June 2023
Volume 64, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2023
Development of a modular IL-1 trap and anti-HTRA1 bispecific for the treatment of dry AMD
Author Affiliations & Notes
  • Kiho Song
    Kodiak Science, Palo Alto, California, United States
  • Fernando Correa
    Kodiak Science, Palo Alto, California, United States
  • Yimeng Shen
    Kodiak Science, Palo Alto, California, United States
  • Lili Liu
    Kodiak Science, Palo Alto, California, United States
  • Namrata Prasad
    Kodiak Science, Palo Alto, California, United States
  • Jason Lin
    Kodiak Science, Palo Alto, California, United States
  • Long Pham
    Kodiak Science, Palo Alto, California, United States
  • Carrie Su
    Kodiak Science, Palo Alto, California, United States
  • Carrie Lin
    Kodiak Science, Palo Alto, California, United States
  • William Ngo
    Kodiak Science, Palo Alto, California, United States
  • Xiaojian Huang
    Kodiak Science, Palo Alto, California, United States
  • Hong Liang
    Kodiak Science, Palo Alto, California, United States
  • Victor Perlroth
    Kodiak Science, Palo Alto, California, United States
  • Footnotes
    Commercial Relationships   Kiho Song Kodiak Sciences Inc., Code E (Employment); Fernando Correa Kodiak Sciences Inc., Code E (Employment); Yimeng Shen Kodiak Sciences Inc., Code E (Employment); Lili Liu Kodiak Sciences Inc., Code E (Employment); Namrata Prasad Kodiak Sciences Inc., Code E (Employment); Jason Lin Kodiak Sciences Inc., Code E (Employment); Long Pham Kodiak Sciences Inc., Code E (Employment); Carrie Su Kodiak Sciences Inc., Code E (Employment); Carrie Lin Kodiak Sciences Inc., Code E (Employment); William Ngo Kodiak Sciences Inc., Code E (Employment); Xiaojian Huang Kodiak Sciences Inc., Code E (Employment); Hong Liang Kodiak Sciences Inc., Code E (Employment); Victor Perlroth Kodiak Sciences Inc., Code E (Employment)
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science June 2023, Vol.64, 1152. doi:
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      Kiho Song, Fernando Correa, Yimeng Shen, Lili Liu, Namrata Prasad, Jason Lin, Long Pham, Carrie Su, Carrie Lin, William Ngo, Xiaojian Huang, Hong Liang, Victor Perlroth; Development of a modular IL-1 trap and anti-HTRA1 bispecific for the treatment of dry AMD. Invest. Ophthalmol. Vis. Sci. 2023;64(8):1152.

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

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Abstract

Purpose : Dry age-related macular degeneration (AMD) is a multifaceted disease and likely requires a multispecific drug inhibiting different pathological pathways. The aggravated inflammatory response by interleukin-1 (IL-1) and dysregulated activity of the serine protease HTRA1 are associated with the pathogenesis of dry AMD. Therefore, we engineered an IL-1 trap anti-HTRA1 bispecific using the native heterodimeric IL-1 receptors. This novel trap-antibody format allows fusion of heterodimeric receptor-based traps in a modular fashion and is compatible with the ABC Platform™ to maximize durability of the bispecifics.

Methods : An IL-1 trap was designed and optimized by fusing the heterodimeric IL-1 receptors to an anti-HTRA1 antibody. Dual binding to both IL-1β and HTRA1 was evaluated by surface plasmon resonance (SPR) and mass photometry. Inhibition of IL-1β and HTRA1 were assayed in a competitive ELISA and an in vitro enzyme inhibition assay, respectively. The modular nature of this trap-antibody format was explored by fusing other heterodimeric receptor-based traps (IL-6 and IL-33) or a homodimeric receptor-based trap (VEGF) in combination with different antibody moieties. Furthermore, these novel bispecifics were conjugated with a biopolymer and the resultant bioconjugates tested for their inhibitory activities.

Results : The IL-1 trap anti-HTRA1 bispecific binds to IL-1β and HTRA1 with picomolar affinities and can engage both targets simultaneously. In in vitro activity assays, the bispecific prevents IL-1β binding to the IL-1β receptor and inhibits the enzymatic activity of HTRA1. When the antibody moiety is replaced with an anti-IL-6 antibody or Fab, the new bispecifics equivalently bind to IL-1β while now binding to IL-6. Similarly, the trap moiety is interchangeable with heterodimeric IL-6 or IL-33 receptors or homodimeric VEGF receptors to direct its binding to the respective target. Finally, these bispecifics retained their inhibitory activities after biopolymer conjugation.

Conclusions : We have developed a potent trap-antibody bispecific which simultaneously inhibits both IL-1 and HTRA1. This novel trap-antibody format is modular and compatible with the ABC Platform™. Our study presents a versatile strategy to engineer a bispecific targeting the complex pathology of dry AMD and other retinal or systemic diseases.

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

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