Development of therapeutics monoclonal antibodies against mutant IL7R homodimer in acute lymphoblastic leukemia

• Grant number: 12/03660-9
• Support type: Scholarships in Brazil - Post-Doctorate
• Effective date (Start): June 01, 2012
• Effective date (End): August 31, 2016
• Field of knowledge: Health Sciences - Medicine
• Principal Investigator: José Andrés Yunes
• Grantee: Priscila Pini Zenatti
• Home Institution: Centro Infantil de Investigações Hematológicas Dr Domingos A Boldrini (CIB). Campinas , SP, Brazil
• Associated scholarship(s): 14/23353-9 - Properties of IgG anti-tumor antibodies in IgG-receptor humanized mice, BE.EP.PD

Abstract

The acute lymphoblastic leukemia (ALL) is a leading cause of death in children. We recently described a new mechanism of leukemogenesis found in 9% of pediatric T-ALL patients, caused by activating mutations on the interleukin-7 receptor (IL7R). These mutations, which are exclusive of leukemic cells, lead to the homodimerization and constitutive activation of the alpha chain (IL7Ra) of the IL-7 receptor. In normal cells, the IL7R is a heterodimer of IL7Ra and IL2Rg. Therefore the mutant IL7Ra-IL7Ra homodimer represents a leukemia-specific target for the development of therapeutic monoclonal antibodies (Mabs). The purpose of this project is to generate and test MAbs against mutant IL7R. Balb/c mice will be immunized with cells transduced with the mutant IL7R. Thus the antigen (mutant IL7R) will have all appropriate post-translational modifications (glycosylation, disulfide bonds) and in homodimer configuration, as observed in leukemic cells. MAbs with greater specificity to the mutant IL7R will be tested in vitro for its abilities to inhibiting receptor signaling and cell survival/proliferation, induction of CDC and ADCC, and blocking disease progression in RAG1-/- mice.