Development of complement therapeutics for inhibition of immune-mediated red cell destruction

Abstract

A major objective of my National Blood Foundation (NBF)-funded proposal was to produce recombinant soluble forms of a complement regulatory protein called complement receptor 1 (CR1) that carries the Knops blood group system antigens to perform antibody neutralization studies. By generating these recombinant proteins, we were able to inhibit several Knops antibodies in patient serum samples, thereby demonstrating their usefulness for clinical use. Interestingly, the recombinant CR1 proteins generated through NBF funding were also found to strongly reduce complement-mediated red cell destruction in a mouse hemolytic transfusion model. In this review, I will outline our NBF-funded studies, give an overview of recent advances from our group and others in the development of complement therapeutics, and highlight their potential use in the transfusion medicine setting.

Fig. 1

The complement system. The classical pathway is activated by antigen-antibody complex and the alternative and lectin pathways by microbial surfaces. Activation of these pathways results in the generation of the key enzymes C3 and C5 convertases, which in turn results in the release of C3a, C4a, and C5a anaphylatoxins (inflammatory response) and C3b (opsonization of target cells) and the generation of the membrane attack complex in the target cell (lysis). The different steps of the cascade where some of the complement regulatory proteins inhibit complement activation are shown. MBL = mannose-binding lectin; MASP = MBL-associated serine protease; C4bp = C4-binding protein, CR1; DAF = decay-accelerating factor; MCP = membrane cofactor protein. Adapted from Makrides.

Fig. 2

Schematic representation of the common isotype of CR1. The 30 SCRs are represented by square blocks and are numbered according to Klickstein and colleagues. Groups of seven SCRs are further subdivided into four LHRs. TM = transmembrane; cyto = cytoplasmic; aa = amino acids.