Anti-human SIRP antibody is a new tool for cancer immunotherapy

Interaction of signal regulatory protein (SIRP) 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 SIRP 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) invitro 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 SIRP in preclinical cancer models have remained unclear given that such Abs have failed to interact with endogenous SIRP expressed on macrophages of immunodeficient mice. With the use of Rag2(c)(-/-)(-/-) mice harboring a transgene for human SIRP under the control of human regulatory elements (hSIRP-DKO mice), we here show that a blocking Ab to human SIRP significantly enhanced the ADCP activity of macrophages derived from these mice for human cancer cells. The anti-human SIRP Ab also markedly enhanced the inhibitory effect of rituximab on the growth of tumors formed by Raji cells in hSIRP-DKO mice. Our results thus suggest that the combination of Abs to human SIRP with therapeutic Abs specific for tumor antigens warrants further investigation for potential application to cancer immunotherapy. In addition, humanized mice, such as hSIRP-DKO mice, should prove useful for validation of the antitumor effects of checkpoint inhibitors before testing in clinical trials