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Properties of IgG anti-tumor antibodies in IgG-receptor humanized mice

Grant number: 14/23353-9
Support type:Scholarships abroad - Research Internship - Post-doctor
Effective date (Start): February 01, 2015
Effective date (End): January 31, 2016
Field of knowledge:Biological Sciences - Immunology - Cellular Immunology
Principal researcher:José Andrés Yunes
Grantee:Priscila Pini Zenatti
Supervisor abroad: Pierre Bruhns
Home Institution: Centro Infantil de Investigações Hematológicas Dr Domingos A Boldrini (CIB). Campinas , SP, Brazil
Research place: Institut Pasteur, France  
Associated to the scholarship:12/03660-9 - Development of therapeutics monoclonal antibodies against mutant IL7R homodimer in Acute Lymphoblastic Leukemia, BP.PD

Abstract

Overexpression of particular receptors (e.g. receptor tyrosine Kinase HER2) or mutations modifying the function of some receptors (e.g. interleukin-7 receptor IL7R) have been described to stimulate cancer cell growth and in some cases are associated with increased disease recurrence and worse prognosis. Therapeutic IgG antibodies targeting overexpressed or mutated receptors on tumor cells may reduce and even stop tumor growth. Human tumor xenografts in immunodeficient mice have demonstrated the critical role of murine activating IgG Receptors (Fc³R) in this effect. Among the six Fc³Rs expressed in humans, those involved in mediating anti-tumor effects following injection of IgG anti-tumor remain unknown. Likewise, the effector cell population, expressing these Fc³Rs that are mediating this therapeutic activity remains elusive. This project proposes to exploit mice expressing human activating Fc³Rs instead of mouse Fc³R. These models are crossed onto an immunodeficient background (Nude) to allow the engraftment of human breast cancer cells. We propose to identify (1) the most efficient subclass of human IgG anti-tumor antibodies by generating switch variants of anti-HER2 and anti-IL7R antibodies, (2) the human Fc³Rs involved by using blocking reagents specific for each human Fc³R and (3) the Fc³R-expressing effector population responsible for tumor destruction using depleting reagents for given lymphoid or myeloid populations. This project may thus lead to the identification of novel targets among effector cell populations and among human Fc³Rs to ameliorate treatment. (AU)

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