PT  - JOURNAL ARTICLE
AU  - Kelly M. Loyet
AU  - Jeremy Good
AU  - Teresa Davancaze
AU  - Lizette Sturgeon
AU  - Xiangdan Wang
AU  - Jihong Yang
AU  - Kha N. Le
AU  - Maureen Wong
AU  - Philip E. Hass
AU  - Menno van Lookeren Campagne
AU  - Peter C. Haughney
AU  - Alyssa Morimoto
AU  - Lisa A. Damico-Beyer
AU  - Laura E. DeForge
TI  - 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
AID  - 10.1124/jpet.114.215921
DP  - 2014 Dec 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 527--537
VI  - 351
IP  - 3
4099  - http://jpet.aspetjournals.org/content/351/3/527.short
4100  - http://jpet.aspetjournals.org/content/351/3/527.full
SO  - J Pharmacol Exp Ther2014 Dec 01; 351
AB  - 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.