Thursday, September 19, 2024
9/19/2024
PROJECT SUMMARY Heavy chain antibodies (HCAbs) are an unusual species of immunoglobulins expressed by camelids and sharks. They occur as homodimers in which the variable (V) domain of each polypeptide binds ligand. Without the requirement for the light chain partner in conventional antibodies, HCAb reagents have the advantage of size and molecular manipulability and are promising tools for drug development and immunotherapy. Genes encoding HCAbs evolved separately in two subclasses of cartilaginous fish that diverged 420 million years ago. The role of their HCAbs and pathogen recognition capabilities have not been characterized, although it has been determined that HCAb convex antigen-combining sites can detect epitopes inaccessible or bypassed by conventional antibodies. We have discovered novel antibody genes in a cartilaginous fish whose component gene segments have evolved to encode and rearrange to express lysines and arginines at the ligand-binding sites. An antibody repertoire whose major antigen-combining loop is flexible and electropositive is unique among vertebrates, presenting an opportunity to seek antigenic determinants different from what has been classically defined. Transgenic mice will be generated to express a set of chimeric fish genes. The first aim of this proposal is to generate the mutant mice, the second is to test the ability of the transgene repertoire to respond to various immunogens. Experiments are proposed to test for HCAb detection of novel epitopes in bacterial capsule and cell wall. Future studies will ascertain their protectiveness against disease.
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