The introduction of calcineurin inhibitor to kidney transplantation has significantly improved patient and graft survival and became the standard of treatment. However, nephrotoxicity and significant adverse metabolic effects have stimulated other noncalcineurin inhibitor immunosuppressive strategies. Blockades of critical costimulatory pathways (such as CD28−CD80/86 and CD40−CD154 interaction) were shown to prolong allograft survival in murine transplant models and led to development of clinical trials in humans.1 Belatacept, cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) fused with an immunoglobulin Fc domain (CTLA4-Ig), a potent CD28 antagonist, is the first costimulatory blockage agent with long-term clinical experience. Although, belatacept demonstrated superior measured glomerular filtration rates up to 10 y after transplantation with better lipid profile, blood pressure and glucose control, increased incidence, and severity of acute rejection rates observed at initial studies and chronic intravenous (IV) infusion requirement have limited the widespread adoption.2 While belatacept, which blocks both the activating and inhibitory pathways, there are multiple costimulation blockade drugs are currently in the clinical pipeline that antagonize CD28−CD80/86 interaction while leaving inhibitory signaling mediated by CTLA-4 interaction with CD80/86 unimpaired.3,4 It has been proposed that selectively targeting CD28 might have the benefit of CTLA4-Ig without effecting the coinhibitory CD80/86–CTLA-4 pathway and might present a superior immunosuppressive index as compared with CTLA4-Ig by preserving regulatory T cells functions. First-generation anti-CD40 ligand (CD40L; CD154) antibodies could directly bind to CD40L on platelets, leading to platelet activation, aggregation, and thromboembolic complications were reported in kidney transplant recipients.4 An anti-CD40L-specific monoclonal antibody, AT-1501 (Tegoprubart), was engineered to minimize the risk of thromboembolic complications by reducing binding to Fcγ receptors expressed on platelets while preserving binding to CD40L and was tested in both a cynomolgus macaque model of intrahepatic islet allotransplantation and a rhesus macaque model of kidney allotransplantation.5 AT-1501 is currently being investigated in kidney transplantation (NCT05027906). A phase 2a trial evaluated dual costimulation blockade with dazodalibep (Fc silent CD40L protein antagonist, VIB4920 or HZN4920) and belatacept with thymoglobulin induction for prophylaxis of rejection as the sole maintenance therapy in adults undergoing first, nonidentical kidney transplants from deceased or living donors (NCT04046549).6 Twenty patients received a revised dosing regimen, and 25% experienced biopsy-proven Banff grade 2A or 2B acute T-cell–mediated rejections and discontinued study therapy. No antibody-mediated rejection or thrombotic events were observed. While the prespecified primary endpoint to prevent composite efficacy failure was not met among patients who completed this study, dazodalibep and belatacept dual biologic treatment was generally safe and well-tolerated. Three CD40 antagonists have been studied in kidney transplantation, bleselumab (ASKP1240), iscalimab (CFZ-533), and KPL-404.4 Anti-CD40 antibodies do not interfere with platelet aggregation because platelets do not express CD40 on their surface. A phase 2, randomized, open label, noninferiority study of bleselumab with either mycophenolate mofetil (MMF) or immediate‐release tacrolimus compared with standard of care >36 mo posttransplant.7 Bleselumab with MMF did not meet the noninferiority criteria and demonstrated a greater incidence of biopsy-proven rejection at month 6 or 36 when compared with bleselumab and immediate‐release tacrolimus and standard of the care with tacrolimus and mycophenolate. Iscalimab phase II study8 was discontinued in kidney transplant recipients and KPL-404 was incorporated into a maintenance regimen with MMF and corticosteroids in the first pig-to-human cardiac xenotransplantation. A partly agonistic anti-CD28 antibody used in phase I trial (TGN1214) reported life-threatening complications because of cytokine storm. Lulizumab pegol (BMS 931699) is another anti-CD28 agent investigated in phase II clinical trial of kidney transplant recipients but the trial was prematurely terminated because of limited availability of the study drug and difficulties in enrollment. IV use of VEL-101, also known as pegrizeprument, a monovalent, humanized, anti-CD28 polyethylene glycosylated monoclonal antibody fragment that selectively blocks CD28−CD80/86 interaction while sparing CTLA-4 inhibition was investigated in a randomized, double-blind, placebo-controlled, phase 1 study in healthy adults (FR104-CT01 study).9 Results showed that VEL-101 was well-tolerated, and there were no cases of cytokine release syndrome. Unlike TGN1412, partly agonistic anti-CD28 antibody, VEL-101 targets a nonactivating CD28 epitope, preventing cross-linking CD28 receptors that could result in CD28 activation and avoids cytokine storm. In this issue of Transplantation Journal,10 the safety, tolerability, pharmacokinetics, and pharmacodynamics of single subcutaneous (SC) administration of VEL-101 was investigated in a randomized, double-blind, placebo-controlled, dose escalation, phase 1 study (NCT05238493). Sixty healthy participants were randomly assigned to receive 1 of 7 dose levels of VEL-101 (n = 46) or placebo (n = 14; 2 IV and 5 SC) and followed for 50 d. Treatment-related adverse events occurred in 21 participants (45.7%) who received VEL-101 and 4 participants (28.6%) who received placebo and most related to injection site pain and considered mild or moderate in severity. One serious adverse effect of rhabdomyolysis occurred in a participant who received VEL-101 25 mg SC with an elevated creatine kinase above the upper limit of quantitation of the assay (>50 000 U/L) at day 8 requiring hospitalization. The participant was treated with IV fluids and discharged after an approximately 3-d hospitalization. The event was resolved on study day 15 and did not result in study drug discontinuation or study withdrawal. Some participants at higher and lower doses, as well as participants in the placebo group (>40%), had some transient elevations of creatinine kinase above the upper limit of normal, but all were asymptomatic. Rhabdomyolysis was not reported at the VEL-101 first human phase 1 trial, but 1 participants did not receive the study drug because of taking medications for adverse event of myalgia. The authors mentioned that future studies will monitor creatine kinase as part of routine safety monitoring. No clinically significant elevations in cytokine levels and no cases of cytokine release syndrome were observed in the study. Ten of 41 participants developed anti-drug antibodies, with most being observed on day 50, after participants had cleared or mostly cleared all VEL-101 but it did not impact pharmacokinetic and pharmacodynamic properties. Pharmacodynamic analyses showed that all SC VEL-101 dose levels resulted in sustained ≥50% CD28 receptor occupation, with many dose levels resulting in sustained ≥80% CD28 receptor occupation. In summary, SC administration of VEL-101 was well-tolerated in healthy participants with detectable CD28 receptor occupancy levels acceptable for future study in kidney transplant recipients. Veloxis Pharmaceuticals plans to initiate a phase II randomized, multicenter, partially blinded, active control study to evaluate the safety and effectiveness of VEL-101 compared with tacrolimus in the prevention of rejection in patients undergoing kidney transplantation in July 2026 (RENGEVITY-201 trial, NCT07290777). This phase II trial will give more information about future use of VEL-101 in kidney transplant recipients.
Enver Akalin (Mon,) studied this question.