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Christina Zuch de Zafra, Cindy Farman, Eric Wakshull, Cinthia V. Pastuskovas, Lindsey Geiger, Paul E. Miller, Evan A. Thackaberry, Jacqueline M. Miller, Doris Zane; Repeat-dose intravitreal administration of a humanized monoclonal antibody is poorly tolerated in rabbits. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):3640.
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© ARVO (1962-2015); The Authors (2016-present)
We sought to determine the safety profile of a novel biotherapeutic candidate in rabbits following repeat-dose intravitreal (IVT) administration. Current regulatory guidance recommends the use of two species, when possible, for nonclinical toxicology evaluation. In the case of biologic drugs, if the therapeutic shows cross-reactivity to the target in a lower-order species such as rabbits, dogs, or rodents, that species can be considered for inclusion in a nonclinical toxicology program. However, immunogenicity is a common concern with biotherapeutics, based on the potential impact to the pharmacokinetic and/or safety profile of the drug.
We conducted a 3-month repeat-dose GLP IVT toxicology study of a novel biotherapeutic candidate (mAb X) in rabbits, based on the demonstration of binding to the target protein in this species; this study was designed to support clinical development and also to determine the feasibility of repeat dosing via this route given the risk of immunogenicity in rabbits and the sensitivity of the eye to immune-mediated reactions. New Zealand White rabbits (5/sex/group) were scheduled for IVT dosing (0, 0.5, 1.5, or 4 mg/eye) once every 2 weeks for 3 months (a total of 8 doses). Ocular toxicity was assessed by ophthalmic examination, IOP, OP, and ocular anatomic pathology.
As early as Day 15, several animals had significant ocular inflammation that precluded scheduled dose administration; findings commonly included moderate to severe anterior and posterior segment inflammation (e.g., aqueous flare, aqueous and/or vitreous cell, vitreous haze or floaters, degraded view of fundus, cellular debris on lens capsule, fibrin clot, incomplete pupil dilation). With continued treatment, the proportion of animals with inflammation, as well as the severity, increased and the study was terminated on Day 45 after four doses. mAb X was generally well-tolerated through Day 12 following a single dose in rabbits (n=3), however anti-therapeutic antibodies were detected in the serum and vitreous.
Available data suggest that IVT administration of mAb X results in an immune reaction and that the observed ocular inflammation may be immune-mediated. These findings suggest that repeat-dose IVT toxicity studies of biotherapeutics in rabbits may be compromised by the development of non-pharmacologically-mediated toxicity.
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