Structure, Function, and Therapeutic Use of IgM Antibodies

Abstract

Natural immunoglobulin M (IgM) antibodies are pentameric or hexameric macro-immunoglobulins and have been highly conserved during evolution. IgMs are initially expressed during B cell ontogeny and are the first antibodies secreted following exposure to foreign antigens. The IgM multimer has either 10 (pentamer) or 12 (hexamer) antigen binding domains consisting of paired µ heavy chains with four constant domains, each with a single variable domain, paired with a corresponding light chain. Although the antigen binding affinities of natural IgM antibodies are typically lower than IgG, their polyvalency allows for high avidity binding and efficient engagement of complement to induce complement-dependent cell lysis. The high avidity of IgM antibodies renders them particularly efficient at binding antigens present at low levels, and non-protein antigens, for example, carbohydrates or lipids present on microbial surfaces. Pentameric IgM antibodies also contain a joining (J) chain that stabilizes the pentameric structure and enables binding to several receptors. One such receptor, the polymeric immunoglobulin receptor (pIgR), is responsible for transcytosis from the vasculature to the mucosal surfaces of the lung and gastrointestinal tract. Several naturally occurring IgM antibodies have been explored as therapeutics in clinical trials, and a new class of molecules, engineered IgM antibodies with enhanced binding and/or additional functional properties are being evaluated in humans. Here, we review the considerable progress that has been made regarding the understanding of biology, structure, function, manufacturing, and therapeutic potential of IgM antibodies since their discovery more than 80 years ago.

Role of Polymeric Immunoglobulin Receptor in IgA and IgM Transcytosis

“…Unlike other classes of antibodies (IgD, IgE, IgG), monomers of IgA and IgM can polymerize. Primarily, IgA forms dimers [ 58 ], whereas IgM forms pentamers and sometimes polymers of even higher orders [ 59 ]. This process of immunoglobulin polymerization is mediated by a special protein called joining chain (J chain) that binds to heavy chains of IgA and IgM through disulfide bonds at their C -terminal tailpieces [ 60 ].…”

“…IgM forms the first line of defense against pathogen infections and, in some cases, auto-antigens as a part of the innate immune system in cooperation with other immune cells including mast cells, natural killer cells, dendritic cells and macrophages [ 59 ]. There are two distinct versions of IgM, namely the natural IgM and the adaptive IgM.…”

“…The natural IgM is the predominant subtype, while the adaptive IgM accounts for 10–20% of all IgM antibodies in the serum in humans and mice. Natural IgM antibodies are reported to be produced by B-1 cells in the bone marrow and the spleen, and they are generally encoded by germline V gene segments with limited mutations [ 59 ]. By contrast, adaptive IgM antibodies are produced by post-germinal center plasma cells and memory B cells, so they have highly mutated V regions [ 59 , 134 , 135 ].…”

“…Natural IgM antibodies are reported to be produced by B-1 cells in the bone marrow and the spleen, and they are generally encoded by germline V gene segments with limited mutations [ 59 ]. By contrast, adaptive IgM antibodies are produced by post-germinal center plasma cells and memory B cells, so they have highly mutated V regions [ 59 , 134 , 135 ]. Although each natural IgM monomer has relatively low affinity to antigens as it normally does not undergo somatic hypermutation and affinity maturation, the presence of multivalent antigen-binding sites in IgM pentamers or hexamers confers high avidity, which is pivotal in the capacity of IgM for agglutinating pathogens by binding to specific antigenic motifs [ 101 , 136 ].…”

A Novel Mouse Monoclonal Antibody C42 against C-Terminal Peptide of Alpha-1-Antitrypsin

“…Notably, two independent efforts to obtain a mouse monoclonal immunoglobulin G (IgG) anti-C-36 antibody were unsuccessful, allowing us to conclude that C-peptide of AAT generates an immune response characterized by the persistent production of antibodies of the IgM class. The IgM antibody is more difficult to work with in terms of reagent availability, purification, and specificity; additionally, the antigen binding affinities of IgM antibodies are typically lower than IgG [ 17 ]. On the other hand, the pentameric structure of IgM renders them particularly efficient at binding antigens present at low levels more strongly than monomeric IgGs [ 18 ].…”