A non-covalent antibody complex for the delivery of anti-cancer drugs
| Autor: | Isabella Monia Montagner, Katia Maso, Antonella Grigoletto, Oddone Schiavon, Gianfranco Pasut, Antonio Rosato |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Immunoconjugates
Receptor ErbB-2 medicine.drug_class Pharmaceutical Science Antineoplastic Agents 02 engineering and technology Monoclonal antibody 030226 pharmacology & pharmacy Jurkat Cells 03 medical and health sciences Drug Delivery Systems 0302 clinical medicine Antigen Antibody-drug conjugates PEGylation anticancer therapy drug delivery Cell Line Tumor medicine Humans Cytotoxic T cell biology Chemistry Antibodies Monoclonal General Medicine Trastuzumab 021001 nanoscience & nanotechnology Biochemistry Drug delivery biology.protein Protein G Antibody Rituximab 0210 nano-technology Protein A Biotechnology |
| Zdroj: | European Journal of Pharmaceutics and Biopharmaceutics. 142:49-60 |
| ISSN: | 0939-6411 |
| Popis: | Antibody drug conjugates (ADCs), which are obtained by coupling a potent cytotoxic agent to a monoclonal antibody (mAb), are traditionally bound in a random way to lysine or cysteine residues, with the final product’s heterogeneity having an important impact on their activity, characterization, and manufacturing. A new antibody drug delivery system (ADS) based on a non-covalent linkage between a Fc-binding protein, in this case Protein A or Protein G, and a mAb was investigated in the effort to achieve greater homogeneity and to create a versatile and adaptable drug delivery system. Recombinant staphylococcal Protein A and streptococcal Protein G were chemically PEGylated at the N-terminus with a 5 kDa and a 20 kDa PEG, respectively, yielding two monoconjugates with a mass of ≈50 and ≈45 kDa. Circular dichroism studies showed that both conjugates preserved secondary structures of the protein, and isothermal titration calorimetry experiments demonstrated that their affinity for mAb was approximately 107 M−1. Upon complexation with a mAb (Trastuzumab or Rituximab), in vitro flow-cytometry analysis of the new ADSs showed high selectivity for the specific antigen expressing cells. In addition, the ADS complex based on Trastuzumab and Protein G, conjugated with a heterobifunctional 20 kDa PEG carrying the toxin Tubulysin A, had a marked cytotoxic effect on the cancer cell line overexpressing the HER2/neu receptor, thus supporting its application in cancer therapy. |
| Databáze: | OpenAIRE |
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