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

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.

Nanomedicine Remodels Tumor Microenvironment for Solid Tumor Immunotherapy

“…In addition to the well-known T cells, innate immune cells also express an array of immune checkpoints, including Siglec-9, SIRPα, TIM-3, etc. Inhibiting or downregulating these immune checkpoints can activate their antitumor responses.…”

Nanomedomics

“…Atherosclerosis is a major contributor to heart attack and stroke. − Atherosclerotic plaque can upregulate antiphagocytic CD47 signaling, which would block immune clearance by macrophages through the CD47-SIRPα-SHP-1 signaling axis and facilitate sustained plaque expansion. − However, antibody-based systemic therapies that block CD47 signaling might exert adverse effects on healthy tissues, such as eliminating surrounding red blood cells to generate ischemia . Safety concerns have thus become a key barrier to the clinical translation of such drugs.…”

Research Progress of Bioinspired Nanostructured Systems for the Treatment of Ocular Disorders

“…Red blood cell hitchhiking (RH), a new drug delivery platform developed through the combination of nanocarrier and red blood cells, has dramatically changed the behavior of nanocarriers in vivo and has been widely used in the treatment of disease [ 55 ]. CD47, which is expressed on the surface of the red blood cells, can send a “do not eat me” signal through binding with signal regulatory protein alpha (SIRPα) on macrophages, and thereby present a long cycle life [ 56 , 57 ]. Ding et al [ 58 ] prepared the RH through adsorbing the methylprednisolone sodium succinate (MPSS) loaded chitosan nanoparticles on the surface of red blood cells (RBC-MPSS-CSNPs) via an electrostatic interaction to relieve the side effects caused by long-term administration of high doses of glucocorticoids.…”