作者: Hoffman, Michelle ; Furlan, Scott N ; Outen, Riley ; Yu, Alison ; Radtke, Freddy ; Ludewig, Burkhard ; Gerdemann, Ulrike ; Panoskaltsis-Mortari, Angela ; Zheng, Hengqi ; Thurston, Gavin ; Gómez Atria, Daniela ; Hunt, Daniel J ; Colonna, Lucrezia ; Chen, Guoying ; Rui, Xianliang ; Koch, Ute ; Lane, Jennifer ; Vanderbeck, Ashley ; Kean, Leslie S ; Harari, Olivier ; McGuckin, Connor ; Perkey, Eric ; Shimizu, Yoji ; Allman, Anneka ; Kelly, Samantha ; Burbach, Brandon ; Maillard, Ivan ; Kuhnert, Frank ; Tkachev, Victor ; Blazar, Bruce R ; Carpenter, Stephen M

Notch signaling promotes T cell pathogenicity and graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (allo-HCT) in mice, with a dominant role for the Delta-like Notch ligand DLL4. To assess whether Notch’s effects are evolutionarily conserved and to identify the mechanisms of Notch signaling inhibition, we studied antibody-mediated DLL4 blockade in a nonhuman primate (NHP) model similar to human allo-HCT. Short-term DLL4 blockade improved posttransplant survival with durable protection from gastrointestinal GVHD in particular. Unlike prior immunosuppressive strategies tested in the NHP GVHD model, anti-DLL4 interfered with a T cell transcriptional program associated with intestinal infiltration. In cross-species investigations, Notch inhibition decreased surface abundance of the gut-homing integrin α4β7 in conventional T cells while preserving α4β7 in regulatory T cells, with findings suggesting increased β1 competition for α4 binding in conventional T cells. Secondary lymphoid organ fibroblastic reticular cells emerged as the critical cellular source of Delta-like Notch ligands for Notch-mediated up-regulation of α4β7 integrin in T cells after allo-HCT. Together, DLL4-Notch blockade decreased effector T cell infiltration into the gut, with increased regulatory to conventional T cell ratios early after allo-HCT. Our results identify a conserved, biologically unique, and targetable role of DLL4-Notch signaling in intestinal GVHD.

2020-11-01·Advances in Wound Care3区 · 医学

Dll4 Blockade Promotes Angiogenesis in Nonhealing Wounds of Sox7-Deficient Mice

3区 · 医学

Article

作者: Kim, Il-Kug ; Ryu, Junghwa ; Kim, Injune ; Chang, Hak ; Yang, Jee Myung

Objective: This study aimed to elucidate the role of the proangiogenic transcription factors Sox7 and Sox17 in the wound healing process and investigate the therapeutic potential of Dll4 blockade, which is an upstream regulator of Sox17, for the treatment of nonhealing wounds. Approach: After generating a full-thickness skin defect wound model of endothelial Sox7- and/or Sox17-deficient mice, we measured the wound healing rates and performed histological analysis. The effects of an anti-Dll4 antibody on wound angiogenesis in Sox7-deficient mice and db/db diabetic mice were assessed. Results: Sox7 and/or Sox17 deletion delayed wound healing. Moreover, the loss of Sox7 and Sox17 inhibited wound angiogenesis, without affecting the expression of the other. Of interest, after anti-Dll4 antibody treatment, Sox17 levels were increased and the suppression of angiogenesis was alleviated in Sox7-deficient mice and db/db diabetic mice. Consequently, Dll4 blockade effectively recovered the observed delay in wound healing. Innovation: The proangiogenic role of Sox7 and Sox17 in wound angiogenesis was addressed and effective treatment of nonhealing wounds by Dll4 blockade was suggested. Conclusion: This study revealed the proangiogenic role of the transcription factors Sox7 and Sox17 in wound angiogenesis. Furthermore, we suggest a novel method for treating nonhealing wounds by particularly targeting the Dll4-Sox17 axis.

2019-07-01·Experimental Cell Research3区 · 医学

The bispecific antibody HB-32, blockade of both VEGF and DLL4 shows potent anti-angiogenic activity in vitro and anti-tumor activity in breast cancer xenograft models

3区 · 医学

Article

作者: Wang, Shijing ; Wang, Min ; Wu, Min ; Wen, Hui ; Zhou, Rihong

Increasing preclinical and clinical studies revealed that many tumor models had resistance to anti-VEGF-A and anti-VEGF-R2 therapies. Studies have shown that simultaneously blocked DLL4-Notch and VEGF signaling pathways can synergistically inhibit density and function of tumor blood vessels and reduce tumor growth rate. We successfully developed a bispecific monoclonal antibody (named HB-32) that targeting both human DLL4 and human VEGF. HB-32 showed high binding affinity to VEGF and DLL4. Furthermore, HB-32 inhibited proliferation, migration and tube formation of HUVEC. Finally, in vivo xenograft studies demonstrated that HB-32 inhibited proliferation of breast cancer cells (MDA-MB-231) and induced tumor cell apoptosis more efficiently than an anti-VEGF antibody or anti-DLL4 antibody alone. These findings indicate that our bispecific antibody provide a potential treatment for breast cancer.

100 项与 Anti-DLL4 antibody(Regeneron) 相关的药物交易

登录后查看更多信息