Corticosteroids and methotrexate as adjuvants to costimulation blockade in non-human primate renal transplantation

• Type of Material: Article
• Authors: Douglas J. Anderson, Emory University; Denise Lo, Emory University; Francis Leopardi, Duke University; Mingqing Song, Duke University; Elizabeth Strobert, Emory University; Joe Jenkins, Emory University; Christian Larsen, Emory University; Allan Kirk, Emory University
• Language: English
• Date: 2019-06-01
• Publisher: Wiley
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2019 John Wiley & Sons, Inc. All rights reserved.
• Final Published Version (URL): http://dx.doi.org/10.1111/ctr.13568
• Title of Journal or Parent Work: Clinical Transplantation
• Volume: 33
• Issue: 6
• Start Page: e13568
• End Page: e13568
• Grant/Funding Information: Further grant support of the Yerkes National Primate Research Center was provided by the National Center for Research Resources P51RR165 and is currently supported by the Office of Research Infrastructure Programs/OD P51OD11132.; Dr. Anderson was partially supported by the ASTS-Genentech Scientist Scholarship.; Funding for this research was provided by a grant from the NIH, 1U01AI079223, U01AI084150 and 2U19AI051731-11.
• Keywords: Therapy; costimulation; Transplantation; Science & Technology; Long-term acceptance; non-human primate; Life Sciences & Biomedicine; Versus host disease; methotrexate; Monoclonal antibody; Cyclosporine; Belatacept; Surgery; Phase III; Rheumatoid arthritis; Prolongs allograft survival; Rejection
• Research Categories: Engineering, Biomedical; Health Sciences, Medicine and Surgery; Health Sciences, Health Care Management

Abstract

Belatacept, the CD28-B7 costimulation pathway inhibitor, has been approved as a calcineurin inhibitor (CNI) alternative in kidney transplantation. Although costimulation blockade (CoB) allows for CNI avoidance, it is associated with increased rates of early rejection, prompting a search for agents to pair with belatacept. Methotrexate (MTX) is an antimetabolite that has been found to be complimentary with abatacept, a lower affinity CD28-B7-specific analogue of belatacept, in the treatment of rheumatoid arthritis (RA). We examined whether this synergy would extend to prevention of kidney allograft rejection. Rhesus macaques underwent kidney transplantation treated with abatacept maintenance therapy with either a steroid taper, MTX, or both. The combination of abatacept maintenance with steroids prolonged graft survival compared to untreated historical controls and previous reports of abatacept monotherapy. The addition of MTX did not provide additional benefit. These data demonstrate that abatacept with adjuvant therapy may delay the onset of acute rejection, but fail to show synergy between abatacept and MTX beyond that of steroids. These findings indicate that MTX is unlikely to be a suitable adjuvant to CoB in kidney transplantation, but also suggest that with further modification, a CoB regimen used for advanced RA may suffice for RA patients requiring kidney transplantation.