title: IBI302, a promising candidate for AMD treatment, targeting both the VEGF and complement system with high binding affinity in vitro and effective targeting of the ocular tissue in healthy rhesus monkeys.
abstract: Uncontrolled activation of complement and upregulation of vascular endothelial growth factor (VEGF) play fundamental roles in age-related macular degeneration (AMD). However, most drugs used to treat AMD focus on a single target, and the percentage of effectively treated patients in clinical practice needs to be improved. Therefore, novel AMD treatment approaches are needed. IBI302 is a novel bispecific decoy receptor fusion protein designed with both a VEGF inhibition domain and a complement cascade inhibition domain, which are connected by the Fc region of human immunoglobulin. In this study, we systematically evaluated the binding affinity between IBI302 and VEGF isoforms and complement proteins by using surface plasmon resonance (SPR) technology. Anti-VEGF blockers (aflibercept and bevacizumab) and complement receptor 1 were used as references. The SPR assay results indicated that IBI302 could bind different VEGF isoforms and complement proteins with high affinity. The biological activity of IBI302 was also studied. IBI302 showed an inhibitory effect on human primary umbilical vein endothelial cell proliferation and the activation of complement pathways in vitro. Finally, the pharmacokinetic (PK) properties of IBI302 were evaluated in rhesus monkeys. The PK results showed that after a 0.5 mg/eye intravitreal dosage, IBI302 became rapidly distributed from the vitreous humor into targeted tissues and remained active over 504 h. Overall, the favorable anti-angiogenic and anti-complement effects of IBI302 along with the good PK profiles in rhesus monkeys support the selection and development of IBI302 as a promising candidate for AMD treatment.
authors.affiliation: Department of Pharmacy, Beijing Institute of Microbiology and Epidemiology, Beijing, PR China.
authors.forename: Xinyi
authors.initials: X
authors.lastname: Ren
authors.affiliation: Department of Preclinical Research, Innovent Biologics, Inc., Suzhou, PR China.
authors.forename: Jia
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Pharmacy, Beijing Chaoyang Hospital, Beijing, PR China.
authors.forename: Xianxing
authors.initials: X
authors.lastname: Xu
authors.affiliation: Department of Preclinical Research, Innovent Biologics, Inc., Suzhou, PR China.
authors.forename: Chunming
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Pharmacy, Beijing Institute of Microbiology and Epidemiology, Beijing, PR China. Electronic address: cheng_yg@163.com.
authors.forename: Yuanguo
authors.initials: Y
authors.lastname: Cheng
mesh_terms: D020533:Angiogenesis Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use; D049109:Cell Proliferation / Q000187:drug effects; D003167:Complement Activation / Q000187:drug effects*; D051056:Complement Inactivating Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D003165:Complement System Proteins / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000494:pharmacology*; D058449:Intravitreal Injections; D008253:Macaca mulatta; D008268:Macular Degeneration / Q000188:drug therapy*; D011993:Recombinant Fusion Proteins / Q000493:pharmacokinetics / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*; D014822:Vitreous Body / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D051056:Complement Inactivating Agents; C000620229:IBI302; D007141:Immunoglobulin Fc Fragments; D011993:Recombinant Fusion Proteins; D042461:Vascular Endothelial Growth Factor A; D003165:Complement System Proteins
keywords: Binding affinity; Bispecific; Complement proteins; Pharmacokinetics; VEGF