Abstract
Better understanding of roles of complement in pathology has fuelled an explosion of interest in complement-targeted therapeutics. The C5-blocking monoclonal antibody (mAb) eculizumab, the first of the new wave of complement blocking drugs, was FDA approved for treatment of Paroxysmal Nocturnal Hemoglobinuria in 2007; its expansion into other diseases has been slow and remains restricted to rare and ultra-rare diseases such as atypical hemolytic uremic syndrome. The success of eculizumab has provoked other Pharma to follow this well-trodden track and made C5 blockade the busiest area of complement drug development. C5 blockade inhibits generation of C5a and C5b, the former an anaphylatoxin, the latter the nidus for formation of the pro-inflammatory membrane attack complex. In order to use anti-complement drugs in common complement-driven diseases, more affordable and equally effective therapeutics are needed. To address this, we explored complement inhibition downstream of C5. Novel blocking mAbs targeting C7 and/or the C5b-7 complex were generated, identified using high throughput functional assays and specificity confirmed by immunochemical assays and surface plasmon resonance (SPR). Selected mAbs were tested in rodents to characterize pharmacokinetics, and therapeutic capacity. Administration of a mouse C7-selective mAb to wildtype mice, or a human C7 specific mAb to C7-deficient mice reconstituted with human C7, completely inhibited serum lytic activity for >48 h. The C5b-7 complex selective mAb 2H2, most active in rat serum, efficiently inhibited serum lytic activity in vivo for over a week from a single low dose (10 mg/kg); this mAb effectively blocked disease and protected muscle endplates from destruction in a rat myasthenia model. Targeting C7 and C7-containing terminal pathway intermediates is an innovative therapeutic approach, allowing lower drug dose and lower product cost, that will facilitate the expansion of complement therapeutics to common diseases.
Highlights
The complement system comprises over 50 proteins, regulators and receptors circulating in plasma or on cells
In NMS, monoclonal antibody (mAb) 73D1, 2H2, and 3B11 inhibited in that order of efficiency, but 17E7, 59E7, and the C5-blocking controls 7D4 and eculizumab had no inhibitory activity in NMS (Figure 1C)
To date the use of anti-complement drugs has been restricted to a handful of rare diseases, including hemolytic disorders such as paroxysmal nocturnal hemoglobinuria (PNH) and renal diseases, notably atypical hemolytic uremic syndrome (aHUS), where they have had a transformational impact [1,2,3]
Summary
The complement system comprises over 50 proteins, regulators and receptors circulating in plasma or on cells. Activation of the system by three distinct pathways, classical, lectin, and alternative, the latter comprising a common amplification loop, leads to formation of C3 convertases, followed by C5 convertases which cleave C5 into the potent chemotactic anaphylatoxin C5a, and C5b, the nidus for formation of the cytotoxic proinflammatory membrane attack complex (MAC). C5b while associated with the convertase, sequentially binds the plasma proteins C6 and C7, generating the C5b-7 complex that undergoes conformational change, triggering release from the convertase and exposing a labile hydrophobic membrane binding surface. The drug must be given bi-weekly by intravenous infusion, 0.9 to 1.2 g/dose [1,2,3,4,5] These factors restrict progress toward therapy of more common complement-driven diseases. Anti-complement drugs for common conditions must be safer, cheaper and easier to administer
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