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In-vitro force-based selection of therapeutic antibodies
Immunotherapy is a booming and extremely promising strategy to treat various pathologies. For cancer treatment, it consists in harnessing the immune system against tumour cells. An important therapeutic approach exploits monoclonal antibodies, which recently lead to major improvement of prognosis for several cancers. However, the discovery of efficient therapeutic antibodies is still very empirical and their mechanisms of action are often poorly understood. Moreover, despite their strong potential, these molecules are not efficient for all patients.
Recent fundamental research on antibodies have shown that they are selected in the organism by cells literaly pulling on the bond they make with their target, the antigen. On the other hand, the study of the mechanisms of action has revealed a central role of the antibodies for the recruitment of effector immune cells on tumour cells in order to destroy them. These various biological situations involve mechanical forces and emphasize the role of antibodies as mechanical bridges. We hypothesize that the selection and the efficiency of therapeutic antibodies could be largely improved by taking into account this mechanical dimension, in particular, the way how antigen-antibody bond rupture depends on force, a property which is completely ignored for the discovery of therapeutic antibodies.
The goal of the project is to combine laminar flow chamber using microbeads with filamentous phage display technology to select original single domain antibodies performing optimally under the action of forces. The kinetic properties of these antibodies will be measured using single molecule ligand-receptor force methods based on laminar flow chamber, acoustic force spectroscopy or optical tweezers. Based on this selection, we will construct bispecific antibodies able to recruit and activate innate effector cells to the tumor microenvironment, by targeting low affinity Fc receptors, expressed by NK cells and macrophages, and tumour associated antigens from the HER family, overexpressed in breast cancer. We will test their efficiency to recruit immune effector cells onto model tumour cells under the action of mechanical forces in a new microfluidic Antibody-dependent cell cytotoxicity assay.
The candidate, with a background in experimental biophysics, will work in interaction with two teams collaborating closely within the framework of an Emergence and Innovation grand from the Aix-Marseille University Foundation (AMIDEX). The two partners have a strong interdisciplinary complementarity. Laboratoire Adhésion et Inflammation partner has a unique expertise in measuring single antigen-antibody bond kinetic and designing mechanical assay using microfluidics. CRCM partner (team Therapeutic Antibodies and Immunotargeting) is a national leader in single domain and bispecific antibodies conception using lama antibodies libraries and phage display technology.
Keywords: single-molecule biophysics, drug screening, microfluidics, mechanochemistry, immunotherapy, cell biophysics, optical microscopy.
The funding is for two years, starting October or November 2018.
Candidates should send CV, a motivation letter for the project (1 page) as well as the name of two references to Laurent Limozin (firstname.lastname@example.org, Laboratoire Adhésion et Inflammation) and Patrick Chames (email@example.com, Centre de Recherche en Cancérologie de Marseille) before August 31st 2018.Lire la suite
While a good cover letter makes an explicit connection between how your past experience will help you succeed in the postdoc position, a great cover letter sparks the PI’s interest and ensures they read your CV.