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

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Abstract

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Abstract

Background

Blocking the CD40-CD154 signal pathway has previously shown promise as a strategy to prevent allograft rejection. In this study, the efficacy of a novel fully human anti-CD40 monoclonal antibody—ASKP1240, administered as a monotherapy or combination therapy (subtherapeutic dose of tacrolimus or mycophenolate mofetil), on the prevention of renal allograft rejection was evaluated in Cynomolgus monkeys.

Methods

Heterotopic kidney transplants were performed in ABO-compatible, stimulation index 2.5 or higher in the two-way mixed lymphocyte reaction monkey pairs. Animals were divided into 12 groups and observed for a maximum of 180 days. Histopathologic, hematology, and biochemistry analyses were conducted in all groups. Cytokine release (interleukin [IL]-2, IL-4, IL-5, IL-6, tumor necrosis factor, and interferon-γ) was investigated in several groups.

Results

ASKP1240 prolonged renal allograft survival in a dose-dependent manner in monotherapy. Low-dose (2 mg/kg) or high-dose (5 mg/kg) ASKP1240, in combination with mycophenolate mofetil (15 mg/kg) or tacrolimus (1 mg/kg), showed a significantly longer allograft survival time compared with monotherapy groups. No obvious side effects including drug-related thromboembolic complications were found. Cytokine release was not induced by ASKP1240 administration.

Conclusion

The present study indicates that ASKP1240, alone or in combination with other immunosuppressive drugs, could be a promising antirejection agent in organ transplantation.

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Most cited references 27

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The Banff 97 working classification of renal allograft pathology.

L C Racusen, K Solez, R B Colvin … (1999)

Standardization of renal allograft biopsy interpretation is necessary to guide therapy and to establish an objective end point for clinical trials. This manuscript describes a classification, Banff 97, developed by investigators using the Banff Schema and the Collaborative Clinical Trials in Transplantation (CCTT) modification for diagnosis of renal allograft pathology. Banff 97 grew from an international consensus discussion begun at Banff and continued via the Internet. This schema developed from (a) analysis of data using the Banff classification, (b) publication of and experience with the CCTT modification, (c) international conferences, and (d) data from recent studies on impact of vasculitis on transplant outcome. Semiquantitative lesion scoring continues to focus on tubulitis and arteritis but includes a minimum threshold for interstitial inflammation. Banff 97 defines "types" of acute/active rejection. Type I is tubulointerstitial rejection without arteritis. Type II is vascular rejection with intimal arteritis, and type III is severe rejection with transmural arterial changes. Biopsies with only mild inflammation are graded as "borderline/suspicious for rejection." Chronic/sclerosing allograft changes are graded based on severity of tubular atrophy and interstitial fibrosis. Antibody-mediated rejection, hyperacute or accelerated acute in presentation, is also categorized, as are other significant allograft findings. The Banff 97 working classification refines earlier schemas and represents input from two classifications most widely used in clinical rejection trials and in clinical practice worldwide. Major changes include the following: rejection with vasculitis is separated from tubulointerstitial rejection; severe rejection requires transmural changes in arteries; "borderline" rejection can only be interpreted in a clinical context; antibody-mediated rejection is further defined, and lesion scoring focuses on most severely involved structures. Criteria for specimen adequacy have also been modified. Banff 97 represents a significant refinement of allograft assessment, developed via international consensus discussions.

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Long-term acceptance of skin and cardiac allografts after blocking CD40 and CD28 pathways.

C Larsen, E T Elwood, D Alexander … (1996)

The receptor-ligand pairs CD28-B7 and CD40-gp39 are essential for the initiation and amplification of T-cell-dependent immune responses. CD28-B7 interactions provide 'second signals' necessary for optimal T-cell activation and IL-2 production, whereas CD40-gp39 signals co-stimulate B-cell, macrophage, endothelial cell and T-cell activation. Nonetheless, blockade of either of these pathways alone is not sufficient to permit engraftment of highly immunogenic allografts. Here we report that simultaneous but not independent blockade of the CD28 and CD40 pathways effectively aborts T-cell clonal expansion in vitro and in vivo, promotes long-term survival of fully allogeneic skin grafts, and inhibits the development of chronic vascular rejection of primarily vascularized cardiac allografts. The requirement for simultaneous blockade of these pathways for effective inhibition of alloimmunity indicates that, although they are interrelated, the CD28 and CD40 pathways are critical independent regulators of T-cell-dependent immune responses.

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Treatment with humanized monoclonal antibody against CD154 prevents acute renal allograft rejection in nonhuman primates.

Halbert L. White, Maurice Swanson, David M. Harlan … (1999)

CD154 is the ligand for the receptor CD40. This ligand-receptor pair mediates endothelial and antigen-presenting cell activation, and facilitates the interaction of these cells with T cells and platelets. We demonstrate here that administration of a CD154-specific monoclonal antibody (hu5C8) allows for renal allotransplantation in outbred, MHC-mismatched rhesus monkeys without acute rejection. The effect persisted for more than 10 months after therapy termination, and no additional drug was required to achieve extended graft survival. Indeed, the use of tacrolimus or chronic steroids seemed to antagonize the anti-rejection effect. Monkeys treated with antibody against CD154 remained healthy during and after therapy. The mechanism of action does not require global depletion of T or B cells. Long-term survivors lost their mixed lymphocyte reactivity in a donor-specific manner, but still formed donor-specific antibody and generated T cells that infiltrated the grafted organ without any obvious effect on graft function. Thus, therapy with antibody against CD154 is a promising agent for clinical use in human allotransplantation.

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Author and article information

Journal

Journal ID (nlm-ta): Transplantation

Journal ID (iso-abbrev): Transplantation

Journal ID (publisher-id): TP

Title: Transplantation

Publisher: Lippincott Williams & Wilkins

ISSN (Print): 0041-1337

ISSN (Electronic): 1534-6080

Publication date (Print): 15 August 2014

Publication date (Electronic): 05 August 2014

Volume: 98

Issue: 3

Pages: 267-276

Affiliations

[1] ¹ Department of Surgery, Research Center, CHUM, Notre-Dame Hospital, University of Montreal, Montreal, Quebec, Canada.

[2] ² Laboratory Animals Center, the Academy of Military Medical Sciences, Beijing, China.

[3] ³ Translational and Development Pharmacology-US, Drug Discovery Research, Astellas Research Institute of America LLC, Northbrook, IL.

[4] ⁴ Astellas Research Technology Inc., Osaka, Japan.

[5] ⁵ Drug Metabolism Research Labs. Astellas Pharma Inc., Osaka, Japan.

[6] ⁶ Pharmacological Research Labs., Kyowa Hakko Kirin Co., Ltd., Shizuoka, Japan.

[7] ⁷ Address correspondence to: Huifang Chen, M.D., Ph.D., Laboratory of Experimental Surgery, Research Center, CHUM, Notre-Dame Hospital, University of Montréal, 2099 Alexandre de Sève, Montréal, Room Y1611, Québec, Canada H2L 2W5.

Author notes

E-mail: hui.fang.chen@ 123456umontreal.ca

Article

Publisher ID: TP131226 Accession ID: 00009

DOI: 10.1097/TP.0000000000000236

PMC ID: 4175122

PubMed ID: 24992357

SO-VID: 880bc1a9-5b75-4507-9d6a-f8e3f380c1a6

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This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License, where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially.

History

Date received : 02 December 2013

Date revision requested : 07 December 2013

Date accepted : 04 April 2014

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Keywords: askp1240,costimulation blockade,kidney transplantation,nonhuman primate

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Keywords: askp1240, costimulation blockade, kidney transplantation, nonhuman primate

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

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Most cited references 27

The Banff 97 working classification of renal allograft pathology.

Long-term acceptance of skin and cardiac allografts after blocking CD40 and CD28 pathways.

Treatment with humanized monoclonal antibody against CD154 prevents acute renal allograft rejection in nonhuman primates.

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