Maus-IgM-Standardsatz, A-F

Natural immunoglobulin M (IgM) antibodies are pentameric or hexameric macroimmunoglobulins and have been highly conserved throughout evolution. IgMs are initially expressed during B cell ontogeny and are the first antibodies to be secreted upon 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 that of IgG, their polyvalency allows for high avidity binding and efficient complement binding to induce complement-dependent cell lysis. 

The high avidity of IgM antibodies makes them particularly efficient at binding antigens that are present in low amounts. and non-protein antigens such as carbohydrates or lipids present on microbial surfaces. Pentameric IgM antibodies also contain a connecting (J) chain that stabilizes the pentameric structure and allows binding to multiple receptors. One of these receptors, the polymeric immunoglobulin receptor (pIgR), is responsible for transcytosis from the vasculature to the mucosal surfaces of the lungs and gastrointestinal tract. Several naturally occurring IgM antibodies have been investigated in clinical trials as therapeutics, 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 significant advances that have been made in understanding biology, structure, function, manufacture,

Introduction to Immunoglobulin M (IgM)

During humoral immune responses, immunoglobulins of the IgM, IgD, IgG, IgA, and IgE isotypes can be produced, each expressing a unique profile of effector functions capable of mediating host defenses against invading pathogens. Macro-immunoglobulin, IgM, is initially produced as a surface-bound molecule and expressed in early B-cell differentiation. Later in the immune response, IgM is produced by plasma cells and excreted as soluble pentamers with 10 antigen binding sites and the connecting chain (J) or as hexamers with 12 antigen binding sites and no connecting chain (J chain). IgM has a molecular weight of approximately 900 or 1050 kDa for the pentamer or hexamer, respectively

Because of the polyvalent nature of IgMs, they may have higher avidity for antigen than the bivalent IgG. In addition to neutralizing pathogens, IgM antibodies are highly effective at activating complement to selectively lyse cells and pathogens.

Our understanding of the biology, structure, and functional relationships of IgM antibodies has progressed so far that this antibody isotype can be used therapeutically; however, challenges associated with their manufacture remain. Here we review the progress and therapeutic potential for this class of antibodies, as well as the potential for new classes of genetically engineered IgM antibodies.

 History and Discovery of IgM

Humoral immunity has been studied since the late 19th century when George Nuttall  discovered that animal immune sera could kill bacteria. 

  • Subsequent analysis of the immune serum using technologies such as electrophoresis and ultracentrifugation enabled the biochemical characterization of the various proteins that might mediate immunity, leading to the discovery of immunoglobulins. 
  • Originally, these serum components were assigned as α-globulin, β-globulin, and γ-globulin fractions to name the proteins in order of their electrophoretic mobility
  • The first description of IgM antibodies was in 1939 by Kabat et al.  who evaluated the molecular weight of antibodies produced in horse, cow, pig, monkey and human serum after immunization with pneumococci. 
  • Because of the size (approximately 990 kDa), the new antibody was named γ-macroglobulin. In 1944, it was discovered by Waldenstrom and later independently by Kunkel that γ-macroglobulins are expressed at high levels in patients with multiple myeloma [.
  •  They identified that the γ-macroglobulin migrated close to β-globulin in patient sera using immunoelectrophoresis and ultracentrifugation techniques. In the 1960s, methods were developed to induce plasmacytomas in mice that produced uniform immunoglobulins, including γ-macroglobulin-producing plasmacytomas, recapitulating the data observed in patients with multiple myeloma
  • Because the immunoglobulins discovered during this period were given arbitrary names, the World Health Organization defined a nomenclature system for antibody isotypes in 1964. As a consequence, γ-macroglobulin was renamed IgM and the M referred to “macroglobulin”.

Evolution of IgM antibodies

Immunoglobulins, including IgM antibodies, are found in all jawed vertebrates (gnathosomas), which evolved from jawless fish (agnathans) about 550 million years ago . Similar to mammals, IgM expression precedes the expression of other antibody isotypes, although in teleosts IgD and IgT are the only other isotypes present. The phylogeny of the immunoglobulin heavy and light chain isotypes is shown in figure 2 . However, within certain species there are marked differences in the structure of the IgM antibodies produced. For example, the predominant form of IgM antibodies in mice and humans is pentameric in structure and contains a J chain that stabilizes the pentamer, but hexamers and monomers can also be detected. However , IgM antibodies in frogs, for example  Xenopus,  have a hexameric structure, although  Xenopus  IgM has been reported to contain a J chain [  14  ]. In contrast, IgM from bony fish predominantly forms a tetrameric structure, while the IgM produced by cartilaginous fish such as sharks has a pentameric structure.

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 It is unclear why hexamer IgM was produced, but it was possible that J chain synthesis might be limiting [  17  ]. In addition, there are examples of IgM where the expressed µ chain lacks the cysteine ​​in the tail that is required for proper insertion into the IgM structure [  18  ,  19  ]. Interestingly, pentameric IgM that does not contain J chain can also be present in humans and mice . Indeed, we have observed hexamers, ie pentamer mixtures, produced from recombinant IgM derived from CHO cells in the absence of transfected J chain ( and unpublished observations).

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