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 mg/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.

A Mechanistic Pharmacokinetic/Pharmacodynamic Model of Factor D Inhibition in Cynomolgus Monkeys by Lampalizumab for the Treatment of Geographic Atrophy

“…However, literature on ITV administration of anti-vascular endothelial growth factor therapy suggested that the half-life of ranibizumab (7-9 days) (Krohne et al, 2012;Xu et al, 2013) was only slightly shorter than that for bevacizumab (9.8 days) (Krohne et al, 2012) in humans. Notably, the quasi-steady state equilibrium constant K ss was fixed to the in vitro measured value of the dissociation equilibrium constant (K D ) of 11.7 pM (Loyet et al, 2014) and was able to describe the data quite well. As the quasi-equilibrium approximation is a special case of the quasi-steady state approximation (Gibiansky et al, 2008), and the in vitro and in vivo agreement of the parameters K D and K ss confirms the assumption that the internalization rate constant is much smaller than the dissociation rate constant.…”

“…A target-mediated drug disposition (TMDD) model is critical in explaining the PK and PD of many biologics for which the high antibody-target binding affinity as well as the antibody and target levels can directly influence the PK of the antibody (Mager and Jusko, 2001). Lampalizumab was shown to bind CFD in both human and cynomolgus monkey (Macaca fascicularis) species with high affinity (Loyet et al, 2014). Cynomolgus monkeys were shown to be a relevant preclinical model for evaluating the PK/PD of lampalizumab Loyet et al, 2014).…”

“…Lampalizumab was shown to bind CFD in both human and cynomolgus monkey (Macaca fascicularis) species with high affinity (Loyet et al, 2014). Cynomolgus monkeys were shown to be a relevant preclinical model for evaluating the PK/PD of lampalizumab Loyet et al, 2014). A single ITV dose-escalation study, a 2-week single-dose ITV toxicity study, and a PK study of i.v.…”

“…Despite the moderate systemic target occupancy, the serum lampalizumab molar concentrations for the 1-or 10-mg dose groups either did not or only transiently exceeded the molar concentrations of CFD. This molar excess of lampalizumab was shown to be necessary for systemic alternative complement pathway inhibition based on the alternative complement pathway hemolytic activity assay (Loyet et al, 2014).…”

“…k, k deg , and k inT denote the systemic elimination rate constants of the unbound lampalizumab, free CFD, and lampalizumab-CFD complex, respectively; k syn is the zero-order production rate constant of CFD in the vitreous humor; k is the firstorder clearance rate constant of lampalizumab in the serum; k inC is the first-order rate constant of the lampalizumab-CFD complex from the serum to the vitreous humor and was assumed to be negligible because the concentration of the complex is higher in the ocular environment following ITV administration; k SV is the first-order rate constant of free CFD from the serum to the vitreous humor; and K SS is the quasi-steady state constant of lampalizumab binding to CFD. K SS was fixed to the in vitro parameter of 11.7 pM (Loyet et al, 2014). F1 denotes the fraction of drug that enters the vitreous directly following ITV administration, and the remaining fraction (1-F1) was assumed to leak to the serum by fast absorption, presumably from the microcirculation.…”