Understanding IgM Structure and Biology to Engineer New Antibody Therapeutics

Immunoglobulin M (IgM) antibodies are an essential and conserved part of adaptive immunity. IgMs assemble into pentamers and hexamers that bind to antigens with high avidity. Pentamers incorporate a small protein called J-chain (JC) that is important for their transcytosis via the poly-immunoglobulin receptor (pIgR). IgM antibodies can efficiently activate complement and interact with different Fc receptors (FcμR, Fcα/μR, pIgR) that trigger distinct effector functions and biodistribution. Even if these features have made the clinical use of IgM attractive over the past decades, there are currently no approved therapeutic IgMs on the market. In this review, we summarize the recent advances in the knowledge of IgM biogenesis and structure and discuss the therapeutic opportunities of IgM over IgG arising from high avidity, target clustering, binding to distinct IgM receptors, complement activation, transcytosis, and protein engineering opportunities. In addition, we summarize possibilities and outstanding challenges in the production of therapeutic IgM, including available technologies for IgM purification. Finally, we review recent preclinical and clinical data showing that IgM outperforms IgG in various in vitro assays but still fails to pass through clinical trials successfully. Challenges remain for IgM development, such as the need for a better understanding of IgM biology to facilitate a smoother transition from the preclinic to successful clinical trials.