Drug – bio-affecting and body treating compositions – Radionuclide or intended radionuclide containing; adjuvant... – In an organic compound
Reexamination Certificate
1998-01-21
2001-04-17
Jones, Dameron L. (Department: 1616)
Drug, bio-affecting and body treating compositions
Radionuclide or intended radionuclide containing; adjuvant...
In an organic compound
C530S331000, C424S001650, C424S001110
Reexamination Certificate
active
06217846
ABSTRACT:
This invention relates to the development and use of synthetic peptides for thrombus detection both in human beings and animals, but primarily, of course, in the detection of human disease. The Method and the synthetic peptides used therein are also useful in targetting other sites in vivo, e.g., cell adhesion molecules (CAMs) and tumors, containing an RGD binding site.
In 1984 Pierschbacher and Ruoslahti (Nature, 309, 30-33), showed evidence that the cell attachment activity of fibronectin could be mimicked by small synthetic peptide fragments. The amino acid sequence responsible for this activity was shown to be Arg-Gly-Asp-Ser (RGDS) [SEQ ID NO:1] and it was demonstrated that synthetic peptides containing this sequence were able to inhibit attachment of NRK cells (cells from a neuroblastoma cell line) to fibronectin coated substrates. The inhibition obtained with RGDS [SEQ ID NO:1] containing peptides was shown to be dose-related, whilst peptides which did not contain the RGDS [SEQ ID NO:1] sequence failed to inhibit cell attachment. The serine residue of the tetrapeptide has been shown to be non-essential, although only conservative substitutions may be made in order to retain biological activity.
The RGDS [SEQ ID NO:1] sequence has been shown to occur in fibrinogen, fibronectin and von Willebrand factor. Receptors for these proteins are expressed on the platelet membrane surface following platelet activation. Cross-linking of platelets via these cytoadhesive proteins accounts for the platelet-platelet interactions within a thrombus. It has also been demonstrated that RGDS [SEQ ID NO:1] containing synthetic peptides are capable of inhibiting platelet aggregation in vitro. This would suggest a specific interaction with the GP IIb/IIIa (glycoprotein fibrinogen receptor) complex present on the platelet membrane surface, which contains the fibrinogen binding domains. Extension of the RGDS [SEQ ID NO:1] sequence, by one amino acid residue at the carboxy and amino terminal, results in a ten-fold reduction in its biological activity, although further extension is not associated with a further reduction in binding capacity. Substitution of the serine residue by phenylalanine results in an anti-aggregatory peptide which is 4 to 5 times more potent than RGDS [SEQ ID NO:1]. There has also been suggestion that the residue corresponding to serine in the RGDS [SEQ ID NO:1] sequence may impart a degree of recognition specificity for different RGDS [SEQ ID NO:1] receptors. This raises the possibility that both specificity and affinity could be modified by substitution around the RGD sequence. RGD binding sites are also known to occur on cell adhesion molecules (CAMs) and some tumors.
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Antisoma Research Limited
Jones Dameron L.
Palmer & Dodge LLP
Williams Kathleen M.
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