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Methods. 2019 Feb 1;154:125-135. doi: 10.1016/j.ymeth.2018.10.002. Epub 2018 Oct 4.

Bispecific anti-mPDGFRβ x cotinine scFv-Cκ-scFv fusion protein and cotinine-duocarmycin can form antibody-drug conjugate-like complexes that exert cytotoxicity against mPDGFRβ expressing cells.

Author information

1
Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul 00380, Republic of Korea; Cancer Research Institute, Seoul National University College of Medicine, Seoul 00380, Republic of Korea.
2
Convergence Medicine Research Center, Asan Institute for Life Sciences, Asan Medical Center, Seoul, Republic of Korea; Department of Convergence Medicine, University of Ulsan College of Medicine, Seoul, Republic of Korea.
3
Fight Against Angiogenesis-Related Blindness (FARB) Laboratory, Clinical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea.
4
Fight Against Angiogenesis-Related Blindness (FARB) Laboratory, Clinical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea; Department of Biomedical Science, Seoul National University College of Medicine, Seoul 00380, Republic of Korea; Department of Ophthalmology, Seoul National University College of Medicine, Seoul, Republic of Korea.
5
Department of Life Science, Ewha Womans University, Seoul 03760, Republic of Korea.
6
Department of Biomedical Science, Seoul National University College of Medicine, Seoul 00380, Republic of Korea. Electronic address: dhwang@scripps.edu.
7
Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul 00380, Republic of Korea; Cancer Research Institute, Seoul National University College of Medicine, Seoul 00380, Republic of Korea; Department of Biomedical Science, Seoul National University College of Medicine, Seoul 00380, Republic of Korea. Electronic address: jjhchung@snu.ac.kr.

Abstract

Antibody selection for antibody-drug conjugates (ADCs) has traditionally depended on its internalization into the target cell, although ADC efficacy also relies on recycling of the receptor-ADC complex, endo-lysosomal trafficking, and subsequent linker/antibody proteolysis. In this study, we observed that a bispecific anti-murine platelet-derived growth factor receptor beta (mPDGFRβ) x cotinine single-chain variable fragment (scFv)-kappa constant region (Cκ)-scFv fusion protein and cotinine-duocarmycin can form an ADC-like complex to induce cytotoxicity against mPDGFRβ expressing cells. Multiple anti-mPDGFRβ antibody candidates can be produced in this bispecific scFv-Cκ-scFv fusion protein format and tested for their ability to deliver cotinine-conjugated cytotoxic drugs, thus providing an improved approach for antibody selection in ADC development.

KEYWORDS:

Antibody-drug conjugate; Bispecific antibody; Cotinine; Duocarmycin

PMID:
30292795
DOI:
10.1016/j.ymeth.2018.10.002
[Indexed for MEDLINE]

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