IgA-Mediated Killing of Tumor Cells by Neutrophils Is Enhanced by CD47–SIRPα Checkpoint Inhibition

Abstract

Therapeutic monoclonal antibodies (mAb), directed toward either tumor antigens or inhibitory checkpoints on immune cells, are effective in cancer therapy. Increasing evidence suggests that the therapeutic efficacy of these tumor antigen-targeting mAbs is mediated-at least partially-by myeloid effector cells, which are controlled by the innate immune-checkpoint interaction between CD47 and SIRPa. We and others have previously demonstrated that inhibiting CD47-SIRPa interactions can substantially potentiate antibody-dependent cellular phagocytosis and cytotoxicity of tumor cells by IgG antibodies both in vivo and in vitro. IgA antibodies are superior in killing cancer cells by neutrophils compared with IgG antibodies with the same variable regions, but the impact of CD47-SIRPa on IgA-mediated killing has not been investigated. Here, we show that checkpoint inhibition of CD47-SIRPa interactions further enhances destruction of IgA antibody-opsonized cancer cells by human neutrophils. This was shown for multiple tumor types and IgA antibodies against different antigens, i.e., HER2/neu and EGFR. Consequently, combining IgA antibodies against HER2/neu or EGFR with SIRPa inhibition proved to be effective in eradicating cancer cells in vivo. In a syngeneic in vivo model, the eradication of cancer cells was predominantly mediated by granulocytes, which were actively recruited to the tumor site by SIRPa blockade. We conclude that IgA-mediated tumor cell destruction can be further enhanced by CD47-SIRPa checkpoint inhibition. These findings provide a basis for targeting CD47-SIRPa interactions in combination with IgA therapeutic antibodies to improve their potential clinical efficacy in tumor patients.

Novel chimerized IgA CD20 antibodies: Improving neutrophil activation against CD20-positive malignancies

“…inducing mechanism by neutrophils is profoundly more effective when mediated by the IgA isotype, and can be attributed to a strong triggering of CD89 present on neutrophils. 8,21 Strikingly, we did not observe IgG-mediated B cell reduction with whole blood leukocytes as effector cells, although CD20 IgG1 antibodies have shown clear clinical benefit. One possible explanation could be that IgG-mediated trogocytosis of CD20 by the vast numbers of neutrophils in blood does not reflect the tumor microenvironment in patients.…”

Plasticity in Pro- and Anti-tumor Activity of Neutrophils: Shifting the Balance

“…An important limitation of IgA antibodies in vivo as well as in humans is the short half-life compared to that of IgG isotypes (15 h versus 4 days, respectively, in mice, and 5–6 days versus 21 days, respectively, in humans) ( 237 , 246 , 248 ). Attempts to extend the half-life of such promising antibodies or combine them with immune checkpoint blockade therapy are currently being studied ( 249 , 250 ) and will bring new insights for human application in the near future.…”

When Therapeutic IgA Antibodies Might Come of Age

“…In humans, recycling of albumin and IgG1 through FcRn extends their serum half-life to 19 and 21 days, respectively [140, 142]. Besides pharmacokinetics, combinations of IgA and CD47-SIRPα-blocking agents have provided evidence [143] that targeting phagocytosis checkpoint inhibitors enhanced IgA function, as already demonstrated for IgG antibodies [144].…”