Modulation of ischemia–reperfusion injury-induced thromboinflammation and evaluation of safety regarding novel drug ICM012
Carl Raihle, Clara Paul, Oleg Slivca, Gabriel Strandberg, Bo Nilsson, Alireza BiglarniaAbstract
Introduction
Ischemia–reperfusion injury (IRI) is unavoidable in kidney transplantation. Ischemia induces phenotypic changes in endothelial and parenchymal cells, including glycocalyx degradation and loss of surface-bound regulators. Subsequently, reperfusion triggers prompt activation of the intravascular innate immune system, involving the complement, coagulation, and kinin-kallikrein systems, and consequently a thromboinflammatory response. iCM012 is a novel amphiphilic polymer designed to form a temporary protective layer that shields altered cell surfaces from direct contact with circulating blood components upon reperfusion, thereby attenuating activation of thromboinflammation.
Methods
The safety and efficacy of iCM012 were first evaluated in vitro and in a series of porcine kidney transplantation models using ex vivo intra-arterial administration before transplantation. Effects on thromboinflammation, inflammatory cytokine release, and renal function were assessed and compared with placebo. Following successful preclinical evaluation, iCM012 was investigated in a first-in-human phase 1/2a randomized, double-blind, placebo-controlled trial including 18 kidney transplant recipients. The primary endpoint was safety and tolerability.
Results
Across all porcine models, ex vivo-treated grafts exhibited markedly attenuated IRI-induced thromboinflammation, reduced cytokine release, and improved kidney function. In a randomized, double-blinded, placebo-controlled first-in-human trial (ATMIRe), iCM012 was safe and well tolerated. Consistent with reduced graft injury, urinary levels of sC5b-9 and tubular injury markers were lower in the iCM012 group, with excellent 1-year eGFR.
Discussion
Ex vivo allograft coating with iCM012 is safe and appears to confer protection against IRI. These findings support further evaluation of iCM012 to improve outcome and expand utilization of high-risk donor kidneys.