Therapeutic potential of monoclonal antibodies in myocardial reperfusion injury.
While reperfusion therapy in myocardial infarction is associated with better short- and long-term outcomes, it paradoxically results in reperfusion injury mediated by interactions between leukocytes, endothelial cells, platelets, and the myocardium. Several surface receptors, adhesion molecules, and ligands have been shown to be important in the pathogenesis of myocardial reperfusion injury, and therapeutic strategies employing the use of monoclonal antibodies have been attempted against many of them. These have included monoclonal antibodies against activated complement 5 (C5a) to inhibit leukotaxis, monoclonal antibodies against P-selectin, P-selectin glycoprotein ligand (PSGL)-1, L-selectin and E-selectin to inhibit leukocyte rolling, and monoclonal antibodies against the Mac-1 (CD11b/CD18) receptor and intercellular adhesion molecule (ICAM)-1 to block firm adhesion of leukocytes to endothelial cells. In addition, although initially developed as an antiplatelet agent, the glycoprotein IIb/IIIa receptor antagonist abciximab shows significant ability to diminish or prevent reperfusion injury, presumably through its ability to block the Mac-1 receptor on leukocytes. Finally, monoclonal antibodies have also been tested against several cytokines and adhesion molecules implicated in so-called subacute endothelial activation, including interleukin-8 and vascular cell adhesion molecule (VCAM)-1. Studies in animals evaluating the use of monoclonal antibodies in reperfusion injury against various potential targets have largely been successful; however, studies in humans have been disappointing, underscoring the pitfalls of using animal models for the study of complex diseases. Based upon current knowledge, it is becoming clear that a successful strategy against reperfusion injury will require targeting several pathways at once, rather than attempting to block one final common pathway. In addition, inhibition of subacute endothelial activation through inhibition of transcription factors, namely nuclear factor (NF)-kappa B, may be a prerequisite to significantly reducing the extent of myocardial damage in this condition. The future of monoclonal antibodies in the overall strategy remains unclear. Newer small molecule inhibitors are also under development, and the eventual role of gene therapy remains to be elucidated.
Nigam
Anil
A
Mayo Alliance for Clinical Trials, Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55902, USA.
Kopecky
Stephen L
SL
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D004730:Endothelium, Vascular / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D015428:Myocardial Reperfusion Injury / Q000503:physiopathology / Q000517:prevention & control*
D000911:Antibodies, Monoclonal