Autoantibody disorders are caused by immune-system-produced antibodies that can damage the body's tissues or organs. In the case of warm autoimmune hemolytic anemia (wAIHA), pathogenic autoantibodies lead to the destruction of red blood cells. There is an unmet need for innovative targeted therapies that address the underlying pathogenesis of wAIHA in a safe and efficacious way. Nipocalimab is a fully human, aglycosylated, effectorless IgG1 monoclonal antibody that blocks the IgG binding site on the neonatal Fc receptor (FcRn) which prevents IgG recycling, leading to reduced serum levels of total IgGs, including pathogenic IgG autoantibodies. Nipocalimab is in clinical development for the treatment of multiple IgG-mediated autoantibody diseases, including wAIHA (NCT04119050). Rapid, sustained lowering of IgG was observed in the phase 2 VIVACITY study in generalized myasthenia gravis (gMG) and in phase 1 healthy volunteers. In gMG patients, nipocalimab induced rapid and sustained lowering of anti-AChR autoantibodies and MG-ADL scores, but no serious adverse events including clinically significant infections. Here, we characterize the effect of nipocalimab on immune function.

Nipocalimab was evaluated extensively in vitro and in nonhuman primate-based chronic toxicology studies to evaluate selectivity, tolerability, safety and immunopharmacology. Safety, tolerability and immune-focused assessments in clinical phase 1 and Phase 2 MG studies were also completed (NCT02828046, NCT03772587).

Nipocalimab binds specifically in vitro to FcRn without activation of effector function or inhibition of antigen presentation. In nonhuman primates administered up to 300 mg/kg nipocalimab QW for up to 6 months, sustained lowering of IgG was observed without adverse effects. Immunotoxicology identified no effect on immune cell phenotypes; CD8 T cell, NK or innate cell functions; T-dependent neoantigen IgM responses. Neoantigen IgG production was observed, but with lowered peak IgG titers consistent with the anticipated increase in IgG clearance with nipocalimab. In clinical studies, nipocalimab demonstrated a reproducible selective decrease in total serum IgG, including all subclasses of IgG, with no effect on IgM, IgA, IgE, CH50, C3, C4, inflammatory cytokines or acute phase proteins including, C-reactive protein (CRP).

These data suggest that nipocalimab can selectively lower IgG and IgG autoantibodies while preserving cellular immunity, complete IgM response and IgG production after neoantigen challenge.

Overall, nipocalimab's selective effect on IgG recycling provides a mechanistic rationale for potentially decreased infection risk despite substantial IgG lowering.

LEL *, FY *, CJB *, JB *, RX *, AMBP are employed by the Janssen Pharmaceutical Companies of Johnson & Johnson and may hold stock or stock options in Johnson & Johnson; ST * is an employee of Orna Therapeutics; SK * is an employee of Checkmate Pharmaceuticals; JD * is an employee of Faze Medicines; WA * is an employee of Kisbee Therapeutics. *Former employees of Momenta Pharmaceuticals which was acquired by Janssen Pharmaceutical Companies of Johnson & Johnson.