Claims for Patent: 8,410,045
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Summary for Patent: 8,410,045
Title: | Camptothecin-peptide conjugates and pharmaceutical compositions containing the same |
Abstract: | The present invention relates to a novel compound of use in the improved delivery of therapeutic drug agents into target cells or tissues, composition comprising the same and uses thereof. The compound is more specifically a conjugate of a peptide moiety and a camptothecin, a derivative or analog thereof which provides numerous benefits, including enhancement in terms of aqueous solubility, pharmacokinetics and tissue distribution, enlargement of the therapeutic index, and limitation of the inter-patient metabolic variability, as well as improvement of delivery of the biologically active ingredient to the target cells or tissues. |
Inventor(s): | Michel; Matthieu (Le Vesinet, FR), Ravel; Denis (Paris, FR), Ribes; Fabien (Marseille, FR), Tranchant; Isabelle (Le Kremlin-Bic tre, FR) |
Assignee: | Drais Pharmaceuticals, Inc. (Bridgewater, NJ) |
Application Number: | 12/295,508 |
Patent Claims: | 1. A conjugate comprising at least one camptothecin, wherein said conjugate has the following formula (VI): ##STR00036## wherein X represents a cell penetrating
peptide (CPP), which is attached to the remainder of the conjugate by a thioether bond, wherein the cell penetrating peptide comprises an amino acid sequence selected from the group consisting of: DPV3 (SEQ ID NO: 1): Arg Lys Lys Arg Arg Arg Glu Ser Arg
Lys Lys Arg Arg Arg Glu Ser DPV6 (SEQ ID NO: 2): Gly Arg Pro Arg Glu Ser Gly Lys Lys Arg Lys Arg Lys Arg Leu Lys Pro DPV7 (SEQ ID NO: 3): Gly Lys Arg Lys Lys Lys Gly Lys Leu Gly Lys Lys Arg Asp Pro DPV7b (SEQ ID NO: 4): Gly Lys Arg Lys Lys Lys Gly Lys
Leu GIy Lys Lys Arg Pro Arg Ser Arg DPV10 (SEQ ID NO: 5): Ser Arg Arg Ala Arg Arg Ser Pro Arg His Leu Gly Ser Gly DPV3/10 (SEQ ID NO: 6): Arg Lys Lys Arg Arg Arg Glu Ser Arg Arg Ala Arg Arg Ser Pro Arg His Leu DPV10/6 (SEQ ID NO: 7): Ser Arg Arg Ala Arg
Arg Ser Pro Arg Glu Ser Gly Lys Lys Arg Lys Arg Lys Arg DPV1047 (SEQ ID NO: 8): Val Lys Arg Gly Leu Lys Leu Arg His Val Arg Pro Arg Val Thr Arg Met Asp Val DPV1048 (SEQ ID NO: 9): Val Lys Arg Gly Leu Lys Leu Arg His Val Arg Pro Arg Val Thr Arg Asp Val
DPV15 (SEQ ID NO: 10): Leu Arg Arg Glu Arg Gln Ser Arg Leu Arg Arg Glu Arg Gln Ser Arg and DPV15b (SEQ ID NO: 11): Gly Ala Tyr Asp Leu Arg Arg Arg Glu Arg Gln Ser Arg Leu Arg Arg Arg Glu Arg Gln Ser Arg; Y represents the camptothecin and is represented
by: ##STR00037## wherein t is 0, 1 or 2 and Z is a --COO--group or a substituted or unsubstituted divalent alkyl group; Y is attached to the remainder of the conjugate by an ester bond, a carbonyl-disulfide bond or a carboxy-thioester bond; B is a
cyclo(C.sub.3--C.sub.8)alkyl, R.sub.1 is a (C.sub.1--C.sub.8) alkyl, optionally interrupted by at least one cycloalkyl group, and optionally interrupted by at least one divalent radical selected from --CONR'--and --NR''OC(O) --, wherein R' and R''
independently from each other are selected from hydrogen and (C.sub.1--C.sub.8) alkyl; and R.sub.2 is a (C.sub.1--C.sub.8) alkyl interrupted by at least one cycloalkyl group, said (C.sub.1--C.sub.8) alkyl optionally interrupted by at least one divalent
radical selected from --OC(O)--, --CO.sub.2--, --CONR'--, --NR'CO--, --OC(O)NR'--, and --NR''C(O).sub.2--, wherein R' and R'' independently from each other are selected from hydrogen and (C.sub.1--C.sub.8) alkyl.
2. The conjugate according to claim 1, wherein Y is represented by the following formula (III): ##STR00038## 3. The conjugate according to claim 2, wherein Y is represented by the following formula (IV): ##STR00039## 4. The conjugate according to claim 1, wherein the camptothecin is selected from the group consisting of irinotecan, topotecan, GI-1472 11C, SN38, 7-hydroxymethyl camptothecin, 9-aminocamptothecin, 7-aminomethyl camptothecin, 10-hydroxycamptothecin and (20S)-camptothecin. 5. The conjugate according to claim 1, wherein --R.sub.1 is --CH.sub.2--or --CH.sub.2CH.sub.2--. 6. The conjugate according to claim 1, wherein camptothecin is linked covalently to the cell penetrating peptide with a linker resulting from a compound selected from: 4-[(N-maleimidomethyl)cyclohexane-1-carboxy-6-amidohexanecarboxamido methyl]cyclohexanecarboxylic acid and 4-[((N-maleimidomethyl)cyclohexanecarboxamido)methyl]cyclohexanecarboxyli- c acid. 7. The conjugate according to claim 1, wherein the peptide is derived from a human heparin binding protein and capable of penetrating into a cell or tissue and comprises: - DPV1047 (SEQ ID NO: 8): Val Lys Arg Gly Leu Lys Leu Arg His Val Arg Pro Arg Val Thr Arg Met Asp Val. 8. The conjugate according to claim 7, wherein the peptide presents a cysteine at the C or N position. 9. The conjugate according to claim 1, which is selected from the group consisting of: ##STR00040## ##STR00041## 10. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and at least one conjugate of claim 1. 11. A method for treating cancer comprising administering an effective amount of the pharmaceutical composition according to claim 10 to a subject in need thereof, wherein said cancer is colon cancer, small cell lung cancer, non-small cell lung cancer, bronchic cancer, pancreatic cancer, ovarian cancer, breast cancer, prostate cancer, liver cancer, head cancer, stomach cancer, neck cancer, bladder cancer, non-Hodgkin's lymphoma, melanoma, leukaemia, neuroblastoma, or glioblastoma. 12. The method of claim 11, wherein the composition is administered orally, intra-cranially, intra-spinally, enterally or parenterally. 13. The method of claim 11, wherein the composition is administered simultaneously or sequentially with other therapeutic regimens or agents. 14. The method of claim 11, comprising a simultaneous or sequential administration with other therapeutic regimens or agents, selected from the group consisting of 5-fluorouracil, leucovorin, oxaliplatine, capecitabine, vincristine, celebrex, temozolomide, selenium, thalidomide, cetuximab, gemcitabine, docetaxel, 3-AP, carboplatine, bortezomib, bevacizumab, sorafenib, cisplatin, gefitinib, flavopiridol, elvorine, carboplatin, amrubicin, trastuzumab, pemetrexed, erlotinib, mitomycin C, AMG706, panitumumab, paclitaxel, raltitrexed, imatinib, abciximab, infliximab, palivizumab, rituximab, gemtuzumab ozogamicin, alemtuzumab, and ibritumomab tiuxetan. |
Details for Patent 8,410,045
Applicant | Tradename | Biologic Ingredient | Dosage Form | BLA | Approval Date | Patent No. | Expiredate |
---|---|---|---|---|---|---|---|
Janssen Biotech, Inc. | REOPRO | abciximab | Injection | 103575 | 12/22/1994 | ⤷ Try a Trial | 2026-03-30 |
Genentech, Inc. | RITUXAN | rituximab | Injection | 103705 | 11/26/1997 | ⤷ Try a Trial | 2026-03-30 |
Idec Pharmaceuticals Corp. | RITUXAN | rituximab | Injection | 103737 | 02/19/2002 | ⤷ Try a Trial | 2026-03-30 |
Swedish Orphan Biovitrum Ab (publ) | SYNAGIS | palivizumab | For Injection | 103770 | 06/19/1998 | ⤷ Try a Trial | 2026-03-30 |
Swedish Orphan Biovitrum Ab (publ) | SYNAGIS | palivizumab | Injection | 103770 | 07/23/2004 | ⤷ Try a Trial | 2026-03-30 |
>Applicant | >Tradename | >Biologic Ingredient | >Dosage Form | >BLA | >Approval Date | >Patent No. | >Expiredate |
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