ASKP1240, a Fully Human Anti-CD40 Monoclonal Antibody, Prolongs Pancreatic Islet Allograft Survival in Nonhuman Primates

Watanabe, Masaaki; Yamashita, Kazuo; Suzuki, Tomomi; Kamachi, Hirofumi; Kuraya, Daisuke; Koshizuka, Yasuyuki; Ogura, Masato; Yoshida, Tadashi; Aoyagi, Tetsuji; Fukumori, Daisuke; Shimamura, Tsuyoshi; Okimura, K.; Maeta, K.; Miura, Tsuyoshi; Sakai, Fumihiko; Todo, Satoru

doi:10.1111/ajt.12330

Cited by 54 publications

(35 citation statements)

References 54 publications

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“…An additional promising candidate would be an anti-CD40 antibody, ASKP1240 (4D11); this drug has been demonstrated to be effective in prolonging graft survival in NHP allotransplantation of kidney, liver and islets, and had an excellent safety profile in a phase I clinical trial (31)(32)(33)(34). Another promising alternative to anti-CD154 monoclonal antibody is CDP7657, which is a novel monovalent Fab' PEG anti-human CD154 antibody.…”

Section: Discussionmentioning

confidence: 99%

Long-Term Control of Diabetes in Immunosuppressed Nonhuman Primates (NHP) by the Transplantation of Adult Porcine Islets

Shin

Kim

et al. 2015

American Journal of Transplantation

172

194

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Pig islets are an alternative source for islet transplantation to treat type 1 diabetes (T1D), but reproducible curative potential in the pig-to-nonhuman primate (NHP) model has not been demonstrated. Here, we report that pig islet grafts survived and maintained normoglycemia for >6 months in four of five consecutive immunosuppressed NHPs. Pig islets were isolated from designated pathogen-free (DPF) miniature pigs and infused intraportally into streptozotocin-induced diabetic rhesus monkeys under pretreatment with cobra venom factor (CVF), anti-thymocyte globulin (ATG) induction and maintenance with anti-CD154 monoclonal antibody and low-dose sirolimus. Ex vivo expanded autologous regulatory T cells were adoptively transferred in three recipients. Blood glucose levels were promptly normalized in all five monkeys and normoglycemia (90-110 mg/dL) was maintained for >6 months in four cases, the longest currently up to 603 days. Intravenous glucose tolerance tests during the follow-up period showed excellent glucose disposal capacity and porcine C-peptide responses. Adoptive transfer of autologous regulatory T cells was likely to be associated with more stable and durable normoglycemia. Importantly, the recipients showed no serious adverse effects. Taken together, our results confirm the clinical feasibility of pig islet transplantation to treat T1D patients without the need for excessive immunosuppressive therapy.

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Section: Discussionmentioning

confidence: 99%

Long-Term Control of Diabetes in Immunosuppressed Nonhuman Primates (NHP) by the Transplantation of Adult Porcine Islets

Shin

Kim

et al. 2015

American Journal of Transplantation

172

194

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“…Several anti-CD40mAbs, e.g., Chi220, 3A8, 5D12, 4D12, and 2C10, have shown promise in various transplant models without thromboembolic complication [4-6, 9-19, 21-24]. However, some of these anti-CD40 mAbs (i.e., Chi220, 3A8) have been associated with potentially adverse effects, e.g., as a B cell agonist or associated with substantial peripheral B cell depletion [9, 16, 19, 23].…”

Section: Discussionmentioning

confidence: 99%

“…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%

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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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“…78 Similar results have been obtained for pancreatic islet allografts in nonhuman primates. 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.…”

Section: Cd40-cd40l Pathwaymentioning

confidence: 93%

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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ASKP1240, a Fully Human Anti-CD40 Monoclonal Antibody, Prolongs Pancreatic Islet Allograft Survival in Nonhuman Primates

Cited by 54 publications

References 54 publications

Long-Term Control of Diabetes in Immunosuppressed Nonhuman Primates (NHP) by the Transplantation of Adult Porcine Islets

Long-Term Control of Diabetes in Immunosuppressed Nonhuman Primates (NHP) by the Transplantation of Adult Porcine Islets

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

Costimulation Blockade in Kidney Transplantation

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