Discovery and Characterization of a Fully Human Monoclonal Antibody Inhibitor of Plasma Kallikrein for the Treatment of Plasma Kallikrein-Mediated Edema

FEBRUARY 2013 AB32 Abstracts S A T U R D A Y 116 Discovery and Characterization of a Fully Human Monoclonal Antibody Inhibitor of Plasma Kallikrein for the Treatment of Plasma Kallikrein-Mediated Edema Daniel Sexton, Ryan Faucette, Malini Viswanathan, Niksa Kastrapeli, Kris Kopacz, Greg Conley, Allison Lindberg, Janja Cosic, Stephen Comeau, Shauna Mason, Jon Kenniston,Mike DiLeo, Jie Chen, Robert Ladner, Andrew Nixon, Christopher TenHoor; Dyax Corp. RATIONALE: Plasma kallikrein (pKal) is a serine protease responsible for generating the vasodilator bradykinin, and is mainly regulated by C1 inhibitor (C1-INH). Patients with hereditary angioedema (HAE) have deficient levels of functional C1-INH, leading to unpredictable attacks of debilitating edema via dysregulated pKal-mediated bradykinin generation. Inhibition of pKal is a viable therapeutic option for HAE, as demonstrated by the efficacy of ecallantide, a specific pKal inhibitor, for treatment of acute HAE attacks. There remains an unmet medical need for a nonintravenous, long-lasting prophylactic treatment for HAE. METHODS: We used an antibody phage display library to identify a fully human antibody inhibitor specific for pKal, verified by in vitro enzyme inhibition assays. The in vivo efficacy and pharmacokinetic (PK) properties of the antibody were determined using preclinical rat and cynomolgus monkey models. RESULTS: DX-2930 is a potent antibody inhibitor of pKal (Ki 5 0.14 nM) that does not bind prekallikrein or any other serine protease tested. Using surface plasmon resonance (Biacore), DX-2930 was shown to bind pKal complexed through non-catalytic domain residues with high molecular weight kininogen. It also recognized pKal assembled on human endothelial cell (HUVEC) membranes in culture. DX-2930 effectively reduced carrageenan-induced paw edema in rats. The PK properties of DX2930 in monkeys following subcutaneous injection indicate that the antibody exhibits a high bioavailability (66%) and a half-life (12.5 days) that allometrically scales to ;28 days in humans. CONCLUSIONS: A potent and potentially long acting inhibitor of pKal activity is expected to be an effective prophylactic treatment option for pKal-mediated diseases like HAE.