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Alpha-immunotherapy and cell toxicity

Objective

Specific Objectives 4.1.1.1. Production of Radionuclides and Radiolabelling of biomolecules Production of bismuth-213 for preclinical experiments (and phase I) Consulting/training of Ac-225 production (outsourcing) New alpha-emitters for radiotherapy Evaluation of the Ytrium-90 production for radioimmunotherapy Contribution to EMIR To synthetise new chelators for actinium and radium To conjugate chelates for biomolecules Testing new radiolabeled biomolecules 4.1.1.2. Radiobiology Gene activity variation after alpha, beta, gamma irradiation in leucemic/normal cells Establishing a cell model for Bystander/hormesis effect Functional test for studing cytotoxicity in normal and leucemic cell lines.
Planned Deliverables 4.1.1.1. Production of Radionuclides and Radiolabelling of biomolecules Bismuth-213 generators for hospitals License contract with an external company to produce Ac-225 in the cyclotron A method to produce radium-224 for preclinical and (clinical use) Yttrium-90 for preclinical and (clinical use) Contribution to EMIR Bifunctional OHEC as chelate for Ac and bifunctional Calixarene-crown ether for Ra Chelated antibodies for preclinical use (also consulting hospitals to do clinical grade material) A method to determine stability constants 4.1.1.2. Radiobiology Basic data of alpha, beta and gamma radiation effects in leucemic/normal cells A Model to study bystander effect Effects of the gene activity to function of the cell.
Summary of the Action:
The objective of the work is to develop, test, validate and optimise a drug against different types of cancers, consisting of a suitable alpha-emitter, a cancer specific carrier (antibody, peptide, etc.) and a chelator (combining nuclide and carrier). For this purpose ITU focuses on: the consultation and training to license out the enhanced production processes for the required radionuclides the development and testing of appropriate chelators for various alpha- emitting radionuclides the support of clinical trials and the increase of safety and improvement of quality for using alpha-emitting isotopes at the hospitals the radiobiological analysis of the molecular mechanisms of irradiation- induced cell effects. Rationale Cancer continues to be one of the major preoccupations of the European citizen and one of the great challenges for research. During the Fifth Framework Programme ITU promoted, in cooperation with university hospitals, the development of a new type of cancer therapy based on the use of alpha-particle emitting nuclides.

Their effect on healthy cells is minimal due to high linear energy transfer values of the alpha particles which deposit their energy over a few cell diameters only. Alpha-emitters are also very effective in inducing apoptosis, i.e. programmed cell death, into a tumour cell, even with one single decay. They are therefore estimated to be especially attractive to treat blood- borne cancers and micro-metastatic tumours, i.e. those cases where cancer cells are typically present throughout the body, even when in relatively small amounts, and surgery or e.g. when external irradiation find no application any more. The Institute for Transuranium Elements makes its facilities and expertise in handling highly radioactive alpha-nuclides available to develop and test suitable alpha-emitting immuno-conjugates for cancer treatment. In collaboration with University Hospitals throughout Europe an exploratory programme on radiobiology started to better understand the molecular mechanism of irradiation-induced apoptosis and to support the development of prenormative data and the development of procedures to be used in treating patients with radioactive sources, which include alpha-, beta- and gamma-radiation.

Funding Scheme

JRC - Joint Research Centre research
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Coordinator

Institute for Transuranium Elements
Address
Po Box 2340
D-76125 Karlsruhe
Germany