Polysaccharide-peptide derivatives

Details Polysaccharide-peptide derivatives Polysaccharide-peptide derivatives

1999-10-18

2002-09-24

Russel, Jeffrey E. (Department: 1653)

Drug, bio-affecting and body treating compositions

Radionuclide or intended radionuclide containing; adjuvant...

Attached to cyclopentano-hydrophenanthrene ; derivative thereof

C424S009341, C424S009430, C514S008100, C514S011400, C514S014800, C530S311000, C530S322000, C530S345000

Reexamination Certificate

active

06455025

ABSTRACT:

THE TECHNICAL FIELD
The present invention is related to peptides coupled to charged polydispersive polysaccharides and their radiolabelled derivatives as well as their use in diagnostics and for treatment of cancer and other diseases.
THE BACKGROUND OF THE INVENTION
Technetium-99m is provided with ideal physical properties as a radioactive marker in isotope-imaging. It is easily obtainable from a
99
Mo/
99m
Tc-generator, which is included in the isotope-laboratory equipment of each general hospital. The methods of labelling peptides with technetium-99m can be divided into two main categories, use of bifunctional metal chelates and use for labelling free thiol-groups. Rhenium, the isotopes
186
Re and
188
Re of which are suitable for radiotherapy due to their radiation properties, behaves chemically in the same way as technetium. In addition, many peptides have been labelled for diagnostic and therapeutic purposes with the radioactive isotopes of many other metals by using metal chelates. The most common metal chelates are derivatives of DTPA and EDTA. Further isotopes of halogens, especially iodine, have been used by coupling them to tyrosine and/or histidine residues possibly present in a peptide chain or to separate structures incorporated into the peptide chains.
Due to the general inhibitory effect of somatostatin, it has been tested in treatments of patients suffering from syndromes caused by neuroendocrine tumours. Neuroendocrine cancers are characterized by a large amount of somatostatin-receptors. A crucial problem in medical use of somatostatin is the fact that its biological half-life in blood serum is below three minutes. Due to this fact somatostatin analogs with longer in vivo half-lives have been developed in order to facilitate diagnoses and treatment of neuroendocrine tumours. So far the treatments with somatostatin analogs have mostly been limited to treating hormone-dependent symptoms of the patient.
Radiolabelled somatostatin derivatives are known for example from the following patents/patent applications: U.S. Pat. Nos. 5,225,180; 5,405,597; WO 92/21383 and WO 90/06949.
Successful diagnostic studies have been performed using somatostatin analogs
123
I-Tyr3-octreotide (Lamberts et al., N. Eng. J. Med. 323: 1246-1249, 1990). However, said compound suffers from some disadvantages. It is secreted through the liver-kidney system and thus disturbs the imaging of the lower parts of the body. On the other hand, iodine-123 is an expensive isotope and the labelling technique is complicated.
A (
111
In-DPTA-Phel)octreotide, which is excreted from the body through the kidneys, thus facilitating the diagnoses of tumours inside the stomach without the accumulation of disturbing background-activity, has been developed from the above mentioned somatostatin derivative (Krenning E. P., et al., J. Nucl. Med. 33 :652-658, 1992). Another problem related to the octreotide is also the fact that it does not identify all types of somatostatin receptors. A disadvantage with the use of indium-111 is the fact that it is an expensive isotope and its availability is limited. Indium-111 has to be ordered by the hospital for each patient, separately. In addition, the radiation properties of indium-111 are not well adaptable to diagnostic and therapeutic use.
Somatostatin-dextran (Dextran 10) labelled with technetium-99m has a remarkably longer half-life in blood than native somatostatin(T(1)
½
=4 h and T(2)
½
=8 h) Holmberg, et al., Antibody, Immunoconj. Radiopharm 7: 253-259, 1994).
A further problem related to dextran somatostatin is non-specific binding to the cells, the transfer of the conjugate from the blood circulatory system to the lymphatic system and rather rapid excretion through the kidneys to urine.
THE DISCLOSURE OF THE INVENTION
Analogs of polysaccharide somatostatin with a negative effective surface charge are characterized by non-specific binding. When the transfer of the conjugate to the lymphatic system has been essentially decreased, it has been possible to regulate the transfer of the conjugate through the kidneys to the urine. It has been found that these compounds have special properties in treatment of cancer and they can be radiolabelled for in vivo diagnostics and therapy.
In the present invention the somatostatin analog has been coupled to a soluble polysaccharide with a negative effective surface charge. Hereinafter, said polysaccharides are referred to as charged polysaccharides. In addition, the charged polysaccharide somatostatins can be provided with groups, which in turn are able to bind detecting compounds, such as radionuclides, radiocontrasting substances or paramagnetic ions. Chelation or the production of another in vivo stable bond between the group and the detecting compound is used to carry out the coupling. Hereinafter said groups are referred to as chelates. If the chelate is able to bind only metals, the chelate is referred to as, a metal-chelate. A bond can be formed between the chelate and the detecting group before or after the chelate is coupled to the polysaccharide. It is also possible to couple some compounds directly to the structures of the polysaccharides, in which case a separate chelate is not required. Hereinafter, chelate is written within brackets in order to show that it is also possible to couple the detecting compounds directly to polysaccharides without a chelate. The accordingly formed charged polysaccharide-somatostatin-(chelate)-compounds are capable of binding to somatostatin receptors, which are expressed or over-expressed by tumours and metastases.
Said charged polysaccharide somatostatin (chelate) compounds are hereinafter referred to as the compounds according to the invention.
Compared to previously known methods, it was surprising that with a negative effective total charge a clear decrease in non-specific binding could be obtained and additionally by selecting a suitable polysaccharide size the half-life of the compound according to the invention in blood could be optimized.
A polysaccharide compound with high molecular-weight can be used when it is desired to maximize accumulation into the tumour, but the background concentration is without greater significance. On the contrary, when the background concentration is of importance, as in radiotherapy, the size of the polysaccharide is chosen in such a way that the radiation dose of the critical organ is not exceeded. In said case the size of polysaccharide is optimized in such a way that the accumulation kinetics in the tumour and the elimination of the compound according to the invention produces an optimal radiation dose relation between the tumour and the rest of the organism.
The object is the elimination of the compound according to the invention primarily through the kidneys, in which case the size of the compound should be less than 50 000 g/mol (grams/mole). In many diagnostic applications the background concentration should be low, too. Still, different methods have different clearance times.
One of the essential advantages of the method as compared to known techniques is the fact that it is possible to transport simultaneously to the target cells several somatostatins as well as several radioactive nuclides, if required.
All somatostatin analogs are not capable of identifying all types of somatostatin receptors. In the present invention such a somatostatin analog can be used, which identifies all types of somatostatin receptors or if required a somatostatin analog, which identifies only certain types of somatostatin receptors, thus targeting the compound to find its way to the target cell tissue. The biological half-life in blood is always remarkably dependent on the kind of charged polysaccharide to which the somatostatin analog is bound.
It is generally known that the charge of the polydisperse macromolecule is highly affected by the media in which the macromolecule of interest is situated. Said media dependent so called effective surface charge can deviate remarkably from the theoretical electric charge of the molecule bas

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