July 2018
Volume 59, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2018
Multivalent Conjugates Using Hyaluronic Acid for Sustained Anti-VEGF Therapy
Author Affiliations & Notes
  • Wesley Jackson
    Research and Development, Valitor, Inc., Berkeley, California, United States
  • Livia W Brier
    Research and Development, Valitor, Inc., Berkeley, California, United States
  • Mavish Mahomed
    Research and Development, Valitor, Inc., Berkeley, California, United States
  • Ricardo Lamy
    Ophthalmology, UC San Francisco, San Francisco, California, United States
  • Matilda F Chan
    Ophthalmology, UC San Francisco, San Francisco, California, United States
  • Footnotes
    Commercial Relationships   Wesley Jackson, Valitor, Inc. (E), Valitor, Inc. (I), Valitor, Inc. (P); Livia Brier, Valitor, Inc. (E), Valitor, Inc. (I); Mavish Mahomed, Valitor, Inc. (E), Valitor, Inc. (I); Ricardo Lamy, Valitor, Inc. (F); Matilda Chan, Valitor, Inc. (F)
  • Footnotes
    Support  NIH/NEI (R43EY027229, R01EY022739, and P30EY002162 - Core Grant for Vision Research) and Research to Prevent Blindness Unrestricted Grant.
Investigative Ophthalmology & Visual Science July 2018, Vol.59, 1472. doi:
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      Wesley Jackson, Livia W Brier, Mavish Mahomed, Ricardo Lamy, Matilda F Chan; Multivalent Conjugates Using Hyaluronic Acid for Sustained Anti-VEGF Therapy. Invest. Ophthalmol. Vis. Sci. 2018;59(9):1472.

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

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Abstract

Purpose : Anti-VEGF therapy is critical for treatment of retinal neovascular diseases, such as wet AMD. To maintain or improve visual acuity, current anti-VEGF drugs require administration by intravitreal injection every 1-3 months. To enable less frequent dosing, we conjugated multiple copies (i.e., valency) of anti-VEGF proteins to hyaluronic acid (HyA) biopolymers. We tested whether multivalent conjugation would extend the intravitreal residence time of anti-VEGF drugs.

Methods : Using published methods, we conjugated 30-50 of the following anti-VEGF proteins to HyA (~800 kDa): single-domain antibodies, single-chain antibodies, and designed ankyrin repeat proteins (DARPins). We measured VEGF-A binding affinity of the conjugates using biolayer interferometry (ForteBio Octet). To determine the effect of biopolymer conjugation on diffusivity, we measured the conjugate transport rates out of HyA-based hydrogels in vitro. Finally, we compared the intravitreal half-lives of multivalent anti-VEGF conjugates using a rabbit model. In each eye, we injected 75 μL of a fluorescently tagged protein (300 μg/mL), either unconjugated or as multivalent conjugate. At various times after injection, we measured the concentration of the anti-VEGF protein in the vitreous and the retina by fluorescence imaging (PerkinElmer IVIS). We fit the intravitreal concentrations to exponential curves to determine the half-life of each treatment.

Results : Multivalent anti-VEGF conjugation was sufficient to increase the VEGF affinity of anti-VEGF conjugates by ~10-fold compared to unconjugated anti-VEGF. Multivalent conjugates for each anti-VEGF protein exhibited approximately 5-fold slower in vitro diffusivity than unconjugated proteins (p<0.01, t-test). In the rabbit model, the intravitreal half-life of the multivalent anti-VEGF conjugates was up to 6-fold longer than the corresponding unconjugated anti-VEGF protein (p<0.005, t-tests). Anti-VEGF proteins detected in the retina were similar for both the multivalent conjugates and unconjugated anti-VEGF.

Conclusions : Based on on-going preclinical studies, multivalent conjugation appears to be an effective technology to enable less frequent administration of anti-VEGF therapy. Multivalent anti-VEGF exhibited slower intravitreal diffusivity and no reduction in bioactivity. Multivalent conjugation appears to be compatible with a variety of anti-VEGF drugs currently in clinical use or in preclinical development.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.

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