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.
Highlights
Introduction to ImmunoglobulinM (IgM)During humoral immune responses, immunoglobulins of the immunoglobulin M (IgM), IgD, IgG, IgA, and IgE isotypes may be produced, each expressing a unique profile of effector functions capable of mediating host defense against invading pathogens
Later in the immune response, IgM is produced by plasma cells and secreted as soluble pentamers that contain 10 antigen binding sites and the joining (J) chain, or as hexamers containing 12 antigen binding sites and no joining chain (J-chain)
Similar to Immunoglobulins, including IgM antibodies, are found in all jawed vertebrates mammals, IgM expression precedes the expression of other antibody isotypes, in teleost fish, that diverged in evolution from jawless fish approximately 550 million years ago [8,9]
Summary
Humoral been studied since the late 1800s when George Nuttall [1] discovered that animal immuneimmunity sera couldhas killbeen bacteria. Technologies asmediate electrophoresis andresulting ultracentrifugation allowedoffor biochemical characterization these components were assigned as α-globulin, fractions to designate of theserum various proteins that could mediate immunity, β-globulin, resulting inand the γ-globulin discovery of immunoglobulins. In 1944, antibodies produced in horse, cow,the pig, monkey, after immunization with γ-macroglobulins were discovered to be expressed at high levels in multiple myeloma patients pneumococcus. Due to the large size (approximately 990 kDa), the new antibody was referred to as by Waldenstrom and later γ-macroglobulins independently by were. Ultracentrifugation multiple myeloma patients by Waldenstrom and later independently by Kunkel. 1960s, methods were developed to induce plasmacytomas in mice that produced that the γ-macroglobulin in patient sera migrated close to β-globulin using immuno-electrophoresis uniform immunoglobulins that included γ-macroglobulin producing plasmacytomas, recapitulating and ultracentrifugation techniques. As a consequence γmacroglobulin was renamed IgM, and the M referred to “macroglobulin” [7]
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