Belatacept, the first new agent approved for cornerstone immunosuppression in transplantation in over 20 years, offers a significant benefit to transplant recipients in that it carries a 43% reduced risk of death or graft loss after 7 years as compared to calcineurin inhibitor-based regimens which confer a significant risk of CNI- based renal toxicity. However, belatacept confers an increased risk of acute rejection as compared to tacrolimus, a fact that has limited its uptake in the clinical transplant community and limited access of patients to its considerable benefits. We hypothesized that one reason underlying this increased rejection is due to the fact that belatacept binds to CD80 and CD86, thus blocking the ligands for CTLA-4-mediated coinhibition (in addition to the intended effect of blocking CD28). As such, over the last 7 years we have partnered with Bristol- Myers Squibb to test a new ?next-generation? CD28 blocker that we postulated would better control alloreactive T cell responses and limit graft rejection. In the first phase of pre-clinical investigation in a murine model, we demonstrated that a novel anti-CD28 domain antibody that specifically binds to and blocks CD28 signaling, leaving CTLA-4 coinhibition intact, more potently prolonged graft survival as compared to CTLA-4 Ig. Our team moved on to test the human version of the anti-CD28 dAb (lulizumab) in our non-human primate pre- clinical transplant model. Importantly, results reveal that the anti-CD28 dAb is superior to belatacept in prolonging allogeneic renal allograft survival in rhesus macaques. Moreover, lulizumab is available in a formulation for subcutaneous administration, eliminating the need for intravenous infusions that require sufficient infrastructure as well as frequent patient visits to an infusion center. Thus, based both on its predicted increased efficacy as well as improved ease of administration, lulizumab has the potential to be transformative immunosuppression for transplant recipients. Given the dearth of other novel reagents in the pipeline, lulizumab currently holds the most promise for significantly improving immunosuppression following transplantation. Thus, we propose a randomized, Phase II clinical trial to test the ability of lulizumab as primary immunosuppression to maintain excellent renal function vs. standard-of-care tacrolimus, with the primary endpoint being eGFR at one year post-transplant. Importantly, without federal funding to support this trial it is likely that lulizumab will never have the opportunity to be tested as immunosuppression for transplantation. Thus, the proposed trial is significant because it has the potential to bring to the transplant population a novel immunosuppressive regimen that is 1) less toxic than current CNI-based regimens, 2) more efficacious at preventing acute rejection than current belatacept-based regimens, and 3) easier and more convenient for patients. Advanced monitoring of clinical outcomes coupled with highly granular and hypothesis driven-mechanistic studies will illuminate new knowledge of cosignaling pathways in human immunology, and has the potential to significantly improve quantity and quality of life for renal transplant recipients.
Transplantation is a curative treatment for end-stage organ failure, but rates of significant side effects remain unacceptably high. A new drug targeting T cell costimulatory pathways (belatacept) has shown great promise as a less toxic means of preventing T cell responses, however clinical trials have revealed increased rates of acute rejection in belatacept-treated patients. Selective CD28 blockade that targets only CD28-mediated costimulatory signals and leaves CTLA-4-mediated coinhibitory signals intact may confer better immunosuppression for transplant patients; thus, in this application we will explore the therapeutic potential and mechanisms of targeting this novel pathway to control alloreactive T cell function and inhibit graft rejection following transplantation.
|Crepeau, Rebecca L; Ford, Mandy L (2017) Challenges and opportunities in targeting the CD28/CTLA-4 pathway in transplantation and autoimmunity. Expert Opin Biol Ther 17:1001-1012|