Department of Hematology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Clin Transl Med. 2022 Aug;12(8):e943. doi: 10.1002/ctm2.943.
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-信号调节蛋白α（SIRPα）“别吃我”信号轴或许是迄今为止最突出的先天免疫检查点。然而，从最初的临床试验来看，在最大耐受剂量下，用 CD47-SIRPα 阻断进行单一疗法的治疗效果有限。此外，治疗还会引起严重的副作用，最明显的是贫血，这归因于 CD47 的广泛表达。然而，与肿瘤靶向抗体利妥昔单抗或阿扎胞苷联合使用时，已经报道了有前景的临床反应，尽管毒性问题仍然阻碍了临床应用。
在这里，我们讨论了 CD47-SIRPα 阻断治疗的现状，重点关注当前策略的局限性，例如红细胞耗竭。随后，我们专注于旨在克服这些限制的创新。这些创新包括旨在选择性地针对肿瘤细胞上的 CD47 的新型抗体形式，以及具有改善选择性的肿瘤靶向双特异性抗体。此外，还讨论了通过组合方法来提高 CD47 阻断治疗效果的原理和结果。这些组合包括与肿瘤靶向调理抗体、系统疗法、表观遗传药物、其他免疫调节 T 细胞靶向疗法或双重免疫调节 CD47 双特异性抗体的组合。
随着 CD47-SIRPα 靶向治疗策略设计的这些进展以及对这种先天检查点作用机制的深入了解，包括适应性免疫的作用，预计该检查点的临床应用将取得进一步的进展。
