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Anti-TIRC7 Antibody Acts Synergistically with Tacrolimus in Promoting Graft Survival in a Rat Kidney Transplant Model

S. Tullius,1 Y. Kumamoto,2 U. Nalan.3

1Department of Medicine, Brigham and Women's Hospital, Boston, MA
2Department of Surgery, Kitasato University School of Medicine, Kanagawa, Sagamihara, Japan
3Institute for Medical Immunology, University Hospital Charite, Berlin, Germany.

Meeting: 2018 American Transplant Congress

Abstract number: 159

Keywords: Antibodies, Kidney transplantation, Tissue-specific, Tolerance

Session Information

Date: Sunday, June 3, 2018

Session Name: Concurrent Session: Novel Therapeutics

Session Time: 4:30pm-6:00pm

 Presentation Time: 4:30pm-4:42pm

Location: Room 602/603/604

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Background: Induction of T cell immune response c-DNA (TIRC7) is restricted to activated lymphocytes. Modulation of TIRC7 signalling prevents immune activation specifically at the site of inflammation while preserving immune competency of peripheral lymphocytes. The efficacy of a novel high affinity, chimeric antibody against human TIRC7 was investigated to prevent allograft rejection after transplantation in combination and comparison to a calcineurin inhibitor, FK506.

Method: Rat splenocytes were stimulated with either mitogen or IL2 in presence or absence of anti-TIRC7 antibody (anti-TIRC7 mAb) or control mAb to analyze cross-reactivity. Synergistic effects of anti-TIRC7 mAb with Tacrolimus (Tac) were tested in a strong histoincompatible donor/recipient combination (DA to Lewis). Kidney transplant recipients were treated either with Tac 0.2mg/kg or 0.5mg/kg or anti-TIRC7 mAb 2mg/day in combination with Tac (0.2mg/kg, days 0-7). Low dose FK506 was combined with the anti-TIRC7 mAb to prevent immunogenecity. Serum and spleens were procured by day 7 and for FACS to analyze lymphocyte subsets. Free anti-TIRC7 mAb concentration and allograft reaction was assessed in serum collected at days 1, 4 and 7 after transplantation. Anti-TIRC7 mAb kinetics was analyzed after a single dose administration to rats in serum collected on days 1,2,6,9,14 and 30.

Results: Anti-TIRC7 antibody in combination with low dose FK506 prolonged graft survival up to 80 days (mean 46d). Graft survival was inferior with Tac treatment only (max. 55d; mean 24d). Immunogenicity was absent after antibody application. Free antibody concentrations were 200 and 50ug/ml on days 1 and 30, respectively. No clinical side-effects was observed in anti-TIRC7 treated animals with unchanged periphereal lymphocyte counts in the peripheral blood. Elevated intragraft TIRC7 expression was observed in biopsies of allografts undergoing rejection.

Conclusion: The results suggest a pharmacodynamic synergism between the anti-TIRC7 mAb and FK506. No anti-drug antibody reaction was observed indicating no immunogenecity relevant epitops are presented to induce immune activation. Targeting of TIRC7 may provide a highly specific, novel approach for modulation of immune response restricted solely to tissue infiltrating lymphocytes in transplantation.

CITATION INFORMATION: Tullius S., Kumamoto Y., Nalan U. Anti-TIRC7 Antibody Acts Synergistically with Tacrolimus in Promoting Graft Survival in a Rat Kidney Transplant Model Am J Transplant. 2017;17 (suppl 3).

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To cite this abstract in AMA style:

Tullius S, Kumamoto Y, Nalan U. Anti-TIRC7 Antibody Acts Synergistically with Tacrolimus in Promoting Graft Survival in a Rat Kidney Transplant Model [abstract]. https://atcmeetingabstracts.com/abstract/anti-tirc7-antibody-acts-synergistically-with-tacrolimus-in-promoting-graft-survival-in-a-rat-kidney-transplant-model/. Accessed December 12, 2019.

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