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• W2912642433 abstract "Monoclonal antibodies (mAbs) are extensively used in several therapeutic fields and in particular are used against cancer as therapeutic entity and/or targeting agents. The last application belongs to the several strategies to promote selective drug delivery in order to spare healthy tissues from unspecific toxicities of invasive therapies, as anticancer treatments, and to improve final clinical outcomes. Among all, targeted therapy includes antibody-drug conjugates (ADCs) approach, which exploit the synergic action of potent cytotoxic agents conjugated to a monoclonal antibody (mAb) coupled by specific linkers. The antibody acts as drug-carrier and targeting agent, and eventually also as a drug per se, in order to selectively kill cancer cells. As single therapeutic agents, both mAbs and highly cytotoxic drugs present critical issues in their clinical use. mAbs usually have to be used in combination therapy with other drugs because the majority of them show an insufficient, although specific, clinical response. On the other hand, chemotherapeutic drugs, especially the very potent ones, have a narrow therapeutic window and, therefore, their therapeutic doses are close to the maximum tolerated dose. Consequently, they present heavy side effects owing to the lack of tumour cells selectivity. The bright idea to combine mAbs and cytotoxic drugs in a unique entity offers the possibility to overcome their limitations. Traditionally, drugs have been coupled in a random way to lysine or cysteine residues, and the final product heterogeneity unfortunately has relevant impact on ADC activity, characterization and manufacturing, thus affecting the efficacy of the therapy. In an era in which product homogeneity and batch-to-batch reproducibility are essential pre-requisites for pharmaceutics, the development of new technologies for site-directed coupling have become a primary focus. New methodologies for site-specific conjugation are now widely investigated, and some example are the introduction of cysteine residues using site-directed mutagenesis, the use of enzymes, the insertion of un-natural amino acids and the conjugation to Fc N-Glycans. Nevertheless, such approaches require a specific development of each new ADC, thus offering few opportunities of know-how sharing between different projects, in fact these are often limited to the linker stability and the drug activity.In this work, a new construct for the delivery of active drugs has been proposed based on mAbs non-covalently interacting with a Fc-binding moiety (FcBM) that carries also the drugs. The aim is to achieve a higher degree of homogeneity and create a versatile and adaptable drug delivery system. Drug is not linked directly to the FcBM but through a linker constituted of a linear PEG chain. The drug-PEG-FcBM/antibody systems, from here called Antibody-Drug Systems (ADSs), present some advantages with respect to ADCs: they can be a versatile platform with which different mAbs can be used by simple mixing on demand with a drug-Fc binding module on the basis of the target tumour/disease to be treated. FcBM is the core of the system and must present unique binding properties for the Fc of antibodies. In this work, Protein G (22.8 kDa), a bacterial Fc binding receptor, and a goat Fab’ (≈ 50 kDa) against human Fc were tested as FcBM candidate, while a PEG chain was selected as linker for drug/dye attachment. Protein G was selectively PEGylated at the N-terminus with a PEG 20kDa, while Fab’ was mono-, bi- and tri-PEGylated with a PEG 5 kDa after the reduction of the sulfhydryl bridges at the hinge region of the progenitor F(ab’)2. Circular dichroism studies showed that the conjugates preserved protein secondary structure and isothermal titration calorimetry experiments determined that their affinity for Fc is about 107-108 M-1. After the complexation with a model mAb (Trastuzumab or Rituximab), NIR labelled ADSs were tested in vitro by cytometry analysis showing a high selectivity for antigen expressing cells. Furthermore, when a FcBM is conjugated to labelling molecule instead of a drug it would allow the switch from therapeutic application to diagnosis purposes. Tubulysin A (TubA), a potent inhibitor of tubulin polymerisation, was selected as drug model and tethered to the free end of PEG through a disulphide bond. TubA-PEG-Protein G/Trastuzumab ADS showed a preferential cytotoxic activity against the HER2+ cell line (SKBR-3), thus supporting the approach for both diagnostic and therapeutic purposes in cancer. A preliminary biodistribution study was performed in immunodeficient NSG mice, inoculated via subcutaneous injection with IGROV-1 (HER2-) and SKOV-3 (HER2+) tumour cells. Total body scanning showed a very rapid accumulation of Cy5-PEG-Protein G/Trastuzumab within 8 hours from ADS injection. Finally, uptake and intracellular trafficking of an ADS composed by a mouse IgG2a against ICAM-1 and Protein G as FcBM were evaluated in human umbilical vein endothelial cells (HUVECs). HUVECs were stimulated with TNFα to promote the expression of ICAM-1 receptor toward which the ADS was targeted. Fluorescence microscopy was used to follow ADS internalization by endothelial cells. The results disclosed that mechanism of uptake was based on CAM-mediate endocytosis, which relies in the binding between the receptor and anti ICAM-1 antibody. After internalization, the ADS followed the classical pathway toward the lysosomes to be degraded. This proves the possibility to achieve a selective intracellular delivery of active agents through ADS approach and open the way of new applications of this technology." @default.
• W2912642433 created "2019-02-21" @default.
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• W2912642433 date "2018-01-14" @default.
• W2912642433 modified "2023-09-23" @default.
• W2912642433 title "Development of new antibody-drug conjugates based on Fc binding moieties for therapeutic and diagnostic applications" @default.
• W2912642433 hasPublicationYear "2018" @default.
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