AT-1501 for Kidney Transplant
Recruiting in Palo Alto (17 mi)
+5 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1 & 2
Recruiting
Sponsor: Eledon Pharmaceuticals
Must not be taking: Immunosuppressants, Biologics, Steroids
Disqualifiers: Previous transplants, Anticoagulation, others
No Placebo Group
Trial Summary
What is the purpose of this trial?This study will evaluate the safety, PK, and efficacy of AT 1501 in patients undergoing kidney transplantation.
Do I have to stop taking my current medications for the trial?
The trial requires that you are not currently treated with any systemic immunosuppressive regimen, except for 5 mg prednisone or equivalent daily. If you are on other immunosuppressive medications, you may need to stop them to participate.
What data supports the idea that AT-1501 for Kidney Transplant is an effective drug?
The available research shows that AT-1501, when tested in nonhuman primates, led to long-term survival of kidney transplants. This suggests that it effectively prevents the body from rejecting the new kidney. Additionally, AT-1501 was found to be safer than previous treatments because it was designed to reduce the risk of blood clots. Compared to conventional treatments, AT-1501 also resulted in better overall health outcomes, such as higher levels of a protein that indicates good kidney function and fewer viral infections. This data supports the idea that AT-1501 is an effective and safer option for kidney transplant patients.
12345What safety data exists for AT-1501 (Tegoprubart) in kidney transplants?
AT-1501, also known as Tegoprubart, is an anti-CD40 ligand monoclonal antibody designed to minimize thromboembolic complications. In nonhuman primate models, AT-1501 demonstrated long-term graft survival and function in both islet and kidney transplants without significant safety concerns. It showed reduced cytomegalovirus reactivation and no thromboembolic events, supporting its safety and efficacy for further clinical trials.
13567Eligibility Criteria
This trial is for adults over 18 receiving their first kidney transplant from a living or deceased donor. It's not for those who've had previous transplants, are on current immunosuppressives (except low-dose prednisone), have used AT-1501 or similar drugs before, or will get kidneys with long cold times (>30 hours) or from donors meeting certain criteria like age and health conditions.Inclusion Criteria
I am 18 years old or older.
Agree to comply with contraception requirements during and for at least 90 days after the last administration of study drug
I have received my first kidney transplant.
Exclusion Criteria
My kidney donor matches one of the specific criteria needed.
I have never been treated with AT 1501 or any anti CD40LG therapy.
I am not on strong immune system suppressing drugs, except for a low dose of prednisone.
+4 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
1 visit (in-person)
Treatment
Participants receive AT-1501 in combination with rATG induction, corticosteroids, and mycophenolate as maintenance therapy
12 months
Multiple visits (in-person) on Days 0, 7, 14, 21 and Months 1, 3, 6, 9, 12
Follow-up
Participants are monitored for safety and effectiveness after treatment
8 months
Visits at Months 12 and 15
Open-label extension (optional)
Participants may opt into continuation of treatment long-term
Long-term
Participant Groups
The study tests the safety, how the body processes (pharmacokinetics), and effectiveness of a drug called AT-1501 in patients getting a kidney transplant. Participants will receive this medication to see if it helps prevent organ rejection without causing significant harm.
1Treatment groups
Experimental Treatment
Group I: AT-1501 Single ArmExperimental Treatment1 Intervention
AT-1501 monoclonal antibody targeting CD40L given as an IV infusion
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Vancouver General HospitalVancouver, Canada
McGill University Health Care CentreMontréal, Canada
Providence Health Care - St. Paul's HospitalVancouver, Canada
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Who Is Running the Clinical Trial?
Eledon PharmaceuticalsLead Sponsor
References
The anti-CD40L monoclonal antibody AT-1501 promotes islet and kidney allograft survival and function in nonhuman primates. [2023]Prior studies of anti-CD40 ligand (CD40L)-based immunosuppression demonstrated effective prevention of islet and kidney allograft rejection in nonhuman primate models; however, clinical development was halted because of thromboembolic complications. An anti-CD40L-specific monoclonal antibody, AT-1501 (Tegoprubart), was engineered to minimize risk of thromboembolic complications by reducing binding to Fcγ receptors expressed on platelets while preserving binding to CD40L. AT-1501 was tested in both a cynomolgus macaque model of intrahepatic islet allotransplantation and a rhesus macaque model of kidney allotransplantation. AT-1501 monotherapy led to long-term graft survival in both islet and kidney transplant models, confirming its immunosuppressive potential. Furthermore, AT-1501-based regimens after islet transplant resulted in higher C-peptide, greater appetite leading to weight gain, and reduced occurrence of cytomegalovirus reactivation compared with conventional immunosuppression. These data support AT-1501 as a safe and effective agent to promote both islet and kidney allograft survival and function in nonhuman primate models, warranting further testing in clinical trials.
Effects of ASKP1240 combined with tacrolimus or mycophenolate mofetil on renal allograft survival in Cynomolgus monkeys. [2021]Blocking the CD40-CD154 signal pathway has previously shown promise as a strategy to prevent allograft rejection. In this study, the efficacy of a novel fully human anti-CD40 monoclonal antibody-ASKP1240, administered as a monotherapy or combination therapy (subtherapeutic dose of tacrolimus or mycophenolate mofetil), on the prevention of renal allograft rejection was evaluated in Cynomolgus monkeys.
Treatment with humanized monoclonal antibody against CD154 prevents acute renal allograft rejection in nonhuman primates. [2022]CD154 is the ligand for the receptor CD40. This ligand-receptor pair mediates endothelial and antigen-presenting cell activation, and facilitates the interaction of these cells with T cells and platelets. We demonstrate here that administration of a CD154-specific monoclonal antibody (hu5C8) allows for renal allotransplantation in outbred, MHC-mismatched rhesus monkeys without acute rejection. The effect persisted for more than 10 months after therapy termination, and no additional drug was required to achieve extended graft survival. Indeed, the use of tacrolimus or chronic steroids seemed to antagonize the anti-rejection effect. Monkeys treated with antibody against CD154 remained healthy during and after therapy. The mechanism of action does not require global depletion of T or B cells. Long-term survivors lost their mixed lymphocyte reactivity in a donor-specific manner, but still formed donor-specific antibody and generated T cells that infiltrated the grafted organ without any obvious effect on graft function. Thus, therapy with antibody against CD154 is a promising agent for clinical use in human allotransplantation.
A novel fully human anti-CD40 monoclonal antibody, 4D11, for kidney transplantation in cynomolgus monkeys. [2021]CD40-CD154 pathway blockade by anti-CD154 monoclonal antibodies (mAbs) significantly prolongs allograft survival in nonhuman primates. However, thromboembolic complications have prevented clinical application. Thus, blockade of the counter molecule by a novel fully human anti-CD40 mAb, 4D11, is an attractive alternative.
The Inhibition of CD40/CD154 Costimulatory Signaling in the Prevention of Renal Transplant Rejection in Nonhuman Primates: A Systematic Review and Meta Analysis. [2022]The prevention of allograft transplant rejection by inhibition of the CD40/CD40L costimulatory pathway has been described in several species. We searched pubmed for studies reporting the prevention of kidney transplant rejection in nonhuman primates utilizing either anti CD40 or anti CD40L (CD154) treatment. Inclusion of data required treatment with anti CD40 or anti CD154 as monotherapy treatment arms, full text available, studies conducted in nonhuman primate species, the transplant was renal transplantation, sufficient duration of treatment to assess long term rejection, and the reporting of individual graft survival or survival duration. Eleven publications were included in the study. Rejection free survival was calculated using the Kaplan-Meier (KM) life test methods to estimate the survival functions. The 95% CI for the medians was also calculated. A log-rank test was used to test the equality of the survival curves between control and treatment arms (CD40 and CD154). The hazard ratio for CD154 compared to CD40 and 95% CI was calculated using a Cox proportional-hazards model including treatment as the covariate to assess the magnitude of the treatment effect. Both anti CD40 and anti CD154 treatments prevented acute and long term graft rejection. The median (95% CI) rejection free survival was 131 days (84,169 days) in the anti CD40 treated animals and 352 days (173,710 days) in the anti CD154 treated animals. Median survival in the untreated animals was 6 days. The inhibition of transplant rejection was more durable in the anti CD154 group compared to the anti CD40 group after cessation of treatment. The median (95% CI) rejection free survival after cessation of treatment was 60 days (21,80 days) in the anti CD40 treated animals and 230 days (84,552 days) in the anti CD154 treated animals.
Fc-Silent Anti-CD154 Domain Antibody Effectively Prevents Nonhuman Primate Renal Allograft Rejection. [2023]The advent of costimulation blockade provides the prospect for targeted therapy with improved graft survival in transplant patients. Perhaps the most effective costimulation blockade in experimental models is the use of reagents to block the CD40/CD154 pathway. Unfortunately, successful clinical translation of anti-CD154 therapy has not been achieved. In an attempt to develop an agent that is as effective as previous CD154 blocking antibodies but lacks the risk of thromboembolism, we evaluated the efficacy and safety of a novel anti-human CD154 domain antibody (dAb, BMS-986004). The anti-CD154 dAb effectively blocked CD40-CD154 interactions but lacked crystallizable fragment (Fc) binding activity and resultant platelet activation. In a nonhuman primate kidney transplant model, anti-CD154 dAb was safe and efficacious, significantly prolonging allograft survival without evidence of thromboembolism (Median survival time 103 days). The combination of anti-CD154 dAb and conventional immunosuppression synergized to effectively control allograft rejection (Median survival time 397 days). Furthermore, anti-CD154 dAb treatment increased the frequency of CD4+ CD25+ Foxp3+ regulatory T cells. This study demonstrates that the use of a novel anti-CD154 dAb that lacks Fc binding activity is safe without evidence of thromboembolism and is equally as potent as previous anti-CD154 agents at prolonging renal allograft survival in a nonhuman primate preclinical model.
The CD40-CD154 co-stimulation pathway mediates innate immune injury in adriamycin nephrosis. [2017]Blockade of CD40-CD40 ligand (CD154) interactions protects against renal injury in adriamycin nephropathy (AN) in immunocompetent mice. To investigate whether this protection relied on adaptive or cognate immunity, we tested the effect of CD40-CD154 blockade in severe combined immunodeficient (SCID) mice.
TNX-1500, a crystallizable fragment-modified anti-CD154 antibody, prolongs nonhuman primate renal allograft survival. [2023]The blockade of the CD154-CD40 pathway with anti-CD154 monoclonal antibody has been a promising immunomodulatory approach to prevent allograft rejection. However, clinical trials of immunoglobulin G1 antibodies targeting this pathway revealed thrombogenic properties, which were subsequently shown to be mediated by crystallizable fragment (Fc)-gamma receptor IIa-dependent platelet activation. To prevent thromboembolic complications, an immunoglobulin G4 anti-CD154 monoclonal antibody, TNX-1500, which retains the fragment antigen binding region of ruplizumab (humanized 5c8, BG9588), was modified by protein engineering to decrease Fc binding to Fc-gamma receptor IIa while retaining certain other effector functions and pharmacokinetics comparable with natural antibodies. Here, we report that TNX-1500 treatment is not associated with platelet activation in vitro and consistently inhibits kidney allograft rejection in vivo without clinical or histologic evidence of prothrombotic phenomena. We conclude that TNX-1500 retains efficacy similar to that of 5c8 to prevent kidney allograft rejection while avoiding previously identified pathway-associated thromboembolic complications.