A non-covalent antibody complex for the delivery of anti-cancer drugs.
Eur J Pharm Biopharm
; 142: 49-60, 2019 Sep.
Article
em En
| MEDLINE
| ID: mdl-31201855
ABSTRACT
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 5â¯kDa and a 20â¯kDa PEG, respectively, yielding two monoconjugates with a mass of ≈50 and ≈45â¯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 20â¯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.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Imunoconjugados
/
Anticorpos Monoclonais
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Antineoplásicos
Limite:
Humans
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article