US2002156034A1PendingUtilityA1
CXCR4 antagonist treatment of hematopoietic cells
Priority: May 9, 2000Filed: May 9, 2001Published: Oct 24, 2002
Est. expiryMay 9, 2020(expired)· nominal 20-yr term from priority
Inventors:Christopher R. TudanAhmed MerzoukLakhdar ArabGeeta SaxenaConnie EavesJohanne CashmanIan Clark-LewisHassan Salari
A61P 35/00A61K 48/00C07K 14/522C07K 14/4703A61P 35/02A61K 38/1709C12N 5/0647A61K 38/10C12N 2501/21A61P 43/00
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Claims
Abstract
In accordance with various aspects of the invention, CXCR4 antagonists may be used to treat hematopoietic cells, such as progenitor or stem cells, to promote the rate of cellular multiplication, self-renewal, proliferation or expansion. CXCR4 antagonists may be used therapeutically to stimulate hematopoietic stem/progenitor cell multiplication/self-renewal.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A method of promoting the rate of hematopoietic cell multiplication, comprising administering an effective amount of a CXCR4 antagonist to hematopoietic cells.
2 . The method of claim 1 , wherein the hematopoietic cells are hematopoietic stem or progenitor cells.
3 . A method of increasing the circulation of hematopoietic cells in a patient in need of such treatment, comprising administering to the patient an effective amount of a CXCR4 antagonist to mobilize the hematopoietic cells from a marrow locus to a peripheral blood locus.
4 . The method of claim 1 , further comprising introducing a heterologous gene into the hematopoietic cells for gene therapy.
5 . The method of claim 1 , wherein the hematopoietic cells are ex vivo.
6 . The method of claim 1 , wherein the hematopoietic cells are in vivo.
7 . The method of claim 1 , wherein the hematopoietic cells are selected from the group consisting of hematopoietic stem cells and hematopoietic progenitor cells (including CFU-GEMM, BFU-E, CFU-Meg, CFU-GM, CFU-M/DC CFU-Eo, CFU-Bas, Pro-B cells and lymphoid stem cells), that are known to differentiate into mature myeloid and lympoid blood cells, including erythrocytes, platelets, neutrophils, monocytes, macrophages, dendritic cells (myeloid and lymphoid related), eosinophils, basophils, mast cells, B cells. and T cells.
8 . The method of claim 1 , wherein the CXCR4 antagonist comprises a CXCR4 antagonist peptide.
9 . The method of claim 8 , wherein the CXCR4 antagonist peptide is selected from the group consisting of:
KGVSLSYRCPCRFFESHVARANVKHLKILNTPNCALQIVARLKNNNRQ
(SEQ ID No. 1)
VCIDPKLKWIQEYLEKALN;
KGVS P SYRCPCRFFESHVARANVKHLKILNTPNCALQIVARLKNNNRQ
(SEQ ID No. 2)
VCIDPKLKWIQEYLEKALN;
KGVSL P YRCPCRFFESHVARANVKHLKILNTPNCALQIVARLKNNNRQ
(SEQ ID No. 3)
VCIDPKLKWIQEYLEKALN;
KGVSLS P RCPCRFFESHVARANVKHLKILNTPNCALQIVARLKNNNRQ
(SEQ ID No. 4)
VCIDPKLKWIQEYLEKALN;
KGVSLSY P CPCRFFESHVARANVKHLKILNTPNCALQIVARLKNNNRQ
(SEQ ID No. 5)
VCIDPKLKWIQEYLEKALN;
KGVS P* SYRGPCRFFESHVARANVKHLKILNTPNCALQIVARLKNNNR
(SEQ ID No. 6)
QVCIDPKLKW1QEYLEKALN;
KGVSL P* YRCPCRFFESHVARANVKHLKILNTPNCALQIVARLKNNNR
(SEQ ID No. 7)
QVCIDPKLKWIQEYLEKALN;
KGVSLS P* RCPCRFFESHVARANVKHLKILNTPNCALQIVARLKNNNR
(SEQ ID No. 8)
QVCIDPKLKWIQEYLEKALN;
KGVSLSY P* CPCRFFESHVARANVKHLKILNTPNCALQIVARLKNNNR
(SEQ ID No. 9)
QVCIDPKLKWIQEYLEKALN;
KGVS Btd YRCPCRFFESHVARANVKHLKILNTPNCALQIVARLKNNNR
(SEQ ID No. 10)
QVCIDPKLKWIQEYLEKALN;
KGVSL Btd RCPCRFFESHVARANVKHLKILNTPNCALQIVARLKNNNR
(SEQ ID No. 11)
QVCIDPKLKWIQEYLEKALN;
KGVSLS Btd CPCRFFESHVARANVKHLKILNTPNCALQIVARLKNNNR
(SEQ ID No. 12)
QVCIDPKLKWIQEYLEKALN;
wherein P*=
with X=Ar, Ar—OH, alkyl and more
and Btd=
X=Alkyl, Ar, Ar—OH and more
10 . The method of claim 8 , wherein the CXCR4 antagonist peptide is selected from the group consisting of:
a) KGVSLSYRCPCRFFESH b) KGVSLSYRC
11 . The method of claim 8 , wherein the CXCR4 antagonist peptide is selected from the group consisting of:
KGVS P SYRCPCRFFESH
(SEQ ID No. 17)
KGVSL P YRCPCRFFESH
(SEQ ID No. 18)
KGVSLS P RCPCRFFESH
(SEQ ID No. 19)
KGVSLSY P CPCRFFESH
(SEQ ID No. 20)
KGVS P* SYRCPCRFFESH
(SEQ ID No. 21)
KGVSL P* YRCPCRFFESH
(SEQ ID No. 22)
KGVSLS P* RCPCRFFESH
(SEQ ID No. 23)
KGVSLSY P* CPCRFFESH
(SEQ ID No. 24)
KGVS Btd YRCPCRFFESH
(SEQ ID No. 25)
KGVSL Btd RCPCRFFESH
(SEQ ID No. 26)
KGVSLSBtdCPCRFFESH
(SEQ ID No. 27)
KGVS P SYRC
(SEQ ID No. 28)
KGVSL P YRC
(SEQ ID No. 29)
KGVSLS P RC
(SEQ ID No. 30)
KGVSLSY P C
(SEQ ID No. 31)
KGVS P* SYRC
(SEQ ID No. 32)
KGVSL P* YRC
(SEQ ID No. 33)
KGVSLS P* RC
(SEQ ID No. 34)
KGVSLSY P* C
(SEQ ID No. 35)
KGVS Btd YRC
(SEQ ID No. 36)
KGVSL Btd RC
(SEQ ID No. 37)
KGVSLS Btd C
(SEQ ID No. 38)
wherein P*=
with X=Ar, Ar—OH, alkyl and more
and Btd=
X=Alkyl, Ar, Ar—OH and more
12 . The method of claim 8 , wherein the CXCR4 antagonist peptide is selected from the group consisting of:
KGVS P SYRC
KGVSL P YRC
KGVSLS P RC
KGVSLSY P C
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KGVS P SYRC
KGVSL P YRC
KGVSLS P RC
KGVSLSY P C
KGVS P* SYRC
KGVSL P* YRC
KGVSLS P* RC
KGVSLSY P* C
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KGVS P* SYRC
KGVSL P* YRC
KGVSLS P* RC
KGVSLSY P* C
KGVS Btd YRC
KGVSL Btd RC
KGVSLS Btd C
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KGVS Btd YRC
KGVSL Btd RC
KGVSLS Btd C
wherein P*=
with X=Ar, Ar—OH, alkyl and more and Btd=
X=Alkyl, Ar, Ar—OH and more
13 . The method of claim 8 , wherein the CXCR4 antagonist peptide is selected from the group consisting of:
KGVS P SYR
KGVSL P YR
KGVSLS P R
KGVSLSY P
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X
X
X
X
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KGVS P SYR
KGVSL P YR
KGVSLS P R
KGVSLSY P
KGVS P* SYR
KGVSL P* YR
KGVSLS P* R
KGVSLSY P*
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X
X
X
X
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KGVS P* YR
KGVSL P* YR
KGVSLS P* R
KGVSLSY P*
KGVS Btd YR
KGVSL Btd R
KGVSLS Btd
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X
X
X
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KGVS Btd YR
KGVSL Btd R
KGVSLS Btd
wherein X is a natural or unnatural amino acid linker between each of the arginines at position 8 in each sequencel; and,
wherein P*=
with X=Ar, Ar—OH, alkyl and more
and Btd=
X=Alkyl, Ar, Ar—OH and more
14 . The method of claim 8 , wherein the CXCR4 antagonist peptide is selected from the group consisting of:
KGVSLSYRCPCRFF-G n -LKWIQEYLEKALN
(SEQ No. 63)
KGVSLSYRCPCRFFESH-G n -LKWIQEYLEKALN
(SEQ No. 64)
wherein n is an integer from 0 to 10.
15 . The method of claim 8 , wherein the CXCR4 antagonist peptide is selected from the group consisting of:
KGVSLSYRCPCRFF-(CH 2 ) n -LKWIQEYLEKALN
(SEQ
No. 65)
KGVSLSYRCPCRFFESH-(CH 2 ) n -LKWIQEYLEKALN
(SEQ
No. 66)
where n is an integer from 1 to 20.
16 . The method of claim 8 , wherein the CXCR4 antagonist peptide is selected from the group consisting of:
KGVS P SYRCPCRFF-GGGG-LKWIQEYLEKALN;
KGVSL P YRCPCRFF-GGGG-LKWIQEYLEKALN;
KGVSLS P RCPCRFF-GGGG-LKWIQEYLEKALN;
KGVSLSY P CPCRFF-GGGG-LKWIQEYLEKALN;
KGVS P SYRCPCRFFESH-GGGG-LKWIQEYLEKALN;
KGVSL P YRCPCRFFESH-GGGG-LKWIQEYLEKALN;
KGVSLS P RCPCRFFESH-GGGG-LKWIQEYLEKALN;
KGVSLSY P CPCRFFESH-GGGG-LKWIQEYLEKALN;
KGVS P SYRCPCRFF-(CH 2 ) n -LKWIQEYLEKALN;
KGVSL P YRCPCRFF-(CH 2 ) n -LKWIQEYLEKALN;
KGVSLS P RCPCRFF-(CH 2 ) n -LKWIQEYLEKALN;
KGVSLSY P CPCRFF-(CH 2 ) n -LKWIQEYLEKALN;
KGVS P SYRCPCRFFESH-(CH 2 ) n -LKWIQEYLEKALN;
KGVSL P YRCPCRFFESH-(CH 2 ) n -LKWIQEYLEKALN;
KGVSLS P RCPCRFFESH-(CH 2 ) n -LKWIQEYLEKALN;
KGVSLSY P CPCRFFESH-(CH 2 ) n -LKWIQEYLEKALN,
wherein n is an integer from 1 to 20.
17 . The method of claim 8 , wherein the CXCR4 antagonist peptide is selected from the group consisting of:
KGVSP*SYRCPCRFF-GGGG-LKWIQEYLEKALN;
KGVSLP*YRCPCRFF-GGGG-LKWIQEYLEKALN;
KGVSLSP*RCPCRFF-GGGG-LKWIQEYLEKALN;
KGVSLSYP*CPCRFF-GCGG-LKWIQEYLEKALN;
KGVSP*SYRCPCRFFESH-GGGG-LKWIQEYLEKALN;
KGVSLP*YRCPCRFFESH-GGGG-LKWIQEYLEKALN;
KGVSLSP*RCPCRFFESH-GGGG-LKWIQEYLEKALN;
KGVSLSYP*CPCRFFESH-GGGG-LKWIQEYLEKALN;
KGVSP*SYRCPCRFF-(CH 2 ) n -LKWIQEYLEKALN;
KGVSLP*YRCPCRFF-(CH 2 ) n -LKWIQEYLEKALN;
KGVSLSP*RCPCRFF-(CH 2 ) n -LKWIQEYLEKALN;
KGVSLSYP*CPCRFF-(CH 2 ) n -LKWIQEYLEKALN;
KGVSP*SYRCPCRFFESH-(CH 2 ) n -LKWIQEYLEKALN;
KGVSLP*YRCPCRFFESH-(CH 2 ) n -LKWIQEYLEKALN;
KGVSLSP*RCPCRFFESH-(CH 2 ) n -LKWIQEYLEKALN;
KGVSLSYP*CPCRFFESH-(CH 2 ) n -LKWIQEYLEKALN;
KGVSBtdSYRCPCRFF-GGGG-LKWIQEYLEKALN;
KGVSLBtdRCPCRFF-GGGG-LKWIQEYLEKALN;
KGVSLSBtdCPCRFF-GGGG-LKWIQEYLEKALN;
KGVSBtdYRCPCRFFESH-GGGG-LKWIQEYLEKALN;
KGVSLBtdRCPCRFFESH-GGGG-LKWIQEYLEKALN;
KGVSLSBtdCPCRFFESH-GGGG-LkWIQEYLEKALN;
KGVSBtdYRCPCRFF-(CH 2 ) n -LKWIQEYLEKALN;
KGVSLBtdRCPCRFF-(CH 2 ) n -LKWIQEYLEKALN;
KGVSLSBtdCPCRFF-(CH 2 ) n -LKWIQEYLEKALN;
KGVSBtdYRCPCRFFESH-(CH 2 ) n -LKWIQEYLEKALN
KGVSLBtdRCPCRFFESH-(CH 2 ) n -LKWIQEYLEKALN;
KGVSLSBtdCPCRFFESH-(CH 2 ) n -LKWIQEYLEKALN,
wherein n is an integer from 0 to 20 and
wherein P*=
with X=Ar, Ar—OH, alkyl and more
and Btd=
X=Alkyl, Ar, Ar—OH and more
18 . The method of claim 8 , wherein the CXCR4 antagonist peptide is selected from the group consisting of:
19 . A CXCR4 antagonist peptide selected from the group consisting of:
20 . The method of claim 8 , wherein the CXCR4 antagonist peptide is selected from the group consisting of:
KGVSLSYRCPCRFFGGGGSKPGVIFLTKRSRQV;
KGVSLSYRCPCRFF(CH 2 ) n SKPGVIFLTKRSRQV;
KGVSLSYRCPCRFFGGGGEEWVQKYVDDLELSA;
KGVSLSYRCPCRFF(CH 2 ) n EEWVQKYVDDLELSA,
where n is 0 or an integer between 1 and 20.
21 . A method of treating a cancer in a patient in need of such treatment comprising administering an effective amount of a CXCR4 antagonist to the patient to promote the rate of hematopoietic cell multiplication.
22 . A method of treating an autoimmune disease in a patient in need of such treatment comprising administering an effective amount of a CXCR4 antagonist to the patient to promote the rate of hematopoietic cell multiplication.Join the waitlist — get patent alerts
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