Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
2001-06-11
2004-08-03
Russel, Jeffrey E. (Department: 1654)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S013800, C514S014800, C514S015800, C514S016700, C514S017400, C514S018700, C514S423000
Reexamination Certificate
active
06770628
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to methods and products for producing increased numbers of hematopoietic cells, of restoring to preselected normal levels numbers of hematopoietic cells, to therapies for treating deficiencies in hematopoietic cells and to in vitro methodologies for culturing hematopoietic cells.
PT-100 is a dipeptide consisting of valine-prolineboronic acid (ValboroPro) designed to interact with the cell surface receptor CD26. CD26, a type II transmembrane protein is expressed on the cell surface of a number of cell types, including lymphocytes (Marguet, D. et al.,
Advances in Neuroimmunol.
3:209-215 (1993)), hematopoietic cells (Vivier, I. et al.,
J. Immunol.
147:447-454 (1991); Bristol, et al.,
J. Immunol.
149:367 (1992)) thymocytes (Dang, N. H. et al.,
J. Immunol.
147:2825-2832 (1991), Tanaka, T. et al.,
J. Immunol.
149:481-486 (1992), Darmoul, D. et al.,
J Biol. Chem.
267:4824-4833 (1992)), intestinal brush border membrane and endothelial cells. Cell surface associated CD26 is a sialoglycoprotein, with most of its mass on the outside of the cell.
CD26 has been best characterized on peripheral T cells where it functions as a potent costimulatory signal for T cell activation. Its surface expression is upregulated upon T cell activation (Dong, R. P. et al.,
Cell
9:153-162 (1996), Torimoto, Y. et al.,
J. Immunol
147:2514 (1991), Mittrucker, H-W. et al., Eur.
J Immun.
25:295-297 (1995), Hafler, D. A. et al,
J. Immunol.
142:2590-2596 (1989), Dang, N. H. et al.,
J. Immunol
144:409 (1990)). CD26 has also been identified in rodents as an important regulatory surface receptor in hematopoiesis and lymphoid development (Vivier, I. et al.,
J. Immunol.
147:447-454 (1991)). The primary structure of CD26 is highly conserved between species (Ogata, S. et al.,
J. Biol. Chem.
264:3596-3601 (1998)). In humans CD26 seems to be involved in the regulation of thymocyte activation, differentiation and maturation (Dang, N. H. et al.,
J. Immunol.
147:2825-2832 (1991); Kameoka, J. et al.,
Blood
85:1132-1137 (1995)). We have evidence that CD26 is expressed within the human and murine hematopoietic systems.
CD26 is an ectoenzyme with activity identical to that of Dipeptidyl Peptidase IV (DPP-IV), a serine type exopeptidase with high substrate specificity. It cleaves N-terminal dipeptides from proteins if the penultimate amino acid is proline, or in some cases alaninie (Fleischer, B.
Immunol. Today
15:180 (1994)). PT-100 is a potent inhibitor of DPP-IV activity.
The prior art PCT published application WO94/03055 teaches methods of producing increased numbers of hematopoietic cells by administering inhibitors of DPP-IV. The teaching of this published application, however, is that dosages of at least 1 mg/kg body weight are necessary to achieve such hematopoietic cell increases. This published application also teaches that inhibitors are administered to mammals which have an established deficiency of hematopoietic cells. The teaching also suggests that cytokines be administered in conjunction with the inhibitors to increase the production of hematopoietic cells in a subject.
SUMMARY OF THE INVENTION
The invention is based upon a variety of surprising and unexpected findings. It has been discovered, unexpectedly, that the agents useful according to the invention stimulate growth factor production by stromal cells. It also has been discovered, unexpectedly, that the agents useful according to the invention stimulate proliferation of primitive hematopoietic progenitor cells, but do not stimulate directly the differentiation or proliferation of committed progenitor cells. It further has been discovered, unexpectedly, that the agents useful according to the invention can be administered at doses much lower than would have been expected according to the teachings of the prior art. Another unexpected finding is that the agents according to the invention can accelerate the time it takes to achieve hematopoietic cell recovery after treatment with an hematopoietic cell inhibitor. Another unexpected finding is that the agents useful according to the invention can at relatively low doses, restore normal levels of neutrophils at least as fast as the most successful commercially available product used worldwide for this purpose, except that the agents useful according to the invention can be used orally, whereas the commercially available product (which represents more than a billion dollar market) must be injected. These unexpected results have important therapeutic and experimental research implications.
According to one aspect of the invention, a method is provided for treating a subject to stimulate hematopoiesis in the subject. The invention involves administering to a subject in need of such treatment an amount of an agent effective to increase the number of hematopoietic cells or mature blood cells in the subject, wherein the amount is less than 1 mg/kg body weight per day and wherein the agent is a compound of Formula I.
The agents useful according to the invention are compounds of Formula I:
wherein m is an integer between 0 and 10, inclusive; A and A
1
are L-amino acid residues (for glycine there is no such distinction) such that the A in each repeating bracketed unit can be a different amino acid residue; the C bonded to B is in the L-configuration; the bonds between A and N, A
1
and C, and between A
1
and N are peptide bonds; and each X, and X
2
is, independently, a hydroxyl group or a group capable of being hydrolysed to a hydroxyl group in aqueous solution at physiological pH. By “the C bonded to B is in the L-configuration” is meant that the absolute configuration of the C is like that of an L-amino acid.
Thus, the
group has the same relationship to the C as the —COOH group of an L-amino acid has to its &agr; carbon. In some embodiments, A and A
1
are independently proline or alanine residues; m is 0; X
1
and X
2
are hydroxyl groups; the inhibitor is L-Ala-L-boroPro; and the inhibitor is L-Pro-L-boroPro.
In one important aspect of the invention, the subject has an abnormally low level of hematopoietic cells or mature blood cells and the agent is administered in an amount effective to restore levels of a hematopoietic cell-type or mature blood cell-type to a preselected normal or protective level. The agent preferably is administered to the subject in at least 2 doses in an 18 hours period. The invention has particularly important applications in the restoration of normal or protective levels of neutrophils, erythrocytes and platelets. The most preferred agent is ValBoroPro.
According to another aspect of the invention, a method is provided for shortening or eliminating the time that a subject has an abnormally low level of hematopoietic or mature blood cells resulting from treatment with a hematopoietic cell inhibitor. An agent is administered to a subject in need of such treatment in an amount effective to increase the number of hematopoietic cells or mature blood cells in the subject, wherein the administration of the agent begins prior to or substantially simultaneous with administration of the hematopoietic cell inhibitor. The agents and the preferred agent are as described above. In one important embodiment, the hematopoietic cell inhibitor causes an abnormally low level of hematopoietic cells or mature blood cells in the subject and the agent is administered in an amount effective to restore levels of a hematopoietic cell type to a preselected normal or protective level. Preferably, the agent is administered to the subject in at least 2 doses in an 18 hour period. In important embodiments, the agent is used to restore in the subject normal or protective levels of neutrophils, erythrocytes or platelets. The preferred effective amount of agent is as described above.
According to another aspect of the invention, a method is provided for preparing a subject for treatment with a hematopoietic cell inhibitor. The method involves administering to the subject prior to the subject receiving the hematopoietic cell inhibitor a
Adams Sharlene
Jones Barry
Miller Glenn T.
Wallner Barbara P.
Point Therapeutics, Inc.
Russel Jeffrey E.
Wolf Greenfield and Sacks, P.C.
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