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

Soohyun Kim; Hyori Kim; Dong Hyun Jo; Jeong Hun Kim; Su Ree Kim; Dongmin Kang; Dobeen Hwang; Junho Chung

doi:10.1016/j.ymeth.2018.10.002

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

Soohyun Kim, Hyori Kim, Dong Hyun Jo, Jeong Hun Kim, Su Ree Kim, Dongmin Kang, Dobeen Hwang, Junho Chung

Department of Life Science

Research output: Contribution to journal › Article › peer-review

9 Scopus citations

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 (C_κ)-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-C_κ-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.

Original language	English
Pages (from-to)	125-135
Number of pages	11
Journal	Methods
Volume	154
DOIs	https://doi.org/10.1016/j.ymeth.2018.10.002
State	Published - 1 Feb 2019

Bibliographical note

Funding Information:
This work was supported by the National Research Foundation funded by the Korean government (MSIP) (grant no. NRF-2017M3A9C8032204 , NRF-2015R1D1A1A09057154 and NRF-2015M3A9E6028949 ). This research was also partially supported by the New Drug Development Center, Asan Medical Center (2017-758).

Funding Information:
This work was supported by the National Research Foundation funded by the Korean government (MSIP) (grant no. NRF-2017M3A9C8032204, NRF-2015R1D1A1A09057154 and NRF-2015M3A9E6028949). This research was also partially supported by the New Drug Development Center, Asan Medical Center (2017-758).

Publisher Copyright:
© 2018 Elsevier Inc.

Keywords

Antibody-drug conjugate
Bispecific antibody
Cotinine
Duocarmycin

Access to Document

10.1016/j.ymeth.2018.10.002

Cite this

@article{174811496b4f42508a9d2198d98c722c,

title = "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",

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",

author = "Soohyun Kim and Hyori Kim and Jo, {Dong Hyun} and Kim, {Jeong Hun} and Kim, {Su Ree} and Dongmin Kang and Dobeen Hwang and Junho Chung",

note = "Funding Information: This work was supported by the National Research Foundation funded by the Korean government (MSIP) (grant no. NRF-2017M3A9C8032204 , NRF-2015R1D1A1A09057154 and NRF-2015M3A9E6028949 ). This research was also partially supported by the New Drug Development Center, Asan Medical Center (2017-758). Funding Information: This work was supported by the National Research Foundation funded by the Korean government (MSIP) (grant no. NRF-2017M3A9C8032204, NRF-2015R1D1A1A09057154 and NRF-2015M3A9E6028949). This research was also partially supported by the New Drug Development Center, Asan Medical Center (2017-758). Publisher Copyright: {\textcopyright} 2018 Elsevier Inc.",

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AU - Kim, Soohyun

AU - Kim, Hyori

AU - Jo, Dong Hyun

AU - Kim, Jeong Hun

AU - Kim, Su Ree

AU - Kang, Dongmin

AU - Hwang, Dobeen

AU - Chung, Junho

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N2 - 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.

AB - 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.

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