The research of the Group Neri focuses on the development of therapeutic proteins, with a particular emphasis on the isolation and in vivo characterization of antibody-derivatives, capable of selective localization on new blood vessels (e.g., tumor blood vessels). Further research topics of the group include transcriptomic and proteomic studies for the discovery of novel markers of angiogenesis, and the development of encoded self-assembling chemical libraries, as an avenue towards the isolation of non-peptidic high-affinity binding molecules, to be used in targeted therapeutic applications.
Antibody phage technology
[sponsors: ETH Zürich, EU, Philochem]
Advances in Protein Engineering and in combinatorial mutagenesis technologies have made it possible to clone and express repertoires of proteins (e.g., antibody fragments), containing billions of mutants carrying mutations at judiciously chosen aminoacid positions. Consequently, it is possible to raise antibodies against >10 different antigens/week, without immunization. The group Neri has a track record in the construction of human monoclonal antibodies specific to pharmaceutically relevant antigens. Seven derivatives of three antibodies developed by the group Neri are currently investigated in Phase I and Phase II clinical trials, in collaboration with Philogen, Philochem and Bayer-Schering Pharma.
Antibody-based targeting of neo-vasculature [with L. Zardi]
[sponsors: ETH Zürich, Swiss National Science Foundation, EU, Swiss Cancer League, Swiss Bridge Foundation]
Over the last few years, in collaboration with Prof L. Zardi (Genova, Italy), we have validated the alternatively-spliced domains of fibronecin and of tenascin-C as good-quality markers of angiogenesis. We have developed high-affinity human antibodies specific for these domains, which have been tested extensively by immunohistochemistry and by biodistribution studies in animal models.
A number of derivatives of L19 have been developed in the lab (and are continuously being developed), and tested in immunocompetent animal models of angiogenesis related pathologies. These derivatives include antibody conjugated to drugs, photosensitizers, cytokines, radionuclides, pro-coagulant factors. More recently, we have started to apply vascular targeting strategies for the therapy of angiogenesis-related chronic inflammatory conditions (e.g., rheumatoid arthritis).
DNA-encoded chemical libraries (ESACHEL)
[sponsors: ETH Zürich, KTI, Philochem]
Drugs are, in first instance, molecules which modulate the activity of key components of our body named proteins. This modulation is always associated to a physical interaction between the drug and its target protein (“binding”). When pharmaceutical companies hunt for new drugs to treat disease, they typically embark in a “screening campaign”, where large collections of chemical compounds (“chemical libraries”) are individually assayed. These discovery campaigns are not always successful, thus leading to the inability to develop drugs even when suitable target protein for pharmacological intervention would be available. Thus, the identification of specific binding molecules to target proteins of interest remains a central problem in medicinal chemistry, medicine and biology.
DNA-encoded chemical libraries promise to revolutionize the drug discovery process, by allowing the construction and screening of libraries of unprecedented size and quality. In this new methodology, chemical compounds in a chemical library are individually conjugated to short DNA fragments that serve as identification bar codes. In contrast to conventional screening procedures such as high-throughput screening, biochemical assays are not required for binder identification, allowing the isolation of binders to a wide range of proteins that were historically difficult to tackle with conventional screening technologies. The availability of binders to such pharmacologically important, but so-far “undruggable” target proteins promises to facilitate the development of new generations of drugs for diseases that could not be treated thus far. Advances in library construction and in ultra-high-throughput DNA sequencing methodologies are rapidly increasing the performance and applicability of DNA-encoded chemical library technology.
Chemical Proteomics for the discovery of markers of angiogenesis
[sponsors: ETH Zürich, EU]
Our group has developed a general chemical proteomics methodology for the identification of proteins which are readily accessible from the vasculature. The method relies on a covalent biotinylation of vascular proteins by the in vivo perfusion of laboratory animals or the ex vivo perfusion of surgically resected organs from patients, using reactive ester derivatives of biotin. Biotinylated proteins can be efficiently recovered from normal tissues and pathologic specimens (e.g., tumors) by lysis in the presence of strong detergents, followed by capture on streptavidin-sepharose. On-resin tryptic digestion of biotinylated proteins, followed by nano-HPLC separation of eluted peptides and their identification and relative quantification in the presence of internal standards , allows the characterization of atlases of vascular proteins in normal organs and at sites of disease, thus facilitating the discovery of accessible markers of pathology.
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