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Polymer Cancerostatics Targeted with an Antibody Fragment Bound via a Coiled Coil Motif: In Vivo Therapeutic Efficacy against Murine BCL1 Leukemia
Author(s) -
Pechar Michal,
Pola Robert,
Janoušková Olga,
Sieglová Irena,
Král Vlastimil,
Fábry Milan,
Tomalová Barbora,
Kovář Marek
Publication year - 2018
Publication title -
macromolecular bioscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.924
H-Index - 105
eISSN - 1616-5195
pISSN - 1616-5187
DOI - 10.1002/mabi.201700173
Subject(s) - conjugate , linker , chemistry , pirarubicin , monoclonal antibody , in vivo , coiled coil , biophysics , cytotoxicity , in vitro , biochemistry , antibody , medicine , biology , immunology , chemotherapy , surgery , mathematical analysis , mathematics , microbiology and biotechnology , computer science , operating system
A BCL1 leukemia‐cell‐targeted polymer–drug conjugate with a narrow molecular weight distribution consisting of an N ‐(2‐hydroxypropyl)methacrylamide copolymer carrier and the anticancer drug pirarubicin is prepared by controlled radical copolymerization followed by metal‐free click chemistry. A targeting recombinant single chain antibody fragment (scFv) derived from a B1 monoclonal antibody is attached noncovalently to the polymer carrier via a coiled coil interaction between two complementary peptides. Two pairs of coiled coil forming peptides (abbreviated KEK/EKE and KSK/ESE) are used as linkers between the polymer–pirarubicin conjugate and the targeting protein. The targeted polymer conjugate with the coiled coil linker KSK/ESE exhibits 4× better cell binding activity and 2× higher cytotoxicity in vitro compared with the other conjugate. Treatment of mice with established BCL1 leukemia using the scFv‐targeted polymer conjugate leads to a markedly prolonged survival time of the experimental animals compared with the treatment using the free drug and the nontargeted polymer–pirarubicin conjugate.