CD47‐SIRPα blocking‐based immunotherapy: Current and prospective therapeutic strategies. Issue 8 (31st July 2022)

• Record Type: Journal Article
• Authors: Bouwstra, Renée; van Meerten, Tom; Bremer, Edwin
• Is Part Of: Clinical and translational medicine. Volume 12:Issue 8(2022)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-07-31
• Subjects: bispecific antibody -- CD47 -- immunotherapy -- patient selection -- tumour selective; Clinical medicine -- Periodicals; Medicine, Experimental -- Periodicals; Medical innovations -- Periodicals; Molecular biology -- Periodicals; Pathology, Molecular -- Periodicals; 616.027
• DOI: 10.1002/ctm2.943
• Languages: English
• ISSNs: 2001-1326

Abstract

Abstract: Background: The CD47‐signal regulatory protein alpha (SIRPα) 'don't eat me' signalling axis is perhaps the most prominent innate immune checkpoint to date. However, from initial clinical trials, it is evident that monotherapy with CD47‐SIRPα blocking has a limited therapeutic effect at the maximum tolerated dose. Furthermore, treatment is associated with severe side effects, most notably anaemia, that are attributable to the ubiquitous expression of CD47. Nevertheless, promising clinical responses have been reported upon combination with the tumour‐targeting antibody rituximab or azacytidine, although toxicity issues still hamper clinical application. Main body: Here, we discuss the current state of CD47‐SIRPα blocking therapy with a focus on limitations of current strategies, such as depletion of red blood cells. Subsequently, we focus on innovations designed to overcome these limitations. These include novel antibody formats designed to selectively target CD47 on tumour cells as well as tumour‐targeted bispecific antibodies with improved selectivity. In addition, the rationale and outcome of combinatorial approaches to improve the therapeutic effect of CD47 blockade are discussed. Such combinations include those with tumour‐targeted opsonizing antibodies, systemic therapy, epigenetic drugs, other immunomodulatory T‐cell‐targeted therapeutics or dual immunomodulatory CD47 bispecific antibodies. Conclusion: With these advances in the design of CD47‐SIRPα‐targeting therapeutic strategies and increasing insight into the mechanism of action of this innate checkpoint, including the role of adaptive immunity, further advances in the clinical application of this checkpoint can be anticipated. Abstract : CD47‐SIRPα blocking has met with several challenges in clinical application including lack of therapeutic effect and toxicity. Novel (bispecific) formats can increase tumor‐selectivity and reduced toxicity of CD47‐SIRPα‐based immunotherapy. Combination strategies improve efficacy of CD47‐SIRPα‐based immunotherapy. Increasing insight into the mechanism‐of‐action, including the role of adaptive immunity and timing can bring further advances in clinical application.