Monoclonal antibodies against pediatric Acute Lymphoblastic Leukemia

• Grant number: 21/04137-7
• Support Opportunities: Research Grants - Young Investigators Grants
• Start date: February 01, 2023
• End date: January 31, 2028
• Field of knowledge: Biological Sciences - Immunology - Applied Immunology
• Principal Investigator: Priscila Pini Zenatti Salles
• Grantee: Priscila Pini Zenatti Salles
• Host Institution: Centro Infantil de Investigações Hematológicas Dr Domingos A Boldrini (CIB). Campinas , SP, Brazil
• Associated researchers: Fabio Cesar Gozzo ; Fernando Guimarães ; Giovanna Rosa Degasperi ; José Andrés Yunes ; Pedro Otavio de Campos Lima ; Renata Stripecke ; Thierry Rose
• Associated scholarship(s): 24/07219-2 - Training in handling laboratory mice for use in scientific research, BP.TT; 24/01331-5 - Development of a humanized mice model for the study of humanized anti-IL7R antibodies in the treatment of acute lymphocytic leukemia, BP.MS; 23/11088-8 - Characterization and functional validation of humanized anti-IL7Ra antibody for the treatment of Pediatric Leukemia, BP.DD; 23/11129-6 - Establishment and standardization of the humanization process of the anti-IL-7R therapeutic antibody by the CDR-grafting technique, BP.DD; 23/02754-4 - Training in establishing PDX (patient-derived xenograft) models in mice for research, BP.TT

Abstract

The use of therapeutic monoclonal antibodies has been very efficient against these malignancies and, when used in combination with conventional protocols, has sensitized malignant cells to treatment, resulting in a better response and fewer side effects. A good therapeutic target should be able to lead to the destruction of the malignant cell, causing little or no damage to healthy cells. Thus, we have previously identified that IL7Ra, a protein expressed on the surface of lymphocytes that is responsible for their development and maturation, has oncogenic potential. Approximately 10% of T-ALL and 1% of B-ALL show this protein constitutively activated. In this project, we propose to humanize 3 anti-IL7Ra antibodies for the treatment of acute lymphoid leukemia. We already have preliminary preclinical data that show that the murine versions of these 3 antibodies have great potential to block the progression of leukemia and show a synergistic therapeutic effect when used as a cocktail. The availability of these antibodies for clinical testing has great relevance not only for the treatment of leukemia but also for other diseases in which IL7R signaling pathways play a role. It is expected that protocols for the treatment of leukemia that includes anti-IL7Ra could improve the patients' survival rates compared to current therapies. We also propose to establish and standardize a humanized animal model that will serve as a tool for pre-clinical trials for these reagents and for future research. (AU)