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Chimeric anti-hCD73 production and validation of its therapeutic potential in acute lymphoblastic leukemia and other malignancies

Grant number: 19/24228-7
Support type:Scholarships in Brazil - Scientific Initiation
Effective date (Start): August 01, 2020
Effective date (End): July 31, 2021
Field of knowledge:Biological Sciences - Immunology - Applied Immunology
Principal researcher:Priscila Pini Zenatti
Grantee:Gabriella Lima dos Reis
Home Institution: Centro Infantil de Investigações Hematológicas Dr Domingos A Boldrini (CIB). Campinas , SP, Brazil

Abstract

One of the major failures in the treatment of acute lymphoblastic leukemia (ALL) is the relapse process, in which leukemic cells resistant to chemotherapy do not respond to treatment. Currently, new therapeutic approaches have been incorporated into leukemia treatments, contributing to significant progress in the outcome of these malignancies. Targeted therapies, such as the use of monoclonal antibodies (Mab), offer advantages over conventional methods and in combination with chemotherapy or radiotherapy can contribute to a significant improvement in the treatment of various malignancies. One of the subgroups of ALL-B, Philadelphia-like leukemia ("Ph like") occurs in about 10% of children and is related to high rates of post-treatment relapse. A method used to identify ph-like ALL by qRT-PCR, uses 15 marker genes, including NT5E. NT5E encodes the enzyme CD73, an ecto-5'-nucleotidase, which has the ability to hydrolyze extracellular adenosine monophosphate (AMP) into adenosine, a potent immunosuppressant. Therefore, CD73 is an excellent target for the development of specific immunotherapies against several types of cancer, in addition to ALL. In this project, we propose to obtain a chimeric anti-CD73 antibody from an already existing murine antibody in our laboratory. This chimeric antibody is obtained by fusing the murine variable region (VH and VL) of our antibody to the human constant region (CH and CL) of the IgG1 immunoglobulin, which is cloned in plasmid pUC19. If there is time, we propose to verify the therapeutic potential of this antibody in immunodeficient mice (NSG) engrafted with the Daoy cell line. Given the association of CD73 with other tumors, the antibody developed here may be tested in the future in other malignancies as a modulating agent of the tumor microenvironment.

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