A humanized anti-DLL4 antibody promotes dysfunctional angiogenesis and inhibits breast tumor growth. Sci Rep 2016 Jun 15;6:27985
Date
06/16/2016Pubmed ID
27301650Pubmed Central ID
PMC4908374DOI
10.1038/srep27985Scopus ID
2-s2.0-84974794732 (requires institutional sign-in at Scopus site) 26 CitationsAbstract
Blockage of Delta-like 4 (DLL4)-directed Notch signaling induces excessive tip cell formation and endothelial proliferation resulting in dysfunctional angiogenesis in tumors. MMGZ01, as a murine anti-human DLL4 monoclonal antibody, specifically binds to human DLL4 and blocks Notch pathway. Here, the structure of MMGZ01 variable fragment (Fv) was established and framework region (FR) residues which supported complementarily determining region (CDR) loop conformation were identified. Important residues interactions were also identified through docking MMGZ01 Fv with antigen epitope in DLL4. To humanize the murine antibody, we modified MMGZ01 Fv through CDR grafting and the reconstructed antibody (H3L2) maintained similar structure and binding affinity to parental MMGZ01 after back mutation of 12 canonical murine residues in the FRs. Meanwhile, H3L2 promoted human umbilical vein endothelial cell (HUVEC) proliferation through inhibiting DLL4-directed Notch pathway. Moreover, in MDA-MB-231-bearing nude mice, H3L2 induced dysfunctional angiogenesis and tumor cell apoptosis and showed superior anti-tumor activity. In conclusion, H3L2 is an ideal humanized antibody that inhibits tumor growth through targeting DLL4-Notch pathway and has attracting potentials for clinical applications.
Author List
Jia X, Wang W, Xu Z, Wang S, Wang T, Wang M, Wu MAuthor
Shijing Wang Postdoctoral Researcher in the Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Adaptor Proteins, Signal TransducingAnimals
Antibodies, Monoclonal
Antineoplastic Agents
Breast Neoplasms
Calcium-Binding Proteins
Disease Models, Animal
Humans
Intercellular Signaling Peptides and Proteins
Mice, Nude
Molecular Docking Simulation
Neovascularization, Pathologic
Protein Conformation
Receptors, Notch
Signal Transduction
Treatment Outcome
