Complement inhibition in cynomolgus monkeys by anti-factor d antigen-binding fragment for the treatment of an advanced form of dry age-related macular degeneration.

Autor:	Loyet KM; Departments of Biochemical and Cellular Pharmacology (K.M.L., L.S., L.E.D.), Assay Development and Technologies (J.G., T.D., M.W., A.M.), BioAnalytical Sciences (X.W., J.Y.), Pharmacokinetics and Pharmacodynamics (K.N.L., P.C.H., L.A.D.-B.), Protein Chemistry (P.E.H.), and Immunology (M.v.L.C.), Genentech, South San Francisco, California loyet.kelly@gene.com., Good J; Departments of Biochemical and Cellular Pharmacology (K.M.L., L.S., L.E.D.), Assay Development and Technologies (J.G., T.D., M.W., A.M.), BioAnalytical Sciences (X.W., J.Y.), Pharmacokinetics and Pharmacodynamics (K.N.L., P.C.H., L.A.D.-B.), Protein Chemistry (P.E.H.), and Immunology (M.v.L.C.), Genentech, South San Francisco, California., Davancaze T; Departments of Biochemical and Cellular Pharmacology (K.M.L., L.S., L.E.D.), Assay Development and Technologies (J.G., T.D., M.W., A.M.), BioAnalytical Sciences (X.W., J.Y.), Pharmacokinetics and Pharmacodynamics (K.N.L., P.C.H., L.A.D.-B.), Protein Chemistry (P.E.H.), and Immunology (M.v.L.C.), Genentech, South San Francisco, California., Sturgeon L; Departments of Biochemical and Cellular Pharmacology (K.M.L., L.S., L.E.D.), Assay Development and Technologies (J.G., T.D., M.W., A.M.), BioAnalytical Sciences (X.W., J.Y.), Pharmacokinetics and Pharmacodynamics (K.N.L., P.C.H., L.A.D.-B.), Protein Chemistry (P.E.H.), and Immunology (M.v.L.C.), Genentech, South San Francisco, California., Wang X; Departments of Biochemical and Cellular Pharmacology (K.M.L., L.S., L.E.D.), Assay Development and Technologies (J.G., T.D., M.W., A.M.), BioAnalytical Sciences (X.W., J.Y.), Pharmacokinetics and Pharmacodynamics (K.N.L., P.C.H., L.A.D.-B.), Protein Chemistry (P.E.H.), and Immunology (M.v.L.C.), Genentech, South San Francisco, California., Yang J; Departments of Biochemical and Cellular Pharmacology (K.M.L., L.S., L.E.D.), Assay Development and Technologies (J.G., T.D., M.W., A.M.), BioAnalytical Sciences (X.W., J.Y.), Pharmacokinetics and Pharmacodynamics (K.N.L., P.C.H., L.A.D.-B.), Protein Chemistry (P.E.H.), and Immunology (M.v.L.C.), Genentech, South San Francisco, California., Le KN; Departments of Biochemical and Cellular Pharmacology (K.M.L., L.S., L.E.D.), Assay Development and Technologies (J.G., T.D., M.W., A.M.), BioAnalytical Sciences (X.W., J.Y.), Pharmacokinetics and Pharmacodynamics (K.N.L., P.C.H., L.A.D.-B.), Protein Chemistry (P.E.H.), and Immunology (M.v.L.C.), Genentech, South San Francisco, California., Wong M; Departments of Biochemical and Cellular Pharmacology (K.M.L., L.S., L.E.D.), Assay Development and Technologies (J.G., T.D., M.W., A.M.), BioAnalytical Sciences (X.W., J.Y.), Pharmacokinetics and Pharmacodynamics (K.N.L., P.C.H., L.A.D.-B.), Protein Chemistry (P.E.H.), and Immunology (M.v.L.C.), Genentech, South San Francisco, California., Hass PE; Departments of Biochemical and Cellular Pharmacology (K.M.L., L.S., L.E.D.), Assay Development and Technologies (J.G., T.D., M.W., A.M.), BioAnalytical Sciences (X.W., J.Y.), Pharmacokinetics and Pharmacodynamics (K.N.L., P.C.H., L.A.D.-B.), Protein Chemistry (P.E.H.), and Immunology (M.v.L.C.), Genentech, South San Francisco, California., van Lookeren Campagne M; Departments of Biochemical and Cellular Pharmacology (K.M.L., L.S., L.E.D.), Assay Development and Technologies (J.G., T.D., M.W., A.M.), BioAnalytical Sciences (X.W., J.Y.), Pharmacokinetics and Pharmacodynamics (K.N.L., P.C.H., L.A.D.-B.), Protein Chemistry (P.E.H.), and Immunology (M.v.L.C.), Genentech, South San Francisco, California., Haughney PC; Departments of Biochemical and Cellular Pharmacology (K.M.L., L.S., L.E.D.), Assay Development and Technologies (J.G., T.D., M.W., A.M.), BioAnalytical Sciences (X.W., J.Y.), Pharmacokinetics and Pharmacodynamics (K.N.L., P.C.H., L.A.D.-B.), Protein Chemistry (P.E.H.), and Immunology (M.v.L.C.), Genentech, South San Francisco, California., Morimoto A; Departments of Biochemical and Cellular Pharmacology (K.M.L., L.S., L.E.D.), Assay Development and Technologies (J.G., T.D., M.W., A.M.), BioAnalytical Sciences (X.W., J.Y.), Pharmacokinetics and Pharmacodynamics (K.N.L., P.C.H., L.A.D.-B.), Protein Chemistry (P.E.H.), and Immunology (M.v.L.C.), Genentech, South San Francisco, California., Damico-Beyer LA; Departments of Biochemical and Cellular Pharmacology (K.M.L., L.S., L.E.D.), Assay Development and Technologies (J.G., T.D., M.W., A.M.), BioAnalytical Sciences (X.W., J.Y.), Pharmacokinetics and Pharmacodynamics (K.N.L., P.C.H., L.A.D.-B.), Protein Chemistry (P.E.H.), and Immunology (M.v.L.C.), Genentech, South San Francisco, California., DeForge LE; Departments of Biochemical and Cellular Pharmacology (K.M.L., L.S., L.E.D.), Assay Development and Technologies (J.G., T.D., M.W., A.M.), BioAnalytical Sciences (X.W., J.Y.), Pharmacokinetics and Pharmacodynamics (K.N.L., P.C.H., L.A.D.-B.), Protein Chemistry (P.E.H.), and Immunology (M.v.L.C.), Genentech, South San Francisco, California.
Jazyk:	angličtina
Zdroj:	The Journal of pharmacology and experimental therapeutics [J Pharmacol Exp Ther] 2014 Dec; Vol. 351 (3), pp. 527-37. Date of Electronic Publication: 2014 Sep 17.
DOI:	10.1124/jpet.114.215921
Abstrakt:	Anti-factor D (AFD; FCFD4514S, lampalizumab) is a humanized IgG Fab fragment directed against factor D (fD), a rate-limiting serine protease in the alternative complement pathway (AP). Evaluation of AFD as a potential intravitreal (IVT) therapeutic for dry age-related macular degeneration patients with geographic atrophy (GA) is ongoing. However, it is unclear whether IVT administration of AFD can affect systemic AP activation and potentially compromise host-immune responses. We characterized the pharmacologic properties of AFD and assessed the effects of AFD administered IVT (2 or 20 mg) or intravenous (0.2, 2, or 20 mg) on systemic complement activity in cynomolgus monkeys. For the IVT groups, serum AP activity was reduced for the 20 mg dose group between 2 and 6 hours postinjection. For the intravenous groups, AFD inhibited systemic AP activity for periods of time ranging from 5 minutes (0.2 mg group) to 3 hours (20 mg group). Interestingly, the concentrations of total serum fD increased up to 10-fold relative to predose levels following administration of AFD. Furthermore, AFD was found to inhibit systemic AP activity only when the molar concentration of AFD exceeded that of fD. This occurred in cynomolgus monkeys at serum AFD levels ≥2 µg/ml, a concentration 8-fold greater than the maximum serum concentration observed following a single 10 mg IVT dose in a clinical investigation in patients with GA. Based on these findings, the low levels of serum AFD resulting from IVT administration of a clinically relevant dose are not expected to appreciably affect systemic AP activity. (Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.)
Databáze:	MEDLINE
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