Ig Constant Region Effects on Variable Region Structure and Function

Janda, Alena; Bowen, Anthony; Greenspan, Neil S.; Casadevall, Arturo

doi:10.3389/fmicb.2016.00022

Cited by 108 publications

(119 citation statements)

References 81 publications

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“…We also note that the C H is known to have significant effects on the catalytic activities of at least two different antibodies (28,29,50). Thus, if the hydrolytic active site is present in the V L , this would imply that major inter-domain and inter-chain conformational changes can be propagated in immunoglobulins, a topic that warrants further investigation (61,62). Monoclonal antibodies have become one of the most versatile options for pharmaceutical development and have been approved to treat a wide variety of illnesses.…”

Section: Discussionmentioning

confidence: 86%

A Monoclonal Antibody to Cryptococcus neoformans Glucuronoxylomannan Manifests Hydrolytic Activity for Both Peptides and Polysaccharides

Bowen

Wear

Cordero

et al. 2017

Journal of Biological Chemistry

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Edited by Luke O'NeillStudies in the 1980s first showed that some natural antibodies were "catalytic" and able to hydrolyze peptide or phosphodiester bonds in antigens. Many naturally occurring catalytic antibodies have since been isolated from human sera and associated with positive and negative outcomes in autoimmune disease and infection. The function and prevalence of these antibodies, however, remain unclear. A previous study suggested that the 18B7 monoclonal antibody against glucuronoxylomannan (GXM), the major component of the Cryptococcus neoformans polysaccharide capsule, hydrolyzed a peptide antigen mimetic. Using mass spectrometry and Förster resonance energy transfer techniques, we confirm and characterize the hydrolytic activity of 18B7 against peptide mimetics and show that 18B7 is able to hydrolyze an oligosaccharide substrate, providing the first example of a naturally occurring catalytic antibody for polysaccharides. Additionally, we show that the catalytic 18B7 antibody increases release of capsular polysaccharide from fungal cells. A serine protease inhibitor blocked peptide and oligosaccharide hydrolysis by 18B7, and a putative serine protease-like active site was identified in the light chain variable region of the antibody. An algorithm was developed to detect similar sites present in unique antibody structures in the Protein Data Bank. The putative site was found in 14 of 63 (22.2%) catalytic antibody structures and 119 of 1602 (7.4%) antibodies with no annotation of catalytic activity. The ability of many antibodies to cleave antigen, albeit slowly, supports the notion that this activity is an important immunoglobulin function in host defense. The discovery of GXM hydrolytic activity suggests new therapeutic possibilities for polysaccharide-binding antibodies.A central tenet in immunology is that immunoglobulin (Ig) variable (V) 2 regions bind antigen (Ag) and that the molecule's constant regions activate complement components or cellular receptors, triggering downstream immune pathways such as phagocytosis, granule release, cell-mediated cytotoxicity, and complement-mediated cytotoxicity. Research has also shown that antibodies possess important direct effects on Ag, such as neutralization of toxins or virions, bacterial agglutination, and precipitation of soluble Ag. Although it has long been accepted that each of these Ig functions are mediated by the binding of an antibody paratope to an Ag epitope, research in 1975 first showed that antibodies could be generated that not only bound Ag but also catalyzed a chemical reaction in the Ag substrate (1). Over the next 2 decades, many catalytic antibodies were generated against haptenic transition state analogues to catalyze a wide array of chemical reactions, a strategy first proposed by enzymologist W. Jencks in 1969 (2). This strategy has since been used to generate antibody catalysts for many distinct chemical reactions, albeit with reaction rates usually much slower than natural enzymes. The first indication that some naturally occurri...

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Section: Discussionmentioning

confidence: 86%

A Monoclonal Antibody to Cryptococcus neoformans Glucuronoxylomannan Manifests Hydrolytic Activity for Both Peptides and Polysaccharides

Bowen

Wear

Cordero

et al. 2017

Journal of Biological Chemistry

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“…These domains can differentially influence the structure of the antigen-combining site and/or the overall flexibility of the Ab structure, both of which can change the affinity of the Ab for its epitope and consequently, its neutralization potency (Janda et al, 2016). To relate these in vivo findings to those in vitro , neutralization potency of the various CH31 mAbs was assessed using the TZM-bl assay and defined by IC50 and IC80 measurements.…”

Section: Resultsmentioning

confidence: 99%

Neutralization Takes Precedence Over IgG or IgA Isotype-related Functions in Mucosal HIV-1 Antibody-mediated Protection

et al. 2016

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HIV-1 infection occurs primarily through mucosal transmission. Application of biologically relevant mucosal models can advance understanding of the functional properties of antibodies that mediate HIV protection, thereby guiding antibody-based vaccine development. Here, we employed a human ex vivo vaginal HIV-1 infection model and a rhesus macaque in vivo intrarectal SHIV challenge model to probe the protective capacity of monoclonal broadly-neutralizing (bnAb) and non-neutralizing Abs (nnAbs) that were functionally modified by isotype switching. For human vaginal explants, we developed a replication-competent, secreted NanoLuc reporter virus system and showed that CD4 binding site bnAbs b12 IgG1 and CH31 IgG1 and IgA2 isoforms potently blocked HIV-1JR-CSF and HIV-1Bal26 infection. However, IgG1 and IgA nnAbs, either alone or together, did not inhibit infection despite the presence of FcR-expressing effector cells in the tissue. In macaques, the CH31 IgG1 and IgA2 isoforms infused before high-dose SHIV challenge were completely to partially protective, respectively, while nnAbs (CH54 IgG1 and CH38 mIgA2) were non-protective. Importantly, in both mucosal models IgG1 isotype bnAbs were more protective than the IgA2 isotypes, attributable in part to greater neutralization activity of the IgG1 variants. These findings underscore the importance of potent bnAb induction as a primary goal of HIV-1 vaccine development.

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“…Approximately hundred antibody-forming clones may be stimulated by immunization with a small, chemically well-defined molecule. A specific antibody is produced by each clone; each antibody possesses a unique sequence of the amino acid within its variable region [1]. The epitope is a site on the antigen with which an antibody binds.…”

Section: Structural Analysis Of Antibodymentioning

confidence: 99%

Recapitulation of the anti-Idiotype antibodies as vaccine candidate

et al. 2018

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The foreign antigen that enters into the body is detected by the immune system through antigen presenting cells leading to the production of antibodies. The use of anti-idiotype antibodies is a new way to excite the immune response that identifies and eliminates the foreign antigens entered into the body. These Anti-idiotype antibodies have the ability to decrease the non-specific binding of the antigenic protein epitopes because of high specificity for the antigenic determinants. The anti-idiotype antibodies attach to the paratope of idiotype antibody and stimulate a precise immune reaction same as that of external antigen. The anti-idiotype antibodies are the peerless therapeutic candidate as they mimic the antigenic structure and potentiate antibody and cell-mediated immunity. Even in the absence of foreign antigen, these anti-idiotype antibodies have the potential to provide long-lasting immunity. The present review is about immune regulations by anti-idiotype antibodies with some success therapeutic stories. The previous research analysis is evidence of anti-idiotype antibodies as an excellent candidate for the development of both human and animal vaccines although it has some gaps that are needed to be addressed.

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Ig Constant Region Effects on Variable Region Structure and Function

Cited by 108 publications

References 81 publications

A Monoclonal Antibody to Cryptococcus neoformans Glucuronoxylomannan Manifests Hydrolytic Activity for Both Peptides and Polysaccharides

A Monoclonal Antibody to Cryptococcus neoformans Glucuronoxylomannan Manifests Hydrolytic Activity for Both Peptides and Polysaccharides

Neutralization Takes Precedence Over IgG or IgA Isotype-related Functions in Mucosal HIV-1 Antibody-mediated Protection

Recapitulation of the anti-Idiotype antibodies as vaccine candidate

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