Tolerating CD47

Abstract

Cluster of differentiation 47 (CD47) occupies the outer membrane of human cells, where it binds to soluble and cell surface receptors on the same and other cells, sculpting their topography and resulting in a pleiotropic receptor‐multiligand interaction network. It is a focus of drug development to temper and accentuate CD47‐driven immune cell liaisons, although consideration of on‐target CD47 effects remain neglected. And yet, a late clinical trial of a CD47‐blocking antibody was discontinued, existent trials were restrained, and development of CD47‐targeting agents halted by some pharmaceutical companies. At this point, if CD47 can be exploited for clinical advantage remains to be determined. Herein an airing is made of the seemingly conflicting actions of CD47 that reflect its position as a junction connecting receptors and signalling pathways that impact numerous human cell types. Prospects of CD47 boosting and blocking are considered along with potential therapeutic implications for autoimmune diseases and cancer.

Blockade of SIRPα-CD47 axis by anti-SIRPα antibody enhances anti-tumor activity of DXd antibody-drug conjugates

“…Further, Sim J et al showed that anti-human SIRPα Ab clone 21 enhanced cetuximab-induced ADCP both with and without Fc fragment of the anti-SIRPα Ab [ 38 ], suggesting the blocking of SIRPα-CD47 interaction is sufficient to enhance ADCP. It is well-known that SIRPα-CD47 interaction occurs both in trans and cis orientation, the latter occurs in monocytes and other myeloid cells where both SIRPα and CD47 are expressed on the same cell surface [ 9 , 19 , 39 ]. Despite the potential cis-interaction, DS-1103a successfully bound to human macrophages and enhanced the ADCP of Dato-DXd and T-DXd ( Fig 2B and 6A ).…”

“…Further studies are needed to address the difference between anti-CD47 and anti-SIRPα Abs in the T cell dependency. Apart from its role in suppressing macrophages, CD47 has been found to have various other functions [ 9 ]. For instance, CD47 has shown to be essential for the survival of T cells in mouse and human chimeric-antigen receptor T cells [ 47 , 48 ].…”

“…One promising pathway is signal regulatory protein alpha (SIRPα)-CD47 interaction between myeloid and tumor cells [ 5 , 6 ]. SIRPα is a type-I transmembrane protein expressed on various myeloid cells and binds to CD47, a pleiotropic cell surface protein [ 7 – 9 ]. While CD47 interacts with various proteins in the immune system such as thrombospondin-1 and integrins [ 9 ], SIRPα-CD47 interaction has been shown to inhibit cellular activation of macrophages such as phagocytosis [ 7 , 10 , 11 ], which is the so called “Don’t-eat-me” signal.…”

“…SIRPα is a type-I transmembrane protein expressed on various myeloid cells and binds to CD47, a pleiotropic cell surface protein [ 7 – 9 ]. While CD47 interacts with various proteins in the immune system such as thrombospondin-1 and integrins [ 9 ], SIRPα-CD47 interaction has been shown to inhibit cellular activation of macrophages such as phagocytosis [ 7 , 10 , 11 ], which is the so called “Don’t-eat-me” signal. In the tumor microenvironment, CD47-SIRPα axis is exploited by cancer cells to suppress the myeloid cell function [ 12 ].…”

Metabolic reprograming mediated by tumor cell-intrinsic type I IFN signaling is required for CD47-SIRPα blockade efficacy

“…However, while CD47-SIRPα blockade showed impressive efficacy in some animal models, clinical efficacy is limited and especially poor for solid tumors 7 , 14 , 15 . Just recently, a late clinical trial of a CD47-blocking antibody was discontinued, and some other trials were also restrained 16 . Thus, at this time point, whether CD47-SIRPα blockade strategy can still be exploited for clinical advantage is facing a challenge.…”