Human endoglin-CD3 bispecific T cell engager antibody induces anti-tumor effect in vivo.

Abstract

Rationale: Endoglin, also known as CD105, is a homo-dimeric membrane glycoprotein required for angiogenesis and serves as a marker for cancer vasculature. In this study, we constructed a bispecific T-cell engager (BiTE) antibody that targets human endoglin and CD3 (hEND-CD3/BiTE). We examined BiTE binding to endoglin-expressing cells and its effects on the cytolytic activity of T cells and cancer development. Methods: The in vitro effects of hEND-CD3/BiTE, including binding to target cells, T-cell activation, proliferation, and cytotoxicity, were examined in endoglin-expressing 293T cells, human umbilical vascular endothelial cells, tumor-derived endothelial cells, and CD3+ T cells. An in vivo xenograft tumor model was established using A549 human lung cancer cells. The therapeutic efficacy of hEND-CD3/BiTE was assessed by monitoring tumor growth, angiogenesis, and mouse survival. Results: hEND-CD3/BiTE specifically bound to endoglin-expressing cells and CD3+ T cells in vitro and stimulated T-cell activation, proliferation, and Th1 cytokine secretion, and promoted T-cell-mediated cytolysis of endoglin-expressing cells. The hEND-CD3/BiTE in vivo caused minimal toxicity to major organs, reduced tumor neoangiogenesis, inhibited tumor growth, and significantly improved mouse survival. Conclusions: Our study demonstrated the therapeutic potential of hEND-CD3/BiTE and provided a novel approach to clinical cancer treatment.

• Authors: Liping Zhong, Wei Shi, Lu Gan, Xiuli Liu, Yu Huo, Pan Wu, Zhikun Zhang, Tao Wu, Hongmei Peng, Yong Huang, Yongxiang Zhao, Yulin Yuan, Zhiming Deng, Hongliang Tang
• Journal: Theranostics (Theranostics) Vol. 11 Issue 13 Pg. 6393-6406 ( 2021) ISSN: 1838-7640 [Electronic] Australia
• PMID: 33995664 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The author(s).

Chemical References

• Angiogenesis Inhibitors
• Antibodies, Bispecific
• Antineoplastic Agents, Immunological
• CD3 Complex
• Cytokines
• ENG protein, human
• Endoglin
• Recombinant Proteins

Topics

• A549 Cells
• Amino Acid Sequence
• Angiogenesis Inhibitors (therapeutic use)
• Animals
• Antibodies, Bispecific (genetics, immunology, therapeutic use)
• Antineoplastic Agents, Immunological (therapeutic use)
• Base Sequence
• CD3 Complex (immunology)
• Cytokines (metabolism)
• Cytotoxicity, Immunologic
• Endoglin (immunology)
• Endothelial Cells (immunology)
• Female
• Human Umbilical Vein Endothelial Cells
• Humans
• Lymphocyte Activation
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Neovascularization, Pathologic (drug therapy, immunology)
• Recombinant Proteins (administration & dosage, immunology)
• T-Lymphocytes (immunology)
• Th1 Cells (immunology)
• Xenograft Model Antitumor Assays