Anti-mIgA Antibody Lysis via Chimeric Immunogen
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Solution Overview
Problem
Current antibodies targeting the migis-α antigenic site on membrane-bound IgA (mIgA) expressing B cells have limited binding capability and inability to induce lysis or reduce IgA production effectively.
Innovation Solution
Development of an anti-migis-α antibody, specifically MAb 8G7, with defined complementary-determining regions (CDRs) that can bind to mIgA on B lymphocytes, causing lysis and reducing IgA production by IgA-secreting cells, using a chimeric immunogen to overcome conformational accessibility issues.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Strength
If antibodies are prepared to bind to synthetic migis-α polypeptides and recombinant proteins, then binding affinity to purified antigens is improved, but binding capability to mIgA on B cells and ability to induce lysis remain insufficient
Solution Approach 1:
The patent uses a chimeric protein as an intermediary immunogen that contains both the migis-α antigenic sequence and a carrier protein (Keyhole Limpet Hemocyanin, KLH). This chimeric structure serves as a mediator that presents the epitope in a conformation accessible to B cell receptors while also providing strong immunogenicity through the carrier protein, thereby generating antibodies that can effectively bind to and lyse mIgA-expressing B cells
Solution Approach 2:
The patent changes the physical and chemical parameters of the immunogen by creating a chimeric protein structure that fuses the migis-α peptide sequence with the KLH carrier protein. This structural parameter change allows the epitope to be presented in a conformation that is both immunogenic and accessible to B cell receptors, resolving the contradiction between binding affinity and functional efficacy
2Quantity of substance
If conventional immunization methods are used with synthetic peptides, then antibody production is achieved, but the antibodies fail to effectively lyse mIgA-expressing B cells or reduce IgA production
Solution Approach 1:
The patent creates a composite immunogen by chemically conjugating the migis-α peptide to the KLH carrier protein through glutaraldehyde crosslinking. This composite structure combines the specific antigenic determinant with a highly immunogenic carrier, producing antibodies that not only bind to the target but also effectively mediate lysis of mIgA-expressing B cells and reduce IgA production
Solution Approach 2:
The patent performs preliminary characterization of the chimeric immunogen to ensure proper folding and epitope accessibility before immunization. This preliminary action ensures that the resulting antibodies will have the correct specificity and functional activity for lysing B cells and reducing IgA production, rather than merely binding to denatured peptide sequences
Data Source
AI summary
Disclosed herein is an anti-migis-ααantibody specific for the migis-α of human mα chain that can bind to mIgA on B lymphocytes, cause the lysis of mIgA-expressing B lymphocytes, and decrease IgA production by IgA-secreting B lymphocytes. Disclosed further is a pharmaceutical composition comprising the anti-migis-α antibody and a pharmaceutically acceptable carrier. Disclosed further is a method for lysing mIgA-expressing B lymphocytes and reducing IgA production in a human subject in vivo by employing an antibody specific for the migis-α of human mα chain that can bind to mIgA on B lymphocytes, cause the lysis of mIgA-expressing B lymphocytes, and decrease IgA production by IgA-secreting B lymphocytes. Disclosed herein is also a method for treating a disease in a subject, comprising administering to the subject an antibody specific for the migis-α of human mα chain that can bind to mIgA on B lymphocytes, thereby lysing mIgA-expressing B lymphocytes and reducing IgA production in the immune system of the subject. In addition, Disclosed also is use of said anti-migis-α antibody or said fragment thereof for treating a disease in a subject that can benefit from the elimination of mIgA-expressing cells or the reduction of IgA antibodies in the immune system.