{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,2]],"date-time":"2026-11-02T18:13:02Z","timestamp":1793643182608,"version":"4.5.1"},"reference-count":83,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"647","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Sci. Transl. Med."],"published-print":{"date-parts":[[2022,6]]},"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.1126\/scitranslmed.abj2177","type":"journal-article","created":{"date-parts":[[2022,6,1]],"date-time":"2022-06-01T13:53:55Z","timestamp":1654091635000},"source":"Crossref","is-referenced-by-count":70,"title":["Targeting C3b\/C4b and VEGF with a bispecific fusion protein optimized for neovascular age-related macular degeneration therapy"],"prefix":"10.1126","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1314-951X","authenticated-orcid":true,"given":"Shiqi","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China."},{"name":"National Clinical Research Center for Ophthalmic Diseases, Shanghai 200080, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2544-1254","authenticated-orcid":true,"given":"Tong","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China."},{"name":"National Clinical Research Center for Ophthalmic Diseases, Shanghai 200080, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9341-5587","authenticated-orcid":true,"given":"Huixun","family":"Jia","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China."},{"name":"National Clinical Research Center for Ophthalmic Diseases, Shanghai 200080, China."},{"name":"Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai 200080, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8253-0587","authenticated-orcid":true,"given":"Min","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiming","family":"Li","sequence":"additional","affiliation":[{"name":"Innovent Biologics Inc., Suzhou 215000, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4583-8686","authenticated-orcid":true,"given":"Xiaoling","family":"Wan","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China."},{"name":"Shanghai Key Laboratory of Fundus Diseases, Shanghai 200080, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhen","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Wuhan General Hospital of Guangzhou Military Region, Wuhan 430070, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China."},{"name":"Shanghai Key Laboratory of Fundus Diseases, Shanghai 200080, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanqi","family":"Zhai","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China."},{"name":"Shanghai Key Laboratory of Fundus Diseases, Shanghai 200080, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaomeng","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China."},{"name":"National Clinical Research Center for Ophthalmic Diseases, Shanghai 200080, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaotong","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China."},{"name":"National Clinical Research Center for Ophthalmic Diseases, Shanghai 200080, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China."},{"name":"Shanghai Key Laboratory of Fundus Diseases, Shanghai 200080, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Liang","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China."},{"name":"Shanghai Key Laboratory of Fundus Diseases, Shanghai 200080, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing","family":"Gu","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China."},{"name":"Shanghai Key Laboratory of Fundus Diseases, Shanghai 200080, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xueting","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China."},{"name":"Shanghai Key Laboratory of Fundus Diseases, Shanghai 200080, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Qian","sequence":"additional","affiliation":[{"name":"Innovent Biologics Inc., Suzhou 215000, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shujie","family":"Lu","sequence":"additional","affiliation":[{"name":"Innovent Biologics Inc., Suzhou 215000, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junjian","family":"Liu","sequence":"additional","affiliation":[{"name":"Innovent Biologics Inc., Suzhou 215000, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanping","family":"Song","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Wuhan General Hospital of Guangzhou Military Region, Wuhan 430070, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9670-1036","authenticated-orcid":true,"given":"Fenghua","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China."},{"name":"National Clinical Research Center for Ophthalmic Diseases, Shanghai 200080, China."},{"name":"Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai 200080, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5015-0945","authenticated-orcid":true,"given":"Xiaodong","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China."},{"name":"National Clinical Research Center for Ophthalmic Diseases, Shanghai 200080, China."},{"name":"Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai 200080, China."},{"name":"Shanghai Key Laboratory of Fundus Diseases, Shanghai 200080, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dechao","family":"Yu","sequence":"additional","affiliation":[{"name":"Innovent Biologics Inc., Suzhou 215000, China."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S2214-109X(13)70145-1"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0039-6257(03)00030-4"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1001\/archopht.1984.01040031330019"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(18)31550-2"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa054481"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa062655"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ophtha.2012.09.006"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.preteyeres.2017.12.002"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1102673"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ophtha.2016.03.045"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ophtha.2013.03.046"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ophtha.2016.09.012"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ophtha.2019.03.036"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ophtha.2015.12.030"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ophtha.2019.07.011"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ophtha.2020.08.027"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.15252\/emmm.201505889"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1001\/jamaophthalmol.2020.2685"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/ni.1923"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1097\/IAE.0b013e318184661d"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1109557"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1110189"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2640"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa072618"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng1750"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-genom-090413-025610"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1006\/exer.2001.1094"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9394(02)01624-0"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1038\/srep32548"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1038\/eye.2016.328"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.226266"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2010.091168"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0408835103"},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110.214593"},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ophtha.2013.09.044"},{"key":"e_1_3_3_37_2","doi-asserted-by":"publisher","DOI":"10.1080\/14712598.2019.1575358"},{"key":"e_1_3_3_38_2","doi-asserted-by":"publisher","DOI":"10.2147\/DDDT.S206355"},{"key":"e_1_3_3_39_2","unstructured":"Apellis announces three oral presentations of the phase 3 DERBY and OAKS data in geographic atrophy (GA) to be Highlighted at the AAO Annual Meeting. Releaseed at November 10 2021 from https:\/\/investors.apellis.com\/news-releases\/news-release-details\/apellis-announces-three-oral-presentations-phase-3-derby-and."},{"key":"e_1_3_3_40_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-25745-7"},{"key":"e_1_3_3_41_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.exer.2016.02.004"},{"key":"e_1_3_3_42_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.exer.2015.03.009"},{"key":"e_1_3_3_43_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.preteyeres.2020.100844"},{"key":"e_1_3_3_44_2","doi-asserted-by":"publisher","DOI":"10.1038\/srep30933"},{"key":"e_1_3_3_45_2","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.03-0097"},{"key":"e_1_3_3_46_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2013.02.032"},{"key":"e_1_3_3_47_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms8847"},{"key":"e_1_3_3_48_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2013.03.009"},{"key":"e_1_3_3_49_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pmed.0030310"},{"key":"e_1_3_3_50_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI32430"},{"key":"e_1_3_3_51_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M113.535765"},{"key":"e_1_3_3_52_2","doi-asserted-by":"publisher","DOI":"10.1111\/jpi.12660"},{"key":"e_1_3_3_53_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.preteyeres.2013.07.003"},{"key":"e_1_3_3_54_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-physiol-022516-034339"},{"key":"e_1_3_3_55_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1479-666X(09)80042-5"},{"key":"e_1_3_3_56_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.01426"},{"key":"e_1_3_3_57_2","first-page":"1857","article-title":"Resistance to anti-VEGF therapy in neovascular age-related macular degeneration: A comprehensive review","volume":"10","author":"Yang S.","year":"2016","unstructured":"S. Yang, J. Zhao, X. Sun, Resistance to anti-VEGF therapy in neovascular age-related macular degeneration: A comprehensive review. Drug Des. Devel. Ther. 10, 1857\u20131867 (2016).","journal-title":"Drug Des. Devel. Ther."},{"key":"e_1_3_3_58_2","first-page":"485","article-title":"Resistance to antivascular endothelial growth factor treatment in age-related macular degeneration","volume":"7","author":"Tranos P.","year":"2013","unstructured":"P. Tranos, A. Vacalis, S. Asteriadis, S. Koukoula, A. Vachtsevanos, G. Perganta, I. Georgalas, Resistance to antivascular endothelial growth factor treatment in age-related macular degeneration. Drug Des. Devel. Ther. 7, 485\u2013490 (2013).","journal-title":"Drug Des. Devel. Ther."},{"key":"e_1_3_3_59_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.oret.2017.03.003"},{"key":"e_1_3_3_60_2","doi-asserted-by":"publisher","DOI":"10.1080\/19420862.2016.1268305"},{"key":"e_1_3_3_61_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(22)00010-1"},{"key":"e_1_3_3_62_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.177.3.1872"},{"key":"e_1_3_3_63_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molimm.2010.12.016"},{"key":"e_1_3_3_64_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-019-0031-6"},{"key":"e_1_3_3_65_2","doi-asserted-by":"publisher","DOI":"10.1001\/jamaophthalmol.2018.1544"},{"key":"e_1_3_3_66_2","doi-asserted-by":"publisher","DOI":"10.1089\/nat.2015.0573"},{"key":"e_1_3_3_67_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejpb.2015.02.020"},{"key":"e_1_3_3_68_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.exer.2019.05.006"},{"key":"e_1_3_3_69_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.2371562"},{"key":"e_1_3_3_70_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.174.6.1451"},{"key":"e_1_3_3_71_2","doi-asserted-by":"publisher","DOI":"10.1136\/bjophthalmol-2012-302307"},{"key":"e_1_3_3_72_2","doi-asserted-by":"publisher","DOI":"10.1089\/jop.2011.0212"},{"key":"e_1_3_3_73_2","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.08-2222"},{"key":"e_1_3_3_74_2","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.18-23892"},{"key":"e_1_3_3_75_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ophtha.2009.04.030"},{"key":"e_1_3_3_76_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajo.2015.11.033"},{"key":"e_1_3_3_77_2","doi-asserted-by":"publisher","DOI":"10.1007\/s12149-021-01607-6"},{"key":"e_1_3_3_78_2","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2013.135"},{"key":"e_1_3_3_79_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11095-008-9718-9"},{"key":"e_1_3_3_80_2","doi-asserted-by":"publisher","DOI":"10.1089\/jop.2015.0049"},{"key":"e_1_3_3_81_2","doi-asserted-by":"crossref","first-page":"1329","DOI":"10.1001\/archopht.117.10.1329","article-title":"Photodynamic therapy of subfoveal choroidal neovascularization in age-related macular degeneration with verteporfin: One-year results of 2 randomized clinical trials--TAP report. Treatment of age-related macular degeneration with photodynamic therapy (TAP) study group","volume":"117","year":"1999","unstructured":"Photodynamic therapy of subfoveal choroidal neovascularization in age-related macular degeneration with verteporfin: One-year results of 2 randomized clinical trials--TAP report. Treatment of age-related macular degeneration with photodynamic therapy (TAP) study group. Arch. Ophthalmol. 117, 1329\u20131345 (1999).","journal-title":"Arch. Ophthalmol."},{"key":"e_1_3_3_82_2","doi-asserted-by":"publisher","DOI":"10.1017\/S0952523806231080"},{"key":"e_1_3_3_83_2","doi-asserted-by":"publisher","DOI":"10.1038\/mt.2011.212"},{"key":"e_1_3_3_84_2","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.14-14238"}],"container-title":["Science Translational Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/scitranslmed.abj2177","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,1,16]],"date-time":"2024-01-16T13:01:49Z","timestamp":1705410109000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.science.org\/doi\/10.1126\/scitranslmed.abj2177"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6]]},"references-count":83,"journal-issue":{"issue":"647","published-print":{"date-parts":[[2022,6]]}},"alternative-id":["10.1126\/scitranslmed.abj2177"],"URL":"https:\/\/doi.org\/10.1126\/scitranslmed.abj2177","relation":{},"ISSN":["1946-6234","1946-6242"],"issn-type":[{"value":"1946-6234","type":"print"},{"value":"1946-6242","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,6]]},"article-number":"eabj2177"}}