Anti‐human SIRPα antibody is a new tool for cancer immunotherapy

Abstract

Interaction of signal regulatory protein α (SIRPα) expressed on the surface of macrophages with its ligand CD47 expressed on target cells negatively regulates phagocytosis of the latter cells by the former. We recently showed that blocking Abs to mouse SIRPα enhanced both the Ab‐dependent cellular phagocytosis (ADCP) activity of mouse macrophages for Burkitt's lymphoma Raji cells opsonized with an Ab to CD20 (rituximab) in vitro as well as the inhibitory effect of rituximab on the growth of tumors formed by Raji cells in nonobese diabetic (NOD)/SCID mice. However, the effects of blocking Abs to human SIRPα in preclinical cancer models have remained unclear given that such Abs have failed to interact with endogenous SIRPα expressed on macrophages of immunodeficient mice. With the use of Rag2−/−γc −/− mice harboring a transgene for human SIRPα under the control of human regulatory elements (hSIRPα‐DKO mice), we here show that a blocking Ab to human SIRPα significantly enhanced the ADCP activity of macrophages derived from these mice for human cancer cells. The anti‐human SIRPα Ab also markedly enhanced the inhibitory effect of rituximab on the growth of tumors formed by Raji cells in hSIRPα‐DKO mice. Our results thus suggest that the combination of Abs to human SIRPα with therapeutic Abs specific for tumor antigens warrants further investigation for potential application to cancer immunotherapy. In addition, humanized mice, such as hSIRPα‐DKO mice, should prove useful for validation of the antitumor effects of checkpoint inhibitors before testing in clinical trials.

CD47‐signal regulatory protein α signaling system and its application to cancer immunotherapy

“…This Ab to human SIRPα also increased the phagocytic activity of macrophages from hSIRPα Tg mice, but not that of those from Rag2 −/− Il2rg −/− mice, as measured in vitro with human cancer cells opsonized with Abs to tumor antigens, suggesting that the interaction of human CD47 on human cancer cells with human SIRPα on mouse macrophages generates an inhibitory signal for macrophage ADCP. Moreover, in both of these genetically modified mouse models transplanted with human tumor cells, the antitumor effects of the Abs to human SIRPα were found to be dependent, at least in part, on macrophages . These mice may thus serve as models for preclinical validation of Abs to human SIRPα in cancer immunotherapy (Figure ).…”

“…In this regard, a blocking Ab to human SIRPα was recently shown to promote the antitumor effects of rituximab and of vorsetuzumab (an Ab to CD70) in human tumor-bearing Rag2 −/− Il2rg −/− immunodeficient mice in which the DNA sequence encoding the extracellular domain of mouse SIRPα was replaced with the corresponding human sequence (hSIRPα KI mice) 63,64. With the use of Rag2 −/− Il2rg −/− mice expressing human SIRPα under the control of human regulatory elements (hSIRPα Tg mice),65 we also showed that a blocking Ab to human SIRPα enhanced the inhibitory effect of rituximab on the growth of tumors formed by s.c. injected Raji cells 66. This Ab to human SIRPα also increased the phagocytic activity of macrophages from hSIRPα Tg mice, but not that of those from Rag2 −/− Il2rg −/− mice, as measured in vitro with human cancer cells opsonized with Abs to tumor antigens, suggesting that the interaction of human CD47 on human cancer cells with human SIRPα on mouse macrophages generates an inhibitory signal for macrophage ADCP.…”

CSF1R‐ and SHP2‐Inhibitor‐Loaded Nanoparticles Enhance Cytotoxic Activity and Phagocytosis in Tumor‐Associated Macrophages

“…Phase I clinical trials involving single agent administration of monoclonal antibodies blocking the CD47‐SIRPα include humanized CD47‐blocking agents such as Hu5F9‐G4, CC‐90002, and SIRPα protein variants such as TTI‐621 and ALX148 . Clinical trial evidence increasingly points to limited anticancer efficacies associated with these therapies owing to limitations such as subpar binding affinities of SIRPα antibodies and systemic toxicities involving anti‐CD47‐based therapies …”

The Immunotherapeutic Effect of SIRPα-Silenced DCs against Cervical Cancer

“…As the reports that the SIRPα antibody markedly enhanced the inhibitory effect of rituximab on the growth of tumors formed by Raji cells [27], KWAR23 as one anti-SIRPα antibody was also a promising candidate for combination therapies to facilitate rapid and complete elimination of tumors [28]. These studies suggested that inhibiting SIRPα may also be more effective in treating cancers.…”