Safe and effective anti CD154 antibodies for therapeutic intervention

DESCRIPTION provided by applicant In both animal proof of concept studies and preliminary clinical trials there is ample data demonstrating the potential therapeutic benefits o CD blockade for treatment of GVHD organ transplantation and autoimmune diseases However development of CD as a therapeutic has been impeded by antibody toxicity observed in early clinical trials GVHD is a complication of allogeneic Hematopoietic Stem Cell Transplantation HSCT GVHD remains a major cause of mortality in approximately of patients who survive andgt year post transplant The standard of care is limited to drugs that need to be taken long term work moderately well and are associated with significant side effects There is therefore profound unmet need and significant potential for drugs that are safe and efficacious Studies in GVHD have demonstrated that anti CD acts as a prophylactic and is effective as a monotherapy as demonstrated in NHP where permanent allograft tolerance can be achieved using short courses of treatments comprised of CD alone This strategy eliminates the use of steroids and calcineurin inhibitors both of which are associated with numerous side effects CD thus has a competitive advantage as most other drugs in development will require some form of combination therapy with either steroids or calcineurin inhibitors A similar opportunity for improved clinical outcomes due to effective induction of tolerance exists in recipients of solid organ transplants Furthermore virtually all autoimmune disease models can be effectively ameliorated with CD therapy with long term remission observed We will target GVHD and chronic rejection associated with transplantation as our first clinical indication for commercial development Existing studies strongly suggest that domains within the Fc region of the CD mAb contribute to its toxicity and therapeutic capacity When toxicity was observed in the clinic and retrospectively in NHP modifications were made to the antibody while these modifications eliminated toxicity in NHP the efficacy of CD as a tolerogenic antibody also was significantly reduced As a result development programs for CD as a therapeutic stalled In Phase studies we identified modifications that resulted in safe and efficacious versions of CD as tested in murine models The goal of this proposal is to build on those observations and generate variant forms of the human CD antibody that retain the beneficial tolerogenic effects of CD while greatly reducing or eliminating toxicity Variant forms of the antibody will be evaluated for both safety and efficacy in NHP models Successful proof of concept in NHP transplant models will be the basis for creating a novel therapeutic which could have far reaching impacts on the treatment of autoimmune diseases and organ transplantation PUBLIC HEALTH RELEVANCE Development of CD as a therapeutic for autoimmune diseases and transplantation has shown great promise in human clinical trials but development has been hindered by problems with antibody toxicity In the past when toxicity was reduced the efficacy of the antibody was dramatically decreased leading to the suspension of developmental programs This project will engineer new variants of the CD antibody that will eliminate toxicity while maintaining tolerogenicity thus allowing the potential of CD to be harnessed as a novel treatment for a wide range of diseases