Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Conjugate or complex
Reexamination Certificate
2000-12-15
2003-07-29
Chan, Christina (Department: 1644)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Conjugate or complex
C424S195110, C530S380000, C558S072000
Reexamination Certificate
active
06599507
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to a new therapeutic composition, in particular an immunomodulating composition or a composition for uses in the treatment of immune deficiencies. The invention also discloses methods for the preparation of said composition and methods for the therapeutic application of the same.
DESCRIPTION OF THE PRIOR ART
Alpha-fetoprotein (AFP), a protein from mammalian fetal blood, has been held to be of a certain scientific interest since the moment it was first discovered in 1958. The biological properties of this protein are subject of numerous investigations: there is however still no final answer as to the role of this protein in the organism. It is known, that unsaturated fatty acids such as arachidonic and docosahexaenoic acid and their metabolites are characterized as natural AFP ligands and can be detected as complexes with the given protein circulating in blood vessels. However, AFP is not only a transport protein for unsaturated fatty acids. It has also been found that it forms complexes with bilirubin, retinoids and copper. In addition to the transport of low molecular weight substances AFP can take part in immune response regulation. Most of the studies on AFP's immunoregulating properties indicate that the protein has immunosuppressing features.
It should also be pointed out, that practically no data on the immunosuppressing properties of AFP were obtained for the pure protein, but using AFP-enriched sera or amniotic fluid during in vitro experiments. The immunoregulating properties of AFP were shown to be dependent on the origins of the preparations and the purification methods. For example, AFP obtained from fetal liver is characterized by a stronger suppression of mitogene-induced lymphocyte transformation in comparison with AFP, obtained from human blood of patients suffering from primary liver cancer.
At the same time it has been demonstrated, that AFP stimulates tissue regeneration after injuries. AFP tended to decrease the inflammatory processes artificially simulated in animals supposedly by blocking the receptors of immunocompetent cells. It has also recently been shown in a series of experiments, that AFP is actively absorbed by growing and differentiating cells, and this process is controlled by the quantity of expressed AFP-receptors. It was found that intracellular AFP concentration increased simultaneously with the increase of the quantity of AFP-receptors on the surface of proliferating T-lymphocytes and malignant cells. It was stated, based on these data, that this protein functions as a shuttle-transporter, bringing the ligand inside the cell and then returning into intercellular liquid to repeat the cycle (Esteban C., et al., Int. J. Cancer, v.49, p. 425-
4
30, 1991).
The most important ligands transported inside the cell are unsaturated fatty acids, namely arachidonic and docosahexaenoic acid and their metabolites. It is experimentally proven, that the presence of AFP significantly increases the flow of these acids into the cytoplasm of activated T-lymphocytes (Torres J. M., et al., J. Cell. Physiol, v. 150, p.456-462, 1992).
The increase of the concentration of unsaturated fatty acids is of great importance as said acids are not only necessary structural components of the cell membrane, but also serve as an additional source of energy for the cells. The metabolites of these acids, in particular those of arachidonic acid, can act as secondary messengers, thus participating in the regulation of cellular growth and differentiation (Bevan S., et al., Nature (London), v. 328, p. 20, 1987).
Anandamide (arachidonyl-2-ethanolamid) is one of the recently discovered fatty acid metabolites. It is characterized by the high physiological effect targeted to brain. Anandamide is a novel lipid neurotransmitter first isolated from porcine brain. It has been shown to be a functional agonist for cannabinoid CB1 and CB2 receptors. Its presence results in many pharmacological effects caused by delta 9-tetra-hydrocannabinol (delta 9-THC). Anandamide parallels delta 9-THC in its specific interaction with the cannabinoid receptor and in the inhibition of adenylate cyclase. For many decades the mechanism of action of cannabinoid compounds, which are structurally similar to delta 9-THC, was unknown. Tremendous progress has recently been made in characterising cannabinoid receptors both centrally and peripherally as well as in studying the role of the second messenger systems at cellular level. Cannabinoid derived drugs have been used for centuries for medicinal purposes. However, these drugs on the market today lack specificity and produce many side effects (Chakrabarti A., et al., Brain. Res. Bull., v.45, 30 p.67-74, 1998).
Anandamide can be formed enzymatically via two separate synthetic pathways in the brain: enzymatic condensation of the free arachidonic acid and ethanolamine; and formation of N-arachidonoyl phosphatidylethanolamine from phosphatidyletanolamine and arachidonic acid esterified at the 1-position of phosphatidylcholine, and subsequent release of anandamide from N-arachidonoyl phosphatydylethanolamine through the action of a phosphodiesterase (phospholipase D) (Suguira T., et al., Eur. J. Biochem., v.240. p.53-62, 1996).
N-acyl-transferase catalyses the transfer of arachidonoyl residue onto the NH2 group of phosphatydylethanolamine. This enzyme is Ca2+dependent and is mostly localised in brain and testis. The pathway of anandamide formation is presented below:
R—Arachidonoyt
R
1
and R
2
—alkyl
N-arachidonoyl phosphatidylethanolamine could also be a substrate for phospholipase C (Brockerhoff H., Jensen R. G., Lipolytic enzymes, Academic press, New York-San Francisco-London, 1974). In this case the enzymatic reaction results in formation of N-arachidonoyl aminoethylphosphate (N-AAP).
The absence of literature data on N-AAP presence in brain supports the assumption, that this phosphate is unstable and can be quickly transformed to anandamide by endogenous phosphatases during processing of the brain preparations. To study the N-AAP biological activity one has to consider a reversible complex of AFP with N-AAP. In this case N-AAP can be protected by the protein molecule from the enzymatic influence in blood vessels as well as in the other biological liquids.
The idea to use reversible complexes of transport proteins with the conjugates of their natural ligands with drugs to strengthen their pharmaceutical effect and reduce the side effects, particularly during cancer treatment, was first reported in 1958 (Mathe G. et al., C. R. Seances Acad. Sci. v. 246, p. 1626-1628, 1958; Magnenat R. et al., Eur. J. Cancer., v. 5. p. 3340, 1969). The reversible complex of AFP with the conjugates of daunomicin with arachidonic and docosohexaenoic acids appeared to be more effective cytostatic agent for hepatoma AH-66 cells, generating more AFP than the free daunomicin (Deutsch H. F. et al., Cancer Res. v. 43, p.2668-2662, 1983), and the conjugate of 2-deoxy-5-fluorouridine-oleic and docoso hexaenoic acids with AFP had much greater cytotoxic activity for cancer cell lines H 1-29, than the free 2-deoxy-5-fluorouridine (Halmos T. et al., Biochem. Pharmacol v. 44., p. 149-156, 1992).
Some direct immunologic response observations on the role of a factor that appears to be AFP have been reported (Abramsky, O., et al., Isr. Med., vol. 15, p. 943, 1979; Brenner T., et al., Immunol. Lett., vol. 3, p. 163, 1981). They found that what is likely to be fetal AFP prevented the development of myasthenia gravis in rabbits and, furthermore, that clinical signs of the disease in these animals disappeared when they were treated with the assumed AFP. It was shown that experimental allergic encephalomyelitis induced in guinea pigs was successfully treated as well as partially prevented by administration of AFP (Abramsky O., et al., J. Neuroimmunol., vol. 2, p. 1, 1982).
It has thus been shown that AFP, depending on its origin and surrounding conditions, exerts different functions by different mechanisms. Firstly, there is a regulatory effect on t
Ardenia Investments Ltd.
Chan Christina
Huynh Phoung N.
Morrison & Foerster / LLP
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