Objective
The main aim of the Concerted Action is to develop immunoconjugates for a clinical trial so that their potential in the treatment of cancer can be assessed.
It is unclear at present what kind of quality control and production specifications are required within Europe for clinical trials with materials of this nature in a non-commercial venture. A secondary aim is therefore to clarify this position.
Neocarzinostatin (NCS) has been conjugated to the 4 antibodies SWA11, PR1A3, BW431/26 and OVTL3 and tested for cytotoxicity and selectivity, and also toxicity in vitro. In addition therapy experiments were carried out with BW431/26 on nude mice. In vitro properties were poor, there was no toxicity advantage over free drug, and no therapeutic effects were seen. Encapsulation of NCS into immunoliposomes did not solve the problems. Studies on the mechanism of action showed that toxicity was mediated by the diffusible chromophore, and entry of the antibody into the cell was not required. Bystander effects and the poor stability of NCS due to dissociation of chromophore are now thought to account for these disappointing results.
Assessment of both Abrin and Ricin A chain conjugates with the antibodies SWA20, SWA11, HMFG-1, and OVTL3 were also completed, but only the SWA11 conjugates were found to be suitable. Abrin A chain immunoconjugate had encouraging antitumour effects. Even better results were obtained from deglycosylated Ricin A chain conjugate due to its lower toxicity. This antibody Ricin A chain conjugate is one of the most potent and selective toxin conjugates reported for a solid cancer target.
However immunoscintigraphy and histological studies revealed that in humans there was an unexpectedly high reaction with bone marrow that prevented localization of SWA11 antibody.
The programme is divided into two main areas of work and two stages. One area will be the development and assessment of NCS conjugates and the other area that of toxin conjugates. In the first stage seven conjugates will be synthesised and screened for activity using both in vitro and in vivo assays that have been standardised as much as possible to protocols on appropriate models. These will include antibody binding assays, cytotoxicity and selectivity assays, therapy experiments and basic biodistribution data. When all of these data have been collated, the best NCS and best toxin conjugate will each be selected for further development. All the necessary background work remaining to conduct a clinical trial will then be carried out on the selected conjugates. This will include further therapy and biodistribution studies to determine optimal dosing schedules, minimisation of unwanted immune responses, toxicity studies, and development of quality control and clinical trial protocols.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- medical and health sciences basic medicine immunology
- medical and health sciences clinical medicine oncology
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Programme(s)
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Multi-annual funding programmes that define the EU’s priorities for research and innovation.
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Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
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Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
Coordinator
4400 Muenster
Germany
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