Development of a new high-affinity human antibody with antitumor activity against solid and blood malignancies.

Abstract

mAbs have emerged as a promising strategy for the treatment of cancer. However, in several malignancies, no effective antitumor mAbs are yet available. Identifying therapeutic mAbs that recognize common tumor antigens could render the treatment widely applicable. Here, a human single-chain variable fragment (scFv) antibody library was sequentially affinity selected against a panel of human cancer cell lines and an antibody fragment (named MS5) that bound to solid and blood cancer cells was identified. The MS5 scFv was fused to the human IgG1 Fc domain to generate an antibody (MS5-Fc fusion) that induced antibody-dependent cellular cytotoxicity and phagocytosis of cancer cells by macrophages. In addition, the MS5-Fc antibody bound to primary leukemia cells and induced antibody-dependent cellular cytotoxicity. In the majority of analyzed cancer cells, the MS5-Fc antibody induced cell surface redistribution of the receptor complexes, but not internalization, thus maximizing the accessibility of the IgG1 Fc domain to immune effector cells. In vitro stability studies showed that the MS5-Fc antibody was stable after 6 d of incubation in human serum, retaining ∼60% of its initial intact form. After intravenous injections, the antibody localized into tumor tissues and inhibited the growth of 3 different human tumor xenografts (breast, lymphoma, and leukemia). These antitumor effects were associated with tumor infiltration by macrophages and NK cells. In the Ramos B-cell lymphoma xenograft model, the MS5-Fc antibody exhibited a comparable antitumor effect as rituximab, a chimeric anti-CD20 IgG1 mAb. These results indicate that human antibodies with pan-cancer abilities can be generated from phage display libraries, and that the engineered MS5-Fc antibody could be an attractive agent for further clinical investigation.-Sioud, M., Westby, P., Vasovic, V., Fløisand, Y., Peng, Q. Development of a new high-affinity human antibody with antitumor activity against solid and blood malignancies.

• Authors: Mouldy Sioud, Phuong Westby, Vlada Vasovic, Yngvar Fløisand, Qian Peng
• Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 32 Issue 9 Pg. 5063-5077 (09 2018) ISSN: 1530-6860 [Electronic] United States
• PMID: 29913558 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Immunoglobulin Fc Fragments
• Single-Chain Antibodies

Topics

• Antibodies, Monoclonal (immunology, pharmacology)
• Antibody Affinity (immunology)
• Antibody-Dependent Cell Cytotoxicity (drug effects, immunology)
• Cell Line, Tumor
• Humans
• Immunoglobulin Fc Fragments (metabolism)
• Killer Cells, Natural (drug effects, immunology)
• Neoplasms (drug therapy, immunology)
• Single-Chain Antibodies (pharmacology)
• Xenograft Model Antitumor Assays (methods)