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Structure, Function, and Therapeutic Use of Igm Antibodies

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Structure, Function, and Therapeutic Use of Igm Antibodies antibodies Review Structure, Function, and Therapeutic Use of IgM Antibodies Bruce A. Keyt *, Ramesh Baliga, Angus M. Sinclair, Stephen F. Carroll and Marvin S. Peterson IGM Biosciences Inc, 325 East Middlefield Road, Mountain View, CA 94043, USA; [email protected] (R.B.); [email protected] (A.M.S.); [email protected] (S.F.C.); [email protected] (M.S.P.) * Correspondence: [email protected]; Tel.: +1-650-265-6458 Received: 16 September 2020; Accepted: 9 October 2020; Published: 13 October 2020 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. Keywords: IgM (immunoglobulin M); hexameric; pentameric; polymeric; polyvalency; joining chain (J-chain); avidity; complement dependent cytotoxicity (CDC); poly Ig receptor (pIgR) 1. Introduction to Immunoglobulin M (IgM) During humoral immune responses, immunoglobulins of the 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. Macro-immunoglobulin, IgM, is initially produced as a surface bound molecule and is expressed in early B cell differentiation. 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). IgM has a molecular weight of approximately 900 or 1050 kDa for the pentamer or hexamer, respectively (Figure1). Antibodies 2020, 9, 53; doi:10.3390/antib9040053 www.mdpi.com/journal/antibodies Antibodies 2020, 9, 53 2 of 35 Antibodies 2020, 9, x FOR PEER REVIEW 2 of 35 Figure 1. Schematic diagram of an immunoglobulinimmunoglobulin M (IgM) antibody pentamer ( left) and hexamer (right). Constant regions are shown in gray and variab variablele regions in green, and also shown on the IgM pentamer is the small joiningjoining chain (J-chain) in red. Due toto thethe polyvalent polyvalent nature nature of IgMs,of IgMs, they they may ma exhibity exhibit higher higher avidity avidity for antigen for antigen than the than bivalent the IgG.bivalent In addition IgG. In toaddition neutralizing to neut pathogens,ralizing pathogens, IgM antibodies IgM areantibodies highly e areffective highly at engaging effective complementat engaging tocomplement target lysis to of target cells andlysis pathogens. of cells and pathogens. Our understanding understanding of of the the biology, biology, structure, structure, an andd function function relationships relationships for forIgM IgM antibodies antibodies has hasprogressed progressed to the to thepoint point where where this this antibody antibody isot isotypeype can can be be exploited exploited therapeutically; therapeutically; however, however, challenges associatedassociated with with their their manufacture manufacture remain. remain. Here, Here, we review we thereview progress the andprogress the therapeutic and the potentialtherapeutic for potential this class for of antibodies, this class of as antibodies, well as the potentialas well as for the new potential classes for of engineerednew classes IgM of engineered antibodies. IgM antibodies. 1.1. History and Discovery of IgM 1.1. HistoryHumoral and immunity Discovery hasof IgM been studied since the late 1800s when George Nuttall [1] discovered that animalHumoral immune immunity sera could has kill been bacteria. studied Subsequent since the analysis late 1800s ofthe when immune George serum Nuttall using [1] technologies discovered suchthat animal as electrophoresis immune sera and ultracentrifugationcould kill bacteria. allowed Subsequent for biochemical analysis of characterization the immune ofserum the various using proteinstechnologies that such could asmediate electrophoresis immunity, and resultingultracentrifugation in the discovery allowed of for immunoglobulins. biochemical characterization Originally, theseof the serumvarious components proteins that were coul assignedd mediate as α immunity,-globulin, βresulting-globulin, in and the γdiscovery-globulin of fractions immunoglobulins. to designate theOriginally, proteins these by order serum of electrophoreticcomponents were mobility assigned [2]. Theas α first-globulin, description β-globulin, of IgM and antibodies γ-globulin was reportedfractions into 1939designate by Kabat the proteins et al. [3] by who order evaluated of electrophoretic the molecular mobility weight [2]. of antibodiesThe first description produced inof horse,IgM antibodies cow, pig, was monkey, reported and in human 1939 serumby Kabat after et immunizational. [3] who evaluated with pneumococcus. the molecular Due weight to the of largeantibodies size (approximately produced in horse, 990 kDa), cow, the pig, new monk antibodyey, and was human referred serum to as γafte-macroglobulin.r immunization In 1944,with γpneumococcus.-macroglobulins Due were to the also large discovered size (approximatel to be expressedy 990 at kDa), high the levels new in antibody multiple myelomawas referred patients to as byγ-macroglobulin. Waldenstrom andIn 1944, later γ independently-macroglobulins by were Kunkel also [4 ,discovered5]. They identified to be expressed that the γat-macroglobulin high levels in inmultiple patient myeloma sera migrated patients close by Waldenstrom to β-globulin and using later immuno-electrophoresis independently by Kunkel and [4,5]. ultracentrifugation They identified techniques.that the γ-macroglobulin In the 1960s, methodsin patient were sera developedmigrated close to induce to β-globulin plasmacytomas using immuno-electrophoresis in mice that produced uniformand ultracentrifugation immunoglobulins techniques. that included In theγ 1960s,-macroglobulin methods were producing developed plasmacytomas, to induce plasmacytomas recapitulating thein mice data observedthat produced in multiple uniform myeloma immunoglobulins patients [6]. As thethat immunoglobulins included γ-macroglobulin discovered duringproducing this timeplasmacytomas, were being givenrecapitulating arbitrary names, the data in 1964 observed the World in Healthmultiple Organization myelomadefined patients a nomenclature[6]. As the systemimmunoglobulins for antibody discovered isotypes. As during a consequence this time γwere-macroglobulin being given was arbitrary renamed names, IgM, andin 1964 the Mthe referred World toHealth “macroglobulin” Organization [7 ].defined a nomenclature system for antibody isotypes. As a consequence γ- macroglobulin was renamed IgM, and the M referred to “macroglobulin” [7]. 1.2. Evolution of IgM Antibodies 1.2. EvolutionImmunoglobulins, of IgM Antibodies including IgM antibodies, are found in all jawed vertebrates (gnathosomes) that diverged in evolution from jawless fish (agnathans) approximately 550 million years ago [8,9]. Similar to Immunoglobulins, including IgM antibodies, are found in all jawed vertebrates (gnathosomes) mammals, IgM expression precedes the expression of other antibody isotypes, although, in teleost fish, that diverged in evolution from jawless fish (agnathans) approximately 550 million years ago [8,9]. IgD and IgT are the only other isotypes present [10]. The phylogeny of the immunoglobulin heavy Similar to mammals, IgM expression precedes the expression of other antibody isotypes, although, and light chain isotypes is illustrated in Figure2. However, within certain species, there are distinct in teleost fish, IgD and IgT are the only other isotypes present [10]. The phylogeny of the differences in the structure of the IgM antibodies produced [11]. For example, the predominant form immunoglobulin heavy and light chain isotypes is illustrated in Figure 2. However, within certain species, there are distinct differences in the structure of the IgM antibodies produced [11]. For example, the predominant form of IgM antibodies in mice and humans are pentameric in structure Antibodies 2020, 9,
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