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Construction of chemically defined antibody-drug conjugates using carbonylacrylic reagents

Grant number: 17/13168-8
Support type:Scholarships abroad - Research Internship - Post-doctor
Effective date (Start): December 01, 2017
Effective date (End): November 30, 2018
Field of knowledge:Physical Sciences and Mathematics - Chemistry
Principal Investigator:Márcio Weber Paixão
Grantee:Barbara Bernardim de Souza
Supervisor abroad: Gonçalo José Lopes Bernardes
Home Institution: Centro de Ciências Exatas e de Tecnologia (CCET). Universidade Federal de São Carlos (UFSCAR). São Carlos , SP, Brazil
Local de pesquisa : University of Cambridge, England  
Associated to the scholarship:16/18771-1 - Total synthesis of anticancer pseudo-peptide tubulysin: application to the construction of chemically defined antibody-drug conjugates, BP.PD


Common chemotherapeutic agents available in traditional anti-cancer treatments require administration at near the maximum tolerated dosage, lacking tumor selectivity and killing of proliferating normal cells. A recent class of therapy with considerable promise in the treatment of various cancers is the selective targeting of cytotoxic drugs to tumours by conjugating the drug to specific antibodies. This antibody-drug conjugate (ADC) therapy is able to deliver a particularly toxic drug molecule that is conventionally excluded from use in chemotherapy directly to a target with minimal "off-target" toxicity. Studies demonstrated that first and second generation ADCs usually suffered from premature cleavage of the drug from the antibody, thus leading to associated toxicity. In addition, most of these ADCs were build using non-specific conjugations technologies resulting in poor pharmacokinetics and efficacy. Indeed, ADCs built with precise drug-to-antibody ratio(s) through the use site-specific methods have showed a significant improvement in efficacy. In this way, there is a considerable and progressive interest in the development of efficient methods for the preparation of ADCs in a site-specific fashion, controlling the ratio of drug to antibody. In this project, we propose to build stable ADCs with defined chemical properties based on drugs such as tubulysin, epoxomicin, carfilzomib and auristatin E using a bioconjugation protocol recently described by the group of Dr. Bernardes (University of Cambridge, UK). The drugs epoxomicin and carfilzomib were synthesized in the group of Prof. Dr. Márcio Paixão group (UFSCar). (AU)

Scientific publications (4)
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
HAKALA, TUULI A.; DAVIES, SARAH; TOPRAKCIOGLU, ZENON; BERNARDIM, BARBARA; BERNARDES, GONCALO J. L.; KNOWLES, TUOMAS P. J. A Microfluidic Co-Flow Route for Human Serum Albumin-Drug-Nanoparticle Assembly. CHEMISTRY-A EUROPEAN JOURNAL, v. 26, n. 27 APR 2020. Web of Science Citations: 0.
LINDSTEDT, PHILIP R.; APRILE, FRANCESCO A.; MATOS, MARIA J.; PERNI, MICHELE; BERTOLDO, JEAN B.; BERNARDIM, BARBARA; PETER, QUENTIN; JIMENEZ-OSES, GONZALO; KNOWLES, TUOMAS P. J.; DOBSON, CHRISTOPHER M.; CORZANA, FRANCISCO; VENDRUSCOLO, MICHELE; BERNARDES, GONCALO J. L. Enhancement of the Anti-Aggregation Activity of a Molecular Chaperone Using a Rationally Designed Post-Translational Modification. ACS CENTRAL SCIENCE, v. 5, n. 8, p. 1417-1424, AUG 28 2019. Web of Science Citations: 1.
MATOS, MARIA J.; NAVO, CLAUDIO D.; HAKALA, TUULI; FERHATI, XHENTI; GUERREIRO, ANA; HARTMANN, DAVID; BERNARDIM, BARBARA; SAAR, KADI L.; COMPANON, ISMAEL; CORZANA, FRANCISCO; KNOWLES, TUOMAS P. J.; JIMENEZ-OSES, GONZALO; BERNARDES, GONCALO J. L. Quaternization of Vinyl/Alkynyl Pyridine Enables Ultrafast Cysteine-Selective Protein Modification and Charge Modulation. ANGEWANDTE CHEMIE-INTERNATIONAL EDITION, v. 58, n. 20, p. 6640-6644, MAY 13 2019. Web of Science Citations: 1.
BERNARDIM, BARBARA; MATOS, MARIA J.; FERHATI, XHENTI; COMPANON, ISMAEL; GUERREIRO, ANA; AKKAPEDDI, PADMA; BURTOLOSO, ANTONIO C. B.; JIMENEZ-OSES, GONZALO; CORZANA, FRANCISCO; BERNARDES, GONCALO J. L. Efficient and irreversible antibody-cysteine bioconjugation using carbonylacrylic reagents. Nature Protocols, v. 14, n. 1, p. 86-99, JAN 2019. Web of Science Citations: 2.

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