Preventing organ rejection after transplantation

DGF incidence ranges from 40-60 % in high-risk kidneys, depending on organ donor state, and is caused by immune-mediated ischaemia-reperfusion injury. Dialysis is required for about seven days until the organ regains its function, increasing the chances of transplant failure. In the case of the kidney, immune system activation to damage the grafted organ is driven by toll-like receptor 2 (TLR2).

The EU-funded MABSOT project was designed to test a novel antibody, OPN-305, for use in the prevention of DGF. The scientific basis of this development is the inhibition of TLR2-mediated injury in a range of organ transplantation scenarios.

Pre-clinical evaluation of the antibody formulation determined the maximum dose in non-human primates with no adverse side-effects. Molecular analysis of the damage-associated molecular patterns recognised by TLR2 identified serum amyloid A (SAA) as a TLR2 agonist. Ongoing work after the project end will determine the role of SAA as a driver of ischaemia-reperfusion injury.

An important line of work in the MABSOT study entailed identification of novel early biomarkers of kidney damage. Microarray studies in a mouse renal transplant model identified 20 genes of significant interest that are differentially regulated within 6 hours post-transplant. Analysis of the qPCR and ELISA results confirmed two early biomarkers of kidney damage, SPP-1 and TIMP-1, for validation in human transplant samples.

A phase I healthy volunteer clinical trial with OPN-305 has been completed, demonstrating the safety and tolerability of intravenous antibody administration. A phase II trial in renal transplant patients is currently underway and the initial study determined doses of OPN-305 for the trial. The recruitment of Part A patients for the treatment is now completed. Part B has been initiated.

Overall, MABSOT work in delineating the DGF mechanism coupled with the discovery of clinically relevant markers of early kidney damage will improve DGF diagnosis. The advancement of OPN-305 into trials has significant clinical ramifications for alleviating DGF in organ-transplanted patients and enhancing longevity. The inhibition of TLR2-mediated injury has implications for the drug's use in the treatment of other solid organ transplantations where similar injury occurs.