IgA antibodies require higher antigen levels to induce ADCC compared to IgG.

Abstract

Immunotherapy with IgG monoclonal antibodies (mAbs) is frequently used in cancer treatment alongside surgery, radio or chemotherapy, and also combined with other immunotherapies such as immune checkpoint inhibition (ICI). Despite their promising efficacy, IgG mAbs have been reported to cause adverse effects in some cases where the tumor associated antigen (TAA) is also expressed on healthy cells, thus targeting and destroying healthy tissue. This is described as on-target off-tumor side effects. Healthy cells generally have lower antigen expression levels compared to tumor cells; therefore, directing the antibodies against high antigen-expressing tumor cells would prevent these side effects. IgG antibodies have been proven to require relatively low TAA-expression levels in order to induce efficient ADCC, therefore possibly targeting healthy cells. In contrast, IgA antibodies, which have been suggested as an alternative to IgG-based therapies, are thought to require higher TAA-expression levels to induce ADCC. In addition, combination therapy of IgA with CD47/SIRPα (signal regulatory protein alpha) immune checkpoint blockade has been shown effective to enhance IgA-mediated ADCC, but it is unknown whether this enhancement has an effect on the antigen levels required for ADCC. In this study, we compared ADCC capacity of IgG and IgA using cell lines with different antigen expression levels, and also the effect of combining IgA with CD47/SIRPα axis blockade in this context. We demonstrated that IgA antibodies require higher antigen expression levels than IgG in order to induce effective ADCC against tumor cells both in vitro and in vivo, and that the IgA threshold can be lowered by combination with CD47/SIRPα blockade. Consequently, using IgA antibodies would prevent targeting low antigen-expressing healthy cells, focusing solely on high-antigen expressing tumor cells, and thus potentially reducing on-target off-tumor side effects of cancer immunotherapy.