First-in-class anti-human CD45RC antibody targets CD45RC^high T and B cells to mitigate pathogenic immune responses

CD45RC, an isoform of the transmembrane tyrosine phosphatase CD45, regulates T and B cell antigen receptor signaling and is highly expressed on Th1 precursors, Th1 cells, T effector memory CD45RA⁺ cells, and most B cells. Preclinical studies have shown that anti-CD45RC monoclonal antibodies (mAbs) can prevent or control diseases such as transplant rejection, graft-versus-host disease (GvHD), Duchenne muscular dystrophy (DMD), and autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED or APS-1). However, their mechanism of action remained unclear. Here, we elucidate the mechanism of anti-human CD45RC mAbs, showing that it selectively induces apoptosis in CD45RC^high T and B cells through binding to cells expressing >24 CD45RC molecules/μm². This interaction triggers intracellular signaling without cytokine release. Cytotoxicity by apoptosis is enhanced by crosslinking with a secondary antibody. The mAb also promotes antibody-dependent cellular phagocytosis by monocyte-derived macrophages, without inducing antibody-dependent cellular cytotoxicity or complement-dependent cytotoxicity, likely due to the length of CD45RC. In CD34⁺-humanized NSG mice, anti-CD45RC mAbs demonstrated dose-dependent depletion of CD45RC^high T and B cells and defined a minimum effective dose to prevent xenogeneic GvHD. These findings define the mechanism of action of this first-in-class anti-human CD45RC therapeutic mAb and supports its potential for the treatment of transplant rejection, GvHD, and autoimmune diseases.