Establishment and standardization of the humanization process of the anti-IL-7R therapeutic antibody by the CDR-grafting technique

• Grant number: 23/11129-6
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Start date: September 01, 2023
• End date: January 31, 2028
• Field of knowledge: Biological Sciences - Immunology - Applied Immunology
• Principal Investigator: Priscila Pini Zenatti Salles
• Grantee: Joey Ramone Ferreira Fonseca
• Host Institution: Centro Infantil de Investigações Hematológicas Dr Domingos A Boldrini (CIB). Campinas , SP, Brazil
• Associated research grant: 21/04137-7 - Monoclonal antibodies against pediatric Acute Lymphoblastic Leukemia, AP.JP

Abstract

Acute lymphoblastic leukemia (ALL) is a type of malignant hematological neoplasm, frequent in children and characterized by overproduction of blasts in the bone marrow and extramedullary regions. Somatic mutations in exon 6 of the IL-7Ra gene are related to the leukemogenesis process and are expressed in approximately 9% of patients with T-ALL. Anti-IL7R murine monoclonal antibodies, called hIL7R#55 and hIL7R#69 (hereinafter, mAb#55 and mAb#69, respectively) obtained in our research group, from the hybridoma technology, recognize the IL7 receptor both in its wild-type (WT) conformation, as a mutant and show therapeutic potential against ALL, both in vitro and in vivo in PDX models. However, these 100% murine antibodies can lead to the development of a disease called HAMA (human anti-murine antibodies) in approximately 50 to 80% of patients after a single dose of treatment. The antibody humanization process reduces the murine portions of the antibody sequence to 3% and, consequently, makes it less immunogenic. The humanization process called antibody CDR-Grafting basically consists of transplanting the 3 CDRs sequences (Complementarity Determining Region) of the murine antibody to sequences of a framework of a human antibody. For this project, we propose to establish and standardize the humanization process of two murine antibody clones with therapeutic potential against pediatric ALL. (AU)