HED, a Human-Engineered Domain, Confers a Unique Fc-Binding Activity to Produce a New Class of Humanized Antibody-like Molecules

Autor:	Zhiqiang Zhu, Peeyush N. Goel, Cai Zheng, Yasuhiro Nagai, Lian Lam, Arabinda Samanta, Meiqing Ji, Hongtao Zhang, Mark I. Greene
Rok vydání:	2023
Předmět:	Inorganic Chemistry Organic Chemistry General Medicine Physical and Theoretical Chemistry engineered antibody humanized HED bodies breast cancer IFN-γ Molecular Biology Spectroscopy Catalysis Computer Science Applications
Zdroj:	International Journal of Molecular Sciences; Volume 24; Issue 7; Pages: 6477
ISSN:	1422-0067
DOI:	10.3390/ijms24076477
Popis:	Our laboratory has identified and developed a unique human-engineered domain (HED) structure that was obtained from the human Alpha-2-macroglobulin receptor-associated protein based on the three-dimensional structure of the Z-domain derived from Staphylococcal protein A. This HED retains µM binding activity to the human IgG1CH2-CH3 elbow region. We determined the crystal structure of HED in association with IgG1’s Fc. This demonstrated that HED preserves the same three-bundle helix structure and Fc-interacting residues as the Z domain. HED was fused to the single chain variable fragment (scFv) of mAb 4D5 to produce an antibody-like protein capable of interacting with the p185Her2/neu ectodomain and the Fc of IgG. When further fused with murine IFN-γ (mIFN-γ) at the carboxy terminus, the novel species exhibited antitumor efficacy in vivo in a mouse model of human breast cancer. The HED is a novel platform for the therapeutic utilization of engineered proteins to alleviate human disease.
Databáze:	OpenAIRE
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