TNX-1500, an Fc-Modified Anti-CD154 Antibody, Prolongs Nonhuman Primate Cardiac Allograft Survival

Miura, S.; Abady, Zahra; Pollok, F.; Moskowitz, Mark A.; Kinoshita, Kohei; Fogarty, Siobhan; Maguire, Patrick; Daugherty, Bruce L.; Lederman, Seth; Pierson, Richard N.

doi:10.1016/j.healun.2022.01.348

Cited by 5 publications

(9 citation statements)

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“…Sanofi also has multiple currently active phase 2 trials with a CD40L-blocking compound for Sjogren’s syndrome, systemic lupus erythematosus, and multiple sclerosis. Another Fc-modified anti-CD40L mAb developed by Tonix has been shown to prolong both renal ( 42 ) and cardiac ( 45 ) allograft survival in NHP models but has not yet been trialed in the clinic. Biological differences exist between anti-CD40L agents and are thought to lead to different efficacies ( 15 ).…”

Section: Discussionmentioning

confidence: 99%

The anti-CD40L monoclonal antibody AT-1501 promotes islet and kidney allograft survival and function in nonhuman primates

Anwar,

Berman,

DeLaura

et al. 2023

Sci. Transl. Med.

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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.

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Section: Discussionmentioning

confidence: 99%

The anti-CD40L monoclonal antibody AT-1501 promotes islet and kidney allograft survival and function in nonhuman primates

Anwar,

Berman,

DeLaura

et al. 2023

Sci. Transl. Med.

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“…In view of the excellent results being obtained at our center in NHP models of allo transplantation by the administration of a novel anti‐CD154 mAb (Tonix‐1500 ‐ see below) without any induction therapy, 4,5 we initiated the study with the aim of assessing the minimal immunosuppressive regimen that would prove successful in maintaining long‐term graft function in the absence of the development of acute AMR.…”

Section: Methodsmentioning

confidence: 99%

Novel factors potentially initiating acute antibody‐mediated rejection in pig kidney xenografts despite an efficient immunosuppressive regimen

Kinoshita,

Maenaka,

Rosales

et al. 2024

Xenotransplantation

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Antibody‐mediated rejection (AMR) is a common cause of graft failure after pig‐to‐nonhuman primate organ transplantation, even when the graft is from a pig with multiple genetic modifications. The specific factors that initiate AMR are often uncertain. We report two cases of pig kidney transplantation into immunosuppressed baboons in which we identify novel factors associated with the initiation of AMR. In the first, membranous nephropathy was the initiating factor that was then associated with the apparent loss of the therapeutic anti‐CD154 monoclonal antibody in the urine when severe proteinuria was present. This observation suggests that proteinuria may be associated with the loss of any therapeutic monoclonal antibody, for example, anti‐CD154 or eculizumab, in the urine, resulting in xenograft rejection. In the second case, the sequence of events and histopathology tentatively suggested that pyelonephritis may have initiated acute‐onset AMR. The association of a urinary infection with graft rejection has been well‐documented in ABO‐incompatible kidney allotransplantation based on the expression of an antigen on the invading microorganism shared with the kidney graft, generating an immune response to the graft. To our knowledge, these potential initiating factors of AMR in pig xenografts have not been highlighted previously.

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“…Dazodalibep (HZN-4920/VIB4920) Kidney transplantation 45 Prevents renal allograft rejection Phase 2a TNX-1500 Kidney transplantation 46 Cardiac transplantation 47 Monotherapy prolongs the renal allograft survival without thrombotic complications SLE, systemic lupus erythematosus.…”

Section: Clinical Trial Statusmentioning

confidence: 99%

“…It has an antibody binding fragment (Fab) region of hu5C8 and a modified Fc region (type 4 immunoglobulin G [IgG4]) engineered to reduce FcγRIIa-binding associated with the risk of thrombosis. Efficacy of TNX-1500 has been tested in a heterotopic kidney 46 and heart 47 allotransplant model in NHPs. Lassiter et al demonstrate that monotherapy of TNX-1500 prolongs the renal allograft survival, whereas treatment with MMF resulted in increased allograft failure.…”

Section: Tnx-1500mentioning

confidence: 99%

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

et al. 2023

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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.

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TNX-1500, an Fc-Modified Anti-CD154 Antibody, Prolongs Nonhuman Primate Cardiac Allograft Survival

Cited by 5 publications

References 0 publications

The anti-CD40L monoclonal antibody AT-1501 promotes islet and kidney allograft survival and function in nonhuman primates

The anti-CD40L monoclonal antibody AT-1501 promotes islet and kidney allograft survival and function in nonhuman primates

Novel factors potentially initiating acute antibody‐mediated rejection in pig kidney xenografts despite an efficient immunosuppressive regimen

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

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