Abstract
Most therapeutic antibodies are based on immunoglobulin G (IgG) due to their potent effector functions and long plasma half-life. However, also monomeric IgA has emerged as an attractive candidate for cancer treatment as, upon specific binding to tumor cells, it can activate myeloid cells, like polymorphonuclear leukocytes and macrophages, to kill the tumor cells by engaging the Fc α receptor I (FcαRI). Despite this favorable property, human IgA has a short plasma half-life in both mice and humans, which is clearly limiting preclinical studies in a translational perspective. Here, we report on albumin-equipped designs of human IgA antibodies that are long acting due to tailored binding to the human form of neonatal Fc receptor (FcRn), which is a natural plasma half-life regulator of albumin. Importantly, this was achieved without compromising the ability of IgA to engage and activate FcαRI-expressing effector cells for tumor cell killing in vitro and in vivo in a new mouse model transgenic for the human forms of FcRn and FcαRI. We further show that the potency of the engineered long-acting human IgA against tumor cells with intermediate target antigen expression levels could be enhanced by myeloid checkpoint inhibitors targeting the signal regulatory protein α-CD47 axis.