A bispecific aptamer targeting both VEGF and Angiopoietin-2 for treating retinal diseases

Abstract

Purpose : Despite the use of anti-VEGF agents, many patients of neovascular retinal diseases still fail to achieve meaningful vision gain. Combination therapy is a promising strategy to further improve efficacy, which combines VEGF inhibition with complementary mechanisms of action (MOA). Multi-specific targeting has the potential to inhibit multiple MOAs with a single drug, and thus is the preferred approach to develop combination therapy. However, few such programs are being developed due to the significant technical challenges. Nucleic acid aptamers are uniquely suited for multi-specific targeting given their modular composition and flexible chemical synthesis. To fully realize this potential, we invented a technology for discovering multi-specific aptamers, and developed a VEGF/Angiopoietin-2 (Ang2) bispecific aptamer as the initial program.

Methods : We developed Particle Display, which enables high-throughput screening of the affinity and specificity of individual aptamers and yields fully modified aptamers. First, we discovered aptamers targeting VEGF or Ang2 separately, and confirmed their in vivo efficacy in multiple models. We then synthesized multiple bispecific aptamers by connecting a VEGF aptamer and an Ang2 aptamer with different linkers, and identified the top sequence by comparing their binding properties with the parental aptamers.

Results : We discovered a VEGF aptamer (AMS0421) targets all isoforms of VEGF-A and possesses potent in vivo efficacy (reported separately). Moreover, we discovered an Ang2 aptamer (AMS0525) that cross-reacts with both mouse and human Ang2 but not human Ang1. Combining AMS0525 and Aflibercept achieved superior inhibition of both neovascularization and leakage than Aflibercept alone in the mouse oxygen-induced retinopathy (OIR) model. Finally, we developed a bispecific aptamer (AMSB103) that binds to both VEGF and Ang2 with pM affinity, comparable to the parental aptamers. AMSB103 can be formulated at 120 mg/ml, resulting in a ~10-fold higher molar dose than typically achieved with bispecific antibodies.

Conclusions : We demonstrated the capability of our platform by developing a potent VEGF/Ang2 bispecific aptamer (AMSB103). AMSB103 accommodates a much higher molar dose than antibodies, which has the potential to enable better efficacy. We are evaluating this aptamer in animal models, and also leveraging our platform to develop multi-specific aptamers for other MOA.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.