May 2003
Volume 44, Issue 13
Free
ARVO Annual Meeting Abstract  |   May 2003
26-Week Intravitreal Injection Toxicity Study with rhuFab Vegf in Cynomolgus Monkeys with an 8-Week Recovery
Author Affiliations & Notes
  • C.A. O'Neill
    Dept of Toxicology, Genentech Inc, South San Francisco, CA, United States
  • P.E. Miller
    Comparative Ophthalmic Research Laboratories, Madison, WI, United States
  • B.J. Christian
    Covance Laboratories, Madison, WI, United States
  • J.C. Beyer
    Covance Laboratories, Madison, WI, United States
  • E. Bentley
    Covance Laboratories, Madison, WI, United States
  • J.N. VerHoeve
    Covance Laboratories, Madison, WI, United States
  • T.M. Nork
    Covance Laboratories, Madison, WI, United States
  • R.A. Leedle
    Covance Laboratories, Madison, WI, United States
  • R.R. Dubielzig
    Covance Laboratories, Madison, WI, United States
  • D.M. Albert
    Covance Laboratories, Madison, WI, United States
  • Footnotes
    Commercial Relationships  C.A. O'Neill, Genentech, Inc. E; P.E. Miller, Comparative Ophthalmic Research Laboratories F; B.J. Christian, Covance Laboratories F; J.C. Beyer, Genentech, Inc. E; E. Bentley, Comparative Ophthalmic Research Laboratories F; J.N. VerHoeve, Comparative Ophthalmic Research Laboratories F; T.M. Nork, Comparative Ophthalmic Research Laboratories F; R.A. Leedle, Covance Laboratories F; R.R. Dubielzig, Comparative Ophthalmic Research Laboratories F; D.M. Albert, Comparative Ophthalmic Research Laboratories F.
Investigative Ophthalmology & Visual Science May 2003, Vol.44, 3929. doi:https://doi.org/
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      C.A. O'Neill, P.E. Miller, B.J. Christian, J.C. Beyer, E. Bentley, J.N. VerHoeve, T.M. Nork, R.A. Leedle, R.R. Dubielzig, D.M. Albert; 26-Week Intravitreal Injection Toxicity Study with rhuFab Vegf in Cynomolgus Monkeys with an 8-Week Recovery . Invest. Ophthalmol. Vis. Sci. 2003;44(13):3929. doi: https://doi.org/.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Abstract: : Purpose: To evaluate the toxicity of intravitreal administration of an antibody-binding fragment to VEGF (rhuFab VEGF) intended for the treatment of AMD. Methods: Monkeys were randomized into 4 groups to receive q 2 week OU intravitreal injections of: Vehicle (n=12, Group 1), 500 (n=8, Group 2), 1000 (n=8, Group 3), or 2000 (n=12, Group 4) µg/eye of rhuFab VEGF in 50 µl. The initial dose of 500 µg/eye was increased to 1000 µg/eye in Groups 3 and 4, and finally to 2000 µg/eye in Group 4. Four animals in Groups 1 and 4 were followed for 8 weeks after final dosing. Ophthalmic examinations including ERG, VEP, and FA were performed regularly. Results: The first dose of rhuFab VEGF produced a substantial anterior chamber/vitreal cellular inflammatory response that became negligible by one-week post-dose. Doses 2-3 resulted in substantially less inflammation even though ≥ amounts of rhuFab VEGF were given. With doses 4-14, however, the inflammatory response increased in intensity and persistence in a dose- and time-dependent fashion over Dose 2 and 3 values, but still tended to spontaneously diminish between doses. Clinically, inflammation was characterized by varying degrees of anterior chamber and vitreal cell, multifocal retinal perivascular sheathing, vitreal inflammatory debris, and, in some animals, white inflammatory material over the surface of the optic nerve and/or an incipient inflammatory cataract. Retinal perivascular sheathing occurred in most eyes in Groups 2-4. Histologically, lymphocytes, macrophages, neutrophils and rare eosinophils were seen in the retina, optic nerve, ciliary body and iris. Dosing was ultimately stopped in five Group 4 animals because the fundus could not be examined 2 weeks post-dose. Serum antibodies to rhuFab VEGF generally correlated with the more severe inflammatory responses. Lesions diminished with cessation of dosing and the ERG, VEP, and FA were unaltered versus baseline with few exceptions. Conclusions: The principle adverse effect of rhuFab VEGF appears to be an immune-mediated response by monkeys to a humanized protein. Intravitreal rhuFab VEGF at all doses produced a dose-dependent anterior and posterior segment inflammation that diminished or resolved on recovery.

Keywords: age-related macular degeneration • choroid: neovascularization • animal model 
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