb targeting of CD47 with tumor-associated antigens as a viable strategy to induce selective phagocytosis of tumor cells and recapitulate the synergy of combination antibody therapy. This approach may be broadly applied to cancer to add a CD47 blocking component to existing antibody therapies.
Insights
Bispecific antibodies targeting CD47 and CD20 enhance cancer cell phagocytosis. This approach overcomes CD47 antigen sink issues, improving therapeutic efficacy for non-Hodgkin lymphoma and potentially other cancers.
Area of Science:
- Immunology
- Oncology
- Biotechnology
Background:
- CD47 blockade synergizes with anti-tumor antibodies to enhance phagocytosis.
- CD47 overexpression on normal tissues can limit CD47-blocking agent efficacy via an 'antigen sink' effect.
- CD20 is a validated therapeutic target for non-Hodgkin lymphoma (NHL).
Purpose of the Study:
- To develop bispecific antibodies (BsAbs) co-targeting CD47 and CD20.
- To engineer BsAbs with reduced CD47 affinity but retained CD20 binding for tumor cell selectivity.
- To evaluate the efficacy of these BsAbs in preclinical models of NHL.
Main Methods:
- Design and development of CD47xCD20 bispecific antibodies with differential affinities.
- In vitro characterization of BsAb binding to CD47 and CD20.
- In vivo efficacy studies in human NHL-engrafted mouse models.
Main Results:
- BsAbs selectively bound to CD20-expressing tumor cells, mediating phagocytosis.
- Treatment with BsAbs significantly reduced lymphoma burden and extended survival in mice.
- BsAb therapy recapitulated the synergistic efficacy of combined anti-CD47 and anti-CD20 antibodies.
Conclusions:
- Bispecific antibody targeting of CD47 and tumor-associated antigens is a viable strategy for selective tumor cell phagocytosis.
- This approach effectively mimics combination antibody therapy synergy.
- This bispecific antibody strategy holds broad potential for enhancing existing cancer antibody therapies.
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