TNX-1500, a crystallizable fragment–modified anti-CD154 antibody, prolongs nonhuman primate renal allograft survival

Lassiter, Grace; Otsuka, Ryo; Hirose, Takayuki; Rosales, Ivy A.; Karadagi, Ahmad; Tomosugi, Toshihide; Dehnadi, A.; Lee, Hang; Colvin, Robert B.; Baardsnes, Jason; Moraitis, Anna; Smith, Emma E; Ali, Zahida; Berhe, Phil; Mulder, Andrew T.; Meibohm, Bernd; Daugherty, Bruce; Fogarty, Siobhan; Pierson, Richard N.; Lederman, Seth; Kawai, Tatsuo

doi:10.1016/j.ajt.2023.03.022

Cited by 10 publications

(5 citation statements)

References 24 publications

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“…This experience was in contrast to the results of Tonix-1500 monotherapy in monkeys with kidney allografts in which graft survival often extends throughout the period of treatment, that is, for >6 months. 5 Based on this single case, we infer that at least some induction therapy (or additional maintenance therapy) is required to prevent AMR in models of xenotransplantation, though not in allotransplantation.…”

Section: Graft and Recipient Survivalmentioning

confidence: 86%

“…Tonix-1500 contains the human 5c8 Fab domain from ruplizumab 6 and an IgG4 Fc region engineered to encode amino acid transitions S228P and L235A to prevent chain switching and reduce FcγRIIabinding, respectively (Tonix Pharmaceuticals, Chatham, NJ, patent # WO2021001458A1). 4,5 Its administration to monkeys with kidney 5 or cardiac 4 allografts has been associated with excellent results, and the results of its administration to monkeys with pig kidney xenografts have been very encouraging. 7,8…”

Section: Immunosuppressive and Adjunctive Therapymentioning

confidence: 99%

“…In view of the excellent results being obtained at our center in NHP models of allotransplantation 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 longterm graft function in the absence of the development of acute AMR.…”

Section: Immunosuppressive and Adjunctive Therapymentioning

confidence: 99%

“…Serum trough concentrations of Tonix-1500 were measured retrospectively in all baboons at multiple time-points throughout the study period using a human IgG4-Fc-specific enzyme-linked immunosorbent assay (ELISA) (Cayman Chemical, Ann Arbor, MI) according to the kit manufacturer's protocol, performed at a contract research organization (Charles River Laboratories, Skokie, IL). 4,5 In our extensive studies of Tonix-1500 in models of NHP kidney and heart allotransplantation, a trough level of >500 μg/mL attained within 2 weeks after transplantation and maintained at >700 μg/mL thereafter has largely been associated with continuing graft function (Kinoshita unpublished). 4,5…”

Section: Monitoring Of Tonix-1500 Trough Concentrationsmentioning

confidence: 99%

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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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Section: Graft and Recipient Survivalmentioning

confidence: 86%

Section: Immunosuppressive and Adjunctive Therapymentioning

confidence: 99%

Section: Immunosuppressive and Adjunctive Therapymentioning

confidence: 99%

Section: Monitoring Of Tonix-1500 Trough Concentrationsmentioning

confidence: 99%

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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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“…54 Our results are particularly relevant with the ongoing clinical trials of improved biologics to block the CD40/CD154 axis that have solved the initial thromboembolic complications. 55,56 For example, we can envision that individual polymorphisms of the IL10/IL10R axis 57 will probably have a profound influence on the therapeutic outcome of these biologics. Investigations are needed to better delineate the molecular underpinning of the reliance of blocking CD154 on IL-10 signaling.…”

Section: Discussionmentioning

confidence: 99%

T cell responsiveness to IL-10 defines the immunomodulatory effect of costimulation blockade via anti-CD154 and impacts transplant survival

Iglesias,

Bibicheff,

Komin

et al. 2024

Preprint

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Costimulation blockade (CoB)-based immunotherapy is a promising alternative to immunosuppression for transplant recipients; however, the current limited understanding of the factors that impact its efficacy restrains its clinical applicability. In this context, pro- and anti-inflammatory cytokines are being recognized as having an impact on T cell activation beyond effector differentiation. This study aims at elucidating the impact of direct IL-10 signaling in T cells on CoB outcomes. We used a full-mismatch skin transplantation model where recipients had a T cell-restricted expression of a dominant negative IL-10 receptor (10R-DN), alongside anti-CD154 as CoB therapy. Unlike wild-type recipients, 10R-DN mice failed to benefit from CoB. This accelerated graft rejection correlated with increased accumulation of T cells producing TNF-α, IFN-γ, and IL-17. In vitro experiments indicated that while lack of IL-10 signaling did not change the ability of anti-CD154 to modulate alloreactive T cell proliferation, the absence of this pathway heightened TH1 effector cell differentiation. Furthermore, deficiency of IL-10 signaling in T cells impaired Treg induction, a hallmark of anti-CD154 therapy. Overall, these findings unveil an important and novel role of IL-10 signaling in T cells that defines the success of CoB therapies and identifies a target pathway for obtaining robust immunoregulation.

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TNX-1500, a crystallizable fragment–modified anti-CD154 antibody, prolongs nonhuman primate cardiac allograft survival

Miura

Habibabady

Pollok

et al. 2023

American Journal of Transplantation

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TNX-1500, a crystallizable fragment–modified anti-CD154 antibody, prolongs nonhuman primate renal allograft survival

Cited by 10 publications

References 24 publications

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

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

T cell responsiveness to IL-10 defines the immunomodulatory effect of costimulation blockade via anti-CD154 and impacts transplant survival

TNX-1500, a crystallizable fragment–modified anti-CD154 antibody, prolongs nonhuman primate cardiac allograft survival

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