How important is the Fc-portion for CD40/CD40L costimulation blockade in orthotopic pig-to-baboon heart transplantation?
Martin Bender1, Bruno Reichart2, Franziska Barclay-Steuart3, Julia Radan2, Sebastian Michel4, Eckhard Wolf5, David Ayares6, Siobhan Fogarty7, Bruce Daugherty7, Seth Lederman7, Uli Binder8, Michaela Gebauer8, Arne Skerra9, Paolo Brenner4, Jan-Michael Abicht1, Matthias Längin1.
1Department of Anaesthesiology, University Hospital, LMU Munich, Munich, Germany; 2Walter Brendel Centre of Experimental Medicine, LMU Munich, Munich, Germany; 3Department of Anaesthesiology, University Hospital Hamburg-Eppendorf (UKE), Hamburg, Germany; 4Department of Cardiac Surgery, University Hospital, LMU Munich, Munich, Germany; 5Institute of Molecular Animal Breeding and Biotechnology, Gene Center, and Department of Veterinary Sciences, LMU Munich, Munich, Germany; 6Revivicor, Blacksburg, VA, United States; 7Tonix Pharmaceuticals, Chatham, NJ, United States; 8XL-protein GmbH, Freising, Germany; 9Chair of Biological Chemistry, School of Life Sciences, Technical University of Munich, Munich, Germany
Background: Orthotopic cardiac xenotransplantation is close to a clinical pilot study. For clinical use, immunosuppression based on costimulation blockade with humanized antibodies is required. In addition to full antibodies, Fab fragments have been developed. These Fabs lack the Fc region, which has been reported to be thrombogenic in the case of first-generation anti-CD40L antibodies. It remains unclear whether the Fc region is essential for immunosuppression in xenotransplantation.
Methods: Hearts from genetically modified (GGTA1-KO, hCD46/hTBM transgenic) juvenile pigs were orthotopically transplanted into male baboons using cold, non-ischemic organ preservation. In group I (n = 4), costimulation blockade was performed with anti-CD40L PAS-Fab at 20 mg/kg body weight (b.w.); in group II (n = 3), the anti-CD40L mAb TNX-1500*, which possesses the identical variable region as anti-CD40L PAS-Fab, was administered initially at 25 mg/kg b.w. and subsequently at 20 mg/kg b.w.. Additionally, all recipients were treated with an mTOR inhibitor, anti-hypertensive medication, and a fast corticoid tapering.
Results: In each group, one animal was lost due to technical failure. The mean survival of the remaining animals in group I was 33 ± 10 days (n = 3), and in group II, it was 181 ± 15 days (n = 2). In group I, all grafts were lost due to either acute humoral (day 18; n = 1) or cellular rejection (days 29 and 51; n = 2). In group II, one graft was lost due to acute cellular rejection (day 196) and the other due to acute myocardial infarction caused by an embolus in the right coronary artery (day 166).
Conclusions: With identical variable regions, the two antibodies differed only in the presence or absence of the Fc region. Therefore, we hypothesize that the Fc region or the bivalency of the full-size mAb – apart from differences in the dosing scheme – is essential for an effective anti-CD40L costimulation blockade in orthotopic pig-to-baboon xenotransplantation.
* TNX-1500 is an investigational new drug, its efficacy and safety have not been established and it has not been approved for any indication
This research was funded by the German Research Foundation (Deutsche Forschungsge- meinschaft, DFG) TRR 127 and—in part—by the Swiss National Science Foundation (CR-SII5_198577), the Bavarian Research Foundation (AZ-1543-22) and the Leducq Foundation (23CVD01)..
[1] Heart
[2] Xenotransplantation
[3] Orthotopic Pig-to-Baboon Cardiac Xenotransplantation
[4] Costimulation Blockade
[5] Immunosuppression