Improving the developability of an anti-EphA2 single-chain variable fragment for nanoparticle targeting
| Autor: | Alexey Lugovskoy, Rachel Rennard, Dmitri B. Kirpotin, Melissa Geddie, Tad Kornaga, Birgit Schoerberl, James D. Marks, Maja Razlog, Lihui Xu, Neeraj Kohli, Yang Jiao, Daryl C. Drummond |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Immunoconjugates Immunoglobulin Variable Region Nanoparticle protein A binding Protein Engineering 0302 clinical medicine Drug Delivery Systems Immunology and Allergy Nanotechnology Thermostability Cancer Pediatric biology antibody engineering Chemistry Protein Stability Receptor EphA2 Ephrin-A2 Pharmacology and Pharmaceutical Sciences 5.1 Pharmaceuticals 030220 oncology & carcinogenesis Drug delivery liposome Public Health and Health Services manufacturability Development of treatments and therapeutic interventions Receptor Biotechnology Antibody-drug conjugate Immunology Bioengineering antibody fragment EphA2 03 medical and health sciences Affinity chromatography Fragment (logic) Report developability Single-chain variable fragment Animals Humans stability Combinatorial chemistry 030104 developmental biology biology.protein Nanoparticles Immunization Protein A Single-Chain Antibodies |
| Zdroj: | mAbs, vol 9, iss 1 |
| Popis: | Antibody-targeted nanoparticles have great promise as anti-cancer drugs; however, substantial developmental challenges of antibody modules prevent many candidates from reaching the clinic. Here, we describe a robust strategy for developing an EphA2-targeting antibody fragment for immunoliposomal drug delivery. A highly bioactive single-chain variable fragment (scFv) was engineered to overcome developmental liabilities, including low thermostability and weak binding to affinity purification resins. Improved thermostability was achieved by modifying the framework of the scFv, and complementarity-determining region (CDR)-H2 was modified to increase binding to protein A resins. The results of our engineering campaigns demonstrate that it is possible, using focused design strategies, to rapidly improve the stability and manufacturing characteristics of an antibody fragment for use as a component of a novel therapeutic construct. |
| Databáze: | OpenAIRE |
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