Thanks to their exquisite specificity and sensitivity, monoclonal antibodies (Mab) have found a broad application in research, diagnosis and therapy. For treatment of human diseases, fully human antibodies are the most desirable as they are generally not immunogenic and well-tolerated. While there are several existing approaches for generation of antibodies, the processes are still time-consuming, labor-intensive, and unpredictable of success. To simplify and to accelerate the generation of fully human antibodies, a novel non-animal approach for antibody production is proposed. The objective will be achieved by using a Self-Diversifying Human Antibody Library (SHALib) effectively displayed on yeast cell surface. SHALib will provide a diverse array of antibodies in vitro, without the need of animal immunization and potential necessary humanization of the antibody. Starting from a naive antibody library from healthy human donors, antibodies with high-affinity and specificity to various targets will be generated and selected through repeated rounds of systematic evolution by somatic hypermutation, target-specific enrichment and fluorescence-activated cell sorting. Since this is a non-animal system, the platform can generate human antibodies against toxins, pathogens, self-antigens, and the like which are by nature difficult to obtain. As a proof-of-principle, in phase I, we will develop human antibodies to five selected targets of therapeutic importance. The targets are for the treatment of high cholesterol (PCSK9), rheumatoid arthritis (MMP1 and MMP13) and cancer (MMP7 and regulatory T cell protein CD25). In Phase II, the platform will be used to develop human monoclonal antibodies to at least 50 targets that are involved in different human diseases. The platform will allow generating quickly human monoclonal antibodies that are of therapeutic potential.
As result of this project, an innovative approach for rapid generation of human monoclonal antibodies will be developed and valuable antibody reagents for treatment of human diseases will be generated. The platform will have a broad application in accelerating generation of human antibodies of therapeutic significance.
