July 2018
Volume 59, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2018
KSI-301: An anti-VEGF antibody biopolymer conjugate with extended half-life for treatment of neovascular retinal diseases
Author Affiliations & Notes
  • hong liang
    Kodiak Sciences Inc, Palo Alto, California, United States
  • Xiaojian Huang
    Kodiak Sciences Inc, Palo Alto, California, United States
  • William Ngo
    Kodiak Sciences Inc, Palo Alto, California, United States
  • Dan Dang
    Kodiak Sciences Inc, Palo Alto, California, United States
  • Janine Lu
    Kodiak Sciences Inc, Palo Alto, California, United States
  • Rachel DeVay Jacobson
    Kodiak Sciences Inc, Palo Alto, California, United States
  • Ons Harrabi
    Alexo Therapeutics, South San Francisco, California, United States
  • D. Victor Perlroth
    Kodiak Sciences Inc, Palo Alto, California, United States
  • Footnotes
    Commercial Relationships   hong liang, Kodiak Sciences Inc (E); Xiaojian Huang, Kodiak Sciences Inc (E); William Ngo, Kodiak Sciences Inc (E); Dan Dang, Kodiak Sciences Inc (E); Janine Lu, Kodiak Sciences Inc (E); Rachel Jacobson, Kodiak Sciences Inc (E); Ons Harrabi, Kodiak Sciences Inc (E); D. Victor Perlroth, Kodiak Sciences Inc (E)
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science July 2018, Vol.59, 211. doi:
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      hong liang, Xiaojian Huang, William Ngo, Dan Dang, Janine Lu, Rachel DeVay Jacobson, Ons Harrabi, D. Victor Perlroth; KSI-301: An anti-VEGF antibody biopolymer conjugate with extended half-life for treatment of neovascular retinal diseases. Invest. Ophthalmol. Vis. Sci. 2018;59(9):211.

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

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Abstract

Purpose : Inhibition of VEGF-A has been shown to be an effective treatment for neovascular retinal diseases. However, frequent intraocular dosing is required with existing therapeutics and can be challenging for patients. To ease patient burden by extending dosing frequency, we engineered a high molecular weight monoclonal (1,000KDa) antibody biopolymer conjugate, KSI 301, that potently inhibits VEGF function and has an extended ocular half-life.

Methods : We engineered a humanized, high affinity anti-VEGF monoclonal antibody conjugated to a high molecular weight phosphorylcholine based biopolymer. Affinity of the resulting molecule, KSI 301, to VEGF was determined by Surface Plasmon Resonance (SPR) and Kinetic Exclusion Assay (KinExA). KSI 301 inhibition of VEGF binding to its receptor, VEGF receptor (VEGFR), was tested in a competitive ELISA and directly compared to existing anti-VEGF therapeutic molecules. We also tested the effects of KSI 301 on VEGF mediated angiogenic functions in a Human retinal microvascular endothelial cells (HRMVEC) proliferation assay and a vascular sprouting assay that uses bead-based three-dimensional co-culture of HRMVECs and human mesenchymal pericytes (HMPs).

Results : KSI 301 interacts with VEGF-A with single digit pM affinity, as measured by both SPR and KinExA. This interaction inhibits VEGF from binding to its receptor in the competitive ELISA, with improved maximal inhibition relative to all other molecules tested and a similar IC50 compared to Lucentis and Eylea. KSI 301 inhibited HRMVEC cell proliferation with an IC50 similar to Eylea and superior to Lucentis and Avastin. Moreover, maximal inhibition of KSI 301 treated cells was significantly improved over Eylea or Avastin treated cells. In the HRMVEC/HMP coculture assay, KSI 301 significantly reduced the number and length of vascular sprouts similarly to Lucentis and Eylea.

Conclusions : KSI 301 binds specifically and with high affinity to VEGF, and in doing so blocks VEGF interaction with its cognate receptor VEGFR. KSI 301 thereby effectively neutralizes downstream VEGF mediated effects with relevance to retinal vascular diseases such as macular degeneration and diabetic retinopathy. We therefore conclude that KSI 301 is a specific, high-affinity inhibitor of VEGF that may provide an important new treatment option for patients with retinal neovascular conditions.

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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