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Since the first monoclonal antibody approved by the FDA for clinical use, monoclonal antibodies as biotherapeutic drugs have increasingly become an important means for humans to fight tumors, inflammation, autoimmune diseases,etc. Tumor immunotherapy was also named one of the annual scientific and technological breakthroughs in 2013 by Science magazine. Among them, anti-CTLA-4 and PD-1 antibodies made breakthrough progress in tumor immunotherapy. Currently, all monoclonal antibody drugs on the market are IgG-type antibodies or their derivatives (fragments, bispecific antibodies, antibody-conjugated drugs), while the clinical application of IgA-type monoclonal antibodies is still relatively rare. The amount of IgA synthesized by the human body every day is approximately 66 mg/Kg of body weight, which is more than the sum of all other immunoglobulins combined. In serum, the content of IgA type antibodies is second only to IgG type antibodies (about 12 mg/ml), and the concentration is about 2 to 3 mg/ml. In the research on IgA-type antibodies, on the one hand, the traditional concept is that IgA-type antibodies mainly play a role in mucosal immunity. Related studies have shown that IgA-type antibodies are expected to become vaccines and therapeutic drugs for infectious diseases; on the other hand, with the Further elucidation of the structure and function of IgA-type antibodies and their receptor FcαRI (CD89) revealed that IgA-type antibodies have unique ADCC effects and immunomodulatory effects, and have application prospects in the treatment of tumors, inflammation and autoimmune diseases; furthermore, , IgA type antibodies have the property of not passing through the placenta, and as therapeutic antibodies they have the potential to expand the application population. Although IgA-type antibodies have the above advantages, the therapeutic application of IgA-type antibodies still faces problems such as high heterogeneity and immature purification processes. This article will mainly start from the structure of IgA type antibodies, explore its application prospects as a new antibody drug, and discuss some of the problems that still exist when it becomes a therapeutic antibody.
IgA type antibodies can be divided into two subtypes, IgA1 and IgA2, of which IgA2 can be further divided into three allotypes: IgA2m (1), IgA2m (2) and IgA2n. The main structural difference between IgA1 and IgA2 is that the hinge region of IgA2 lacks 16 amino acids rich in O-glycosylation sites. The difference between the two allotypes IgA2m(1) and IgA2m(2) is mainly in the position of the disulfide bond. IgA2m(2) has the usual light and heavy chain disulfide bond connection, while the heavy and light chains of IgA2m(1) There are no disulfide bonds between them, instead there are inter-chain disulfide bonds between light chains. As a type of glycoprotein, IgA antibodies have more complex glycosylation modifications than IgG antibodies. In addition to the O-glycosylation modification of the IgA1 hinge region, IgA1 also has two N-sugar modification sites, located at CH2 (Asn263) and CH3 (Asn459); IgA2 does not have a hinge region. O-glycosylation modification, In addition to CH2 (Asn263) and CH3 (Asn459) sites, there are also two other N-sugar modification sites (CH1 (Asn166) and CH2 (Asn33) 7)), and IgA2m(2) and IgA2n are also found in CH1(Asn211) There is a fifth N-sugar modification site.
Figure 1. Secretory IgA is formed by the combined function of plasma cells producing multimeric IgA and epithelial cells expressing pIgR.(Source: Pabst O, et al. 2020)
IgA-type antibodies exist in the human body in the form of monomers, dimers, and multimers. The form of IgA in serum is generally a monomer, while secretory IgA is mainly a dimer. The IgA dimer produced by most mucosal plasma cells is composed of two IgA monomers linked by a J chain. Dimeric IgA containing J chain can bind to the polyimmunoglobulin receptor (pIgR) of epidermal cells, then enter the epidermal cells and be secreted into the lumen.
IgA participates in the body's immune response to influenza viruses. Prenatal influenza vaccination will increase the level of anti-influenza virus IgA in breast milk and reduce the prevalence of respiratory diseases in infants. A comparison of the antiviral abilities of IgA and IgG that recognize the same epitope found that both IgA and IgG monoclonal antibodies have strong ability to bind to H3 subtype influenza virus, and both have the ability to neutralize this subtype of virus. There is no significant difference. However, the cross-antiviral ability of IgA type monoclonal antibodies against H1, H2 and H13 subtype viruses is significantly greater than that of IgG. The neutralizing ability of IgG type monoclonal antibodies and IgA type monoclonal antibodies against the H1N1 virus was evaluated in guinea pigs. It was found that intramuscular injection and intranasal instillation of IgA antibodies could block the spread through the air of the virus, while IgG could not. Therefore, compared with IgG-type neutralizing antibodies, IgA-type antibodies have broader clinical application prospects. In addition, in addition to HIV and influenza viruses, IgA-type antibodies can produce neutralizing effects against rotavirus and measles virus, as well as antibacterial effects against bacteria such as Shigella flexneri and Mycobacterium tuberculosis.
More and more studies have shown that IgA antibodies and their Fc receptor FcαRI play a role in tumor immunity. FcαRI is widely expressed on the surface of myeloid cells, including neutrophils, eosinophils, monocytes, and some macrophages and dendritic cells. Targeting specific tumor antigens, IgA or bispecific antibodies can rely on FcαRI to produce a killing effect on tumor cells. The researchers used the variable region of the anti-EGFR monoclonal antibody cetuximab to construct an IgA-type antibody and evaluated its in vivo anti-tumor effect in FcαRI transgenic mice. The results showed that IgA-type antibodies had significant anti-tumor effects in the A431 mouse tumor model and the B16F10-EGFR lung metastasis mouse model, and were more effective than cetuximab in the EGFR-transfected Ba/F3 cell tumor model. In addition, some researchers constructed IgA monoclonal antibodies against CD20 and found that in the absence of complement, the ability of poly-IgA antibodies to mediate direct killing or proliferation inhibition was significantly greater than that of IgG1 antibodies. Monomeric IgA antibodies showed effective tumor inhibition in FcαRI transgenic mice.
The clinical symptoms of patients with IgA type antibody deficiency and asthma patients indicate that IgA type antibodies are involved in the body's immune regulation process. Clinical symptoms of patients with IgA antibody deficiency include recurrent infections, allergies or autoimmune diseases. And IgA is closely related to allergic asthma and inflammation. IgA-type antibodies regulate the immune system and trigger different downstream effects depending on their configuration and interaction with receptors. FcαRI (CD89) is an IgA Fc receptor expressed on neutrophils, eosinophils, monocytes/macrophages, dendritic cells and Kupffer cells. The IgA-antigen immune complex cross-links FcαRI and redistributes it to the cell membrane lipid rafts. Lyn of the Src kinase family phosphorylates the tyrosine in ITAM in the FcRγ chain and recruits Blk, Syk, and phospholipases. PLC-γ, Shc, Grb2 then further activate PI3K, PLC-γ, etc., ultimately leading to the generation of phagocytosis, ADCC, respiratory burst, degranulation, cytokine release and other effects. Monomeric IgA in serum can exert a negative immune regulatory effect by interacting with FcαRI receptors. IgA type antibodies play an important role in maintaining the homeostasis of the immune system. For inflammation and autoimmune diseases that occur after the immune system is imbalanced, the use of IgA-type antibodies to interact with their Fc receptor FcαRI to transmit inhibitory signals provides new treatment ideas for such diseases.
References
| Target | Cat. No. | Product Name | Size | Species Reactivity | Application | Detection Sample | |
| IgA | DEIABL406 | Monkey IgA ELISA Kit | 96T | Quantitative | Milk, Plasma, Serum | Inquiry |
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