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Jinpeng Wang, Qin Yang, Jingwen Yu, Hui Kang, Matthew Vukovich, Wen-Chuan Chou, Scott Ferguson, Qiang Gong; A highly soluble and fully modified aptamer that targets all VEGF-A isoforms for treating retinal diseases. Invest. Ophthalmol. Vis. Sci. 2019;60(9):107.
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Current anti-VEGF drugs, despite their success, still suffer from limited efficacy and duration. Increasing the dosage of anti-VEGF agents may improve both drug potency and duration. Nucleic acid aptamers possess a high solubility and a small molecular weight (~15 kDa), and thus may achieve a much higher molar dosage. However, the previous anti-VEGF aptamer (Macugen) cannot realize this potential due to 2 key limitations: 1. Macugen fails to recognize all VEGF-A isoforms and thus has inferior potency; 2. Macugen contains natural RNA bases which limit its in vivo stability. We developed a novel anti-VEGF aptamer to overcome the limitations of Macugen to be competitive with the standard of care, unlock aptamers’ dosage advantage, and maximize the potential clinical benefits of suppressing VEGF.
We have invented a discovery technology (Particle Display) that uniquely enables high-throughput screening of the affinity and specificity of individual aptamers and yields fully modified aptamers. We explicitly screened for aptamers that target the receptor binding site and thus inhibit all VEGF-A isoforms. We then characterized the potency and solubility of the lead aptamer, and tested its in vivo efficacy in the rat laser-induced choroidal neovascularization (CNV) model.
We confirmed that our VEGF aptamer (AMS0421) inhibits both VEGF-165 and VEGF-121, the two main VEGF-A isoforms with pM affinity, whereas Macugen fails to recognize VEGF-121. We tested AMS0421 in a rat laser-induced CNV model, and demonstrated potent efficacy comparable to Combercept, an approved anti-VEGF agent. Moreover, we found that our aptamer can be formulated at a concentration of 200 mg/ml, which results in a ~50-fold higher molar dose than current anti-VEGF drugs given aptamers’ small size (~15 kDa).
We developed the first fully 2’-F modified aptamer for VEGF, and confirmed its capability to recognize all VEGF-A isoforms, potently inhibit CNV in vivo, and accommodate a much higher dosage than existing anti-VEGF agents. Next, we plan to dose at peak concentration to test the potential to improve efficacy and duration compared to standard anti-VEGF agents. This VEGF aptamer may also be used as the backbone for next-gen therapeutics, such as multi-specific targeting to leverage complementary mechanisms of action and sustained release formulation to greatly extend treatment duration.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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