CD40-CD40L Blockade: Update on Novel Investigational Therapeutics for Transplantation

Abstract

Effective immune responses require antigen presentation by major histocompatibility complexes with cognate T-cell receptor and antigen-independent costimulatory signaling for T-cell activation, proliferation, and differentiation. Among several costimulatory signals, CD40-CD40L is of special interest to the transplantation community because it plays a vital role in controlling or regulating humoral and cellular immunity. Blockade of this pathway has demonstrated inhibition of donor-reactive T-cell responses and prolonged the survival of transplanted organs. Several anti-CD154 and anti-CD40 antibodies have been used in the transplantation model and demonstrated the potential of extending allograft and xenograft rejection-free survival. The wide use of anti-CD154 antibodies was hampered because of thromboembolic complications in transplant recipients. These antibodies have been modified to overcome the thromboembolic complications by altering the antibody binding fragment (Fab) and Fc (fragment, crystallizable) receptor region for therapeutic purposes. Here, we review recent preclinical advances to target the CD40-CD40L pair in transplantation.

Causality of genetically proxied immunophenotypes on cardiovascular diseases: a Mendelian randomization study

“…Conversely, another study showed that CD40L was associated with markers of inflammation, it did not independently serve as a risk marker for stroke ( 33 ). In addition, severe immunosuppression and unexpected thromboembolic events have been reported in preclinical and clinical trials involving anti-CD40L ( 34 , 35 ). However, these observational associations are insufficient to establish a causal relationship between CD40 and stroke.…”

Costimulatory Blockade and Solid Organ Transplantation: The Past, Present, and Future

“…Beyond the CD28-CD80/86 costimulatory pathways, other therapeutics targeting the CD40-CD154 costimulatory pathway are also in preclinical study and have shown special promise as the cornerstone of immunosuppression in several preclinical xenotransplant models, 125 and early phase efforts in kidney allotransplantation persist with Fc modified agents that do not precipitate platelet aggregation or thrombosis ( ClinicalTrials.gov NCT05027906). The most notable of these studies is a phase 2a trial evaluating dual costimulation blockade with dazodalibep (Fc silent CD40L protein antagonist, VIB4920 or HZN4920) and belatacept with thymoglobulin induction for prophylaxis of kidney allograft rejection (NCT04046549).…”

Genetic diversity, growth and heart function of Auckland Island pigs, a potential source for organ xenotransplantation

“… 8, 9 ), other important steps for successful cardiac xenotransplantation involve perfusion preservation of the pig hearts, 10 non‐nephrotoxic immunosuppression of the recipients involving T cell co‐stimulation blockade ( 1 ; reviewed in ref. 11 ), and controlling the post‐transplantation growth of the pig hearts (reviewed in refs. 9, 12 ).…”