Abstract
SummaryOver the last decade there has been an explosion in complement therapies; one‐third of the drugs in the clinic or in development target C5 protein. Eculizumab, a monoclonal antibody (mAb) that binds C5 and blocks its cleavage by the convertase, is the current reference standard treatment for atypical haemolytic uraemic syndrome (aHUS) and paroxysmal nocturnal haemoglobinuria (PNH) and in clinical trials for many other diseases. Here we describe a panel of novel anti‐C5 mAb, including mAb that, like Eculizumab, are efficient inhibitors of complement but, unlike Eculizumab, inhibit across species, including human, rat, rabbit and guinea pig. Several inhibitory anti‐C5 mAb were identified and characterized for C5 binding and lytic inhibitory capacity in comparison to current therapeutic anti‐C5 mAb; three clones, 4G2, 7D4 and 10B6, were selected and further characterized for ligand specificity and affinity and cross‐species inhibitory activity. The mAb 10B6 was human‐specific whereas mAb 4G2 and 7D4 efficiently inhibited lysis by human, rabbit and rat serum, and weakly inhibited guinea pig complement; 7D4 also weakly inhibited mouse complement in vitro The rat C5‐cross‐reactive mAb 4G2, when administered intraperitoneally in a rat model of myasthenia gravis, effectively blocked the disease and protected muscle endplates from destruction. To our knowledge this is the first report of an anti‐C5 function blocking mAb that permits preclinical studies in rats.
Highlights
The complement system is a central component of innate immunity responsible for recognition and killing of bacteria and promotion of phagocytosis through opsonization
Over the last decade there has been an explosion in complement therapies; one-third of the drugs in the clinic or in development target complement component 5 (C5) protein
We describe a panel of novel anti-C5 monoclonal antibody (mAb), including mAb that, like Eculizumab, are efficient inhibitors of complement but, unlike Eculizumab, inhibit across species, including human, rat, rabbit and guinea pig
Summary
The complement system is a central component of innate immunity responsible for recognition and killing of bacteria and promotion of phagocytosis through opsonization. The system evolved to protect from pathogens; recent reports have highlighted other homeostatic roles of complement, including as a driver of inflammation, modulator of adaptive immunity and metabolism, and architect of neural development.[1,2,3] Dysregulation of complement leads to pathology, important in a large number of inflammatory and degenerative diseases.[4]. Over the last decade there has been an explosion in complement drug development. Eculizumab, an anti-C5 monoclonal antibody (mAb), was a landmark in this work, approved by the US Food and Drug Administration (FDA)
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