Claims for Patent: 8,900,588

Summary for Patent: 8,900,588

Title:	Methods for treating breast cancer
Abstract:	The present disclosure is directed to methods of treating and preventing breast cancer or recurrence of breast cancer with compositions comprising anti-progastrin antibodies.
Inventor(s):	Floch; Jean-Francois (Sete, FR), Houhou; Leila (Montpellier, FR), Cailler; Francoise (Montpellier, FR), Joubert; Dominique (Sete, FR), Hollande; Frederic (Les Matelles, FR)
Assignee:	Les Laboratories Servier (Suresnes, FR) Institut National de la Sante et de la Recherche Medicale (INSERM) (Paris, FR) Centre National de la Recherche Scientifique (CNRS) (Paris, FR)
Application Number:	12/984,509
Patent Claims:	1. A method for treating breast cancer, comprising the step of administering to a patient in need of treatment for breast cancer a therapeutically effective amount of a composition comprising a neutralizing anti-hPG monoclonal antibody that specifically binds to hPG and competes for binding to hPG with a reference antibody selected from: (a) a monoclonal antibody comprising a heavy variable domain sequence of SEQ ID NO:12 and a light chain variable domain sequence of SEQ ID NO:13; (b) a monoclonal antibody comprising a heavy variable domain sequence of SEQ ID NO:59 and a light chain variable domain sequence of SEQ ID NO:63; (c) a monoclonal antibody comprising a heavy variable domain sequence of SEQ ID NO:60 and a light chain variable domain sequence of SEQ ID NO:64; (d) a monoclonal antibody comprising a heavy variable domain sequence of SEQ ID NO:61 and a light chain variable domain sequence of SEQ ID NO:65; and (e) a monoclonal antibody comprising a heavy variable domain sequence of SEQ ID NO:62 and a light chain variable domain sequence of SEQ ID NO:66. 2. The method of claim 1, wherein said breast cancer is a primary breast cancer. 3. The method of claim 1, wherein said breast cancer is metastatic breast cancer. 4. The method of claim 1, wherein the step of administering said composition is effected before surgical resection of a breast tumor. 5. The method of claim 1, wherein the step of administering said composition is effected after surgical resection of a breast tumor. 6. The method of claim 1, wherein said composition is administered adjunctive to chemotherapy or radiation therapy. 7. The method of claim 6, wherein said chemotherapy includes treatment with a chemotherapeutic agent selected from the group consisting of folate antagonists, purine antagonists, pyrimidine antagonists, DNA alkylating agents, DNA cross-linking drugs, antibiotics, platinum complexes, proteosome inhibitors, mitotic spindle poisons, topoisomerase inhibitors, and tyrosine kinase inhibitors. 8. The method of claim 1, wherein the composition is administered adjunctive to a hormone therapy agent. 9. The method of claim 8, in which the hormone therapy agent is bicalutamide, flutamide, fulvestrant, leuprolide acetate, megestrol acetate, tamoxifen, raloxifene, anastrozole, exemestane or letrozole. 10. The method of claim 1, wherein the composition is administered adjunctive to a second therapeutic antibody that specifically binds EGFR, VEGF, or HER2. 11. The method of claim 10, in which the second therapeutic antibody is panitumumab, bevacizumab, cetuximab or trastuzumab. 12. The method of claim 1, wherein said composition is administered by a mode of administration selected from among the group consisting of: parenteral administration, intrathecal administration, intravenous administration, subcutaneous administration, intramuscular administration, intraperitoneal administration, infusion administration, and bolus administration. 13. The method of claim 1, wherein said composition is administered at a neutralizing anti-hPG monoclonal antibody dose ranging from about 0.001 mg/kg to about 250 mg/kg. 14. The method of claim 13, wherein said neutralizing anti-hPG monoclonal antibody dose is administered over a plurality of temporally spaced administrations. 15. The method of claim 1, wherein said reference antibody comprises a heavy variable domain sequence of SEQ ID NO:12 and a light chain variable domain sequence of SEQ ID NO:13. 16. The method of claim 15, wherein said neutralizing anti-hPG monoclonal antibody inhibits binding of the reference antibody to hPG with a K.sub.i ranging from 10 pM to 100 nM; wherein said K.sub.i is determined using an assay comprising the following steps: (a) coating the wells of a 96-well plate with a capture anti-hPG antibody using a concentration of capture anti-hPG antibody from 1 to 10 .mu.g/mL overnight at 4.degree. C., wherein said capture anti-hPG antibody binds an epitope different than the neutralizing anti-hPG antibody; (b) blocking the coated wells with a blocking buffer; (c) incubating the coated wells with hPG at a concentration between 10 pM and 1 nM for 2 hours at 22.degree. C.; (d) incubating the coated wells with biotinylated reference antibody and increasing concentrations of unlabeled neutralizing anti-hPG antibodies for 1 hour at 22.degree. C.; (e) removing unbound antibodies; (f) detecting bound labeled biotinylated reference antibody using streptavidin-HRP and a fluorogenic substrate. 17. The method of claim 1, wherein said reference antibody comprises a heavy variable domain sequence of SEQ ID NO:59 and a light chain variable domain sequence of SEQ ID NO:63. 18. The method of claim 17, wherein said neutralizing anti-hPG monoclonal antibody inhibits binding of the reference antibody to hPG with a K.sub.i ranging from 10 pM to 100 nM; wherein said K.sub.i is determined using an assay comprising the following steps: (a) coating the wells of a 96-well plate with a capture anti-hPG antibody using a concentration of capture anti-hPG antibody from 1 to 10 .mu.g/mL overnight at 4.degree. C., wherein said capture anti-hPG antibody binds an epitope different than the neutralizing anti-hPG antibody; (b) blocking the coated wells with a blocking buffer; (c) incubating the coated wells with hPG at a concentration between 10 pM and 1 nM for 2 hours at 22.degree. C.; (d) incubating the coated wells with biotinylated reference antibody and increasing concentrations of unlabeled neutralizing anti-hPG antibodies for 1 hour at 22.degree. C.; (e) removing unbound antibodies; (f) detecting bound labeled biotinylated reference antibody using streptavidin-HRP and a fluorogenic substrate. 19. The method of claim 1, wherein said reference antibody comprises a heavy variable domain sequence of SEQ ID NO:60 and a light chain variable domain sequence of SEQ ID NO:64. 20. The method of claim 19, wherein said neutralizing anti-hPG monoclonal antibody inhibits binding of the reference antibody to hPG with a K.sub.i ranging from 10 pM to 100 nM; wherein said K.sub.i is determined using an assay comprising the following steps: (a) coating the wells of a 96-well plate with a capture anti-hPG antibody using a concentration of capture anti-hPG antibody from 1 to 10 .mu.g/mL overnight at 4.degree. C., wherein said capture anti-hPG antibody binds an epitope different than the neutralizing anti-hPG antibody; (b) blocking the coated wells with a blocking buffer; (c) incubating the coated wells with hPG at a concentration between 10 pM and 1 nM for 2 hours at 22.degree. C.; (d) incubating the coated wells with biotinylated reference antibody and increasing concentrations of unlabeled neutralizing anti-hPG antibodies for 1 hour at 22.degree. C.; (e) removing unbound antibodies; (f) detecting bound labeled biotinylated reference antibody using streptavidin-HRP and a fluorogenic substrate. 21. The method of claim 1, wherein said reference antibody comprises a heavy variable domain sequence of SEQ ID NO:61 and a light chain variable domain sequence of SEQ ID NO:65. 22. The method of claim 21, wherein said neutralizing anti-hPG monoclonal antibody inhibits binding of the reference antibody to hPG with a K.sub.i ranging from 10 pM to 100 nM; wherein said K.sub.i is determined using an assay comprising the following steps: (a) coating the wells of a 96-well plate with a capture anti-hPG antibody using a concentration of capture anti-hPG antibody from 1 to 10 .mu.g/mL overnight at 4.degree. C., wherein said capture anti-hPG antibody binds an epitope different than the neutralizing anti-hPG antibody; (b) blocking the coated wells with a blocking buffer; (c) incubating the coated wells with hPG at a concentration between 10 pM and 1 nM for 2 hours at 22.degree. C.; (d) incubating the coated wells with biotinylated reference antibody and increasing concentrations of unlabeled neutralizing anti-hPG antibodies for 1 hour at 22.degree. C.; (e) removing unbound antibodies; (f) detecting bound labeled biotinylated reference antibody using streptavidin-HRP and a fluorogenic substrate. 23. The method of claim 1, wherein said reference antibody comprises a heavy variable domain sequence of SEQ ID NO:62 and a light chain variable domain sequence of SEQ ID NO:66. 24. The method of claim 23, wherein said neutralizing anti-hPG monoclonal antibody inhibits binding of the reference antibody to hPG with a K.sub.i ranging from 10 pM to 100 nM; wherein said K.sub.i is determined using an assay comprising the following steps: (a) coating the wells of a 96-well plate with a capture anti-hPG antibody using a concentration of capture anti-hPG antibody from 1 to 10 .mu.g/mL overnight at 4.degree. C., wherein said capture anti-hPG antibody binds an epitope different than the neutralizing anti-hPG antibody; (b) blocking the coated wells with a blocking buffer; (c) incubating the coated wells with hPG at a concentration between 10 pM and 1 nM for 2 hours at 22.degree. C.; (d) incubating the coated wells with biotinylated reference antibody and increasing concentrations of unlabeled neutralizing anti-hPG antibodies for 1 hour at 22.degree. C.; (e) removing unbound antibodies; (f) detecting bound labeled biotinylated reference antibody using streptavidin-HRP and a fluorogenic substrate. 25. The method of claim 1, wherein said neutralizing anti-hPG monoclonal antibody comprises a heavy chain variable region in which complementarity determining region (CDR) 1 comprises the amino acid sequence of V.sub.H CDR 1.3 (SEQ ID NO:1), CDR2 comprises the amino acid sequence of V.sub.H CDR 2.3 (SEQ ID NO:2), and CDR3 comprises the amino acid sequence of V.sub.H CDR 3.3 (SEQ ID NO:3), and a light chain variable region in which CDR1 comprises the amino acid sequence of V.sub.L CDR 1.3 (SEQ ID NO:4), CDR2 comprises the amino acid sequence of V.sub.L CDR 2.3 (SEQ ID NO:5), and CDR3 comprises the amino acid sequence of V.sub.L CDR 3.3 (SEQ ID NO:6). 26. The method of claim 1, wherein said neutralizing anti-hPG monoclonal antibody comprises a heavy chain variable region in which CDR1 comprises the amino acid sequence of V.sub.H CDR 1.8 (SEQ ID NO:37), CDR2 comprises the amino acid sequence of V.sub.H CDR 2.8 (SEQ ID NO:41), and CDR3 comprises the amino acid sequence of V.sub.H CDR 3.8 (SEQ ID NO:45), and a light chain variable region in which CDR1 comprises the amino acid sequence of V.sub.L CDR 1.8 (SEQ ID NO:49), CDR2 comprises the amino acid sequence of V.sub.L CDR 2.8 (SEQ ID NO:52), and CDR3 comprises the amino acid sequence of V.sub.L CDR 3.8 (SEQ ID NO:55). 27. The method of claim 1, wherein said neutralizing anti-hPG monoclonal antibody comprises a heavy chain variable region in which CDR1 comprises the amino acid sequence of V.sub.H CDR 1.13 (SEQ ID NO:38), CDR2 comprises the amino acid sequence of V.sub.H CDR 2.13 (SEQ ID NO:42), and CDR3 comprises the amino acid sequence of V.sub.H CDR 3.13 (SEQ ID NO:46), and a light chain variable region in which CDR1 comprises the amino acid sequence of V.sub.L CDR 1.13 (SEQ ID NO:50), CDR2 comprises the amino acid sequence of V.sub.L CDR 2.13 (SEQ ID NO:53), and CDR3 comprises the amino acid sequence of V.sub.L CDR 3.13 (SEQ ID NO:56). 28. The method of claim 1, wherein said neutralizing anti-hPG monoclonal antibody comprises a heavy chain variable region in which CDR1 comprises the amino acid sequence of V.sub.H CDR 1.16 (SEQ ID NO:39), CDR2 comprises the amino acid sequence of V.sub.H CDR 2.16 (SEQ ID NO:43), and CDR3 comprises the amino acid sequence of V.sub.H CDR 3.16 (SEQ ID NO:47), and a light chain variable region in which CDR1 comprises the amino acid sequence of V.sub.L CDR 1.16 (SEQ ID NO:50), CDR2 comprises the amino acid sequence of V.sub.L CDR 2.16 (SEQ ID NO:53), and CDR3 comprises the amino acid sequence of V.sub.L CDR 3.16 (SEQ ID NO:57). 29. The method of claim 1, wherein said neutralizing anti-hPG monoclonal antibody comprises a heavy chain variable region in which CDR1 comprises the amino acid sequence of V.sub.H CDR 1.19 (SEQ ID NO:40), CDR2 comprises the amino acid sequence of V.sub.H CDR 2.19 (SEQ ID NO:44), and CDR3 comprises the amino acid sequence of V.sub.H CDR 3.19 (SEQ ID NO:48), and a light chain variable region in which CDR1 comprises the amino acid sequence of V.sub.L CDR 1.19 (SEQ ID NO:51), CDR2 comprises the amino acid sequence of V.sub.L CDR 2.19 (SEQ ID NO:54), and CDR3 comprises the amino acid sequence of V.sub.L CDR 3.19 (SEQ ID NO:58). 30. The method of any one of claims 1 and 15-29, wherein said neutralizing anti-hPG monoclonal antibody is humanized. 31. The method of any one of claims 1 and 15-24, wherein said neutralizing anti-hPG monoclonal antibody has an hPG binding affinity in a range of about 0.001 nM to about 5000 nM. 32. A method for preventing recurrence of breast cancer, comprising the step of administering to a patient in need of prevention of recurrence of breast cancer a composition comprising a neutralizing anti-hPG monoclonal antibody that specifically binds to hPG in an amount effective to prevent recurrence of breast cancer, wherein said breast cancer is hPG sensitive, and wherein said neutralizing anti-hPG monoclonal antibody competes for binding to hPG with a reference antibody selected from: (a) a monoclonal antibody comprising a heavy variable domain sequence of SEQ ID NO:12 and a light chain variable domain sequence of SEQ ID NO:13; (b) a monoclonal antibody comprising a heavy variable domain sequence of SEQ ID NO:59 and a light chain variable domain sequence of SEQ ID NO:63; (c) a monoclonal antibody comprising a heavy variable domain sequence of SEQ ID NO:60 and a light chain variable domain sequence of SEQ ID NO:64; (d) a monoclonal antibody comprising a heavy variable domain sequence of SEQ ID NO:61 and a light chain variable domain sequence of SEQ ID NO:65; and (e) a monoclonal antibody comprising a heavy variable domain sequence of SEQ ID NO:62 and a light chain variable domain sequence of SEQ ID NO:66. 33. A method of inhibiting proliferation of a breast cancer stem cell, comprising exposing a breast cancer stem cell with a CD44(+)/CD24(-), CD44(+)/CD24(low) or CD44(+)/CD24(-)/ESA(+) marker phenotype to an amount of a neutralizing anti-hPG monoclonal antibody effective to inhibit its proliferation, wherein said neutralizing anti-hPG monoclonal antibody specifically binds to hPG and competes for binding to hPG with a reference antibody selected from: (a) a monoclonal antibody comprising a heavy variable domain sequence of SEQ ID NO:12 and a light chain variable domain sequence of SEQ ID NO:13; (b) a monoclonal antibody comprising a heavy variable domain sequence of SEQ ID NO:59 and a light chain variable domain sequence of SEQ ID NO:63; (c) a monoclonal antibody comprising a heavy variable domain sequence of SEQ ID NO:60 and a light chain variable domain sequence of SEQ ID NO:64; (d) a monoclonal antibody comprising a heavy variable domain sequence of SEQ ID NO:61 and a light chain variable domain sequence of SEQ ID NO:65; and (e) a monoclonal antibody comprising a heavy variable domain sequence of SEQ ID NO:62 and a light chain variable domain sequence of SEQ ID NO:66.

Details for Patent 8,900,588

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	09/25/1998		2039-02-26
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	02/10/2017		2039-02-26
Eli Lilly And Company	ERBITUX	cetuximab	Injection	125084	02/12/2004		2039-02-26