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Platforms developing for obtaining and characterizing non-glycosylated recombinant antibodies against the TIM-3 immune checkpoint and evaluating the role of these antibodies in the reactivation of T lymphocytes in tumors

Grant number: 22/04560-0
Support Opportunities:Regular Research Grants
Duration: December 01, 2022 - November 30, 2024
Field of knowledge:Health Sciences - Collective Health - Public Health
Principal Investigator:Daniela Luz Hessel da Cunha
Grantee:Daniela Luz Hessel da Cunha
Host Institution: Instituto Butantan. Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil
Associated researchers:Robson Luis Ferraz do Amaral ; Rodrigo Nalio Ramos

Abstract

Despite significant advances in research, cancer still poses a threat to global health. This disease chronicity and constant antigenic stimulation leads to the differentiation of CD8+ T cells into populations with altered effector functions, a unique epigenetic profile, and high levels of expression of multiple inhibitory receptors. These negative regulatory receptors have the function of serving as brakes for the immune system, maintaining self-tolerance and preventing tissue damage, being expressed in immune cells under normal physiological conditions. However, these molecules also participate in immune system escape mechanisms in the tumors development. Therapies aimed at blocking these molecules are attractive in the treatment of various tumor types. In this context, immunotherapy emerged using monoclonal antibodies to block receptors such as TIM-3, thus restoring the ability of exhausted T cells to eliminate tumors and viruses. However, to date, despite efforts, the immune response of many patients to immunotherapy reaches a maximum of 40%. The development of recombinant antibodies whose synthesis and production are versatile and diversified, represents the possibility of obtaining new and differentiated molecules which act in the reversal of the condition of T cells exhaustion and that can significantly increase the immunotherapy efficiency, the expression in the microbial system also proposes a faster and lower cost alternative in the production of these specific antibodies. In this context, the project's main objective is to search for new blockers against the immune control receptor TIM-3, from selection by phage display, using a synthetic human antibody library and its subsequent prokaryotic expression in E. coli SHuffle strain, genetically adapted for cytoplasmic non-glycosylated monoclonal antibodies expression. Such antibodies, after characterized for their sensitivity and specificity, will be evaluated for their ability to reactivate T lymphocytes using new in vitro tumor models, with 3D culture and spheroids, in addition to animal models. The present proposal, therefore, consists of an innovation in the development of a platform for obtaining non-glycosylated recombinant antibodies, produced in bacteria against this receptor, opening new therapeutic possibilities against current and future problems, since, once standardized, this platform will be able to extend to other receptors or targets, allowing a significant advance in obtaining immunotherapeutics. (AU)

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