Selective Costimulation Blockade With Antagonist Anti-CD28 Therapeutics in Transplantation

Abstract

Nephrotoxicity of calcineurin inhibitors and uncontrolled effector function of alloreactive T lymphocytes are main drivers of transplant dysfunctions. T lymphocytes either directly damage tissues or indirectly promote inflammation and antibody responses. Beside inhibitors of calcium-dependent pathways and anti-metabolites, modulators of T cell costimulation are elected pharmacological tools to enable interference with immune-mediated transplant dysfunctions. CD28 and CTLA-4 are major co-stimulatory and co-inhibitory cell surface signaling molecules interacting with CD80/86, known to be critically important for immune response of committed T cells and regulation. Initial "bench to beside" translation, two decades ago, resulted in the development of belatacept (CTLA4-Ig), a biologic inhibiting interaction of both CD28 and CTLA-4 with CD80/86. Despite proven effectiveness in inhibiting allo-immune responses, clinical use of belatacept in kidney transplantation revealed a substantially high incidence of acute, cell-mediated rejection. The etiology of « belataceptresistant graft rejection » was allocated to elevated pretransplant frequencies of CD28+ memory T cells. Owing to different requirement in CD28 costimulatory and CTLA-4 coinhibitory signals to control naïve and memory T cells, selective antagonists of CD28-CD80/86 interactions have been developed on the rationale that preservation of CTLA4mediated regulatory mechanisms would result in a better control of alloreactivity and would represent a "Treg-compatible" immunosuppression. After the successful testing of selective CD28 antagonists in First In Human studies, this review delineates how this shift in paradigm performed in preclinical transplantation models and evaluates its clinical potential.

Multimarker profiling identifies protective and harmful immune processes in heart failure: findings from BIOSTAT-CHF

“…However, a related process called co-inhibition is mediated by cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), which also binds to CD80/CD86 but has the opposite effect. 43 Biologicals like abatacept and belatacept are recombinant CTLA-4 molecules attached to a human immunoglobulin tail and selectively bind to CD80/CD86. However, this might again negatively affect Tregs as CTLA-4 plays an important role in their function.…”

“…However, this might again negatively affect Tregs as CTLA-4 plays an important role in their function. 43 More recently, there have been attempts to selectively target CD28, such that costimulation is prevented but co-inhibition remains unaffected. Two such biologicals, FR104 and lulizumab pegol, are in development and have shown safety and efficacy in a Phase I trial and a Phase II trial in systemic lupus erythematosus, respectively.…”

“…Two such biologicals, FR104 and lulizumab pegol, are in development and have shown safety and efficacy in a Phase I trial and a Phase II trial in systemic lupus erythematosus, respectively. 43 Two Phase I/II trials with lulizumab pegol in allograft rejection are also currently underway. CD40LG induces B-cell activation and production of CD80/CD86; 44 however, since B-cell activity was not uniformly protective or harmful, the benefits of CD40LG blockade can potentially be derived by selective CD28 blockade as mentioned previously.…”

Costimulation Blockade in Vascularized Composite Allotransplantation

“…In addition, costimulation blockade with agents targeting the B7 molecule, not only inhibit CD28/B7 interaction, but prevent CTLA4/B7 interaction and programmed death-ligand 1 (PD-L1)/B7 interaction and T-cell co-inhibition. Impairment of T-cell co-inhibition results in ineffective control of alloreactive T-cell activation, including effector memory T cells and Th17 cells ( 119 , 126 , 127 ).…”

Belatacept and CD28 Costimulation Blockade: Preventing and Reducing Alloantibodies over the Long Term

“…As the only costimulation blocker approved for transplantation, belatacept is currently finding its way into broader scale clinical practice. However, we recently reported effective long-term use of costimulation blockade with abatacept (approved for use in rheumatoid arthritis) in a small series of CNI intolerant renal transplant recipients [16], and early phase clinical trials are underway with next-generation selective CD28 costimulation blocking agents by our group and others [17]. Therefore, costimulation blockade as an immunosuppressive strategy, either in the form of belatacept, its predecessor abatacept, or next-generation selective CD28 blockade, is poised to be instrumental in the development of novel methods of combating and reducing the detrimental impact of HLA antibodies in transplantation over the long term.…”