Effects of ASKP1240 Combined With Tacrolimus or Mycophenolate Mofetil on Renal Allograft Survival in Cynomolgus Monkeys

Song, Lijun; Ma, Anlun; Dun, Hao; Hu, Yanxin; Zeng, Lin; Bai, Jing; Zhang, Guangzhou; Kinugasa, Fumitaka; Sudo, Yuji; Miyao, Yasuhiro; Okimura, K.; Miura, Tsuyoshi; Daloze, Pierre; Chen, Huifang

doi:10.1097/tp.0000000000000236

Cited by 33 publications

(18 citation statements)

References 35 publications

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“…A fully human mAb to CD40, clone 4D11 (IgG4 isotype), has recently been shown to prolong renal, hepatic, and islet allograft survival in cynomolgus monkeys [12, 13, 18, 21, 42]. Phase I clinical trials in renal transplantation using 4D11 are currently in progress.…”

Section: Discussionmentioning

confidence: 99%

In vitro testing of an anti-CD40 monoclonal antibody, clone 2C10, in primates and pigs

Lee

Satyananda

Iwase

et al. 2015

Transplant Immunology

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Background The CD40/CD154 and CD28/B7 pathways are important in allo- and xeno-transplantation. Owing to the thrombotic complications of anti-CD154mAb, anti-CD40mAb has emerged as a promising inhibitor of costimulation. Various clones of anti-CD40mAb have been developed against primate species, e.g., clone 2C10 against rhesus monkeys. We have compared the in vitro efficacy of 2C10 to prevent a T cell response in primates and pigs. Methods The binding of 2C10 to antigen-presenting cells (PBMCs [B cells]) of humans, rhesus and cynomolgus monkeys, baboons, and pigs was measured by flow cytometry, and was also tested indirectly by a blocking assay. The functional capacity of 2C10 was tested by mixed lymphocyte reaction (MLR) with polyclonal stimulation by phytohemagglutinin (PHA) and also with wild-type pig aortic endothelial cells (pAECs) as stimulators. Results There was a significant reduction in binding of 2C10 to baboon PBMCs compared to rhesus, cynomolgus, and human PBMCs, and minimal binding to pig PBMCs. The blocking assay confirmed that the binding of 2C10 was significantly lower to baboon PBMCs when compared to the other primate species tested. The functional assay with PHA showed significantly reduced inhibition of PBMC proliferation in humans, cynomolgus monkeys, and baboons compared to rhesus monkeys, which was confirmed on MLR with pAECs. Conclusions Since both the binding and functional activity of 2C10 in the baboon is lower than in rhesus monkeys, in vivo treatment using 2C10 in the baboon might require a higher dose or more frequent administration in comparison to rhesus monkeys. It may also be beneficial to develop species-specific clones of anti-CD40mAb.

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Section: Discussionmentioning

confidence: 99%

In vitro testing of an anti-CD40 monoclonal antibody, clone 2C10, in primates and pigs

Lee

Satyananda

Iwase

et al. 2015

Transplant Immunology

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“…We acknowledge that survival times in life-supporting kidney transplantation in NHPs using other anti-CD40 antibodies extend beyond this predefined protocol endpoint. However, coupled with good graft function and morphology, we regarded these survival times sufficient to trigger early clinical development; although, we acknowledge that we may have failed to identify evidence of rejection of allograft dysfunction (such as chronic allograft nephropathy) observed in other longer term studies (32).…”

Section: Discussionmentioning

confidence: 99%

A Novel, Blocking, Fc-Silent Anti-CD40 Monoclonal Antibody Prolongs Nonhuman Primate Renal Allograft Survival in the Absence of B Cell Depletion

Córdoba

Wieczorek

Audet

et al. 2015

American Journal of Transplantation

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y Both authors contributed equally.CD40-CD154 pathway blockade prolongs renal allograft survival in nonhuman primates (NHPs). However, antibodies targeting CD154 were associated with an increased incidence of thromboembolic complications. Antibodies targeting CD40 prolong renal allograft survival in NHPs without thromboembolic events but with accompanying B cell depletion, raising the question of the relative contribution of B cell depletion to the efficacy of anti-CD40 blockade. Here, we investigated whether fully silencing Fc effector functions of an anti-CD40 antibody can still promote graft survival. The parent anti-CD40 monoclonal antibody HCD122 prolonged allograft survival in MHCmismatched cynomolgus monkey renal allograft transplantation (52, 22, and 24 days) with accompanying B cell depletion. Fc-silencing yielded CFZ533, an antibody incapable of B cell depletion but still able to potently inhibit CD40 pathway activation. CFZ533 prolonged allograft survival and function up to a defined protocol endpoint of 98-100 days (100, 100, 100, 98, and 76 days) in the absence of B cell depletion and preservation of good histological graft morphology. CFZ533 was welltolerated, with no evidence of thromboembolic events or CD40 pathway activation and suppressed a gene signature associated with acute rejection. Thus, use of the Fc-silent anti-CD40 antibody CFZ533 appears to be an attractive approach for preventing solid organ transplant rejection.

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“…79 The association of ASKP1240 with tacrolimus or mycophenolate mofetil further increased kidney allograft survival in the same nonhuman primate model. 80 In addition, good correlations were found between the pharmacokinetic and pharmacodynamic parameters. 81 Specific monitoring for potential prothrombotic effects, both in vitro and in vivo, showed no thromboembolic complications using ASKP1240.…”

Section: Cd40-cd40l Pathwaymentioning

confidence: 91%

Costimulation Blockade in Kidney Transplantation

2016

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In the setting of solid-organ transplantation, calcineurin inhibitor (CNI)-based therapy remains the cornerstone of immunosuppression. However, long-term use of CNIs is associated with some degree of nephrotoxicity. This has led to exploring the blockade of some costimulation pathways as an efficient immunosuppressive tool instead of using CNIs. The only agent already in clinical use and approved by the health authorities for kidney transplant patients is belatacept (Nulojix), a fusion protein that interferes with cytotoxic T lymphocyte-associated protein 4. Belatacept has been demonstrated to be as efficient as cyclosporine-based immunosuppression and is associated with significantly better renal function, that is, no nephrotoxicity. However, in the immediate posttransplant period, significantly more mild/moderate episodes of acute rejection have been reported, favored by the fact that cytotoxic T lymphocyte-associated protein pathway has an inhibitory effect on the alloimmune response; thereby its inhibition is detrimental in this regard. This has led to the development of antibodies that target CD28. The most advanced is FR104, it has shown promise in nonhuman primate models of autoimmune diseases and allotransplantation. In addition, research into blocking the CD40-CD154 pathway is underway. A phase II study testing ASK1240, that is, anti-CD40 antibody has been completed, and the results are pending.

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Effects of ASKP1240 Combined With Tacrolimus or Mycophenolate Mofetil on Renal Allograft Survival in Cynomolgus Monkeys

Abstract: Supplemental digital content is available in the text.

Cited by 33 publications

References 35 publications

In vitro testing of an anti-CD40 monoclonal antibody, clone 2C10, in primates and pigs

In vitro testing of an anti-CD40 monoclonal antibody, clone 2C10, in primates and pigs

A Novel, Blocking, Fc-Silent Anti-CD40 Monoclonal Antibody Prolongs Nonhuman Primate Renal Allograft Survival in the Absence of B Cell Depletion

Costimulation Blockade in Kidney Transplantation

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