Felicitas Bucher1, Ding Zhang1, Edith Aguilar1, Susumu Sakimoto1, Sophia Diaz-Aguilar1, Mauricio Rosenfeld1, Zhao Zha1, Hongkai Zhang1, Martin Friedlander2, Kyungmoo Yea2. 1. From Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, CA (F.B., E.A., S.S., S.D.-A., M.R., Z.Z., H.Z., M.F., K.Y.); and Shanghai Institute for Advanced Immunological Studies, ShanghaiTech University, China (D.Z., K.Y.). 2. From Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, CA (F.B., E.A., S.S., S.D.-A., M.R., Z.Z., H.Z., M.F., K.Y.); and Shanghai Institute for Advanced Immunological Studies, ShanghaiTech University, China (D.Z., K.Y.). kyungmoo@scripps.edu friedlan@scripps.edu.
Abstract
BACKGROUND: Anti-angiogenic biologicals represent an important concept for the treatment of vasoproliferative diseases. However, the need for continued treatment, the presence of nonresponders, and the risk of long-term side effects limit the success of existing therapeutic agents. Although Tspan12 has been shown to regulate retinal vascular development, nothing is known about its involvement in neovascular disease and its potential as a novel therapeutic target for the treatment of vasoproliferative diseases. METHODS: Rodent models of retinal neovascular disease, including the mouse model of oxygen-induced retinopathy and the very low density lipoprotein receptor knockout mouse model were analyzed for Tspan/β-catenin regulation. Screening of a phage display of a human combinatorial antibody (Ab) library was used for the development of a high-affinity Ab against Tspan12. Therapeutic effects of the newly developed Ab on vascular endothelial cells were tested in vitro and in vivo in the oxygen-induced retinopathy and very low density lipoprotein receptor knockout mouse model. RESULTS: The newly developed anti-Tspan12 Ab exhibited potent inhibitory effects on endothelial cell migration and tube formation. Mechanistic studies confirmed that the Ab inhibited the interaction between Tspan12 and Frizzled-4 and effectively modulates β-catenin levels and target genes in vascular endothelial cells. Tspan12/β-catenin signaling was activated in response to acute and chronic stress in the oxygen-induced retinopathy and very low density lipoprotein receptor mouse model of proliferative retinopathy. Intravitreal application of the Ab showed significant therapeutic effects in both models without inducing negative side effects on retina function. Moreover, combined intravitreal injection of the Ab with a known vascular endothelial growth factor inhibitor, Aflibercept, resulted in significant enhancement of the therapeutic efficacy of each monotherapy. Combination therapy with the Tspan12 blocking antibody can be used to reduce anti-vascular endothelial growth factor doses, thus decreasing the risk of long-term off-target effects. CONCLUSIONS: Tspan12/β-catenin signaling is critical for the progression of vasoproliferative disease. The newly developed anti-Tspan12 antibody has therapeutic effects in vasoproliferative retinopathy and can enhance the potency of existing anti- vascular endothelial growth factor agents.
BACKGROUND: Anti-angiogenic biologicals represent an important concept for the treatment of vasoproliferative diseases. However, the need for continued treatment, the presence of nonresponders, and the risk of long-term side effects limit the success of existing therapeutic agents. Although Tspan12 has been shown to regulate retinal vascular development, nothing is known about its involvement in neovascular disease and its potential as a novel therapeutic target for the treatment of vasoproliferative diseases. METHODS: Rodent models of retinal neovascular disease, including the mouse model of oxygen-induced retinopathy and the very low density lipoprotein receptor knockout mouse model were analyzed for Tspan/β-catenin regulation. Screening of a phage display of a human combinatorial antibody (Ab) library was used for the development of a high-affinity Ab against Tspan12. Therapeutic effects of the newly developed Ab on vascular endothelial cells were tested in vitro and in vivo in the oxygen-induced retinopathy and very low density lipoprotein receptor knockout mouse model. RESULTS: The newly developed anti-Tspan12 Ab exhibited potent inhibitory effects on endothelial cell migration and tube formation. Mechanistic studies confirmed that the Ab inhibited the interaction between Tspan12 and Frizzled-4 and effectively modulates β-catenin levels and target genes in vascular endothelial cells. Tspan12/β-catenin signaling was activated in response to acute and chronic stress in the oxygen-induced retinopathy and very low density lipoprotein receptormouse model of proliferative retinopathy. Intravitreal application of the Ab showed significant therapeutic effects in both models without inducing negative side effects on retina function. Moreover, combined intravitreal injection of the Ab with a known vascular endothelial growth factor inhibitor, Aflibercept, resulted in significant enhancement of the therapeutic efficacy of each monotherapy. Combination therapy with the Tspan12 blocking antibody can be used to reduce anti-vascular endothelial growth factor doses, thus decreasing the risk of long-term off-target effects. CONCLUSIONS:Tspan12/β-catenin signaling is critical for the progression of vasoproliferative disease. The newly developed anti-Tspan12 antibody has therapeutic effects in vasoproliferative retinopathy and can enhance the potency of existing anti- vascular endothelial growth factor agents.
Authors: Tetsuo Shoda; Ting Wen; Julie M Caldwell; Netali Ben-Baruch Morgenstern; Garrett A Osswald; Mark Rochman; Lydia E Mack; Jennifer M Felton; J Pablo Abonia; Nicoleta C Arva; Dan Atkins; Peter A Bonis; Kelley E Capocelli; Margaret H Collins; Evan S Dellon; Gary W Falk; Nirmala Gonsalves; Sandeep K Gupta; Ikuo Hirano; John Leung; Paul A Menard-Katcher; Vincent A Mukkada; Philip E Putnam; Amanda K Rudman Spergel; Jonathan M Spergel; Joshua B Wechsler; Guang-Yu Yang; Seema S Aceves; Glenn T Furuta; Marc E Rothenberg Journal: Gastroenterology Date: 2021-10-21 Impact factor: 22.682
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