# CD47‐SIRPα blocking‐based immunotherapy: Current and prospective therapeutic strategies

## TL;DR

This paper reviews CD47-SIRPα immunotherapy, focusing on its current limitations and new strategies to improve its effectiveness and reduce side effects.

## Contribution

The paper highlights novel bispecific antibody formats and combination therapies to enhance tumor selectivity and efficacy of CD47-SIRPα blockade.

## Key findings

- CD47-SIRPα monotherapy has limited efficacy and causes significant toxicity, such as anemia.
- Combination therapies with rituximab or azacytidine show promise but still face toxicity challenges.
- Bispecific antibodies and tumor-targeted formats aim to increase selectivity and reduce off-target effects.

## Abstract

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.

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.

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.

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.

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.