2. Academic Validation
  3. Targeting C3b/C4b and VEGF with a bispecific fusion protein optimized for neovascular age-related macular degeneration therapy

Targeting C3b/C4b and VEGF with a bispecific fusion protein optimized for neovascular age-related macular degeneration therapy

  • Sci Transl Med. 2022 Jun;14(647):eabj2177. doi: 10.1126/scitranslmed.abj2177.
Shiqi Yang 1 2,  Tong Li 1 2,  Huixun Jia 1 2 3,  Min Gao 1,  Yiming Li 4,  Xiaoling Wan 1 5,  Zhen Huang 6,  Min Li 1 5,  Yuanqi Zhai 1 5,  Xiaomeng Li 1 2,  Xiaotong Yang 1 2,  Tao Wang 1 5,  Jian Liang 1 5,  Qing Gu 1 5,  Xueting Luo 1 5,  Lei Qian 4,  Shujie Lu 4,  Junjian Liu 4,  Yanping Song 6,  Fenghua Wang 1 2 3,  Xiaodong Sun 1 2 3 5,  Dechao Yu 4
Affiliations

Affiliations

  • 1 Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China.
  • 2 National Clinical Research Center for Ophthalmic Diseases, Shanghai 200080, China.
  • 3 Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai 200080, China.
  • 4 Innovent Biologics Inc., Suzhou 215000, China.
  • 5 Shanghai Key Laboratory of Fundus Diseases, Shanghai 200080, China.
  • 6 Department of Ophthalmology, Wuhan General Hospital of Guangzhou Military Region, Wuhan 430070, China.
PMID: 35648811 DOI: 10.1126/scitranslmed.abj2177
Abstract

Antiangiogenesis therapies targeting vascular endothelial growth factor (VEGF) have revolutionized the treatment of neovascular ocular diseases, including neovascular age-related macular degeneration (nAMD). Compelling evidence has implicated the vital role of Complement System dysregulation in AMD pathogenesis, implying it as a potential therapeutic strategy for geographic atrophy in dry AMD and to enhance the efficacy of anti-VEGF monotherapies in nAMD. This study reports the preclinical assessment and phase 1 clinical outcomes of a bispecific fusion protein, efdamrofusp alfa (code: IBI302), which is capable of neutralizing both VEGF isoforms and C3b/C4b. Efdamrofusp alfa showed superior efficacy over anti-VEGF monotherapy in a mouse laser-induced choroidal neovascularization (CNV) model after intravitreal delivery. Dual inhibition of VEGF and the complement activation was found to further inhibit macrophage infiltration and M2 macrophage polarization. Intravitreal efdamrofusp alfa demonstrated favorable safety profiles and exhibited antiangiogenetic efficacy in a nonhuman primate laser-induced CNV model. A phase 1 dose-escalating clinical trial (NCT03814291) was thus conducted on the basis of the preclinical data. Preliminary results showed that efdamrofusp alfa was well tolerated in patients with nAMD. These data suggest that efdamrofusp alfa might be effective for treating nAMD and possibly other complement-related ocular conditions.

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