Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 1 de 1
Filter
Add more filters











Database
Language
Publication year range
1.
J Heart Lung Transplant ; 40(10): 1112-1121, 2021 10.
Article in English | MEDLINE | ID: mdl-34334299

ABSTRACT

BACKGROUND: Post-transplant ischemia reperfusion injury (IRI) is a recognized risk factor for subsequent organ dysfunction, alloresponsiveness, and rejection. The complement system is known to play a role in IRI and represents a therapeutic target. Complement is activated in transplanted grafts when circulating IgM antibodies bind to exposed ischemia-induced neoepitopes upon reperfusion, and we investigated the targeting of a human complement inhibitor, CR1, to a post-transplant ischemia-induced neoepitope. METHODS: A fragment of human CR1 was linked to a single chain antibody construct (C2 scFv) recognizing an injury-specific neoepitope to yield C2-CR1. This construct, along with a soluble untargeted counterpart, was characterized in a cardiac allograft transplantation model of IRI in terms of efficacy and safety. RESULTS: CR1 was similarly effective against mouse and human complement. C2-CR1 provided effective protection against cardiac IRI at a lower dose than untargeted CR1. The increased efficacy of C2-CR1 relative to CR1 correlated with decreased C3 deposition, and C2-CR1, but not CR1, targeted to cardiac allografts. At a dose necessary to reduce IRI, C2-CR1 had minimal impact on serum complement activity, in contrast to CR1 which resulted in a high level of systemic inhibition. The circulatory half-life of CR1 was markedly longer than that of C2-CR1, and whereas a minimum therapeutic dose of CR1 severely impaired host susceptibility to infection, C2-CR1 had no impact. CONCLUSION: We show the translational potential of a human complement inhibitor targeted to a universal ischemia-induced graft-specific epitope, and demonstrate advantages compared to an untargeted counterpart in terms of efficacy and safety.


Subject(s)
Complement Activation/physiology , Complement C2/immunology , Complement Inactivating Agents/therapeutic use , Heart Transplantation/adverse effects , Myocardial Reperfusion Injury/prevention & control , Receptors, Complement 3b/immunology , Animals , Disease Models, Animal , Epitopes/immunology , Male , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Single-Chain Antibodies
SELECTION OF CITATIONS
SEARCH DETAIL