ena-STUDY-GATC BIOTECH AG-20-02-2017-10:50:36:526-685
To develop a human monoclonal antibody based passive immunization against fast emerging multi-drug resistant Klebsiella infections that are associated with high lethality in hospitals. To identify patients for the therapy, quick companion diagnostics.
Diagnostic antibodies against the relevant serotypes have been developed. To date, a panel of over 250 clinical isolates has been serotyped immunologically. Besides gaining information on the serotype distribution among multi-drug resistant Klebsiella, this work has led to the identification of two important novel O-types by the consortium. These serve as basis of ongoing patent applications and scientific publications. Genetic serotyping is being established using whole genome sequences as well as the sequencing of O-antigen determining loci in clinical isolates. NMR based serotyping was also validated. In terms of therapeutic mAbs, murine hybridomas generated against the most important serotypes were expressed as human IgG1 chimeras allowing efficacy testing. Selected chimeric mAbs were subjected to humanization in case of O1 and O2 mAbs (i.e. those against the most common serotypes). From the human B-cell platform mAb against all relevant specificities were identified and were or will be expressed. All in vitro and in vivo assay required to access efficacy have been setup. Characterization of the chimeric or humanized mAbs as well as the fully human antibodies in order to select development leads is currently ongoing. The supportive research activities mainly focus on the characterization of the novel serotypes identified, genetic background for identified O-antigen modifications, and epitope mapping for the selected antibodies, as well as the nature of the immune response against specific Klebsiella O-types.
Diagnostic antibodies against the relevant serotypes have been developed. To date, a panel of over 250 clinical isolates has been serotyped immunologically. Besides gaining information on the serotype distribution among multi-drug resistant Klebsiella, this work has led to the identification of two important novel O-types by the consortium. These serve as basis of ongoing patent applications and scientific publications. Genetic serotyping is being established using whole genome sequences as well as the sequencing of O-antigen determining loci in clinical isolates. NMR based serotyping was also validated. In terms of therapeutic mAbs, murine hybridomas generated against the most important serotypes were expressed as human IgG1 chimeras allowing efficacy testing. Selected chimeric mAbs were subjected to humanization in case of O1 and O2 mAbs (i.e. those against the most common serotypes). From the human B-cell platform mAb against all relevant specificities were identified and were or will be expressed. All in vitro and in vivo assay required to access efficacy have been setup. Characterization of the chimeric or humanized mAbs as well as the fully human antibodies in order to select development leads is currently ongoing. The supportive research activities mainly focus on the characterization of the novel serotypes identified, genetic background for identified O-antigen modifications, and epitope mapping for the selected antibodies, as well as the nature of the immune response against specific Klebsiella O-types.