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Targeting CD47: the achievements and concerns of current studies on cancer immunotherapy
Yuting Huang1, Yuchi Ma2, Peng Gao3
1Department of Immunology, Tianjin Key Laboratory of Cellular and Molecular Immunology, Key Laboratory of Educational Ministry of China, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300071, China.
Abstract:
Targeting CD47 is in the spotlight of cancer immunotherapy. Blocking CD47 triggers the recognition and elimination of cancer cells by the innate immunity. There are three CD47 antagonists in phase I clinical trials, but their potential efficacies are highly controversial. We raise our concern that NOD-based xenograft hosts tend to overestimate, while syngeneic mouse models could substantially underestimate the efficacy of anti-CD47 therapy. Such discrepancy may be resulted from specific reagent that alters CD47 clustering, and the highly variable avidities of interspecies and intraspecies CD47-SIRPα interaction. This problem can be addressed by alternative animal models for better recapitulation of human CD47-SIRPα interaction. Both fragment crystallizable (Fc) fragment-dependent effects, like antibody-dependent cell-mediated cytotoxicity (ADCC), and Fc-independent CD47 intrinsic functions are involved in anti-CD47 therapy. The latter may be SIRPα-dependent or SIRPα-independent, such as the case of calreticulin. It has not reached a consensus which of the factors predominate the process, but the answer to this question will determine the optimal pharmaceutical and clinical design of CD47 targeting strategies.
Insights
Cancer immunotherapy targeting CD47 shows controversial efficacy. Animal models may inaccurately predict anti-CD47 therapy outcomes due to species-specific interactions, necessitating better models for clinical success.
Area of Science:
- Immunology
- Cancer Biology
- Pharmacology
Background:
- CD47 (Integrin alpha-Inhibotory)-targeted cancer immunotherapy is a promising field.
- Blocking CD47 enhances innate immune cell recognition and elimination of cancer cells.
- Current clinical trials show controversial efficacy for CD47 antagonists.
Purpose of the Study:
- To address the discrepancy in anti-CD47 therapy efficacy observed in different animal models.
- To highlight the impact of interspecies and intraspecies CD47-SIRPα interactions on therapeutic outcomes.
- To advocate for alternative animal models that better recapitulate human CD47-SIRPα interactions.
Main Methods:
- Analysis of existing data on CD47 antagonist efficacy in NOD-based xenograft and syngeneic mouse models.
- Evaluation of reagent-specific effects on CD47 clustering.
- Assessment of interspecies and intraspecies CD47-SIRPα binding avidities.
- Consideration of Fc-dependent and Fc-independent mechanisms in anti-CD47 therapy.
Main Results:
- NOD-based xenograft models may overestimate anti-CD47 therapy efficacy.
- Syngeneic mouse models may underestimate anti-CD47 therapy efficacy.
- Discrepancies are attributed to reagent-specific CD47 clustering and variable CD47-SIRPα avidities.
- Both Fc-dependent (e.g., ADCC) and Fc-independent (e.g., calreticulin exposure) mechanisms contribute to therapy.
Conclusions:
- Standard animal models present limitations in predicting human anti-CD47 therapy response.
- Development of alternative models is crucial for accurate efficacy assessment.
- Understanding the predominant mechanisms (Fc-dependent vs. Fc-independent) is key for optimizing CD47-targeting strategies.
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