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Multivalent recombinant agents directed against oncogenic receptor tyrosine kinases as novel tools for targeted tumor therapy
Plückthun's laboratory at the UZH offers opportunity for MSc thesis or internship in the area of drug design of antibody-like therapeutics for treatment of cancers expressing oncogenic receptors. A generic tumor-targeting platform will be developed by applying novel approaches of protein engineering
Keywords: Tumor targeting
Protein engineering
Drug design
Bispecific antibodies
DARPins
Recombinant therapeutics
Precision medicine
Biochemistry
Molecular biology
Cell biology
Receptor tyrosine kinases (RTKs) are frequently overexpressed and hyperactivated on the plasma membranes of cancer cells. Such a pathological overexpression drives cancer cell survival and proliferation, as well as epithelial mesenchymal transition (EMT) of primary tumor cells, thereby promoting aggressive tumor growth, formation of metastases and development of acquired resistance to cancer therapy. Therefore, targeted tumor therapy aimed at disengaging of the hyperactivated RTKs holds the promise to substitute, or at least significantly potentiate, the conventional anti-tumor therapeutic approaches. In principle, this is expected to result in an improvement of both therapeutic index and the efficacy of treatment leading, ideally, to a complete eradication of tumor cells. Nevertheless, antibody-based monotherapy still suffers from limited efficacy and rapid emergence of acquired resistance to the treatment, most notably in solid tumors. Moreover, their production is expensive, and the limited stability and tendency to aggregate makes the production of many antibody fragments and, in particular, of advanced antibody fusion proteins with therapeutic protein domains rather difficult. Therefore, complementary approaches are needed.
In our laboratory, we have developed technological platform utilizing synthetic libraries of Designed Ankyrin Repeat Proteins (DARPins). They show high affinities for their targets, outstanding biophysical properties, wide possible range of targets and can be manufactured at low cost and in large amounts in bacteria. Moreover, DARPins provide a complete freedom in the geometric arrangement of their different binding sites, thereby allowing new options for inducing conformational changes in their targets, far beyond what is possible with monoclonal antibodies. By this means, a truly efficient blockade of a single receptor or even pan-inhibition of a given RTK family can be achieved, which is essential to achieve maximum cytotoxic activity while keeping the adverse side effects low. Thus, DARPins have the potential to complement and substitute antibodies in a number of therapeutic applications. Over the last few years, we have selected binders for a variety of oncogenic RTKs (EGFR, HER2, HER3, MET, AXL, PDGFR, IGFR1, RET, ROR and many others). These novel tumor antigen binders represent a unique discovery tool to study the function of RTKs in context of relevant oncogenic networks and, in particular, will pave the way for development of truly efficient cancer therapeutics to be used in personalized and precision medicine.
Receptor tyrosine kinases (RTKs) are frequently overexpressed and hyperactivated on the plasma membranes of cancer cells. Such a pathological overexpression drives cancer cell survival and proliferation, as well as epithelial mesenchymal transition (EMT) of primary tumor cells, thereby promoting aggressive tumor growth, formation of metastases and development of acquired resistance to cancer therapy. Therefore, targeted tumor therapy aimed at disengaging of the hyperactivated RTKs holds the promise to substitute, or at least significantly potentiate, the conventional anti-tumor therapeutic approaches. In principle, this is expected to result in an improvement of both therapeutic index and the efficacy of treatment leading, ideally, to a complete eradication of tumor cells. Nevertheless, antibody-based monotherapy still suffers from limited efficacy and rapid emergence of acquired resistance to the treatment, most notably in solid tumors. Moreover, their production is expensive, and the limited stability and tendency to aggregate makes the production of many antibody fragments and, in particular, of advanced antibody fusion proteins with therapeutic protein domains rather difficult. Therefore, complementary approaches are needed. In our laboratory, we have developed technological platform utilizing synthetic libraries of Designed Ankyrin Repeat Proteins (DARPins). They show high affinities for their targets, outstanding biophysical properties, wide possible range of targets and can be manufactured at low cost and in large amounts in bacteria. Moreover, DARPins provide a complete freedom in the geometric arrangement of their different binding sites, thereby allowing new options for inducing conformational changes in their targets, far beyond what is possible with monoclonal antibodies. By this means, a truly efficient blockade of a single receptor or even pan-inhibition of a given RTK family can be achieved, which is essential to achieve maximum cytotoxic activity while keeping the adverse side effects low. Thus, DARPins have the potential to complement and substitute antibodies in a number of therapeutic applications. Over the last few years, we have selected binders for a variety of oncogenic RTKs (EGFR, HER2, HER3, MET, AXL, PDGFR, IGFR1, RET, ROR and many others). These novel tumor antigen binders represent a unique discovery tool to study the function of RTKs in context of relevant oncogenic networks and, in particular, will pave the way for development of truly efficient cancer therapeutics to be used in personalized and precision medicine.
The monovalent DARPins can serve as building blocks for generation of variety of multivalent binding reagents that affect the function of tumor-driving RTKs and, consequently, possess pleiotropic effects on the growth, survival and other cancerous phenotypes of tumor cells. This tumor targeting strategy represents a novel rational approach to engineer tumor cell-specific cytotoxicity based on a structurally and mechanistically understood principle. The high tumoricidal effects are achieved by structural and spatial receptor lockdown yielding disengaged RTK pairs as well as enforcement of inactive receptor conformations and geometries, or both.
The goal of this project is to further develop the multispecific tumor targeting platform for use in tumor fingerprinting as well as in drug lead identification and target validation, employing high-throughput flow cytometry and high-content microscopy in conjunction with other state-of-the-art techniques used for protein design and cell profiling. With a defined set of monoclonal antibody and DARPin binders against selected RTKs, new approaches of design of cancer therapeutics will be explored to create multipotent molecules retaining not only strong anti-tumor activity against selected oncogenic targets, but also possessing a build-in function to prevent emergence of drug resistance. Altogether, this concept forms a base for prospective therapeutic leads as well as for novel discovery tools in cancer research.
The monovalent DARPins can serve as building blocks for generation of variety of multivalent binding reagents that affect the function of tumor-driving RTKs and, consequently, possess pleiotropic effects on the growth, survival and other cancerous phenotypes of tumor cells. This tumor targeting strategy represents a novel rational approach to engineer tumor cell-specific cytotoxicity based on a structurally and mechanistically understood principle. The high tumoricidal effects are achieved by structural and spatial receptor lockdown yielding disengaged RTK pairs as well as enforcement of inactive receptor conformations and geometries, or both. The goal of this project is to further develop the multispecific tumor targeting platform for use in tumor fingerprinting as well as in drug lead identification and target validation, employing high-throughput flow cytometry and high-content microscopy in conjunction with other state-of-the-art techniques used for protein design and cell profiling. With a defined set of monoclonal antibody and DARPin binders against selected RTKs, new approaches of design of cancer therapeutics will be explored to create multipotent molecules retaining not only strong anti-tumor activity against selected oncogenic targets, but also possessing a build-in function to prevent emergence of drug resistance. Altogether, this concept forms a base for prospective therapeutic leads as well as for novel discovery tools in cancer research.
Laboratory of Prof. Dr. Andreas Plückthun, PhD
Department of Biochemistry
University of Zurich
Winterthurerstr. 190
8057 Zürich
Supervisor: Dr. Rastislav Tamaskovic, PhD
Lab: 44-M-76, +41
Phone: 044 635 65 68
E-mail: r.tamaskovic@bioc.uzh.ch
Laboratory of Prof. Dr. Andreas Plückthun, PhD Department of Biochemistry University of Zurich Winterthurerstr. 190 8057 Zürich