Monotherapy with the novel human anti-CD154 monoclonal antibody ABI793 in rhesus monkey renal transplantation model1

Kanmaz, Turan; Fechner, John J H; Torrealba, José; Kim, Hyoung Tae; Dong, Yinchen; Oberley, Terry D.; Schultz, Jacqueline M.; Bloom, Debra D.; Katayama, Masaaki; Dar, Wasim; Markovits, Judith; Schüler, W.; Hu, Huaizhong; Hamawy, Majed M.; Knechtle, Stuart J.

doi:10.1097/01.tp.0000116392.72152.75

Cited by 80 publications

(68 citation statements)

References 24 publications

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“…Unfortunately, one of the most promising reagents, anti-CD154, has been hampered by clinical complications. These same sequelae have now been observed in primate models as well (35,36). Importantly, a comprehensive gross and histologic assessment in both toxicity and transplant studies using Chi220 in rhesus and cynomolgus macaques showed no evidence of thromboembolism.…”

Section: Discussionmentioning

confidence: 64%

Development of a Chimeric Anti-CD40 Monoclonal Antibody That Synergizes with LEA29Y to Prolong Islet Allograft Survival

Adams

Shirasugi

Jones

et al. 2005

The Journal of Immunology

172

139

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In recent years, reagents have been developed that specifically target signals critical for effective T cell activation and function. Manipulation of the CD28/CD80/86 and CD40/CD154 pathways has exhibited extraordinary efficacy, particularly when the pathways are blocked simultaneously. Despite the reported efficacy of anti-CD154 in rodents and higher models, its future clinical use is uncertain due to reported thromboembolic events in clinical trials. To circumvent this potential complication, we developed and evaluated a chimeric Ab targeting CD40 (Chi220, BMS-224819) as an alternative to CD154. Although Chi220 blocks CD154 binding, it also possesses partial agonist properties and weak stimulatory potential. The anti-CD40 was tested alone and in combination with a rationally designed, high affinity variant of CTLA4-Ig, LEA29Y (belatacept), in a nonhuman primate model of islet transplantation. Although either agent alone only modestly prolonged islet survival (Chi220 alone: 14, 16, and 84 days; LEA29Y alone: 58 and 60 days), their combination (LEA29Y and Chi220) dramatically facilitated long term survival (237, 237, 220, >185, and 172 days). We found that the effects of Chi220 treatment were not mediated solely through deletion of CD20-bearing cells and that the combined therapy did not significantly impair established antiviral immunity.

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Section: Discussionmentioning

confidence: 64%

Development of a Chimeric Anti-CD40 Monoclonal Antibody That Synergizes with LEA29Y to Prolong Islet Allograft Survival

Adams

Shirasugi

Jones

et al. 2005

The Journal of Immunology

172

139

View full text Add to dashboard Cite

show abstract

“…In contrast, stable, rejection-free tolerance induced in NHP following brief therapy with anti-CD3 IT plus DSG is associated with the absence of TGF-␤1 from graft biopsies (32). Thus, the mechanisms underpinning long-term durable NHP tolerance (32,34,46) appear to be distinct from NHP metastable tolerance with approaching chronic rejection (57)(58)(59).…”

Section: Discussionmentioning

confidence: 76%

Elevated T Regulatory Cells in Long-Term Stable Transplant Tolerance in Rhesus Macaques Induced by Anti-CD3 Immunotoxin and Deoxyspergualin

Asiedu

Goodwin

Balgansuren

et al. 2005

The Journal of Immunology

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Regulatory T cells (Tregs) are implicated in immune tolerance and are variably dependent on IL-10 for in vivo function. Brief peritransplant treatment of multiple nonhuman primates (NHP) with anti-CD3 immunotoxin and deoxyspergualin has induced stable (5–10 years) rejection-free tolerance to MHC-mismatched allografts, which associated with sustained elevations in serum IL-10. In this study, we demonstrate that resting and activated PBMC from long-term tolerant NHP recipients are biased to secrete high levels of IL-10, compared with normal NHP PBMC. Although IL-10-producing CD4+ Tregs (type 1 regulatory cells (TR1)/IL-10 Tregs) were undetectable (<0.5%) in normal rhesus monkeys, 7.5 ± 1.7% of circulating CD4+ T cells of tolerant rhesus recipients expressed IL-10. In addition to this >15-fold increase in Tr1/IL-10 Tregs, the tolerant monkeys exhibited a nearly 3-fold increase in CD4+CD25+ Tregs, 8.1 ± 3.0% of CD4 T cells vs 2.8 ± 1.4% in normal cohorts (p < 0.02). The frequency of CD4+CD25+IL-10+ cells was elevated 5-fold in tolerant vs normal NHP (1.8 ± 0.9% vs 0.4 ± 0.2%). Rhesus CD4+CD25+ Tregs exhibited a memory phenotype, and expressed high levels of Foxp3 and CTLA-4 compared with CD4+CD25− T cells. Also, NHP CD4+CD25+ Tregs proliferated poorly after activation and suppressed proliferation of CD4+CD25− effector T cells, exhibiting regulatory properties similar to rodent and human CD4+CD25+ Tregs. Of note, depletion of CD4+CD25+ Tregs restored indirect pathway antidonor responses in tolerant NHP. Our study demonstrates an expanded presence of Treg populations in tolerant NHP recipients, suggesting that these adaptations may be involved in maintenance of stable tolerance.

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“…It is a human IgG1:C k , obtained from a hybridoma following immunization of human Ig transgenic mice. Efficacy has been determined in allogeneic kidney Tx in both cynomolgus [20] and rhesus [21] monkeys. Long-term graft survival was achieved when it was administered intravenously (i.v.)…”

Section: Human Anti-human Cd154 Monoclonal Antibody (Abi 793)mentioning

confidence: 99%

Suppression of Natural and Elicited Antibodies in Pig-to-Baboon Heart Transplantation Using a Human Anti-Human CD154 mAb-Based Regimen

Kuwaki¹,

Knosalla²,

Dor³

et al. 2004

American Journal of Transplantation

134

140

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Natural and elicited antipig antibodies (Abs) lead to acute humoral xenograft rejection (AHXR).Ten baboons underwent heterotopic heart transplantation (Tx) from human decay-accelerating factor (hDAF) pigs. Depletion of anti-Gala1, 3Gal (Gal) Abs was achieved by the infusion of a Gal glycoconjugate from day -1. Immunosuppression included induction of antithymocyte globulin, thymic irradiation, and cobra venom factor, and maintenance with a human antihuman CD154 mAb, mycophenolate mofetil, and methylprednisolone; heparin and prophylactic ganciclovir were also administered. Pig heart survival ranged from 4 to 139 (mean 37, median 27) days, with three functioning for >50 days. Graft failure (n = Kenji Kuwaki and Christoph Knosalla contributed equally.=

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Monotherapy with the novel human anti-CD154 monoclonal antibody ABI793 in rhesus monkey renal transplantation model1

Abstract: ABI793 induces prolonged renal allograft survival in rhesus monkeys. Nevertheless, thromboembolic complications may occur and chronic allograft nephropathy may develop after anti-CD154 treatment is discontinued.

Cited by 80 publications

References 24 publications

Development of a Chimeric Anti-CD40 Monoclonal Antibody That Synergizes with LEA29Y to Prolong Islet Allograft Survival

Development of a Chimeric Anti-CD40 Monoclonal Antibody That Synergizes with LEA29Y to Prolong Islet Allograft Survival

Elevated T Regulatory Cells in Long-Term Stable Transplant Tolerance in Rhesus Macaques Induced by Anti-CD3 Immunotoxin and Deoxyspergualin

Suppression of Natural and Elicited Antibodies in Pig-to-Baboon Heart Transplantation Using a Human Anti-Human CD154 mAb-Based Regimen

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