June 2023
Volume 64, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2023
Biological Benefits of KSI-501: Novel Bispecific Anti-Inflammatory and Anti-Angiogenic Therapy for the Treatment of both Retinal Vascular and Inflammatory Diseases
Author Affiliations & Notes
  • Kim Williams
    Kodiak Science, Palo Alto, California, United States
  • Mirna Rodriguez
    Kodiak Science, Palo Alto, California, United States
  • Wolf-Nicolas Fischer
    Kodiak Science, Palo Alto, California, United States
  • Rachel Jacobson
    Kodiak Science, Palo Alto, California, United States
  • Michael Ngo
    Kodiak Science, Palo Alto, California, United States
  • Namrata Prasad
    Kodiak Science, Palo Alto, California, United States
  • Lili Liu
    Kodiak Science, Palo Alto, California, United States
  • Janine Lu
    Kodiak Science, Palo Alto, California, United States
  • Fernando Correa
    Kodiak Science, Palo Alto, California, United States
  • Victor Perlroth
    Kodiak Science, Palo Alto, California, United States
  • Hong Liang
    Kodiak Science, Palo Alto, California, United States
  • Footnotes
    Commercial Relationships   Kim Williams Kodiak Science, Code E (Employment); Mirna Rodriguez Kodiak Science, Code E (Employment); Wolf-Nicolas Fischer Kodiak Science, Code C (Consultant/Contractor); Rachel Jacobson Kodiak Science, Code E (Employment); Michael Ngo Kodiak Science, Code E (Employment); Namrata Prasad Kodiak Science, Code E (Employment); Lili Liu Kodiak Science, Code E (Employment); Janine Lu Kodiak Science, Code E (Employment); Fernando Correa Kodiak Science, Code E (Employment); Victor Perlroth Kodiak Science, Code E (Employment); Hong Liang Kodiak Science, Code E (Employment)
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science June 2023, Vol.64, 2215. doi:
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      Kim Williams, Mirna Rodriguez, Wolf-Nicolas Fischer, Rachel Jacobson, Michael Ngo, Namrata Prasad, Lili Liu, Janine Lu, Fernando Correa, Victor Perlroth, Hong Liang; Biological Benefits of KSI-501: Novel Bispecific Anti-Inflammatory and Anti-Angiogenic Therapy for the Treatment of both Retinal Vascular and Inflammatory Diseases. Invest. Ophthalmol. Vis. Sci. 2023;64(8):2215.

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

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Abstract

Purpose : Despite the therapeutic success of anti-vascular endothelial growth factor (VEGF) biologic drugs for the treatment of neovascular retinal diseases, they do not completely address any underlying immune component, and patients are often undertreated due to the need for frequent intravitreal injections. Here, we report the development and biological activity of KSI-501, an ultra-high molecular weight novel bi-specific biologic agent that potently inhibits both VEGF and IL-6 function and has an extended ocular half-life.

Methods : We engineered a humanized, high affinity trap antibody fusion protein which binds and inhibits both VEGF and IL-6. The VEGF portion is expected to be similar to commercially available anti-VEGF biologics (e.g., aflibercept). Effects on both VEGF-A and IL-6 mediated transcriptional activity were measured by both cell-based reporter assays and qPCR. The effects of KSI-501 on VEGF-A and IL-6 mediated angiogenic functions were tested in a endothelial cell proliferation assay, tube formation, and morphology assessment. Finally, KSI-501 was evaluated with respect to inner and outer blood retinal barrier tight junction maintenance in cultured retinal endothelial and pigmented epithelial cells.

Results : KSI-501 inhibited both VEGF-A and IL-6 dependent transcription. In addition, KSI-501 effectively reduced human endothelial cell proliferation mediated by both VEGF-A and IL-6. In contrast, neither aflibercept nor the IL-6 binding moiety of KSI-501 suppressed endothelial cell proliferation mediated by simultaneously activating both pathways. KSI-501 blocked VEGF-A and IL-6 as well as LPS mediated tube formation of endothelial cells in a more potent manner than single inhibitor dosing as measured by multiple morphological parameters. Lastly, KSI-501 normalized VEGF-A and IL-6 stimulated changes in cell morphology and tight junctions in both human retinal endothelial and epithelial cells to a similar or greater extent than the IL-6 binding moiety of KSI-501 or aflibercept.

Conclusions : KSI-501 behaves as well or better than current single agent VEGF and IL-6 neutralizing molecules in physiological models of retinal disease, with the added advantage of an extended half-life. Thus, we predict that KSI-501 will more effectively treat neovascular retinal pathologies with a lower dosing frequency.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.

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