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Research ArticleCellular and Molecular

New Proline, Alanine, Serine Repeat Sequence for Pharmacokinetic Enhancement of Anti-VEGF Single-Domain Antibody

Farnaz Khodabakhsh, Morteza Salimian, Ardavan Mehdizadeh, Mohammad Sadeq Khosravy, Alireza Vafabakhsh, Elmira Karami and Reza Ahangari Cohan
Journal of Pharmacology and Experimental Therapeutics October 2020, 375 (1) 69-75; DOI: https://doi.org/10.1124/jpet.120.000012
Farnaz Khodabakhsh
Department of Genetics and Advanced Medical Technology, Medical Biotechnology Research Center, Faculty of Medicine, AJA University of Medical Sciences, Tehran, Iran (F.K.); Department of Medical Laboratory, Kashan University of Medical Sciences, Kashan, Iran (M.S.); Department of Civil Engineering, Sharif University of Technology, Tehran, Iran (A.M.); Department of Rabies, Virology Research Group (S.K.) and Department of Nanobiotechnology, New Technologies Research Group (R.A.C.), Pasteur Institute of Iran, Tehran, Iran; and Department of Biology, School of Basic Science, Science and Research Branch, Islamic Azad University, Tehran, Iran (A.V., E.K.)
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Morteza Salimian
Department of Genetics and Advanced Medical Technology, Medical Biotechnology Research Center, Faculty of Medicine, AJA University of Medical Sciences, Tehran, Iran (F.K.); Department of Medical Laboratory, Kashan University of Medical Sciences, Kashan, Iran (M.S.); Department of Civil Engineering, Sharif University of Technology, Tehran, Iran (A.M.); Department of Rabies, Virology Research Group (S.K.) and Department of Nanobiotechnology, New Technologies Research Group (R.A.C.), Pasteur Institute of Iran, Tehran, Iran; and Department of Biology, School of Basic Science, Science and Research Branch, Islamic Azad University, Tehran, Iran (A.V., E.K.)
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Ardavan Mehdizadeh
Department of Genetics and Advanced Medical Technology, Medical Biotechnology Research Center, Faculty of Medicine, AJA University of Medical Sciences, Tehran, Iran (F.K.); Department of Medical Laboratory, Kashan University of Medical Sciences, Kashan, Iran (M.S.); Department of Civil Engineering, Sharif University of Technology, Tehran, Iran (A.M.); Department of Rabies, Virology Research Group (S.K.) and Department of Nanobiotechnology, New Technologies Research Group (R.A.C.), Pasteur Institute of Iran, Tehran, Iran; and Department of Biology, School of Basic Science, Science and Research Branch, Islamic Azad University, Tehran, Iran (A.V., E.K.)
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Mohammad Sadeq Khosravy
Department of Genetics and Advanced Medical Technology, Medical Biotechnology Research Center, Faculty of Medicine, AJA University of Medical Sciences, Tehran, Iran (F.K.); Department of Medical Laboratory, Kashan University of Medical Sciences, Kashan, Iran (M.S.); Department of Civil Engineering, Sharif University of Technology, Tehran, Iran (A.M.); Department of Rabies, Virology Research Group (S.K.) and Department of Nanobiotechnology, New Technologies Research Group (R.A.C.), Pasteur Institute of Iran, Tehran, Iran; and Department of Biology, School of Basic Science, Science and Research Branch, Islamic Azad University, Tehran, Iran (A.V., E.K.)
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Alireza Vafabakhsh
Department of Genetics and Advanced Medical Technology, Medical Biotechnology Research Center, Faculty of Medicine, AJA University of Medical Sciences, Tehran, Iran (F.K.); Department of Medical Laboratory, Kashan University of Medical Sciences, Kashan, Iran (M.S.); Department of Civil Engineering, Sharif University of Technology, Tehran, Iran (A.M.); Department of Rabies, Virology Research Group (S.K.) and Department of Nanobiotechnology, New Technologies Research Group (R.A.C.), Pasteur Institute of Iran, Tehran, Iran; and Department of Biology, School of Basic Science, Science and Research Branch, Islamic Azad University, Tehran, Iran (A.V., E.K.)
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Elmira Karami
Department of Genetics and Advanced Medical Technology, Medical Biotechnology Research Center, Faculty of Medicine, AJA University of Medical Sciences, Tehran, Iran (F.K.); Department of Medical Laboratory, Kashan University of Medical Sciences, Kashan, Iran (M.S.); Department of Civil Engineering, Sharif University of Technology, Tehran, Iran (A.M.); Department of Rabies, Virology Research Group (S.K.) and Department of Nanobiotechnology, New Technologies Research Group (R.A.C.), Pasteur Institute of Iran, Tehran, Iran; and Department of Biology, School of Basic Science, Science and Research Branch, Islamic Azad University, Tehran, Iran (A.V., E.K.)
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Reza Ahangari Cohan
Department of Genetics and Advanced Medical Technology, Medical Biotechnology Research Center, Faculty of Medicine, AJA University of Medical Sciences, Tehran, Iran (F.K.); Department of Medical Laboratory, Kashan University of Medical Sciences, Kashan, Iran (M.S.); Department of Civil Engineering, Sharif University of Technology, Tehran, Iran (A.M.); Department of Rabies, Virology Research Group (S.K.) and Department of Nanobiotechnology, New Technologies Research Group (R.A.C.), Pasteur Institute of Iran, Tehran, Iran; and Department of Biology, School of Basic Science, Science and Research Branch, Islamic Azad University, Tehran, Iran (A.V., E.K.)
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Abstract

Therapeutic fragmented antibodies show a poor pharmacokinetic profile that leads to frequent high-dose administration. In the current study, for the first time, a novel proline, alanine, serine (PAS) repeat sequence called PAS#208 was designed to extend the plasma half-life of a nanosized anti–vascular endothelial growth factor-A single-domain antibody. Polyacrylamide gel electrophoresis, circular dichroism, dynamic light scattering, and electrophoretic light scattering were used to assess the physicochemical properties of the newly designed PAS sequence. The effect of PAS#208 on the biologic activity of a single-domain antibody was studied using an in vitro proliferation assay. The pharmacokinetic parameters, including terminal half-life, the volume of distribution, elimination rate constant, and clearance, were determined in mice model and compared with the native protein and PAS#1(200) sequence. The novel PAS repeat sequence showed comparable physicochemical, biologic, and pharmacokinetic features to the previously reported PAS#1(200) sequence. The PAS#208 increased the hydrodynamic radius and decreased significantly the electrophoretic mobility of the native protein without any change in zeta potential. Surprisingly, the fusion of PAS#208 to the single-domain antibody increased the binding potency. In addition, it did not alter the biologic activity and did not show any cytotoxicity on the normal cells. The PAS#208 sequence improved the terminal half-life (14-fold) as well as other pharmacokinetic parameters significantly. The simplicity as well as superior effects on half-life extension make PAS#208 sequence a novel sequence for in vivo pharmacokinetic enhancement of therapeutic fragmented antibodies.

Significance Statement In the current study, a new proline, alanine, serine (PAS) sequence was developed that showed comparable physicochemical, biological, and pharmacokinetic features to the previously reported PAS#1(200) sequence. The simplicity as well as superior effects on half-life extension make PAS#208 sequence a novel sequence for in vivo pharmacokinetic enhancement of recombinant small proteins.

Footnotes

    • Received March 23, 2020.
    • Accepted July 10, 2020.
  • This project was financially supported by a grant from Iran National Science Foundation [Grant 97000450].

  • The authors declare there is no conflict of interest.

  • https://doi.org/10.1124/jpet.120.000012.

  • Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 375 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 375, Issue 1
1 Oct 2020
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Research ArticleCellular and Molecular

New PAS Repeat Sequence for Pharmacokinetic Enhancement

Farnaz Khodabakhsh, Morteza Salimian, Ardavan Mehdizadeh, Mohammad Sadeq Khosravy, Alireza Vafabakhsh, Elmira Karami and Reza Ahangari Cohan
Journal of Pharmacology and Experimental Therapeutics October 1, 2020, 375 (1) 69-75; DOI: https://doi.org/10.1124/jpet.120.000012

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Research ArticleCellular and Molecular

New PAS Repeat Sequence for Pharmacokinetic Enhancement

Farnaz Khodabakhsh, Morteza Salimian, Ardavan Mehdizadeh, Mohammad Sadeq Khosravy, Alireza Vafabakhsh, Elmira Karami and Reza Ahangari Cohan
Journal of Pharmacology and Experimental Therapeutics October 1, 2020, 375 (1) 69-75; DOI: https://doi.org/10.1124/jpet.120.000012
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