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

Miura, Shuhei; Habibabady, Zahra; Pollok, Franziska; Ma, Madelyn; Rosales, Ivy A.; Kinoshita, Kohei; Pratts, Shannon; McGrath, Gannon; Chaban, Ryan; Fogarty, Siobhan; Meibohm, Bernd; Daugherty, Bruce; Lederman, Seth; Pierson, Richard N.

doi:10.1016/j.ajt.2023.03.025

Cited by 6 publications

(3 citation statements)

References 36 publications

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“…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 FcγRIIa‐binding, 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: Methodsmentioning

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 allo transplantation, 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700 μg/mL thereafter has largely been associated with continuing graft function (Kinoshita unpublished) 4,5 …”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: Methodsmentioning

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%

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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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