دورية أكاديمية
Notch1 and Notch4 core binding domain peptibodies exhibit distinct ligand-binding and anti-angiogenic properties.
العنوان: | Notch1 and Notch4 core binding domain peptibodies exhibit distinct ligand-binding and anti-angiogenic properties. |
---|---|
المؤلفون: | Sargis T; Department of Physiology and Biophysics, University of Illinois College of Medicine, Chicago, IL, 60612, USA., Youn SW; Department of Physiology and Biophysics, University of Illinois College of Medicine, Chicago, IL, 60612, USA., Thakkar K; Department of Physiology and Biophysics, University of Illinois College of Medicine, Chicago, IL, 60612, USA., Naiche LA; Department of Physiology and Biophysics, University of Illinois College of Medicine, Chicago, IL, 60612, USA., Paik NY; Department of Pharmacology and Regenerative Medicine, University of Illinois College of Medicine, Chicago, IL, 60612, USA., Pajcini KV; Department of Pharmacology and Regenerative Medicine, University of Illinois College of Medicine, Chicago, IL, 60612, USA.; University of Illinois Cancer Center, University of Illinois Chicago, Chicago, IL, 60612, USA., Kitajewski JK; Department of Physiology and Biophysics, University of Illinois College of Medicine, Chicago, IL, 60612, USA. kitaj@uic.edu.; University of Illinois Cancer Center, University of Illinois Chicago, Chicago, IL, 60612, USA. kitaj@uic.edu. |
المصدر: | Angiogenesis [Angiogenesis] 2023 May; Vol. 26 (2), pp. 249-263. Date of Electronic Publication: 2022 Nov 15. |
نوع المنشور: | Journal Article; Research Support, U.S. Gov't, Non-P.H.S.; Research Support, N.I.H., Extramural |
اللغة: | English |
بيانات الدورية: | Publisher: Springer Country of Publication: Germany NLM ID: 9814575 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1573-7209 (Electronic) Linking ISSN: 09696970 NLM ISO Abbreviation: Angiogenesis Subsets: MEDLINE |
أسماء مطبوعة: | Publication: Dec. 2004- : Berlin : Springer Original Publication: London ; Philadelphia : Rapid Science Publishers, |
مواضيع طبية MeSH: | Angiogenesis Inhibitors*/genetics , Angiogenesis Inhibitors*/metabolism , Angiogenesis Inhibitors*/pharmacology , Endothelial Cells*/drug effects , Endothelial Cells*/metabolism , Receptor, Notch1*/antagonists & inhibitors , Receptor, Notch1*/genetics , Receptor, Notch1*/metabolism , Receptor, Notch4*/genetics , Receptor, Notch4*/metabolism, Animals ; Mice ; Epidermal Growth Factor/metabolism ; Immunoprecipitation ; Inflammation/drug therapy ; Inflammation/genetics ; Inflammation/metabolism ; Ligands ; Neoplasms/drug therapy ; Neoplasms/genetics ; Neoplasms/metabolism ; Recombinant Fusion Proteins/genetics ; Recombinant Fusion Proteins/metabolism ; Retinal Vessels/drug effects ; Surface Plasmon Resonance |
مستخلص: | The Notch signaling pathway is an important therapeutic target for the treatment of inflammatory diseases and cancer. We previously created ligand-specific inhibitors of Notch signaling comprised of Fc fusions to specific EGF-like repeats of the Notch1 extracellular domain, called Notch decoys, which bound ligands, blocked Notch signaling, and showed anti-tumor activity with low toxicity. However, the study of their function depended on virally mediated expression, which precluded dosage control and limited clinical applicability. We have refined the decoy design to create peptibody-based Notch inhibitors comprising the core binding domains, EGF-like repeats 10-14, of either Notch1 or Notch4. These Notch peptibodies showed high secretion properties and production yields that were improved by nearly 100-fold compared to previous Notch decoys. Using surface plasmon resonance spectroscopy coupled with co-immunoprecipitation assays, we observed that Notch1 and Notch4 peptibodies demonstrate strong but distinct binding properties to Notch ligands DLL4 and JAG1. Both Notch1 and Notch4 peptibodies interfere with Notch signaling in endothelial cells and reduce expression of canonical Notch targets after treatment. While prior DLL4 inhibitors cause hyper-sprouting, the Notch1 peptibody reduced angiogenesis in a 3-dimensional in vitro sprouting assay. Administration of Notch1 peptibodies to neonate mice resulted in reduced radial outgrowth of retinal vasculature, confirming anti-angiogenic properties. We conclude that purified Notch peptibodies comprising EGF-like repeats 10-14 bind to both DLL4 and JAG1 ligands and exhibit anti-angiogenic properties. Based on their secretion profile, unique Notch inhibitory activities, and anti-angiogenic properties, Notch peptibodies present new opportunities for therapeutic Notch inhibition. (© 2022. The Author(s).) |
References: | Proc Natl Acad Sci U S A. 2007 Feb 27;104(9):3219-24. (PMID: 17296940) Biopolymers. 2017 Dec 21;:. (PMID: 29266205) Leukemia. 2006 Jul;20(7):1279-87. (PMID: 16688224) Curr Opin Immunol. 2007 Apr;19(2):239-45. (PMID: 17291742) Leukemia. 2006 Nov;20(11):1963-6. (PMID: 17008890) MAbs. 2012 Sep-Oct;4(5):586-91. (PMID: 22820181) J Biol Chem. 2000 Mar 31;275(13):9604-11. (PMID: 10734111) Front Cell Dev Biol. 2021 May 28;9:649205. (PMID: 34124039) Proc Natl Acad Sci U S A. 2014 Dec 16;111(50):18007-12. (PMID: 25468970) Biochim Biophys Acta. 2014 Jul;1843(7):1272-84. (PMID: 24667410) Oncotarget. 2015 Sep 15;6(27):24404-23. (PMID: 26213336) Mol Med. 1998 May;4(5):286-95. (PMID: 9642680) Nature. 2010 Feb 11;463(7282):E6-7. (PMID: 20147986) J Biol Chem. 2003 Nov 14;278(46):46107-16. (PMID: 12949072) Proc Natl Acad Sci U S A. 2008 Feb 12;105(6):1955-9. (PMID: 18245384) Science. 2004 Oct 8;306(5694):269-71. (PMID: 15472075) Proc Natl Acad Sci U S A. 2007 Feb 27;104(9):3225-30. (PMID: 17296941) Mol Cell Biol. 2003 Jan;23(1):14-25. (PMID: 12482957) J Biol Chem. 2008 Dec 19;283(51):35486-95. (PMID: 18948267) Cell. 2008 Jan 25;132(2):247-58. (PMID: 18243100) Proc Natl Acad Sci U S A. 2008 Feb 5;105(5):1539-44. (PMID: 18227520) Nat Struct Mol Biol. 2008 Aug;15(8):849-57. (PMID: 18660822) Cell. 1991 Nov 15;67(4):687-99. (PMID: 1657403) Proc Natl Acad Sci U S A. 2014 May 20;111(20):7290-5. (PMID: 24803430) Cancer Res. 2010 Jan 15;70(2):632-8. (PMID: 20068176) Cell Rep. 2019 Nov 12;29(7):2054-2066.e6. (PMID: 31722217) Science. 2015 Feb 20;347(6224):847-53. (PMID: 25700513) Nat Rev Clin Oncol. 2015 Aug;12(8):445-64. (PMID: 25850553) EXCLI J. 2021 Apr 26;20:819-827. (PMID: 34121974) Nature. 2006 Dec 21;444(7122):1083-7. (PMID: 17183323) EMBO J. 2008 Jul 9;27(13):1886-95. (PMID: 18528438) Toxicol Sci. 2004 Nov;82(1):341-58. (PMID: 15319485) Nature. 2006 Dec 21;444(7122):1032-7. (PMID: 17183313) Science. 2017 Mar 24;355(6331):1320-1324. (PMID: 28254785) Genes Dev. 2006 Aug 1;20(15):2096-109. (PMID: 16847353) Cell. 2009 Jun 12;137(6):1124-35. (PMID: 19524514) Genes Dev. 2000 Jun 1;14(11):1343-52. (PMID: 10837027) Cancer Discov. 2015 Feb;5(2):182-97. (PMID: 25387766) Angiogenesis. 2022 May;25(2):205-224. (PMID: 34665379) Nature. 2005 Jun 16;435(7044):959-63. (PMID: 15959515) Vasc Cell. 2013 Apr 20;5(1):7. (PMID: 23601498) Circulation. 2005 Apr 12;111(14):1826-32. (PMID: 15809373) Development. 1996 Jul;122(7):2251-9. (PMID: 8681805) Proc Natl Acad Sci U S A. 2005 Jul 12;102(28):9884-9. (PMID: 15994223) Development. 2003 Dec;130(26):6411-21. (PMID: 14627724) |
معلومات مُعتمدة: | R01 HL112626 United States HL NHLBI NIH HHS; R01 HL134971 United States HL NHLBI NIH HHS; T32 HL144459 United States HL NHLBI NIH HHS; R01 HL151720 United States HL NHLBI NIH HHS |
فهرسة مساهمة: | Keywords: Angiogenesis; Inhibitor; Notch; Notch core binding domain; Peptibody |
المشرفين على المادة: | 0 (Angiogenesis Inhibitors) 0 (DLL4 protein, mouse) 62229-50-9 (Epidermal Growth Factor) 0 (Jag1 protein, mouse) 0 (Ligands) 0 (Notch1 protein, mouse) 146991-60-8 (Notch4 protein, mouse) 0 (Receptor, Notch1) 0 (Receptor, Notch4) 0 (Recombinant Fusion Proteins) |
تواريخ الأحداث: | Date Created: 20221115 Date Completed: 20230426 Latest Revision: 20231003 |
رمز التحديث: | 20231003 |
مُعرف محوري في PubMed: | PMC10119233 |
DOI: | 10.1007/s10456-022-09861-6 |
PMID: | 36376768 |
قاعدة البيانات: | MEDLINE |
تدمد: | 1573-7209 |
---|---|
DOI: | 10.1007/s10456-022-09861-6 |