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Novel Approaches to Block Complement

Böhmig, Georg A., MD1; Wahrmann, Markus, PhD1; Eskandary, Farsad, MD1; Rostaing, Lionel, MD, PhD2

doi: 10.1097/TP.0000000000002267
Reviews

The complement system may contribute in many ways to transplant injury, being a promising target for specific therapeutic interventions. There is evidence that the monoclonal anti-C5 antibody eculizumab is effective in the prevention and treatment of early antibody-mediated rejection, but terminal complement blockade might be of limited efficiency in chronic rejection. Given the diversity of immunological events triggered by activation steps upstream to C5, in particular, opsonin and anaphylatoxin formation through C3 cleavage, one may argue that, in the specific context of antibody-mediated rejection, inhibition of antibody-triggered classical pathway (CP) activation might be beneficial. Strategies to interfere with key CP component C1 are currently under clinical evaluation and include the therapeutic use of purified C1-inhibitor, which, besides targeting the integrity and function of the C1 complex, also affects components of the LP, the contact system, the coagulation cascade or surface molecules mediating leukocyte-endothelial interactions. In addition, a monoclonal anti-C1s antibody (BIVV009) has now entered clinical evaluation and was shown to effectively block antibody-triggered CP activation in rejecting kidney allografts. Moreover, modified apheresis techniques for preferential removal of macromolecules, including C1q, may allow for efficient complement depletion, in addition to antibody removal. The availability of effective strategies to interfere with the CP, as well as innovative approaches targeting other pathways, some of them already being tested in clinical trials, will help us figure out how complement contributes to acute and chronic graft injury, and hopefully provide us with new ways to more efficiently counteract rejection.

The complement system contributes to transplant injury has prompted the development of new therapies to control complement activation. Böhmig et al discus the latest strategies under investigation to control complement activation and antibody-mediated rejection in the clinic.

1 Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria.

2 Service de Néphrologie, Hémodialyse, Aphérèses et Transplantation, Centre Hospitalier Universitaire Grenoble-Alpes, La Tronche, France.

Received 31 December 2017. Revision received 8 April 2018.

Accepted 29 April 2018.

G.A.B. received research support (unrestricted grants) from Fresenius Medical Care, Bad Homburg, Germany, and True North Therapeutics, Inc., South San Francisco, CA, USA. F.E., M.W. and L.R. declare no conflicts of interest.

G.A.B. participated in the conception, writing and revision of the article. F.E. participated in the conception, writing and revision of the article. M.W. participated in the conception, writing and revision of the article. L.R. participated in the conception, writing, and revision of the article.

Correspondence: Georg A. Böhmig, MD, Division of Nephrology and Dialysis, Department of Medicine III, Medical University Vienna, Währinger Gürtel 18-20, A-1090 Vienna, Austria. (georg.boehmig@meduniwien.ac.at).

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