Novel Dual-Targeting Antibody Fragment IDB0062 Overcomes Anti-Vascular Endothelial Growth Factor Drug Limitations in Age-Related Macular Degeneration.

Abstract

Purpose:

Repeated administration of anti-vascular endothelial growth factor drugs to treat age-related macular degeneration leads to resistance. To overcome this drawback, we developed the novel recombinant dual-targeting antibody fragment IDB0062, which is comprised of the anti-vascular endothelial growth factor A Fab and neuropilin 1-targeting peptide, and we assessed its properties.

Methods:

We compared the in vitro activity of IDB0062 and conventional drugs using cell proliferation, wound healing, and Transwell assays. The in vivo efficacy of IDB0062 was determined using mouse choroidal neovascularization and oxygen-induced retinopathy models. To evaluate the ocular distribution of IDB0062, we intravitreally administered IDB0062 and ranibizumab to cynomolgus monkeys and measured the retinal drug levels.

Results:

IDB0062 effectively inhibited not only vascular endothelial growth factor A in vitro but also placenta growth factor 2, vascular endothelial growth factor B, and platelet-derived growth factor BB, which induce vascular endothelial growth factor A-independent angiogenesis. In addition, IDB0062 showed non-inferior efficacy compared with aflibercept in vivo despite the low selectivity for mouse vascular endothelial growth factor A. In the monkey intravitreal pharmacokinetic study, IDB0062 improved drug distribution in the retina compared with ranibizumab, confirming the accelerated onset of pharmacological action when IDB0062 is injected in the vitreous humor.

Conclusions:

Through neuropilin 1 binding, IDB0062 can improve the efficacy and accelerate the onset of pharmacological action in the posterior segment, which is targeted for macular degeneration, thereby improving drug responsiveness in drug-resistant patients.

Translational Relevance:

Considering its novel mechanism of action, IDB0062 may help in controlling resistance to conventional anti-vascular endothelial growth factor drugs in clinical settings.

• Authors: Seongbeom Kim, Gihong Min, Bomin Kim, Doseop Lee, Myongjae Lee, Jong-Hee Ko, Hyuk-Sang Kwon
• Journal: Translational vision science & technology (Transl Vis Sci Technol) Vol. 10 Issue 14 Pg. 35 (12 01 2021) ISSN: 2164-2591 [Electronic] United States
• PMID: 34967833 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Angiogenesis Inhibitors
• Immunoglobulin Fragments
• Pharmaceutical Preparations
• Vascular Endothelial Growth Factor A
• Vascular Endothelial Growth Factor B

Topics

• Angiogenesis Inhibitors (therapeutic use)
• Animals
• Humans
• Immunoglobulin Fragments (therapeutic use)
• Intravitreal Injections
• Macular Degeneration (drug therapy)
• Mice
• Pharmaceutical Preparations
• Vascular Endothelial Growth Factor A (therapeutic use)
• Vascular Endothelial Growth Factor B (therapeutic use)