Pegylated Trastuzumab Fragments Acquire an Increased in Vivo Stability but Show a Largely Reduced Affinity for the Target Antigen
| Autor: | Giancarlo Tonon, Annamaria Sandomenico, Giuseppina Focà, Gloria Saccani Jotti, Silvia Scaramuzza, Fabio Selis, Concetta Di Mauro, Menotti Ruvo, Riccardo Sanna, Carla Marra, Annalisa Politano |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Male Receptor ErbB-2 Antibody Affinity Polyethylene Glycols lcsh:Chemistry Rats Sprague-Dawley chemistry.chemical_compound 0302 clinical medicine Trastuzumab lcsh:QH301-705.5 Spectroscopy biology Immunogenicity PEGylation General Medicine 3. Good health Computer Science Applications 030220 oncology & carcinogenesis Antibody pharmacokinetics medicine.drug Proteases pepsin digestion Antineoplastic Agents Polyethylene glycol antibody fragment Catalysis Article Inorganic Chemistry papain digestion 03 medical and health sciences Immunoglobulin Fab Fragments In vivo PEG ratio medicine Animals Humans Fab Physical and Theoretical Chemistry Molecular Biology Organic Chemistry 030104 developmental biology lcsh:Biology (General) lcsh:QD1-999 chemistry Immunology biology.protein Biophysics |
| Zdroj: | International Journal of Molecular Sciences International Journal of Molecular Sciences; Volume 17; Issue 4; Pages: 491 International Journal of Molecular Sciences, Vol 17, Iss 4, p 491 (2016) |
| ISSN: | 1422-0067 |
| Popis: | PEGylation of biomolecules is a major approach to increase blood stream half-life, stability and solubility of biotherapeutics and to reduce their immunogenicity, aggregation potential and unspecific interactions with other proteins and tissues. Antibodies have generally long half-lives due to high molecular mass and stability toward proteases, however their size lowers to some extent their potential because of a reduced ability to penetrate tissues, especially those of tumor origin. Fab or otherwise engineered smaller fragments are an alternative but are less stable and are much less well retained in circulation. We have here investigated the effects of various PEGylations on the binding properties and in vivo half-life of Fab fragments derived from the enzymatic splitting of Trastuzumab. We find that PEGylation increases the half-life of the molecules but also strongly affects the ability to recognize the target antigen in a way that is dependent on the extent and position of the chemical modification. Data thus support the concept that polyethylene glycol (PEG) conjugation on Trastuzumab Fabs increases half-life but reduces their affinity and this is a fine balance, which must be carefully considered for the design of strategies based on the use of antibody fragments. |
| Databáze: | OpenAIRE |
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