In 1986, the first monoclonal antibody (mAb) Muromonab-CD3 was approved by the U.S. Food and Drug Administration (FDA) to relieve organ transplant rejection in humans. Since then, the development of therapeutic mAbs has flourished for these decades. More than 7000 therapeutic mAbs have been recorded in the database (https://tabs.craic.com/) up to now, the overwhelming majority of which are IgG isotypes. In recent years, scientists have gradually turned their attention to non-IgG antibodies, such as IgA, IgM, IgE, and IgY antibodies, and several therapeutic IgM and IgE antibodies have been published for the treatment of different human diseases.
Fig.1 General structures of the five major classes of antibodies. (Owen, 2013)
FcαRI receptor is the major IgA receptor, which can induce effective killing and clearance of tumor cells both in vivo and in vitro when engaged by IgA antibodies (IgA1 and IgA2). Considering the limitations in cancer treatment development: i) IgG antibodies are unable to recognize and bind to the FcαRI receptor; ii) short half-life of IgA antibodies; iii) failure to activate the complement cascade, William et al. (William, 2014) develop a human IgGA antibody by semirational protein engineering method. This engineered IgGA antibody exhibited excellent biological properties, such as, it can bind to not only the FcαRI receptor but also FcgRI and FcgRIIa/b receptors; it is also bound to C1q to activate the complement system mediating complement-dependent cytotoxicity; and more potent in antibody-dependent cell-mediated cytotoxicity and antibody-dependent cellular phagocytosis.
IgA exerts a significant role in mucosal immunity where the immune system of the host fight against the pathogen in mucosal tissues such as the respiratory tract and digestive tract once the pathogens enter. In the early infection of coronavirus 2019 (COVID-19), IgA antibody was detected to be the predominant immunoglobulin in the humoral immunity. And secretory IgA also can neutralize SARS-CoV-2 by binding to the Spike protein on the surface of SARS-Cov-2.
Fig. 2 Mucosal Immunity in the nostril upon SARS-CoV-2 infection. (Chao, 2020)
To identify the antigen of an IgM monoclonal antibody, Teye et al., has prepared a series of engineered chimeric IgM/IgG antibodies by combining different domains of IgM and IgG antibodies, producing functional antibodies such as VH-Cµ1-Cµ2-Cγ3 and VH-Cµ1-Cµ2-Hinge-Cγ2-Cγ3. (Teye, 2017)
IgM antibody is the largest antibody as well as the earliest produced antibody in the response to the pathogens. IgG combined with IgM antibody detection is a preferred method to identify asymptomatic SARS-CoV-2 infection. Moreover, IGM Biosciences Inc. has developed an anti-SARS-CoV-2 IgM antibody in clinical trials, which exhibited effective neutralization activity against COVID-19 including its variants.
Several IgM antibodies have been developed and progressed into clinical trials for the treatment of human diseases. In 2021, IGM Biosciences Inc. has launched an engineered IgM antibody for the prevention or treatment of mild to moderate COVID-19 infections, which progressed into clinical trial phase II (NCT05160402). Another IgM antibody also developed by IGM Biosciences Inc. has been progressed into clinical trial phases I & II for the treatment of CD20-positive cancers and lymphoma (NCT04082936).
Besides an essential role in allergic disease, the IgE antibody also exerts a significant role in cancer recognition and treatment. The first anti-tumor IgE antibody was a mouse/human chimeric IgE antibody against folate receptor alpha (FRα), which has been evaluated in clinical trial phase I for the treatment of human advanced solid tumors (NCT02546921).
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- Owen, J. A.; et al. Kuby immunology (p. 692). New York: WH Freeman. 2013.
- William, K.; et al. IgGA: a "cross-isotype" engineered human Fc antibody domain that displays both IgG-like and IgA-like effector functions. Chemistry & Biology. 2014, 21(12):1603-1609.
- Chao, Y.X.; et al. The role of IgA in COVID-19. Brain, Behavior, and Immunity. 2020, 87: 182-183.
- Teye, K.; et al. Multimerization is required for antigen binding activity of an engineered IgM/IgG chimeric antibody recognizing a skin-related antigen. Scientific Reports. 2017, 7(1): 8212.
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