June 2020
Volume 61, Issue 7
Free
ARVO Annual Meeting Abstract  |   June 2020
Suppression of Murine Choroidal Neovascularization After Systemic Administration of a Targeted Anti-VEGF Therapy
Author Affiliations & Notes
  • Jeffrey L Cleland
    Ashvattha Therapeutics, Inc, Redwood City, California, United States
  • Rishi Sharma
    Ashvattha Therapeutics, Inc, Redwood City, California, United States
  • Santiago Appiani
    Ashvattha Therapeutics, Inc, Redwood City, California, United States
  • Justin Prater
    Powered Research, Research Triangle Park, North Carolina, United States
  • M. Grazia Spiga
    Powered Research, Research Triangle Park, North Carolina, United States
  • David Culp
    Powered Research, Research Triangle Park, North Carolina, United States
  • Footnotes
    Commercial Relationships   Jeffrey Cleland, Ashvattha Therapeutics, Inc (E); Rishi Sharma, Ashvattha Therapeutics, Inc (E); Santiago Appiani, Ashvattha Therapeutics, Inc (E); Justin Prater, Ashvattha Therapeutics, Inc (F); M. Grazia Spiga, Ashvattha Therapeutics, Inc (F); David Culp, Ashvattha Therapeutics, Inc (F)
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science June 2020, Vol.61, 3974. doi:
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    • Get Citation

      Jeffrey L Cleland, Rishi Sharma, Santiago Appiani, Justin Prater, M. Grazia Spiga, David Culp; Suppression of Murine Choroidal Neovascularization After Systemic Administration of a Targeted Anti-VEGF Therapy. Invest. Ophthalmol. Vis. Sci. 2020;61(7):3974.

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

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Abstract

Purpose : To evaluate the efficacy of hydroxyl dendrimers covalently conjugated with analogs of sunitinib in a mouse model of laser-induced choroidal neovascularization (CNV).

Methods : Hydroxyl dendrimers (~14000 Da, 4 nm), which selectively target inflammation, were covalently conjugated to analogs of sunitinib, an FDA-approved potent VEGF receptor tyrosine kinase inhibitor. Conjugates were made with a cleavable sunitinib analog (D-CSA) or a non-cleavable sunitinib analog (D-NSA) and drug release was evaluated at 37oC in PBS, pH 7.4 or citrate buffer, pH 5.5 with esterase. Laser-induced CNV was performed in both eyes of C57BL/6 mice (n=8/group) 24 hr prior to dose administration. Mice were administered IV (100 µL) vehicle, D-CSA (5.25 (low) or 26.25 (high) mg/kg sunitinib equivalent), D-NSA (6.3 (low) or 15.75 (high) mg/kg sunitinib equivalent), or free sunitinib (32.5 mg/kg) or administered aflibercept intravitreally (IVT; 1 µL, 40 µg). The CNV area was measured 7 days after laser treatment by both fluorescein angiography and flat-mounts of the sclera-choroid/RPE complexes stained with isolectin IB4.

Results : D-CSA was prepared with 5 sunitinib analogs per dendrimer (10.5% w/w) and D-NSA was prepared with 7 sunitinib analogs per dendrimer (12.6% w/w). Over 6 days in vitro, D-CSA released ~65% of the sunitinib at pH 5.5 with esterase (intracellular conditions) and ~15% release of sunitinib occurred over 24 hr at pH 7.4 (plasma conditions). As expected, D-NSA did not release the sunitinib analog. Statistically significant reductions in the CNV area were observed for IVT aflibercept and both IV dose levels of D-CSA and D-NSA but not free sunitinib (even at 5-fold higher doses compared to low dose D-CSA), compared with vehicle control (Figure below). Further studies evaluating lower D-CSA and D-NSA dose levels and IP administration in this murine model are planned.

Conclusions : Hydroxyl dendrimers conjugated with sunitinib analogs administered systemically inhibit CNV comparable to IVT aflibercept and free sunitinib. The non-cleavable sunitinib analog efficacy in CNV area reduction suggests that sunitinib release from the dendrimer may not be required. Previous studies have shown hydroxyl dendrimers and dendrimer-drug conjugates are retained in CNV lesions > 28 days and systemically cleared intact within 24 hr in mice and humans without detectable liver or other off-target toxicity.

This is a 2020 ARVO Annual Meeting abstract.

 

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