KEY FEATURES

Ranibizumab (Lucentis, Genentech, South San Francisco, CA; Novartis Pharma, Basel, Switzerland) is a recombinant, humanized, monoclonal antibody Fab fragment against vascular endothelial growth factor A (VEGF-A), which was developed specifically for intraocular use. Ranibizumab has been extensively investigated in clinical trials in neovascular age-related macular degeneration (AMD), and is also being studied in other retinal diseases.

Ranibizumab was the first therapeutic agent to demonstrate improvements in visual acuity (VA) and patient-reported visual function for patients with neovascular AMD, and has been licensed for this indication. Ranibizumab has demonstrated a good tolerability profile in clinical trials, with a low incidence of ocular and systemic serious adverse events (AEs).

INTRODUCTION AND HISTORY

The VEGF family of growth factors, of which VEGF-A is the prototype member, plays an important role in a variety of in vitro processes, including angiogenesis, microvascular permeability, and endothelial cell survival. Whilst these activities are all essential to survival, VEGF has been linked to a number of pathogenic conditions, including neovascular AMD, diabetic retinopathy, and cancer.1,2

The first monoclonal antibody developed to target VEGF-Awas bevacizumab, a humanized murine monoclonal antibody.3 Bevacizumab was initially investigated as a cancer treatment, and received approval as a first-line therapy for widespread colorectal cancer from the US Food and Drugs Administration in 2004. Bevacizumab has subsequently been approved for use in nonsmall-cell lung cancer and breast cancer.

The successful development of VEGF as an oncology target led to interest in the potential of anti-VEGF treatment for other therapeutic indications, including ocular neovascular disorders.

VEGF-A has been identified as the primary angiogenesis mediator in the eye. It is implicated in ocular neovascularization through its promotion of blood vessel formation and permeability.2,4 A role for VEGF-A in neovascular AMD is suggested by immunohistochemistry localization in human choroidal neovascular (CNV) lesions and extra­ polation from other disease models.5 New blood vessel formation and leakage are important facets of the neovascular form of AMD, and clinical trials of agents that block VEGF-A activity have produced more evidence that VEGF-Ais important in the development of this disease.6,7

PHARMACOLOGY

PHARMACOLOGICAL DESIGN

Systemic administration of an anti-VEGF agent was initially considered for the treatment of CNV lesions; however, the possibility of AEs, and

toxicity data from clinical trials of bevacizumab in cancer patients, indicated that a more targeted therapy was warranted. Consequently, ranibizumab was designed specifically for ocular use.

Ranibizumab was generated from a Fab fragment of humanized murine anti-VEGF monoclonal antibody. The use of a Fab fragment, rather than full-length IgG, was indicated by their enhanced retinal penetration and diffusibility. In addition, the absence of the Fc portion of IgG eliminates the possibility of complement-mediated or celldependent cytotoxicity, and the decreased half-life of Fab in comparison with IgG minimizes the extent of systemic exposure.5

Ranibizumab was selected through a combination of phage display technology and engineering of the Fab framework based on previous studies. The resulting construct neutralized the biologic activities of all VEGF-A isoforms and the proteolytic cleavage product VEGF110, and displayed 5–10-fold greater potency than bevacizumab in bioassays measuring human VEGF-induced mitogenesis.5 Furthermore, as ranibizumab is a humanized antibody fragment and is produced in a bacterial vector, such that it does not undergo mammalian glycosylation, the potential for immunogenicity is minimized.

PHARMACOKINETICS

Intraocular pharmacokinetic data derived from studies in monkeys demonstrated that intravitreal doses of ranibizumab (500 or 2000 g/ eye) distributed rapidly to the retina and had a vitreous half-life of 2.6–4.0 days.8 In those animals receiving ranibizumab 500 g/eye, approximately 50% of the intravitreally injected ranibizumab reached the serum after 2 days. However, serum concentrations were negligible and tissue concentrations were undetectable.8

Pharmacokinetic analysis in humans has indicated that circulating ranibizumab does not reach concentrations at which the normal physiological roles of VEGF will be affected. One hour after a 300 g/eye intravitreal injection, mean serum ranibizumab levels were below the level of quantification (<0.3 ng/ml) in 73% of participants (n = 120). Moreover, when ranibizumab 300 or 500 g/eye was administered monthly, ranibizumab concentrations were lower than the Kd of ranibizumab for VEGF-A.9

PHARMACODYNAMICS

Studies in several animal models have confirmed that ranibizumab displays rapid retinal penetration.8,10 This rapid diffusion of the ranibizumab Fab fragment is in stark contrast to full-length recom­ binant humanized IgG which does not penetrate to the retinal layer.11

In a phase III study, ranibizumab (0.3 or 0.5 mg) monthly intravitreal injections resulted in a stabilization of the size of the area of CNV and a decrease in the area of vascular leakage as measured by fluorescein angiography.12 In addition, in patients receiving ranibizumab treatment, optical coherence tomography (OCT) measurements revealed a mean decrease in center point thickness of 123 m; this compared favorably with an average outcome of no change in thickness in sham-treated patients.