Humanized Anti-Renalase Antibodies for Unresectable Melanoma

Project Summary AbstractThis project brings together an experiencedintegrated project team with complementary expertise to advance a new approach to treating melanomas that cannot cured by surgery and have spread in the bodyThe project attacks a new targetrenalasean endogenous protein that can function as a survival factorwhich becomes overexpressed in melanomaand plays a role in suppressing the body s host defense to protect the tumorMelanoma incidence is the highest of all cancersand despite significant advances in systemic therapies that prolong survivalthe death rate from melanoma has increased byfromtoThese statistics underscore the urgent need for new therapiesSeveral lines of data point to renalase as a target for melanomaRenalase expression is higher in metastatic than in primary tumors in patients and these patients have worse outcomesPreventing renalase production in cancer cells through siRNA in tissue culture or in mouse melanoma models dramatically decreases tumorsNormal mice lacking the renalase genehave a normal life expectancy and are resistant to melanomafurther suggesting renalase is a feasible targetRenalase is overexpressed by tumor associated macrophages and facilitates tumor growth through a known cancer signaling pathwaySTATRabbit antibodies have been generated that can recognize renalase and these antibodies block or reduce melanoma in mouse modelsOf high interestin initial studies using melanoma cell lines resistant to current immunotherapiesour antibodies were effective both as single agents and were synergistic when used in combination with existing immunotherapiesThis project is designed to translate these results toward a therapeutic product and specifically to humanize several candidate antibodies and evaluatecharacterize and prioritize them preclinicallyThe project will deliver an innovative lead humanized renalase antibody and back up drugs poised for scale upfurther developmentincluding toxicological and pharmacologic evaluationand ultimatelyan IND submission to conduct clinical trials Project Narrative This is a PhaseSBIR application to develop a new therapy for advanced melanomaa disease for which cures are uncommon anddespite significant advances in systemic therapiesthe death rate has continued to increaseWe have discovered a new drug targetrenalasewhose over expression in patients is associated with the worst outcomesThe therapy being developeda humanized monoclonal antibody directed against renalaseis an innovative therapeutic with potential as a precision medicine to reduce melanoma tumor growthand act synergistically with immune checkpoint inhibitorsincluding in patients resistant to current drugs