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Fernando Correa, Rachel DeVay Jacobson, hong liang, Namrata Prasad, Xiaojian Huang, William Ngo, Dan Dang, Janine Lu, D. Victor Perlroth; Development of potent dual action biopharmaceuticals for the treatment and prevention of neovascular retinal diseases. Invest. Ophthalmol. Vis. Sci. 2018;59(9):5312. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Despite the therapeutic success of anti-vascular endothelial growth factor (VEGF) biologic drugs for the treatment of neovascular retinal diseases, unmet need still exists due to (i) VEGF therapy-resistant patients, (ii) patients who lose efficacy to anti-VEGF agents due to the progression of additional underlying pathologies such as fibrosis, wound-healing, and atrophy (iii) undertreatment due to the requirement for frequent intravitreal injections. Here, we report the development of novel bi-specific biologic agents designed to inhibit both VEGF and additional growth factors or cytokines.
Dual inhibitors were designed and characterized for their binding affinities to their respective targets by surface plasmon resonance (SPR). Functional aspects of the molecules were tested by (1) ELISA assays targeting the competitive blocking of each target to its receptor (2) cytokine-stimulated primary human retinal microvascular endothelial cell (HRMVEC) proliferation assay, and (3) three-dimensional primary cell co-culture assays to assess the inhibition of angiogenic sprouting.
OG1321 is an antibody fusion molecule that binds with low pM affinity to both VEGF and PDGF, as shown by SPR analysis at 37 degrees. It inhibits binding of VEGF (IC50 = 9 nM) and PDGF (IC50 = 36 pM) to their respective receptors by competitive ELISA. OG1321 demonstrates potent inhibition relative to existing anti-VEGF treatments in both human retina microvascular endothelial cell (HRMVEC) cell proliferation and co-culture sprouting assays.OG10C is a similarly constructed antibody fusion molecule that binds with low pM affinity to VEGF and an anti-inflammatory cytokine. Binding kinetics of each target are independent of the presence of the other, indicating that both targets can bind simultaneously without interference. Binding of OG10C to each of its targets inhibits interaction with its respective cognate receptor.
We have developed highly potent, dual-action molecules that inhibit VEGF and other growth factors or cytokines. OG1321 and OG10C demonstrate high binding affinity and bioactivity. When embedded in Kodiak’s antibody biopolymer conjugate platform, these molecules are promising new therapeutic agents for the next generation of treatment and prevention of neovascular retinal diseases such as age related macular degeneration and diabetic retinopathy.
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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