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Obtainment and characterization of non-glycosylated recombinant monoclonal antibodies against immune checkpoint to be used as therapeutic molecules against tumors and virus infections diseases

Grant number: 21/04307-0
Support type:Scholarships in Brazil - Master
Effective date (Start): October 01, 2021
Effective date (End): September 30, 2023
Field of knowledge:Health Sciences - Collective Health - Public Health
Principal researcher:Daniela Luz Hessel da Cunha
Grantee:Gabriel Correia Lima
Home Institution: Instituto Butantan. Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil

Abstract

Immune checkpoints are negative regulatory receptors expressed on immune cells. Under normal physiological conditions, its function is to act as a brake for the immune system, maintaining self-tolerance and preventing immunopathologies. However, these molecules also participate in immune escape mechanisms, causing dysfunctions in T-cell populations in a variety of diseases such as cancer and viral infections, including that caused by the SARS-CoV-2 virus. The blocking of these inhibitory receptors with monoclonal antibodies is used as therapy that aims to rescue the activity of chronically depleted effector cells in order to restore the immune system's response. Currently, there are six immune restriction points involved with a viral infection, in addition to already known antitumor immunotherapy, among them, PD-1, LAG-3, and TIM-3 stand out for their involvement with alterations in the T-cell functions in diseases such as HIV, Influenza, hepatitis, and COVID-19. In this context, this project proposes to obtain and characterize recombinant monoclonal antibodies against immune checkpoint blockers PD-1, TIM-3 and LAG-3, from phage display synthetic libraries expressed in E. coli SHuffle, which is genetically adapted for the cytoplasmic expression of non-glycosylated monoclonal antibodies. Such antibodies, after being characterized in terms of their sensitivity and specificity, will be tested alone or together as therapeutic alternatives for activating T lymphocytes in diseases such as cancer and viral infections, including a possible therapy for severe cases of COVID-19. The proposal, therefore, relies on the innovation of obtaining non-glycosylated recombinant antibodies, produced in bacteria, together with therapeutic possibilities against current and future problems, since the selection of antibodies against these immune checkpoint molecules is standardized, whenever necessary test a new checkpoint there will be an established platform for it. (AU)

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