title: 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.
abstract: 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.
authors.affiliation: 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.
authors.forename: Kelly M
authors.initials: KM
authors.lastname: Loyet
authors.affiliation: 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.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Good
authors.affiliation: 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.
authors.forename: Teresa
authors.initials: T
authors.lastname: Davancaze
authors.affiliation: 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.
authors.forename: Lizette
authors.initials: L
authors.lastname: Sturgeon
authors.affiliation: 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.
authors.forename: Xiangdan
authors.initials: X
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Jihong
authors.initials: J
authors.lastname: Yang
authors.affiliation: 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.
authors.forename: Kha N
authors.initials: KN
authors.lastname: Le
authors.affiliation: 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.
authors.forename: Maureen
authors.initials: M
authors.lastname: Wong
authors.affiliation: 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.
authors.forename: Philip E
authors.initials: PE
authors.lastname: Hass
authors.affiliation: 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.
authors.forename: Menno
authors.initials: M
authors.lastname: van Lookeren Campagne
authors.affiliation: 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.
authors.forename: Peter C
authors.initials: PC
authors.lastname: Haughney
authors.affiliation: 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.
authors.forename: Alyssa
authors.initials: A
authors.lastname: Morimoto
authors.affiliation: 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.
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Damico-Beyer
authors.affiliation: 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.
authors.forename: Laura E
authors.initials: LE
authors.lastname: DeForge
mesh_terms: D000818:Animals; D002417:Cattle; D015926:Complement C3a / Q000037:antagonists & inhibitors* / Q000276:immunology; D011416:Complement Factor D / Q000037:antagonists & inhibitors* / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000008:administration & dosage* / Q000276:immunology; D058449:Intravitreal Injections; D008252:Macaca fascicularis; D008268:Macular Degeneration / Q000097:blood / Q000188:drug therapy* / Q000276:immunology; D008297:Male; D051379:Mice; D016896:Treatment Outcome
chemical_list: D007140:Immunoglobulin Fab Fragments; D015926:Complement C3a; D011416:Complement Factor D; C000603963:lampalizumab