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Engineered radionuclide-labelled antibodies

Experimental production of prototype radioimmunology reagents based on engineered antibodies harbouring all desired properties (e.G. Affinity, stability, non-immunogenicity and high levels of labelling) in combination.

The 'magic bullet' concept predicted a long time ago that antibodies would be used to target cancer. Targeted radiotherapy is an appealing approach to cancer treatment because of the potential for delivering curative doses of radiation to tumour while sparing normal tissues. Radionuclides that decay through the emission of alpha-particles such as the heavy halogen astatine-211 (211At), offer the exciting prospect of combining cell-specific molecular targets with radiation having a range in tissue of only a few cell diameters. Among beta-emitters, Yttrium-90 has been described as one of the best radionuclides for tumour therapy when chelated to antibodies. This evaluation is based on the superior properties of this radionuclide (suitable half-life, pure beta-ray emitter of intermediate energy, stable daughter, and suitable chemical properties) and because it is available as a radionuclide generator product by the decay of its 28-yr parent 90Sr. On the antibody side, initial problems that were related to specificity, purity and immunogenicity of antibody-based reagents, have been gradually eliminated due to developments in technology and increased knowledge. After years of pre-clinical and clinical testing, monoclonal antibodies (mAbs) finally offered new therapeutic choices for patients with malignancies as vectors for targeting radionuclides in radio immunotherapy [Illidge T. M. and Brock S. (2000) Radio immunotherapy of Cancer: Using Monoclonal Antibodies to Target Radiotherapy. Current Pharmaceutical Design 6, 1399-1418]. The emergence of recombinant technologies has revolutionised the selection, humanisation and production of antibodies, superseding hybridoma technology and allowing the design of antibody-based reagents of any specificity and high affinity. Engineered antibodies have been reduced in size, rebuilt into multivalent molecules and fused with radionuclides [Carter P. and Merchant M. (1997) Engineering antibodies for imaging and therapy. Curr. Opinion Biotechnol. 8, 449-454]. For example: The reduction of an antibody molecular size (achieved e.g. with the engineering of single chain variable fragments, scFvs) may offer the antibody useful penetration and clearance properties. Humanisation of an engineered antibody originating in a murine mAb may prevent an otherwise invariable development of antimouse antibodies following the initial administration that may thus preclude repeat therapeutic use. However transparent the principles of antibody engineering seem to be, the practical way forward towards a useful engineered antibody-based reagent is rather complicated as a rule: Reduction of the molecular size, humanisation and other desired changes in the antibody structure can be accompanied by losses in their basic properties - affinity and stability. Overcoming such obstacles is generally achieved by empirical ways (e.g. selection of suitable antibody variants from phage display libraries) or by structure-based design (which includes molecular modelling or protein crystallography). One problem is the introduction of the radionuclide atoms with relatively non-detrimental labelling procedures. The aim of this project is to carry out an experimental production of prototype radioimmunology reagents based on engineered antibodies harbouring all desired properties (e.g. affinity, stability, non-immunogenicity and appropriate levels of labelling with a preferred radionuclide) in combination. The work scheme of this project will be as follows: Antibody engineering will be performed at the Department of Recombinant Expression and Structural Biology, INSTITUTE OF MOLECULAR GENETICS (IMG), with an established protein-engineering group also experienced in tailoring antibody molecules. Chosen display-selected or structure-design based engineered antibodies conforming with the criteria of high affinity and stability at physiologic temperature will be supplied to the other Czech participant, NUCLEAR RESEARCH INSTITUTE A.S., for labelling with radionuclides, testing of radiation and storage stability, and assessment of toxicity to cultivated target cells. The results of these studies will form a basis for consecutive rounds of re-engineering at IMG. In the initial rounds, the antibody structure will be optionally modified with incorporation of a peptide chelator enabling radionuclide labelling under mild conditions. The essential design of such chelators (for e.g. 90Y) will be provided by a research group at the Institute of Molecular Biology, SLOVAK ACADEMY OF SCIENCES, with expertise that includes both metal chelating and protein structural studies. Keywords: protein engineering, recombinant mAbs (monoclonal Antibodies), metal chelators.
Acronym: 
ENGRAB
Project ID: 
3 537
Start date: 
01-01-2006
Project Duration: 
48months
Project costs: 
980 000.00€
Technological Area: 
Cytology, Cancerology, Oncology
Market Area: 
Nuclear imaging

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