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Human monoclonal antibodies (scFv) discovery with cross-reactivity and pH-dependent to metalloproteases from Bothrops spp

Grant number: 20/13176-3
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): October 01, 2021
Effective date (End): September 30, 2023
Field of knowledge:Biological Sciences - Pharmacology - Toxicology
Principal researcher:Eliane Candiani Arantes Braga
Grantee:Isadora Sousa de Oliveira
Home Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Snakebite accidents affect a large number of individuals worldwide, but are prominent in subtropical and tropical countries, causing a large number of deaths, sequelae and deformities. Thus, snakebite was again included in the Neglected Tropical Diseases (NTDs) list in 2017. In Brazil, these accidents are mostly caused by snakes from Bothrops genus (~68% in 2019), which is represented by 27 species distributed throughout the national territory. The venom of this genus is mainly composed of metalloproteases (~30-70%), phospholipases (PLA2, ~7-40%) and serine proteases (~2-24%), varying quantitatively between species. These components make the venoms hemorrhagic, proteolytic and coagulant, characteristics that are responsible for many of their local and systemic manifestations. The treatment for these envenomings is the administration of heterologous antivenom serum, in this case, antibotropic, or mixed sera. However, there are still several disadvantages regarding its use, since they can trigger hypersensitivity reactions, such as anaphylaxis and Serum Disease. Thus, new technologies for antivenom production have become essential for the antivenoms improvement, such as the phage display technique, which allows the selection of fully human antibodies against the most varied antigens. Indeed, this methodology has already been used to produce specific and neutralizing human monoclonal antibodies for different toxins from scorpions, bees and snakes. In the case of Bothrops snakes, only human monoclonal antibodies specific for PLA2 have so far been produced using this technique. However, several preclinical and clinical efforts are still needed so that these new monoclonal antibodies can be commercialized and used as therapy. This research project seeks the selection and production of human monoclonal antibodies of single-chain fragment variable (scFvs) type, through the phage display technique, capable of recognizing and neutralizing metalloproteases from botropic venoms. The project will also produce improved antibodies, that is, they should be pH-depending and cross-reactive for metalloproteases of different botropic species, constituting a new generation antibotropic serum. (AU)

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