TCD601 for Kidney Transplant Rejection Prevention
Recruiting in Palo Alto (17 mi)
+5 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: ITB-Med LLC
Disqualifiers: Cancer, Anti-HLA DSA, others
No Placebo Group
Prior Safety Data
Trial Summary
What is the purpose of this trial?This trial is testing a treatment that uses a special medicine, donor bone marrow cells, and mild pre-treatment to help patients receiving new kidney transplants from living donors accept their new organ.
Will I have to stop taking my current medications?
The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.
What data supports the effectiveness of the drug TCD601 for preventing kidney transplant rejection?
The drug siplizumab, which is part of TCD601, has been studied for its safety and potential to prevent kidney transplant rejection. Additionally, tocilizumab, a similar drug targeting inflammation, has shown promise in managing rejection in kidney transplant patients, suggesting that TCD601 may also be effective.
12345Is TCD601 (Siplizumab) safe for human use?
Siplizumab, also known as TCD601, has been tested in humans and generally shows a good safety profile with only mild, temporary side effects reported. In studies, it caused a quick but temporary reduction in certain immune cells, and any side effects were mild and short-lived.
12678How is the drug TCD601 different from other treatments for kidney transplant rejection prevention?
TCD601, also known as siplizumab, is unique because it is a humanized anti-CD2 monoclonal antibody, which targets a specific protein on immune cells to prevent kidney transplant rejection. This mechanism is different from other treatments that often target different pathways or use a combination of therapies.
125910Eligibility Criteria
This trial is for adults aged 18-60 who are receiving their first or second kidney transplant from a living donor who's at least a half-match. Participants must understand the study and agree to its terms. People with cancer, specific donor antibodies, or women able to have children cannot join.Inclusion Criteria
I am between 18 and 60 years old.
Able to understand the study requirements and provide written informed consent before and study assessment is performed
I have received a kidney transplant from a partially matched living donor.
Exclusion Criteria
I have had cancer before.
I am a woman who could become pregnant.
Donor-specific Antibody
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Participants receive TCD601 with non-myeloablative conditioning and standard of care immunosuppression
24 months
Follow-up
Participants are monitored for safety and effectiveness after treatment
6 months
Participant Groups
The PANORAMA study is testing TCD601 (siplizumab) combined with bone marrow cells from the donor and a special conditioning treatment in new kidney transplant patients to see if it helps them accept the organ without long-term immune suppression.
2Treatment groups
Experimental Treatment
Group I: Arm 2Experimental Treatment1 Intervention
TCD601administered with non-myeloablative conditioning and standard of care immunosuppression
Group II: Arm 1Experimental Treatment1 Intervention
TCD601administered with non-myeloablative conditioning and standard of care immunosuppression
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Columbia University Irving Medical CenterNew York, NY
UCSF Connie Frank Transplant CenterSan Francisco, CA
University of MarylandBaltimore, MD
Saint Barnabas Medical CenterLivingston, NJ
More Trial Locations
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Who Is Running the Clinical Trial?
ITB-Med LLCLead Sponsor
References
Safety profile, pharmacokinetics, and pharmacodynamics of siplizumab, a humanized anti-CD2 monoclonal antibody, in renal allograft recipients. [2019]We report the safety profile, pharmacokinetics (PK), and pharmacodynamics (PD) of siplizumab, a humanized IgG1 anti-CD2 monoclonal antibody and potential agent for preventing renal allograft rejection, in a phase 1 study in renal allograft recipients.
Tocilizumab in the Treatment of Chronic Antibody-Mediated Rejection Post Kidney Transplantation: Clinical and Histological Monitoring. [2022]Introduction: Chronic antibody-mediated rejection (cAMR) has very few effective therapeutic options. Interleukin-6 is an attractive target because it is involved in inflammation and humoral immunity. Therefore, the use of tocilizumab (anti-IL6 receptor, TCZ) is a potential valuable therapeutic option to treat cABMR in kidney-transplant (KT) recipients. Materials and Methods: This single-center retrospective study included all KT recipients that received monthly TCZ infusions in the setting of cABMR, between August 2018 and July 2021. We assessed 12-month renal function and KT histology during follow-up. Results: Forty patients were included. At 12-months, eGFR was not significantly different, 41.6 ± 17 vs. 43 ± 17 mL/min/1.73 m2 (p = 0.102) in patients with functional graft. Six patients (15%) lost their graft: their condition was clinically more severe at the time of first TCZ infusion. Histological follow-up showed no statistical difference in the scores of glomerulitis, peritubular capillaritis, and interstitial fibrosis/tubular atrophy (IFTA). Chronic glomerulopathy score however, increased significantly over time; conversely arteritis and inflammation in IFTA ares improved in follow-up biopsies. Conclusion: In our study, the addition of TCZ prevented clinical and histological worsening of cABMR in KT recipients, except for more severely ill patients. Randomized studies are needed to clarify the risk/benefit of TCZ in cABMR.
[Renal transplantation]. [2014]Recent immunosuppressive drugs, including mycophenolate mofetil and basiliximab in addition to calcineurin inhibitors, have reduced the incidence and severity of acute allograft rejection in kidney transplants. This article introduces newly developed agents such as CTLA4-Ig, LEA29Y, rituximab, and FTY720 and also reviews immunosuppressive protocols which withdraw steroid or calcineurin inhibitors. Unrelated or ABO incompatible living donor kidney transplants have increased due to advancement of immunosuppressive
Randomised trial of basiliximab versus placebo for control of acute cellular rejection in renal allograft recipients. CHIB 201 International Study Group. [2022]Currently available immunosuppressive regimens for cadaver-kidney recipients are far from ideal because acute-rejection episodes occur in about 30% to 50% of these patients. In the phase III study described here we assessed the ability of basiliximab, a chimeric interleukin (IL)-2 receptor monoclonal antibody, to prevent acute-rejection episodes in renal allograft recipients.
Tocilizumab and Active Antibody-Mediated Rejection in Kidney Transplantation: A Literature Review. [2022]Chronic kidney disease (CKD) is a major public-health problem that increases the risk of end-stage kidney disease (ESKD), cardiovascular diseases, and other complications. Kidney transplantation is a renal-replacement therapy that offers better survival compared to dialysis. Antibody-mediated rejection (ABMR) is a significant complication following kidney transplantation: it contributes to both short- and long-term injury. The standard-of-care (SOC) therapy combines plasmapheresis and Intravenous Immunoglobulins (IVIg) with or without steroids, with or without rituximab: however, despite this combined treatment, ABMR remains the main cause of graft loss. IL-6 is a key cytokine: it regulates inflammation, and the development, maturation, and activation of T cells, B cells, and plasma cells. Tocilizumab (TCZ) is the main humanized monoclonal aimed at IL-6R and appears to be a safe and possible strategy to manage ABMR in sensitized recipients. We conducted a literature review to assess the place of the anti-IL-6R monoclonal antibody TCZ within ABMR protocols.
Pharmacokinetic and pharmacodynamic study of a clinically effective anti-CD2 monoclonal antibody. [2020]The humanized IgG1κ monoclonal antibody siplizumab and its rat parent monoclonal IgG2b antibody BTI-322 are directed against the CD2 antigen. Siplizumab is species-specific, reacting with human and chimpanzee cells but not with cells from any other species, including other non-human primates. Because siplizumab treatment has recently shown great potential in clinical transplantation, we now present the results of our previous pharmacokinetic, pharmacodynamic and safety studies of both antibodies. Fourteen chimpanzees received 1-3 doses of 0.143 to 5.0 mg/kg iv The effects were followed with flow cytometry on peripheral lymphocytes and staining of lymph nodes. Side effects were recorded. Serum antibody concentrations were followed. Across the doses, a rapid, transient depletion of CD2, CD3, CD4 and CD8 lymphocytes and NK cells was observed for both antibodies. Immune reconstitution was more rapid for BTI-322 compared to siplizumab. Paracortical lymph node T cell depletion was moderate, estimated at 45% with doses of >0.6 mg/kg. Restoration of lymph node architecture was seen after two weeks to two months for all animals. All four subjects receiving BTI-322 experienced AEs on the first dosing day, while the eight subjects dosed with siplizumab experienced few mild, transient AEs. Infusion with siplizumab and BTI-322 resulted in rapid depletion of CD2+ cells in circulation and tissue. Siplizumab had a longer t1/2 and fewer AEs compared to BTI-322.
Safety and efficacy of eculizumab for the prevention of antibody-mediated rejection after deceased-donor kidney transplantation in patients with preformed donor-specific antibodies. [2023]The presence of preformed donor-specific antibodies in transplant recipients increases the risk of acute antibody-mediated rejection (AMR). Results of an open-label single-arm trial to evaluate the safety and efficacy of eculizumab in preventing acute AMR in recipients of deceased-donor kidney transplants with preformed donor-specific antibodies are reported. Participants received eculizumab as follows: 1200 mg immediately before reperfusion; 900 mg on posttransplant days 1, 7, 14, 21, and 28; and 1200 mg at weeks 5, 7, and 9. All patients received thymoglobulin induction therapy and standard maintenance immunosuppression including steroids. The primary end point was treatment failure rate, a composite of biopsy-proved grade II/III AMR (Banff 2007 criteria), graft loss, death, or loss to follow-up, within 9 weeks posttransplant. Eighty patients received transplants (48 women); the median age was 52 years (range 24-70 years). Observed treatment failure rate (8.8%) was significantly lower than expected for standard care (40%; P
Safety and efficacy of eculizumab in the prevention of antibody-mediated rejection in living-donor kidney transplant recipients requiring desensitization therapy: A randomized trial. [2023]We report results of a phase 2, randomized, multicenter, open-label, two-arm study evaluating the safety and efficacy of eculizumab in preventing acute antibody-mediated rejection (AMR) in sensitized recipients of living-donor kidney transplants requiring pretransplant desensitization (NCT01399593). In total, 102 patients underwent desensitization. Posttransplant, 51 patients received standard of care (SOC) and 51 received eculizumab. The primary end point was week 9 posttransplant treatment failure rate, a composite of: biopsy-proven acute AMR (Banff 2007 grade II or III; assessed by blinded central pathology); graft loss; death; or loss to follow-up. Eculizumab was well tolerated with no new safety concerns. No significant difference in treatment failure rate was observed between eculizumab (9.8%) and SOC (13.7%; P = .760). To determine whether data assessment assumptions affected study outcome, biopsies were reanalyzed by central pathologists using clinical information. The resulting treatment failure rates were 11.8% and 21.6% for the eculizumab and SOC groups, respectively (nominal P = .288). When reassessment included grade I AMR, the treatment failure rates were 11.8% (eculizumab) and 29.4% (SOC; nominal P = .048). This finding suggests a potential benefit for eculizumab compared with SOC in preventing acute AMR in recipients sensitized to their living-donor kidney transplants (EudraCT 2010-019630-28).
Interleukin-6 blockade with tocilizumab increases Tregs and reduces T effector cytokines in renal graft inflammation: A randomized controlled trial. [2023]Interleukin-6 (IL-6) is a proinflammatory cytokine and key regulator of Treg: T effector cell (Teff) balance. We hypothesized that IL-6 blockade with tocilizumab, a monoclonal antibody to IL-6R, would increase Tregs, dampen Teff function, and control graft inflammation. We conducted a randomized controlled clinical trial (2014-2018) of clinically stable kidney transplant recipients on calcineurin inhibitor, mycophenolate mofetil, and prednisone, with subclinical graft inflammation noted on surveillance biopsies during the first year posttransplant. Subjects received tocilizumab (8 mg/kg IV every 4 weeks; 6 doses; n = 16) or no treatment (controls; n = 14) on top of usual maintenance immunosuppression. Kidney biopsies pre- and post-treatment were analyzed using Banff criteria. Blood was analyzed for serum cytokines, Treg frequencies, and T cell effector molecule expression (IFN-γ, IL-17, granzyme B) post-stimulation ex vivo. Tocilizumab-treated subjects were more likely to show improved Banff ti-score (62.5% vs. 21.4%, p = .03), increased Treg frequency (7.1% ± 5.55% vs. 3.6% ± 1.7%, p = .0168), and a blunted Teff cytokine response compared to controls. Changes in Banff i- and t-scores were not significantly different. The treatment was relatively well tolerated with no patient deaths or graft loss. Blockade of IL-6 is a novel and promising treatment option to regulate the T cell alloimmune response in kidney transplant recipients. NCT02108600.
Use of monoclonal antibodies in renal transplantation. [2021]Monoclonal antibodies are applied in various settings in renal transplantation. Depleting T-cell antibodies are used for treatment of steroid-resistant acute rejection and as induction therapy to reduce the intensity of concomitant immunosuppressive drug therapy. Induction therapy with the nondepleting IL-2 receptor antagonists basiliximab and daclizumab, added to cyclosporine-based regimens, reduces the incidence of acute rejection without side effects. However, an increase in long-term graft and patient survival has not been demonstrated yet. The B-cell-targeting antibody rituximab is used in blood group ABO-incompatible transplantation, in desensitization protocols, and for treatment of antibody-mediated rejection. Eculizumab interrupts the complement pathway and is a promising tool for the treatment of antibody-mediated rejection and post-transplant hemolytic-uremic syndrome. Future options are monoclonal antibodies with new molecular targets and antibodies that can be used for maintenance immunosuppression in order to avoid the toxicity of existing drugs. However, in several cases, the development of new monoclonal antibodies has been hampered by safety issues.