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 Opportunities: Scholarships in Brazil - Master
• Start date: October 01, 2021
• End date: July 31, 2023
• Field of knowledge: Health Sciences - Collective Health - Public Health
• Principal Investigator: Daniela Luz Hessel da Cunha
• Grantee: Gabriel Correia Lima
• Host 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)

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)

LIMA, G. C.; CHURA-CHAMBI, R. M.; MORGANTI, L.; SILVA, V. J.; CABRAL-PICCIN, M. P.; ROCHA, V.; MEDINA, T. S.; RAMOS, R. N.; LUZ, D.. Recombinant human TIM-3 ectodomain expressed in bacteria and recovered from inclusion bodies as a stable and active molecule. FRONTIERS IN BIOENGINEERING AND BIOTECHNOLOGY, v. 11, p. 11-pg., 2023-07-31. (22/04560-0, 18/14034-8, 21/04307-0)