Microbiomes in One Health – Doctoral Training Unit
P4: Development of a novel complement-directed strategy using multimeric immunoconjugates that elicit complement activation towards multi-drug resistant P. aeruginosa
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- P4: Development of a novel complement-directed strategy using multimeric immunoconjugates that elicit complement activation towards multi-drug resistant P. aeruginosa
Principal Investigator Carole Devaux
Host Institution LIH
Project Research Question: Is complement directed cytotoxicity or Antibody Dependent Cell-mediated Cytotoxixity efficient enough to kill multi-drug resistant P. aeruginosa?
Abstract
Pseudomonas aeruginosa (P. aeruginosa) is a Gram-negative bacterium that chronically colonizes the airways of patients with COPD and cystic fibrosis, provokes acute exacerbations and is often the causative agent in severe hospital-acquired infections. Due to the multi-resistance of this bacterial strain to antibiotics, new therapeutic approaches are urgently needed. P. aeruginosa is known to bind factor H (FH), thus escaping from host complement-dependent cytotoxicity (CDC). Factor H is essential to support P. aeruginosa survival, and its survival increased in a factor H dose-dependent manner. We previously developped multimeric immunoconjugates displaying a multivalent expression of “complement factor H-related protein 4” (FHR4) to compete with FH binding, combined to a targeting function to activate selectively the complement alternative pathway (CAP) at the surface of tumour cells. We propose here to develop novel FHR4-multimers eliciting complement directed cytotoxicity (CDC) and/or Antibody Dependent Cell-mediated Cytotoxixity (ADCC) on P. aeruginosa using a multivalent scFv targeting moiety derived from the Panobacumab IgM mAb. We will evaluate in vitro and in vivo in a mouse model the therapeutic efficacy of these immunoconjugates, compared to the IgM reference mAb. We will determine the multimer-mediated CDC, ADCC, phagocytosis in a model of bacterial infection by P. aeruginosa.
Methods
Generation of the lead multimeric immunoconjugates displaying multivalent (i) FHR4 effector function for CAP-activation, (ii) multiple Fc-dimers and (iii) the Panobacumab-derived scFv targeting moiety
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In vitro study of the biological function of the multimeric immunoconjugates on aeruginosa
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ADCC, CDC, ADCP, CDCP
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In vivo study of the therapeutic efficacy of the multimeric immunoconjugates in mice. Reduction of bacterial load of acute pneumonia lung infection, compared to the reference Panobacumab mAb