An integrated transcriptomic and proteomic approach to antibody sequencing and repertoire characterization

Antibodies are ideal drug candidates due to their high specificity for targetmoleculesMonoclonal antibodies represent one of the fastest growing segments ofthe drug markethoweverrecent attention has focused on polyclonal antibodiesand monoclonal mixtures to reduce the opportunity for a disease to become drugresistantPolyclonal antibodies sampled from disease survivors or immunizedhosts offer a wealth of new drug candidatesCurrent pipelines for investigating theimmune response rely on hybridoma technologywhich is timeconsuming and doesnot come close to mimicking the diversity of antibodies present in the organismNext generation sequencing of Bcells can deeply interrogate the immune responsehoweverthis technology falls short of providing insight into the best antibody drugcandidatesWe propose the development of ValensPolywhich will integrate massspectrometrybased proteomics data with next generation sequencing of Bcellsanemerging field called immunoproteogenomicsBy interrogating the immuneresponse at the proteinlevelValensPoly will be able to rank antibody sequencesbased on their abundancewhich is a proxy for specificity to the antigen of interestIt is impossible to sequence all memory Bcells in a host organismtherefore theantibody sequences reported would only represent a small fraction of the antibodiesthat could be presentUsing our patented spectral network approachpioneered inour monoclonal antibody sequencing toolValenswe will be able to recovercomplementaritydefining regionsCDRsof antibodies even when the Bcell wasnot captured for next generation sequencingFinallywe will characterize the broad spectrum of antibodies produced aspart of the immune responsecalled the antibody repertoireIdentifying changes ingermline gene usage and tracking clone abundance and lineage in response toimmunization or across patients is an important component of characterizingdiseases and guiding drug discoveryCharacterization of the antibody response to an infection is an important precursorto antibodybased drug developmentHere we propose a toolValensPolywhichidentify abundant antibody species by integrating mass spectrometry andnucleotide sequencing of mature BcellsOur technology will circumvent the needfor hybridoma development saving over a month of development timeand willconsequently enable novel drug discoveries and shorten drug developmenttimelines