Recombinant human IgG1 based Fc multimers, with limited FcR binding capacity, can effectively inhibit complement-mediated disease.

J Autoimmun 2017 Nov 19;84:97-108. Epub 2017 Aug 19.

Department of Otorhinolaryngology-Head and Neck Surgery, University of Maryland School of Medicine, 16 S. Eutaw Street, Baltimore, MD, 21201, USA. Electronic address:

There is a lack of effective targeted therapies for the treatment of complement dependent diseases. We developed two recombinant Fc multimers, G207 and G211, with limited ability to interact with low/moderate affinity FcγRs, but with high avidity for C1q. These drugs effectively inhibited complement dependent cytotoxicity (CDC) in vitro, and prevented the deposition of C1q, C3b and MAC, on the surface of Ab-opsonized cells. Importantly, these inhibitory effects were both C1q dependent and independent. In order to determine the biologic relevance of our findings, we evaluated the clinical efficacy of these drugs in three different animal models, acute RBC hemolysis, anti-Thy-1 nephritis and passive Heymann's nephropathy (PHN), in which disease pathophysiology relies preferentially on complement activation. While G207 was protective in the anti-Thy-1 nephritis and PHN models, G211 was protective in all of the models tested and could effectively treat PHN. In the anti-Thy-1 nephritis model, G211 prevented the characteristic histologic changes associated with the disease and limited glomerular deposition of C3. Collectively, these data suggest that "complement preferential" Fc multimers offer a novel approach to the treatment of complement mediated diseases.

Download full-text PDF

Source
https://linkinghub.elsevier.com/retrieve/pii/S08968411173036
Publisher Site
http://dx.doi.org/10.1016/j.jaut.2017.08.004DOI Listing
November 2017
23 Reads

Publication Analysis

Top Keywords

anti-thy-1 nephritis
12
complement dependent
8
treatment complement
8
c1q dependent
4
dependent independent
4
independent order
4
effects c1q
4
inhibitory effects
4
importantly inhibitory
4
prevented characteristic
4
g211 prevented
4
order determine
4
dependent cytotoxicity
4
relevance findings
4
biologic relevance
4
nephritis model
4
model g211
4
determine biologic
4
cells importantly
4
characteristic histologic
4

Similar Publications