High throughput camelid antibody screening as a drug discovery platform

ABSTRACTMonoclonal antibodies are used for treatment of a wide range of diseases from cancer to infectious diseasesHoweverdevelopment of antibodies with high affinity and specificity is still timeconsuminglabor intensive and unpredictableespecially to low immunogenic or toxic targetsA new approach for rapid development of antibodies against a variety of diseasesespecially against emerging diseases is much neededAbzyme Therapeutics LLC is actively developing animal free antibody discovery platforms to accelerate generation of diagnostic and therapeutic antibodiesPhase I objectives have been successfully completedSpecificallywe have created a so called yeast surface display camelid Self Diversifying VHH Antibody Library or SDALib as a monoclonal antibody generating system providing a diverse array of antibodies in vitrowithout using in vivo immunizationThe main feature of the system is the ability to self generate a library with diversified antibodies by means of hypermutation induction in antibody encoding genesAs proof of principlewe have successfully used the platform to isolate a set of single domain antibodies against NneuraminidaseNAderived from influenza H NvirusObtained VHH antibodies have been shown to express efficiently in a bacterial system providing an opportunity for accelerated scale up of antibody production for therapeutic applicationAnti NA VHH antibodies have been purified and characterized in in vitro assaysAs proof of principle oneFluout of several anti NA VHH antibodiesthat is reactive with NNAs of both H Nand H Ninfluenza viruseshas been humanized preserving the full anti NA activity of the parental moleculeBivalent anti NA antibodies that have been produced in a bacterial system as linear fusions showed a significant increase in antibody activity in in vitro assaysSubsequent efforts of Phase II consist of three specific aims that will be performed simultaneouslyiadvance the Nanti NA antibodies isolated in Phase I toward clinical application by demonstrating both in vitro and in vivo activity against H Nand H Ninfluenza virusesiiexpand the application of the platform for developing antibodies targeting both hemagglutinin and NAs of other influenza virus subtypese gH Nand H Nwhich have unusual zoonotic potential and aiming for antibodies cross reacting with several different neuraminidasesH NH NH Nand H Niiiutilize the antibody discovery platform for developing VHH antibodies against a set of cancer targets followed by production of novel IgG like VHH based bispecific humanized antibodiesPhase II efforts are to further extend the application of the technology for rapid development of novel antibodies to therapeutic targets and to advance humanized anti influenza antibodies isolated in phase I into clinical studies PROPOSED COMMERCIAL APPLICATIONSThe vision of this work is to develop an animal freecosteffective and high throughput platform for rapid generation of monoclonal antibodies against any possible antigenincluding toxinsThe fully developed technology will have broad impact on the accelerated discovery and development of monospecific and multi specific antibodies for treatment of various human diseasesAs a specific result of this projecta set of valuable humanized monospecific and multi specific antibodies against influenza A and cancer targets will be created