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Tumor-Directed Blockade of CD47 with Bispecific Antibodies Induces Adaptive Antitumor Immunity
Elie Dheilly1, Stefano Majocchi2, Valéry Moine3
1Novimmune S.A., 14 chemin des Aulx, CH-1228 Geneva, Switzerland. elie.dheilly@epfl.ch.
Abstract:
CD47 serves as an anti-phagocytic receptor that is upregulated by cancer to promote immune escape. As such, CD47 is the focus of intense immuno-oncology drug development efforts. However, as CD47 is expressed ubiquitously, clinical development of conventional drugs, e.g., monoclonal antibodies, is confronted with patient safety issues and poor pharmacology due to the widespread CD47 "antigen sink". A potential solution is tumor-directed blockade of CD47, which can be achieved with bispecific antibodies (biAbs). Using mouse CD47-blocking biAbs in a syngeneic tumor model allowed us to evaluate the efficacy of tumor-directed blockade of CD47 in the presence of the CD47 antigen sink and a functional adaptive immune system. We show here that CD47-targeting biAbs inhibited tumor growth in vivo, promoting durable antitumor responses and stimulating CD8+ T cell activation in vitro. In vivo efficacy of the biAbs could be further enhanced when combined with chemotherapy or PD-1/PD-L1 immune checkpoint blockade. We also show that selectivity and pharmacological properties of the biAb are dependent on the affinity of the anti-CD47 arm. Taken together, our study validates the approach to use CD47-blocking biAbs either as a monotherapy or part of a multi-drug approach to enhance antitumor immunity.
Insights
Bispecific antibodies targeting CD47 effectively inhibit tumor growth and enhance immune responses, offering a promising strategy for cancer immunotherapy. This approach overcomes limitations of conventional CD47 drugs by focusing blockade on tumors.
Area of Science:
- Immunology
- Oncology
- Pharmacology
Background:
- CD47 is an immune checkpoint receptor overexpressed in cancer, facilitating immune evasion by preventing phagocytosis.
- Conventional CD47-targeting therapies face challenges due to ubiquitous CD47 expression, leading to safety concerns and the 'antigen sink' effect.
Purpose of the Study:
- To evaluate the efficacy of tumor-directed CD47 blockade using bispecific antibodies (biAbs) in a preclinical cancer model.
- To assess the potential of biAbs to overcome the CD47 'antigen sink' and enhance adaptive immune responses.
Main Methods:
- Utilized mouse CD47-blocking biAbs in a syngeneic tumor model.
- Investigated the impact of biAbs on tumor growth, antitumor immunity, and CD8+ T cell activation.
- Assessed combination therapy with chemotherapy or PD-1/PD-L1 blockade and evaluated the role of anti-CD47 arm affinity.
Main Results:
- CD47-targeting biAbs demonstrated significant inhibition of tumor growth in vivo, leading to durable antitumor responses.
- BiAbs stimulated CD8+ T cell activation in vitro and their efficacy was enhanced when combined with chemotherapy or immune checkpoint inhibitors.
- The affinity of the anti-CD47 arm influenced the selectivity and pharmacological profile of the biAbs.
Conclusions:
- Tumor-directed CD47 blockade with biAbs is a validated strategy to enhance antitumor immunity.
- BiAbs represent a viable monotherapy or combination therapy approach for cancer treatment, overcoming limitations of conventional agents.
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