Internalization of CD239 highly expressed in breast cancer cells: a potential antigen for antibody-drug conjugates.

Abstract

Antibody-drug conjugates (ADCs) are attractive in cancer therapy because they can directly bind to cancer cells and provide anticancer activity. To kill cancer cells with ADCs, the target antigens are required not only to be highly and/or selectively expressed on cancer cells but also internalized by the cells. CD239, also known as the Lutheran blood group glycoprotein (Lu) or basal cell adhesion molecule (B-CAM), is a specific receptor for laminin α5, a major component of basement membranes. Here, we show that CD239 is strongly expressed in a subset of breast cancer cells and internalized into the cells. We also produced a human single-chain variable fragment (scFv) specific to CD239 fused with human IgG1 Fc, called C7-Fc. The binding affinity of the C7-Fc antibody is similar to that of mouse monoclonal antibodies. Although the C7-Fc antibody alone does not influence cellular functions, when conjugated with a fragment of diphtheria toxin lacking the receptor-binding domain (fDT), it can selectively kill breast cancer cells. Interestingly, fDT-bound C7-Fc shows anticancer activity in CD239-highly positive SKBR3 cells, but not in weakly positive cells. Our results show that CD239 is a promising antigen for ADC-based breast cancer therapy.

• Authors: Yamato Kikkawa, Yurie Enomoto-Okawa, Aiko Fujiyama, Takeshi Fukuhara, Nozomi Harashima, Yumika Sugawara, Yoichi Negishi, Fumihiko Katagiri, Kentaro Hozumi, Motoyoshi Nomizu, Yuji Ito
• Journal: Scientific reports (Sci Rep) Vol. 8 Issue 1 Pg. 6612 (04 26 2018) ISSN: 2045-2322 [Electronic] England
• PMID: 29700410 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• BCAM protein, human
• Biomarkers, Tumor
• Cell Adhesion Molecules
• Immunoconjugates
• Immunoglobulin Fc Fragments
• Lutheran Blood-Group System
• Single-Chain Antibodies

Topics

• Animals
• Biomarkers, Tumor
• Breast Neoplasms (drug therapy, genetics, metabolism, pathology)
• Cell Adhesion Molecules (antagonists & inhibitors, genetics, metabolism)
• Cell Line, Tumor
• Cytotoxicity Tests, Immunologic
• Endocytosis
• Female
• Humans
• Immunoconjugates (pharmacology)
• Immunoglobulin Fc Fragments (immunology)
• Immunohistochemistry
• Lutheran Blood-Group System (genetics, metabolism)
• Mice
• Protein Binding
• Protein Transport
• Single-Chain Antibodies (pharmacology)