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
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.