CD19 and FcγRIIb co-engagement inhibits processes essential to T cell-dependent B-cell responses

Obexelimab is an investigational, bifunctional humanized monoclonal antibody that inhibits B-lineage cells by binding CD19 via its Fab region and simultaneously co-engaging the inhibitory receptor FcγRIIb through a modified Fc region. Interactions between B cells and T cells specific for the same Ag are essential for the development of germinal center (GC) B-cell responses and high-affinity antibodies. Mutant mice expressing human FcγRIIb and a mouse obexelimab surrogate (mObx) were used to determine if mObx inhibits these critical interactions between cognate B cells and T cells. In ex vivo experiments, mObx blocked B-cell receptor (BCR)-mediated uptake of Ag-coated beads by splenic follicular (Fo) and marginal zone (MZ) B cells and peritoneal cavity (PerC) B1 cells. Similarly, obexelimab treatment of human B cells significantly reduced BCR-mediated bead uptake ex vivo. mObx-treatment inhibited Ag presentation by splenic B cells to co-cultured T cells, as T-cell proliferation and expression of activation markers CD25 and CD44 were significantly reduced when mObx, but not control anti-CD19 antibody, was added to the co-culture. Finally, prophylactic treatment of mice with mObx effectively blocked the activation of human FcγRIIb-expressing B cells and the development of an Ag-specific GC response in vivo. Treatment after GC onset resulted in dissolution of the GC. Collectively, these data demonstrate that CD19/FcγRIIb co-engagement effectively suppresses processes essential to support T cell-dependent B-cell responses, which is consistent with the proposed mechanism of action of obexelimab.