Targeting Complement at the Time of Transplantation

Abstract

Complement activation occurs in at least two phases when an organ is transplanted into a naive recipient: during reperfusion with recipient blood particularly when the donor organ has undergone a significant period of ischaemia and then during acute rejection once the recipient immune system has recognised the donor tissue as non-self. Both of these reactions are most obvious in the extravascular compartment of the transplanted organ and involve local synthesis of some of the key complement components as well as loss of controls that limit the activation of the pivotal component C3. In contrast, sensitised individuals with pre-existing circulating antibodies have an immediate reaction against the transplant organ that is also complement dependent but is enacted in the intravascular space. All three types of injury (ischaemia-reperfusion, acute rejection, hyperacute rejection) have a critical effect on transplant outcome. Here we discuss therapeutic strategies that are designed to overcome the impact of these factors at the start of transplantation with the aim of improving long-term transplant outcomes. These include the concept of treating the donor organ with modified therapeutic regulators that are engineered to be retained by the donor organ after transplantation and prevent inflammatory injury during the critical early period. By targeting the donor organ with anchored therapeutic proteins, the systemic functions of complement including host defence remain intact. The control of complement activation during the first stages of transplantation, including the possibility that this will reduce the capacity of the graft for stimulating the adaptive immune system, offers an important prospect for increasing the longevity of the transplant and offsetting demand on the limited supply of donor organs. It also provides a model in which the benefits and indications for localised therapy to maximise therapeutic efficiency and minimise the systemic disturbance may be instructive in other complement-related disorders.

New insight into the effects of heparinoids on complement inhibition by C1-inhibitor

“…Therapeutic inhibition of the complement system is considered a promising approach for the treatment of numerous pathological conditions [1,2,8,9]. The current study demonstrates that C1-INH might be a potential therapeutic candidate, because it inhibits activation of all three pathways of the complement system.…”

“…In transplantation, mounting evidence from animal studies suggests that intervention in complement pathway activation is a promising method for improving allograft outcome [8,9].…”

Therapeutic complement inhibition in complement-mediated hemolytic anemias: Past, present and future

“…Mirococept has been mostly investigated in models of complement-mediated ischemia/reperfusion injury, such as kidney transplantation in rats [191]. This agent is currently in development for kidney transplantation [192] within a phase III randomized, placebo-controlled trial testing mirococept as a protective agent for the donor kidney to prevent functional impairment of transplanted kidneys [193]. In addition to these two compounds, Alexion has in its pipeline a fusion engineered protein named TT32 consisting (similar to TT30) of the functional domain of CR1 fused with the C3-binding domain of CR2; [194] up to date, no preclinical/clinical development for this compound has been reported.…”

“…These findings demonstrate that the compstatin family prevents early complement activation in PNH, eventually predicting a clinical effect on both MAC-mediated intravascular and on C3-mediated extravascular hemolysis of PNH erythocytes. Amyndas Pharmaceuticals has completed pre-clinical studies of its compounds in non-human primates, showing that unmodified Cp40/AMY-101 has an excellent bioavailability after repeated subcutaneous injec- [190][191][192][193] CAP and CCP C3 convertase TT32 (CR2/CR1) Alexion CR1-based protein Not active. Preclinical (non-PNH) [194] tions (the terminal half-life is estimated in at least 12-24 h), with sustained pharmacological levels which allow a daily or bi-daily treatment schedule [138].…”

Current and Future Pharmacologic Complement Inhibitors

“…107 Mirococept has been demonstrated effective in preventing complement-mediated ischemia/reperfusion injury of transplanted kidneys in rats 108 and is currently under investigation in humans in kidney transplantation. 109 A clinical randomized placebo-controlled trial investigating a method for coating the inner surface of donor kidneys with a protective layer of mirococept is ongoing, aiming to improve the function of transplanted kidneys. 110 All these CR1-based complement inhibitors (including also TT32, a CR2/CR1 fusion protein under development by Alexion) 111 represent good candidates for systemic complement inhibition in PNH and in antibody-mediated hemolytic anemias.…”