Drug – bio-affecting and body treating compositions – Radionuclide or intended radionuclide containing; adjuvant...
Patent
1994-06-13
1997-05-13
Kight, John
Drug, bio-affecting and body treating compositions
Radionuclide or intended radionuclide containing; adjuvant...
424 169, 424 91, 530300, 530324, 530325, 530326, 530327, 530328, 530329, 530330, A61K 5100, A61M 3614
Patent
active
056289790
DESCRIPTION:
BRIEF SUMMARY
FIELD OF INVENTION
This invention relates to in vivo tumor imaging and therapy, and more particularly to a novel reagent for use therein, diagnostic and therapeutic compositions containing that reagent, and methods of tumor imaging and therapy utilising the reagent.
BACKGROUND INFORMATION AND PRIOR ART
In the cause of improving the diagnosis and treatment of cancer numerous attempts have been made to target imaging agents, e.g. radioactive isotopes, and therapeutic reagents onto tumors in vivo using anti-tumor monoclonal antibodies, Mabs, see for example published International Applications WO 89/00583 and WO 90/09197. Because of the size of the average Mab, diffusion rates of, for example, a radio-labelled antibody to the site of a tumor are very low, and the same applies to conjugates formed from a cytotoxic reagent and an anti-tumor antibody.
Tumor imaging and therapy using Mabs is therefore inherently a slow process, often taking several hours, whereas ideally one would like to have the process complete in minutes, rather than hours, particularly in the case of tumor imaging and diagnosis.
In J. Immunol., 145, No, 1, 59-67, 1990, Shimizu et al have reported on the co-stimulation of proliferative responses of resting CD4U.sup.+ T-cells by the interaction of the extracellular matrix (ECM) proteins fibronectin (FN) and laminin (LN) with the VLA integrins VLA-4 and VLA-5 (in the case of fibronectin) or VLA-6 (in the case of laminin) expressed by resting human T-lymphocytes, and have shown inter alia that the 12-amino acid peptide ##STR1## is an effective T-cell adhesion inhibitor and an effective blocking agent for OKT3/FN T-cell proliferation, but does not go beyond a mere investigation into the role of cell adhesion molecules (CAMs) in T-cell recognition and activation. Thus, Shimizu et al suggest no practical outcome or industrial utility resulting from their investigations.
In J. Biol. Chem., 266, No. 6, 3579-3585, 1991, Mould et al have reported their studies of the inhibition of the interaction of the integrin heterodimer .alpha..sub.4 .beta..sub.1 with the CS1 and CS5 sites in the IIICS region of fibronectin, which interaction is believed to play an important role in melanoma cell adhesion, and have shown that the tripeptide X-asp-Y, where X is glycine, leucine or glutamic acid, and Y is serine or valine, represents a minimum recognition sequence within the CS1 site of the fibronectin for the integrin .alpha..sub.4 .beta..sub.1. Inter alia, those studies utilised synthetic CS1 and KKT-CS1-VQK peptides, viz: ##STR2## but again no consequential commercial utility is suggested for such LDV (leu-asp-val) containing peptides.
Subsequent studies of similar kind confirming the significance of the LDV triplet as the minimum recognition site for the .alpha..sub.4 .beta..sub.1 integrin, as opposed to the RGDS sequence which constitutes the minimum recognition site for the .alpha..sub.5 .beta..sub.1 integrin, those two minimum recognition sites occurring in different domains of the fibronectin (FN) molecule, viz. the alternatively spliced type III connecting segment (IIICS) and the central cell binding domain respectively, are reported by Komoriya et al in J. Biol. Chem., 266, No. 23, 15075-15079, 1991, but published after the present priority date.
Earlier studies into the cell binding activity of fibronectin are reported by Pierschbacher and Ruoslahti (Nature, 309, 30-33, 1984) and by Kloczewiak et al in Biochemistry 28, 2915-2919, 1989. Pierschbacher et al recognize the importance of the RGDS sequence as a recognition site in the cell adhesion activity of fibronectin, but report that they were unable to obtain any inhibition of cell adhesion using either soluble fibronectin or by peptides not containing the RGDS sequence. Similarly Kloczewiak et al, investigating the essential role of the terminal region of the fibrinogen .gamma.-chain in the interaction of human fibrinogen with activated platelets, showed that the synthetic dodecapaptide: ##STR3## being an analogue of the .gamma.400-411 FN residue, and
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Mould et al. (1991) Journal of Biological Chemistry, vol. 266, #6 Feb. 25, pp. 3579-3585. The CS5 Peptide is a Second Site in the III CS Region of Fibronectin Recognized by the Integrin L.sub.4 B.sub.1.
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Mathew Van Holde. Biochemistry, Chapter 5:Introduction to Proteins:The Primary Level of Protein Structure, pp. 139-141. .COPYRGT.1990.
Antisoma Limited
Jones Dameron L.
Kight John
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