3 years ago

Polymer Cancerostatics Targeted with an Antibody Fragment Bound via a Coiled Coil Motif: In Vivo Therapeutic Efficacy against Murine BCL1 Leukemia

Polymer Cancerostatics Targeted with an Antibody Fragment Bound via a Coiled Coil Motif: In Vivo Therapeutic Efficacy against Murine BCL1 Leukemia
Barbora Tomalová, Vlastimil Král, Michal Pechar, Marek Kovář, Irena Sieglová, Robert Pola, Olga Janoušková, Milan Fábry
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. Synthesis of actively targeted N-(2-hydroxypropyl)methacrylamide copolymer with an anticancer drug pirarubicin is described. Recombinant targeting fragment derived from B1 monoclonal antibody is attached to the polymer drug conjugate via a coiled coil peptide linker. The targeted polymer conjugate exhibits significantly better therapeutic efficacy against murine BCL1 leukemia in vivo than both the free drug and the nontargeted polymer conjugate.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1002/mabi.201700173

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