The role of novel therapeutic approaches for prevention of allosensitization and antibody-mediated rejection

Abstract

Modification of pathogenic antibodies and their effector functions in autoimmune diseases or use of B cell/plasma cell-directed anticancer therapies have illuminated the biologic relevance of B cells, plasma cells (PCs), and pathogenic antibodies and complement in alloimmunity. They have also rejuvenated interest in how B cells mediate multiple effector functions that include antibody production, antigen presentation to T cells, costimulation, and the production of immune stimulating and immune modulatory cytokines that drive dysfunctional immune responses. Current methods to reduce alloantibodies are only modestly successful. Rituximab is used for desensitization and antibody-mediated rejection (AMR) treatment by targeting CD20 found on B-lymphocytes. However, PCs do not express CD20, likely explaining the limited success of this approach. Intravenous immunoglobulin and plasmapheresis (PLEX) have limited success due to antibody rebound. Despite attempts to develop tolerable therapeutics for management of AMR, none, to date, have been universally accepted or obtained Food and Drug Administration approval. Lack of approved therapeutics often results in patients having a much shorter graft survival due to AMR. Repurposing drugs from autoimmunity and cancer immunotherapy has rapidly yielded important advancements in the care of AMR patients. Here we discuss emerging therapeutics aimed at prevention and treatment of AMR. K E Y W O R D S clinical research/practice, immunosuppression/immune modulation, kidney transplantation/ nephrology, rejection: antibody-mediated (ABMR), sensitization | 43 JORDAN et Al.

IL-6 Directed Therapy in Transplantation

“…A single-center, phase I/II investigator-initiated study (NCT03380377) aims to evaluate the safety and tolerability of monthly clazakizumab administration in 10 DSApositive kidney transplant recipients with biopsy-proven cAMR and transplant glomerulopathy [121,129]. At 18month follow-up, there were sustained reductions in mean DSA relative intensity scores, stabilization of renal function, and increased Tregs, without drug-related serious Abbreviations: TCZ, tocilizumab; cPRA, calculated panel reactive antibody; DES, desensitization; ESRD, end-stage renal disease; DSA, donor-specific antibody; AMR, antibody-mediated rejection; TG, transplant glomerulopathy; ACR, acute cellular rejection; AE, adverse event; SAE, serious adverse event; cAMR, chronic antibody-mediated rejection; Treg, regulatory T-cell; MFI, mean fluorescence intensity adverse events.…”

HLA Desensitization in Solid Organ Transplantation: Anti-CD38 to Across the Immunological Barriers

“…Indeed, antibody rebound due to plasma cells (PC), which do not express CD20, limit the efficacy of the most commonly used strategy combining IGIV, plasmapheresis and B cell depletion by anti-CD20 depleting agent. Targeting PC with new pharmacological tool from autoimmunity and cancer research could allow a better management of the humoral response in desensitization protocols ( 37 ). In the germinal center, after the enhancement of alloantigen responses by T follicular helper (Tfh), activated B cells develop into memory-B cells, progress to plasmablasts and ultimately to antibody-producing PC ( 38 , 39 ).…”

“…These PC are the long-lived mediators of lasting humoral immunity and persist in medullary niche where they can secrete high-affinity complement-activating DSAs ( 38 , 40 ). Several emerging strategies aim to deplete PCs compartment in order to prevent ABMR ( 37 , 41 ). First, Interleukin 6 (IL-6) is a cytokine promoting Tfh and enhancing the progression of B cells to high-affinity antibodies producing PC ( 42 ).…”

“…Clazakizumab is a humanized IgG1 mAb with specificity for IL6 which can also induce circulating DSA reduction ( 45 ). Both Tocilizumab and Clazakizumab are pharmacological agents with major interest in the development of desensitization strategies targeting PC ( 37 , 46 ). On another hand, proteasome inhibitors represent one of the most promising solution to deplete PC in the setting of desensitization, targeting more selectively PCs population.…”

Measuring the Impact of Targeting FcRn-Mediated IgG Recycling on Donor-Specific Alloantibodies in a Sensitized NHP Model

“…A high affinity monoclonal antibody that targets the FcRn, Rozanolixizumab, has been developed and tested in cynomolgus monkeys, as well as humans ( 15 , 16 ). Therapeutically, blocking the FcRn is actively being investigated for its role in the treatment of IgG-mediated diseases, such as myasthenia gravis, and primary immune thrombocytopenia ( 17 ), and has been reported as a potential agent in the setting of AMR in transplantation both for its direct effect on lowering circulating antibody levels, and as a mechanism to be exploited with respect to maintaining circulating drug levels of IgG-based therapeutics ( 18 , 19 ). However, it has not been tested in rhesus macaque models of sensitization or IgG-mediated pathology.…”