Development of Human Monoclonal Antibodies Capable of Blocking Voltage-Dependent Potassium Channels (Kv1.3 and Kv2.1): Innovation for Diabetes Treatment

• Grant number: 24/13258-0
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: December 01, 2024
• End date: March 31, 2028
• Field of knowledge: Engineering - Biomedical Engineering - Bioengineering
• Principal Investigator: Manuela Berto Pucca
• Grantee: Eloise Trostdorf Monteiro Filardi
• Host Institution: Faculdade de Ciências Farmacêuticas (FCFAR). Universidade Estadual Paulista (UNESP). Campus de Araraquara. Araraquara , SP, Brazil

Abstract

The urgent need for new therapeutic strategies to treat diabetes, an ongoing, debilitating condition with widespread global prevalence, is well established. Previous research has highlighted the potential of toxins from the scorpion Tityus serrulatus to inhibit specific potassium channels, such as Kv1.3 and Kv2.1, which play crucial roles in regulating immune response and insulin secretion. This project aims to advance this research by developing human monoclonal antibody fragments targeting these channels, utilizing Phage Display technology.To achieve this, synthetic peptides with amino acid sequences resembling those of the Kv1.3 and Kv2.1 channels (specifically the pore region) will be synthesized and used to select antibody phages. Following the selection and production of these antibody fragments, their neutralizing capabilities will be assessed both in vitro and in vivo. In the in vitro phase, the ability of the selected antibodies to block these channels will be tested in Xenopus laevis oocytes. The immunosuppressive effects will be evaluated through assays measuring the proliferation and function of CD4+ naive, central memory, and effector memory T cells isolated from the spleens of mice treated with the antibodies. Additionally, the function of pancreatic cells will be assessed using human Langerhans islet cells. In the in vivo phase, the antibodies will be tested in animal models of type 1 and type 2 diabetes. This will involve measuring hemoglobin A1c, insulin levels, and cytokines, as well as performing histological analyses of the pancreas. This approach is based on robust scientific evidence and offers the potential to develop an innovative therapy that could significantly transform the treatment of type 1 and type 2 diabetes, potentially moving beyond current palliative options to seek a curative solution.

Scientific publications

(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)

NATTRODT, JANIO J. M.; BEZERRA-DE-FREITAS, VICTORIA A.; MERVAL, ANA PAULA S. S.; FILARDI, ELOISE T.; CERNI, FELIPE A.; DANTAS, DOMINGOS S. M.; LINS, ALYSSON B. M.; GALAN, LUIS E. B.; CARBONELL, ROBERTO C.; PUCCA, MANUELA B.. Case report: Clinical management of freshwater stingray wounds using negative pressure therapy. FRONTIERS IN MEDICINE, v. 12, p. 7-pg., 2025-03-10. (24/13258-0, 24/01801-1)

ROMANAZZI, MARCELA; FILARDI, ELOISE T. M.; PIRES, GEOVANNA M. M.; CERVEJA, MARCOS F.; MELO-DOS-SANTOS, GUILHERME; OLIVEIRA, ISADORA S.; FERREIRA, ISABELA G.; CERNI, FELIPE A.; SANTOS-FILHO, NORIVAL ALVES; MONTEIRO, WUELTON M.; et al. The Versatility of Serine Proteases from Brazilian Bothrops Venom: Their Roles in Snakebites and Drug Discovery. BIOMOLECULES, v. 15, n. 2, p. 25-pg., 2025-02-01. (23/15381-1, 23/11264-0, 24/08990-4, 24/01801-1, 24/13258-0, 20/13176-3)