Structure Based Design of Humanized Monoclonal Antibodies that Recognize Bioactiv

DESCRIPTION (provided by applicant): Currently, there are over 20 therapeutic antibodies on the market. It is the fastest growing segment of therapeutics largely because humanized mAbs have excellent safety profiles. The huge success of antibody molecular sponges like Avastin, Lucentis, Humira and Remicade have demonstrated that use of antibody therapeutics in this mode can be effective in the treatment of cancer, AMD, inflammatory and autoimmune disorders. Rather than directing antibodies against protein targets, Lpath has been successful in generating therapeutic monoclonal antibodies (mAbs) against a novel class of therapeutic targets, bioactive lipids. The first bioactive lipid target was sphingosine-1-phosphate (S1P) and our anti-S1P mAbs are in Phase I clinical trials for both cancer and age-related macular degeneration. We have recently humanized a mAb against lysophosphatidic acid (LPA) which is a validated tumorigenic bioactive lipid that also contributes to diseases of dysregulated fibrosis and neuropathic pain. We intend to use this Phase 1 SBIR grant to solve the crystal structures of our first two humanized mAbs in complex with their ligands, and we have promising preliminary data demonstrating feasibility of this approach. We hypothesize that we can use the Xray-derived structures to assemble a library of antibody framework scaffolds and complementarity determining regions (CDRs) that can be used to develop new therapeutic mAbs that will target novel bioactive lipids involved in inflammatory, heart and other disorders that will be of interest to the general medical community. Depending on the structures we obtain in the Phase 1 effort, we will propose for a Phase 2 SBIR using an in silico rational drug design method to design and produce novel therapeutic antibodies against valuable lipid targets without having to immunize mice, produce monoclonal antibodies and engage in a costly and time- consuming humanization effort. We have two bioactive lipids in mind for the Phase 2 effort but need the structural information that will be obtained in the Phase 1 activities to validate our new drug discovery platform. These techniques will be used to engineer monoclonal antibodies with specificities for other novel lipid targets as the platform grows. This technology will provide researchers a new tool for studying lipid pathways, metabolism and signaling and hopefully arms clinicians with powerful new weapons against lipid-based pathologies. As lipidomics emerges as an important field in medicine and as more bioactive lipids become implicated in human disease, antibodies that recognize lipids and other non-proteinaceous targets will likely play a significant role in biomedical research. PUBLIC HEALTH RELEVANCE: Biologically active lipids are now recognized by the scientific community to be important mediators of several physiologic and pathological processes. These signaling molecules have been implicated in a wide variety of human pathologies including cancer, inflammatory, neurodegenerative diseases, dysfunctional fibrosis and many other grievous illnesses. Lpath Inc. has developed two unique monoclonal antibodies (mAbs) which function as molecular sponges to bind and neutralize the bioactive lipids sphingosine-1-phosphate (S1P) and lysophosphatidic acid (LPA). Considering the huge successes of Avastin, Lucentis and Remicade, this antibody-based therapeutic approach has become the focus of intense investigations in treatment of multiple diseases. An urgent need exists to understand how this novel class of anti- lipid mAbs can recognize their targets and neutralize their biological effects. The information gained from this project will be critical to design and develop new mAbs against the potentially thousands of additional clinically-relevant bioactive lipids.