Labelling techniques of biomolecules for targeted radiotherapy: final report of a co-ordinated research project 1998-2002

Malignant tumour disease accounts for approximately one third of deaths worldwide. Gastrointestinal adenocarcinomas, prostate and breast cancers are among the most frequently appearing tumours. Radiotherapy is an essential mode of treatment of all cancer patients either alone or in conjunction with other modalities like surgery and chemotherapy. In most cases radiotherapy is given using external radiation sources. It is also possible to administer radiotherapy by specifically localizing radioisotopes emitting particulate radiation in the tumour tissue. This targeted therapy has proved to have several advantages over external beam therapy, notably the possibility of selectively delivering higher radiation doses to the targeted tumour cells and treating multiple metastases. Procedures for therapy of thyroid carcinoma and hyper-thyroidism using radioiodine (131I) introduced about five decades ago, have stood the test of time and are still widely used the world over. In addition to the therapeutic nuclides of the first generation 131I, 89Sr, 32P, 90Y, etc., which are still widely utilized and accepted by the medical community, many other beta emitting radionuclides with relatively short half-lives such as 153Sm, 186Re, 188Re, 166Ho, 165Dy, etc. have also been recently made available for therapy and used with promising good results. In spite of the potential of targeted radiotherapy to treat a wide range of malignant conditions, routine clinical use is mostly confined to therapy of thyroid carcinoma, hyperthyroidism, metastatic bone pain and synovectomy. In most of the cases, the limitation is obviously not the availability of suitable radionuclides but rather the lack of suitable carrier molecules that would adequately concentrate these radionuclides in target tissues of interest. Based on the above considerations, the scope of the Co-ordinated Research Project (CRP) has focused on the synthesis of the required BFCAs for MoAbs and peptide labelling, development a diolabelling techniques with beta emitting radioisotopes, including quality control procedures and evaluation of the labelled products in in vitro and in vivo models. Biomolecule carriers that were considered for investigation included somatostatin analogues like lanreotide, Tyr-octreotide, ior-P1394 and vasointestinal peptide (VIP), as well as anti-CEA monoclonal antibody. Using either the bifunctional chelate approach or direct reductive exposure of -SH groups, labelling of these biomolecules with therapeutic radionuclides was pursued. Through these attempts it was expected to identify one or two agents with high radiochemical purity and labelling efficiency for further evaluation. Promising agents would be selected for further investigation using biodistribution studies in animals and uptake in tumour bearing animals. Fifteen selected research institutes from Argentina, Austria, Brazil, Cuba, Greece, Finland, Hungary, India, Italy, Mexico, Pakistan, Peoples Republic of China, Romania, Thailand and Uruguay with recognized expertise in the field of therapeutic radionuclides and radiopharmaceutical research were selected to participate in the CRP. The first research co-ordination meeting to plan the work and define the research protocols to be investigated was held in Milan, Italy in July 1998. At this meeting it was decided to concentrate the efforts on two radionuclides, 188Re and 90Y, which are produced by generator systems and result in carrier free products; lanreotide was selected as a model peptide. Synthesis of the bifunctional chelating agent DOTA was also recommended for the labelling of biomolecules with 90Y. The development of the corresponding coupling techniques, optimization of protocols for direct and indirect labelling of lanreotide and anti-carcino embryonic antigen (CEA) monoclonal antibody and in vitro evaluation in cell lines and membrane receptors were also included in the work plan for the following period. IgG labelled with 131I and 12 luded in the work plan for the initial investigation and method evaluation. The second RCM to review the progress and discuss future work was held in Mumbai, India in February 2000. In view of the progress reported at this meeting, it was recommended that in the remaining period the CRP should concentrate on the testing of in vitro bioactivity of the labelled 188Re lanreotide, confirm the results reported on the direct labelling method for 188Re lanreotide and continue the investigations to label DOTA conjugated peptides with 90Y. The third and final RCM was held in Budapest, Hungary in October 2001 to assess the progress and achievements of the CRP and draft the final report. A list of general references to guide the reader into recent research work done in the field is given in Section VIII