July 2019
Volume 60, Issue 9
Free
ARVO Annual Meeting Abstract  |   July 2019
Development of Novel Bispecific Anti-Inflammatory and Anti-Angiogenic Therapy for the Treatment of both Retinal Vascular and Inflammatory Diseases
Author Affiliations & Notes
  • Fernando Correa
    Kodiak Sciences, Palo Alto, California, United States
  • Rachel Jacobson
    Kodiak Sciences, Palo Alto, California, United States
  • Namrata Prasad
    Kodiak Sciences, Palo Alto, California, United States
  • William Ngo
    Kodiak Sciences, Palo Alto, California, United States
  • Janine Lu
    Kodiak Sciences, Palo Alto, California, United States
  • Carrie Su
    Kodiak Sciences, Palo Alto, California, United States
  • Xiaojian Huang
    Kodiak Sciences, Palo Alto, California, United States
  • hong liang
    Kodiak Sciences, Palo Alto, California, United States
  • D. Victor Perlroth
    Kodiak Sciences, Palo Alto, California, United States
  • Footnotes
    Commercial Relationships   Fernando Correa, Kodiak Sciences (E); Rachel Jacobson, Kodiak Sciences (E); Namrata Prasad, Kodiak Sciences (E); William Ngo, Kodiak Sciences (E); Janine Lu, Kodiak Sciences (E); Carrie Su, Kodiak Sciences (E); Xiaojian Huang, Kodiak Sciences (E); hong liang, Kodiak Sciences (E); D. Victor Perlroth, Kodiak Sciences (E)
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science July 2019, Vol.60, 5396. doi:https://doi.org/
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      Fernando Correa, Rachel Jacobson, Namrata Prasad, William Ngo, Janine Lu, Carrie Su, Xiaojian Huang, hong liang, D. Victor Perlroth; Development of Novel Bispecific Anti-Inflammatory and Anti-Angiogenic Therapy for the Treatment of both Retinal Vascular and Inflammatory Diseases. Invest. Ophthalmol. Vis. Sci. 2019;60(9):5396. doi: https://doi.org/.

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

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Abstract

Purpose : Inflammation has an important role in retinal diseases such as diabetic eye disease and age-related macular degeneration. Currently approved treatments that target only VEGF do not completely address the underlying immune component of these diseases. Elevated intraocular levels of Interleukin-6 (IL-6) have been implicated in diabetic eye disease and are also linked to anti-VEGF treatment resistance in AMD. Similarly, both IL-6 and VEGF are implicated in vision loss in patients with uveitic macular edema. We designed a novel anti-IL-6 anti-VEGF bispecific protein, OG2072, and its biopolymer conjugate, KSI-501, as a next-generation therapeutic candidate for these diseases.

Methods : OG2072 was engineered as a trap antibody fusion protein to bind and inhibit both IL-6 and VEGF with the capability of being conjugated to a high molecular weight phosphorylcholine-based biopolymer to optimize potency, stability, ocular durability and tissue bioavailability. Binding affinity to IL-6 and VEGF-A were determined by surface plasmon resonance (SPR) or Kinetic Exclusion Assay (KinExA). These molecules were also tested for their ability to (1) competitively block IL-6 and VEGF from binding to their respective receptors and (2) to inhibit VEGF and inflammatory activities.

Results : OG2072/KSI-501 are novel trap antibody fusion molecules that bind with picomolar affinity to both VEGF-A and IL-6 at 37 degrees. Binding of each target occurs independently of the other, indicating that IL-6 and VEGF-A interact with OG2072/KSI-501 simultaneously. Functional assays indicate that OG2072 effectively inhibits VEGF-A and IL-6 interactions with their respective receptors. Furthermore, cell-based assays showed that the dual inhibitor effectively inhibited LPS mediated endothelial cell tubule formation and VEGF-A/IL-6 co-stimulated endothelial cell proliferation significantly better than either mono-therapy targeting IL-6 or VEGF alone.

Conclusions : We have engineered a novel and highly potent bispecific molecule targeting VEGF and IL-6 using a trap antibody fusion approach; it demonstrated high binding affinity, bioactivity and synergistic inhibition in vitro. KSI-501 is being developed as a promising and differentiated new therapeutic candidate to address retinal vascular and inflammatory diseases.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.

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