US20140255413A1 - Combination therapy for neoplasia treatment - Google Patents

Combination therapy for neoplasia treatment Download PDF

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US20140255413A1
US20140255413A1 US14/196,231 US201414196231A US2014255413A1 US 20140255413 A1 US20140255413 A1 US 20140255413A1 US 201414196231 A US201414196231 A US 201414196231A US 2014255413 A1 US2014255413 A1 US 2014255413A1
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igf
receptor antagonist
antibody
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Paul Adam
Katrin FRIEDBICHLER
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Boehringer Ingelheim International GmbH
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4166—1,3-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin
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    • A61K39/39558—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against tumor tissues, cells, antigens
    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • C—CHEMISTRY; METALLURGY
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    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/22—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against growth factors ; against growth regulators
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2863—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for growth factors, growth regulators
    • A—HUMAN NECESSITIES
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    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies

Definitions

  • the present invention relates to the pharmaceutical treatment of neoplasia, including benign and malignant tumors.
  • Prostate cancer is the most common malignancy diagnosed in males and a leading cause of mortality in western countries (American Cancer Society, 2010 (http://www.cancer.org/acs/groups/content/ ⁇ epidemiologysurveilance/documents/document/acspc-026238.pdf)). Androgens and stimulation of their receptor, androgen receptor (AR), are essential for the development and function of the normal prostate gland, and the development and progression of prostate cancer (reviewed in Basu S et al., Horm Cancer. 2010 October; 1(5):223-8.; Yadav N et al., Minerva Urol Nefrol. 2012 March; 64(1):35-49).
  • AR androgen receptor
  • CRPC androgen-independent/castration-resistant prostate cancer
  • Benign prostatic hyperplasia can be detected in the vast majority of men as they age (Parsons J K., Curr Bladder Dysfunct Rep. 2010 December; 5(4):212-218).
  • BPH can be defined as a non-cancerous enlargement of the prostate resulting from a proliferation of both benign stromal, and to a lesser extent, epithelial cells (Foster C S. Prostate 2000; 9:4-14.).
  • DHT dihydrotestosterone
  • IGFs Insulin-like growth factors
  • BPH prostate disease
  • IGFBPs IGF binding proteins
  • IGFBP3 is secreted at particularly low levels in stromal cells in BPH tissue (Boudon C et al., J Clin Endocrinol Metab 1996; 81:612-617.) which may favor hyperplastic growth and play a role in the development of BPH.
  • acromegalic patients who have very high levels of IGF1 and concomitantly low levels of testosterone and DHT, present with enlarged prostates and high rates of BPH (Colao A et al J Clin Endocrinol Metab 1999; 84:1986-1991; Colao A et al, Eur J Endocrinol 2000; 143:61-69.).
  • IGF insulin-like growth factor
  • Castration-resistant prostate cancer has been shown to be sensitive, but not resistant, to sustained manipulation of the androgen/AR axis.
  • the androgen axis can be manipulated using anti-androgens (nilutamide, enzalutamide), androgen synthesis inhibitors (ketonazole, abiraterone acetate), corticosteroids (dexamethasone, prednisone) or estrogen treatment.
  • anti-androgens nilutamide, enzalutamide
  • androgen synthesis inhibitors ketonazole, abiraterone acetate
  • corticosteroids diexamethasone, prednisone
  • estrogen treatment Following the emergence of castration-refractory disease, taxane-based chemotherapy has been shown to be therapeutically efficacious and prolong survival.
  • Enzalutamide is a novel AR antagonist that blocks AR signaling more effectively than currently available AR antagonists (Tran et al., Science 2009; 324(5928): 787-790.) and has shown impressive antitumor activity and a similar impact on overall survival as abiraterone.
  • Antagonists to IGF action and their use in cancer therapy have been described in the art.
  • IGF receptor tyrosine kinase inhibitors see WO2009/009016 and WO2010/099139.
  • antibodies against IGF receptor see WO2002/53596, WO2003/093317, WO2003/106621, WO2006/013472, WO2006/069202.
  • antibodies against IGF ligand see WO2003/093317, WO2005/028515, WO2007/022172, WO2007/070432, WO2008/155387, WO2009/137758, WO2010/066868.
  • IGF-1 receptor antibodies WO2008/098917, WO2009/137378) and IGF ligand antibodies (WO2007/118214, WO2008/155387, WO2009/137758, WO2010/066868) have been proposed for use, inter alia, in the treatment of prostate cancer.
  • prostate neoplasia including benign prostatic hyperplasia (BPH), prostate cancer, and particularly CRPC, there is a significant need for improvements in therapy.
  • BPH benign prostatic hyperplasia
  • CRPC CRPC
  • FIG. 1 Inhibitory Effect of IGF and AR Signaling Blockade on VCaP, MDA PCa 2b and DUCaP Cell Proliferation
  • FIG. 1 shows the inhibitory effect of the IGF mAb — 1 (FIG. 1 A+ 1 C+ 1 E) and IGF mAb — 2 (FIG. 1 B+ 1 D+ 1 F) antibodies and MDV-3100, alone and in combination, on the 2D proliferation of prostate cancer-derived VCaP cells (FIG. 1 A+ 1 B), MDA PCa 2b cells (FIG. 1 C+ 1 D) and DUCaP cells (FIG. 1 E+ 1 F) in 10% FCS-containing growth medium.
  • single agent treatment with both IGF antibodies and MDV-3100 resulted in inhibition of cell proliferation which could be enhanced by the combination of both agents leading to a complete inhibition of proliferation.
  • FIG. 2 Inhibitory Effect of IGF Signaling and Androgen Synthesis Blockade on VCaP, MDA PCa 2b and DUCaP Cell Proliferation
  • FIG. 2 demonstrates the effects of the IGF mAb — 1 and IGF mAb — 2 antibodies and abiraterone acetate (AA), as single agents and in combination, on the 2D and 3D proliferation of prostate cancer-derived VCaP, MDA PCa 2b, and DUCaP cells in 10% FCS-containing growth medium.
  • Panel (A) displays the results of the treatment of VCaP cells with IGF mAb — 1 in 2D cell proliferation assays.
  • IGF mAb — 2 was used for the treatment of VCaP cells in (B).
  • Panel C (IGF mAb — 1) and D (IGF mAb — 2) show the results of MDA PCa 2b cells.
  • the treatment of DUCaP cells with IGF mAb — 1 is displayed in panel E and with IGF mAb — 2 in panel F.
  • Single agent treatment with IGF mAb — 1 and mAb — 2 resulted in inhibition of cell proliferation of 70% to 90%.
  • Abiraterone acetate treatment caused inhibition of cell proliferation at higher concentrations which could be enhanced by the combination with either of the antibodies, lowering the doses of AA needed for complete inhibition.
  • VCaP cells were treated with abiraterone acetate and IGF mAb — 2. Similar to the results observed in 2D, single agent treatment with IGF mAb — 2 results in 96% inhibition of cell proliferation.
  • Abiraterone acetate treatment caused inhibition of cell proliferation at higher concentrations which could be enhanced by the combination with IGF mAb — 2.
  • FIG. 3 Protein Analysis in VCaP, MDA PCa 2b and DUCaP Cells Following IGF and AR Signaling Inhibition
  • FIG. 3 shows the effects of IGF mAb — 1 and MDV-3100, alone and in combination, on IGF-1R, AR and PTEN levels, as well as AKT phosphorylation, in VCaP, MDA PCa 2b and DUCaP cells as assessed by Western blot analyses.
  • Cells were seeded in 6-well plates and treated for 24 hours.
  • FIG. 4 IGF Signaling Pathway Inhibition Following Single Agent and Combination Treatment of IGF mAb — 1 And MDV-3100.
  • FIG. 4 demonstrates the effects of IGF mAb — 1 and MDV-3100 used as single agents and in combination on IGF-1R levels and AKT phosphorylation in VCaP cells over 120 hours of treatment.
  • VCaP cells were seeded in 6-well plates and treated with MDV-3100 and IGF mAb — 1 as single agents or in combination for 24, 48, 72, 96, and 120 hours. Lysates prepared from treated cells were compared to untreated controls for phosphorylation of AKT-Ser473. Combination of both agents resulted in a longer lasting inhibition of AKT phosphorylation than the antibody or MDV-3100 treatments alone.
  • FIG. 5 Reduced Proliferative Activity of VCaP Cells Following Single Agent And Combination Treatment of IGF mAb — 1 and MDV-3100
  • VCAP cells Proliferation of VCAP cells was monitored using a H 3 -thymidine incorporation assay. Treated with 10 ⁇ M of MDV-3100 or 1 ⁇ M of IGF mAb — 1 as single agents for 96 hours reduced proliferative activity by approximately 50%. Combination of IGF mAb — 1 and MDV-3100 reduced thymidine incorporation by more than 95% compared to untreated controls.
  • FIG. 6 Diminished Growth Rate of VCaP Cells Following Single Agent and Combination Treatment of IGF mAb — 1 and MDV-3100
  • FIG. 7 Combination Treatment of IGF mAb — 1 and MDV-3100 Increases Induction of Apoptosis in VCaP Cells
  • Caspase 3 activity was used as a measure of the induction of apoptosis in VCaP cells upon treatment with 10 ⁇ M of MDV-3100 and 1 ⁇ M of mAb as single agents and in combination for up to 96 hours. Whereas MDV-3100 treatment did not induce caspase 3 activity within 96 hours of treatment, an increase in apoptotic events were observed upon treatment with IGF mAb — 1. The combination of both agents showed a synergistic effect on the induction of caspase 3 activity, which was approximately 9-fold increased compared to controls and approximately 2.5-fold higher compared to IGF mAb — 1 treatment.
  • FIG. 8 Cell Cycle Profiles of VCaP Cells Treated with MDV-3100 and IGF mAb — 1
  • the first population to the left is the sub-G1 population representing apoptotic cells
  • the second population shows the G1/G0 peak
  • the light grey population shows cells in the S-phase
  • the population to the right represents cells in the G2/M-phase of the cell cycle.
  • FIG. 9 Protein Analysis of Apoptosis and Cell Cycle Regulators Following IGF Signaling Inhibition
  • the present invention pertains to an insulin-like growth factor (IGF) receptor antagonist for use in the treatment of prostate neoplasia, including benign prostatic hyperplasia (BPH), prostate cancer, and particularly CRPC in combination with an androgen receptor antagonist.
  • IGF insulin-like growth factor
  • the invention in another embodiment, relates to a method of treatment of prostate neoplasia, including benign prostatic hyperplasia (BPH), prostate cancer, and particularly CRPC comprising administering a therapeutically effective amount of an IGF receptor antagonist to a patient in need thereof, and additionally administering a therapeutically effective amount of an androgen receptor antagonist to the same patient on the same day, or one, two, three, four, five, six or seven days before or after administration of the IGF receptor antagonist.
  • BPH benign prostatic hyperplasia
  • the present invention relates to the treatment of prostate neoplasia.
  • prostate neoplasia the aspects of the invention include where the prostate neoplasia is prostate cancer, including benign and malignant tumours, and particularly castration resistant prostate cancer; and also benign prostatic hyperplasia.
  • the present invention pertains to an insulin-like growth factor (IGF) receptor antagonist for use in the treatment of prostate cancer.
  • the prostate cancer is hormone-sensitive prostate cancer.
  • the prostate cancer is prostate cancer after combined androgen blockade.
  • the prostate cancer is prostate cancer treated with antiangiogenic therapy.
  • the prostate cancer has been, or will be, treated with a chemotherapeutic agent.
  • the prostate cancer is prostate cancer treated, or will be treated, with radiation therapy.
  • the prostate cancer is prostate cancer treated, or will be treated, with bone loss therapy, for example denosumab, and hormone ablation.
  • the prostate cancer is castration resistant prostate cancer (CRPC).
  • the castration resistant prostate cancer has been, or will be, treated with a chemotherapeutic agent.
  • the castration resistant prostate cancer has been, or will be, treated with radiation therapy.
  • the prostate cancer is castration resistant prostate cancer in a pre- or post-docetaxel setting.
  • the prostate cancer is castration resistant prostate cancer after cabazitaxel treatment.
  • the prostate cancer is castration resistant prostate cancer after treatment with androgen synthesis inhibitors, for example abiraterone acetate.
  • the prostate cancer is castration resistant prostate cancer after treatment with androgen receptor antagonists, for example enzalutamide.
  • the prostate cancer is castration resistant prostate cancer after treatment with immune-modulating agents, for example Sipuleucel-T.
  • the present invention pertains to an insulin-like growth factor (IGF) receptor antagonist for use in the treatment of prostate cancer incombination with an androgen receptor antagonist.
  • the prostate cancer is hormone-sensitive prostate cancer.
  • the prostate cancer is prostate cancer after combined androgen blockade.
  • the prostate cancer is prostate cancer treated with antiangiogenic therapy.
  • the prostate cancer has been, or will be, treated with a chemotherapeutic agent.
  • the prostate cancer is prostate cancer treated, or will be treated, with radiation therapy.
  • the prostate cancer is prostate cancer treated, or will be treated, with bone loss therapy, for example denosumab, and hormone ablation.
  • the prostate cancer is castration resistant prostate cancer.
  • the castration resistant prostate cancer has been, or will be, treated with a chemotherapeutic agent.
  • the castration resistant prostate cancer has been, or will be, treated with radiation therapy.
  • the prostate cancer is castration resistant prostate cancer in a pre- or post-docetaxel setting.
  • the prostate cancer is castration resistant prostate cancer after cabazitaxel treatment.
  • the prostate cancer is castration resistant prostate cancer after treatment with androgen synthesis inhibitors, for example abiraterone acetate.
  • the prostate cancer is castration resistant prostate cancer after treatment with androgen receptor antagonists, for example enzalutamide.
  • the prostate cancer is castration resistant prostate cancer after treatment with immune-modulating agents, for example Sipuleucel-T.
  • the present invention pertains to an insulin-like growth factor (IGF) receptor antagonist for use in the treatment of benign prostatic hyperplasia. In another aspect, the present invention pertains to an insulin-like growth factor (IGF) receptor antagonist for use in the treatment of benign prostatic hyperplasia in combination with an androgen receptor antagonist.
  • IGF insulin-like growth factor
  • an IGF receptor antagonist within the context of the invention is a compound that interferes with, either directly or indirectly, and reduces or blocks IGF receptor signaling.
  • an IGF receptor antagonist is a compound that reduces or blocks binding of IGF ligand to its receptor, or inhibits the tyrosine kinase activity of the IGF receptor.
  • the IGF receptor antagonist of the present invention is an antibody that binds to IGF ligand and thus reduces or prevents binding of the ligand to the receptor.
  • the IGF receptor antagonist is an antibody that binds to the IGF-1 receptor and thus reduces or prevents binding of the ligand to the receptor. By blocking receptor-ligand binding, ligand-induced receptor signaling through the tyrosine kinase activity of the receptor is reduced or prevented.
  • Such antibodies are generally referred to as neutralizing antibodies.
  • the present invention pertains to an IGF receptor antagonist that neutralizes the growth promoting properties of the insulin-like growth factors, IGF-1 and IGF-2.
  • antibody encompasses antibodies, antibody fragments, antibody-like molecules and conjugates with any of the above. Antibodies include, but are not limited to, poly- or monoclonal, chimeric, humanized, human, mono-, bi- or multispecific antibodies.
  • antibody shall encompass complete immunoglobulins as they are produced by lymphocytes and for example present in blood sera, monoclonal antibodies secreted by hybridoma cell lines, polypeptides produced by recombinant expression in host cells, which have the binding specificity of immunoglobulins or monoclonal antibodies, and molecules which have been derived from such immunoglobulins, monoclonal antibodies, or polypeptides by further processing while retaining their binding specificity.
  • the term “antibody” includes complete immunoglobulins comprising two heavy chains and two light chains.
  • the term encompasses a fragment of an immunoglobulin, like Fab fragments.
  • the term “antibody” encompasses a polypeptide having one or more variable domains derived from an immunobulin, like single chain antibodies (scFv), single domain antibodies, and the like.
  • the IGF receptor antagonist of the invention is an antibody against IGF-1, an antibody against IGF-2, an antibody binding both IGF-1 and IGF-2, an antibody against IGF-1 receptor (IGF-1R), or an inhibitor of IGF-1R tyrosine kinase activity.
  • the IGF receptor antagonist is an IGF ligand antibody having heavy chain complementary determining regions of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3) and light chain determining regions of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3).
  • the IGF receptor antagonist is an IGF ligand antibody having heavy chain complementary determining regions of SEQ ID NO: 11 (HCDR1), SEQ ID NO: 12 (HCDR2), and SEQ ID NO: 13 (HCDR3) and light chain determining regions of SEQ ID NO: 14 (LCDR1), SEQ ID NO: 15 (LCDR2), and SEQ ID NO: 16 (LCDR3).
  • the IGF receptor antagonist is an IGF ligand antibody having heavy chain complementary determining regions of SEQ ID NO: 21 (HCDR1), SEQ ID NO: 22 (HCDR2), and SEQ ID NO: 23 (HCDR3) and light chain determining regions of SEQ ID NO: 24 (LCDR1), SEQ ID NO: 25 (LCDR2), and SEQ ID NO: 26 (LCDR3).
  • the IGF receptor antagonist is an IGF ligand antibody having heavy chain complementary determining regions of SEQ ID NO: 31 (HCDR1), SEQ ID NO: 32 (HCDR2), and SEQ ID NO: 33 (HCDR3) and light chain determining regions of SEQ ID NO: 34 (LCDR1), SEQ ID NO: 35 (LCDR2), and SEQ ID NO: 36 (LCDR3).
  • IGF mAb — 1 An example of an antibody containing these complementary determining regions is designated herein as IGF mAb — 1.
  • the IGF receptor antagonist is an IGF ligand antibody having a heavy chain variable region of SEQ ID NO: 7 and a light chain variable region of SEQ ID NO: 8.
  • the IGF receptor antagonist is an IGF ligand antibody having a heavy chain variable region of SEQ ID NO: 17 and a light chain variable region of SEQ ID NO: 18.
  • the IGF receptor antagonist is an IGF ligand antibody having a heavy chain variable region of SEQ ID NO: 27 and a light chain variable region of SEQ ID NO: 28.
  • the IGF receptor antagonist is an IGF ligand antibody having a heavy chain variable region of SEQ ID NO: 37 and a light chain variable region of SEQ ID NO: 38.
  • An example of an antibody containing these variable regions is designated herein as IGF mAb — 1.
  • the IGF receptor antagonist is an IGF ligand antibody having a heavy chain variable region of SEQ ID NO: 41 and a light chain variable region of SEQ ID NO: 42.
  • the IGF receptor antagonist is an IGF ligand antibody having a heavy chain variable region of SEQ ID NO: 43 and a light chain variable region of SEQ ID NO: 44.
  • the IGF receptor antagonist is an IGF ligand antibody having a heavy chain of SEQ ID NO: 9, and a light chain of SEQ ID NO: 10.
  • the IGF receptor antagonist is an IGF ligand antibody having a heavy chain of SEQ ID NO: 19, and a light chain of SEQ ID NO: 20.
  • the IGF receptor antagonist is an IGF ligand antibody having a heavy chain of SEQ ID NO: 29, and a light chain of SEQ ID NO: 30.
  • the IGF receptor antagonist is an IGF ligand antibody having a heavy chain of SEQ ID NO: 39, and a light chain of SEQ ID NO: 40.
  • An example of an antibody containing these heavy and light chains is designated herein as IGF mAb — 1.
  • the IGF receptor antagonist is an IGF receptor antibody having a heavy chain of SEQ ID NO: 45, and a light chain of SEQ ID NO: 46.
  • the IGF receptor antagonist is figitumumab, dalotuzumab, cixutumumab, robatumumab, or ganitumab.
  • the IGF receptor antagonist is linsitinib.
  • the IGF receptor antagonist is IGF mAb — 1, as defined above.
  • Manufacture and therapeutic use of the aforementioned antibodies is disclosed in WO2002/53596, WO2007/070432, WO2008/152422, WO2008/155387, and WO2010/066868.
  • the antibody is produced by recombinant expression in a mammalian host cell, purified by a series of chromatographic and non-chromatographic steps, and formulated in an aqueous buffer composition for parenteral (intravenous) infusion or injection at an antibody concentration of 10 mg/ml, said buffer comprising for example 25 mM Na citrate pH 6, 115 mM NaCl, and 0.02% polysorbate 20.
  • the pharmaceutical composition may be diluted with a physiological solution, e.g. with 0.9% sodium chloride or G5 solution.
  • the antibody may be administered to the patient at a dose between 1 mg/kg to 20 mg/kg, by one or more separate administrations, or by continuous infusion, e.g. infusion over 1 hour.
  • a typical treatment schedule usually involves administration of the antibody once every week to once every three weeks.
  • a weekly dose could be 5, 10, or 15 mg/kg.
  • the antibody is prepared at a concentration of 10 mg/ml of IGF mAb — 1.
  • the antibody may preferably be administered to a patient as a 750 mg (up to 1000 mg) total dose by one hour i.v. infusion, to be repeated once a week until disease progression
  • the IGF receptor antagonist is administered to the patient in combination with administration of an androgen receptor antagonist.
  • “In combination” means that both drugs are administered to the same patient within a certain time frame to achieve a therapeutic effect caused by the combined effects of both modes of action.
  • the androgen receptor antagonist is administered on the same day as the IGF receptor antagonist.
  • the androgen receptor antagonist is administered one, two, three, four, five, six or seven days before or after administration of the IGF receptor antagonist.
  • both active compounds are present within the same pharmaceutical composition.
  • the invention pertains to a pharmaceutical composition, comprising an IGF receptor antagonist and an androgen receptor antagonist, together with a pharmaceutically acceptable carrier.
  • An androgen receptor antagonist is a compound that blocks androgen receptor (AR) signaling. Androgen receptor antagonists prevent androgens from expressing their biological effects on responsive tissues. Such compounds may alter the androgen pathway by blocking the respective receptors, competing for binding sites on the receptor, affecting nuclear translocation, DNA binding of the receptor, or affecting androgen production.
  • the androgen receptor antagonist can be an anti-androgen, an androgen synthesis inhibitor, a 17 ⁇ -hydroxylase/C17,20 lyase (CYP17A1) inhibitor, a 5-alpha-reductase inhibitor, a corticosteroid, a luteinizing hormone-releasing hormone (LH-RH) agonist, or an estrogen agonist.
  • CYP17A1 17 ⁇ -hydroxylase/C17,20 lyase
  • a 5-alpha-reductase inhibitor a corticosteroid
  • a luteinizing hormone-releasing hormone (LH-RH) agonist or an estrogen agonist.
  • the androgen receptor antagonist is flutamide, nilutamide, enzalutamide, bicalutamide, ketonazole, abiraterone, abiraterone acetate, orteronel, finasteride, dutasteride, bexlosteride, izonsteride, turosteride, episteride, dexamethasone, prednisone, leuprolide, goserelin, triptorelin, histrelin, or estrogen.
  • the androgen receptor antagonist is enzalutamide (Tran et al., Science 2009, 324(5928): 787-790.)
  • Enzalutamide can be obtained from, for example, Medivation or Astellas under the name Xtandi®.
  • Enzalutamide is preferably administered as a dosage of 160 mg once daily during each cycle of treatment
  • the androgen receptor antagonist is abiraterone, for example in the form of abiraterone acetate (Agarwal et al., Future Oncology 2010, 6(5): 665-679).
  • Abieraterone can be obtained from, for example, Janssen Biotech, Inc.
  • Another embodiment of the invention is an androgen receptor antagonist for use in the treatment of prostate cancer in combination with an IGF receptor antagonist.
  • the use of an androgen receptor antagonist in combination with an IGF receptor antagonist is for the treatment of benign prostatic hyperplasia.
  • said androgen receptor antagonist is flutamide, nilutamide, enzalutamide, bicalutamide, ketonazole, abiraterone acetate, orteronel, finasteride, dutasteride, bexlosteride, izonsteride, turosteride, episteride, dexamethasone, prednisone, leuprolide, goserelin, triptorelin, histrelin, or estrogen.
  • Another embodiment of the invention pertains to a method of treatment of prostate neoplasia comprising administering a therapeutically effective amount of an IGF receptor antagonist to a patient in need thereof, and additionally administering a therapeutically effective amount of an androgen receptor antagonist to the same patient on the same day, or one, two, three, four, five, six or seven days before or after administration of the IGF receptor antagonist.
  • prostate neoplasia this aspect of the invention include where the prostate neoplasia is prostate cancer, including benign and malignant tumours, and particularly castration resistant prostate cancer; and also benign prostatic hyperplasia.
  • a “therapeutically effective amount” of the IGF or androgen receptor antagonist to be administered is the minimum amount necessary to prevent, ameliorate, or treat a prostate neoplasia, in particular castration-resistant prostate cancer, or benign prostatic hyperplasia.
  • the invention pertains to the use of an IGF receptor antagonist for the manufacture of a medicament for the treatment of prostate neoplasia, wherein the IGF receptor antagonist is to be used in combination with an androgen receptor antagonist.
  • prostate neoplasia this aspect of the invention include where the prostate neoplasia is prostate cancer, including benign and malignant tumours, and particularly castration resistant prostate cancer; and also benign prostatic hyperplasia.
  • the invention pertains to the use of an androgen receptor antagonist for the manufacture of a medicament for the treatment of prostate cancer neoplasia, wherein the androgen receptor antagonist is to be used in combination with an IGF receptor antagonist.
  • prostate neoplasia this aspect of the invention include where the prostate neoplasia is prostate cancer, including benign and malignant tumours, and particularly castration resistant prostate cancer; and also benign prostatic hyperplasia.
  • IGF mAb — 1 is an antibody against IGF ligand having a heavy chain of SEQ ID NO: 39 and a light chain of SEQ ID NO: 40. Its manufacture has been disclosed in WO 2010/066868.
  • IGF mAb — 2 is an antibody against IGF ligand having a heavy chain of SEQ ID NO: 29 and a light chain of SEQ ID NO: 30. Its manufacture has been disclosed in WO 2010/066868.
  • DU-145 ATCC, HTB-81
  • BM-1604 DSMZ, ACC 298
  • PC-3 ATCC, CRL-1435
  • 22Rv1 ATCC, CRL-2505
  • LNCaP ATCC, CRL-1740
  • DUCaP cells generated in the lab of Prof K J.
  • C4-2 and C4-2b (both licensed from MD Anderson Cancer Center; Thalmann G N et al., Cancer Res. 1994; 54:2577-2581) and VCaP (ATCC, CRL-2876) were cultivated in DMEM (Lonza, #12-604F) supplemented with 10% heat inactivated FCS, 2 mM L-glutamine and R1881 (Sigma, #R0908; VCaP with 0.1 nM and C4-2/C4-2b with 1 nM).
  • MDA-PCa-2b (ATCC, CRL-2422) were grown in F-12K (GIBCO, #21127) supplemented with 20% heat-inactivated FCS, 25 ng/ml cholera toxin, 0.005 mM ethanolamine, 100 pg/ml hydrocortisone, and 45 nM selenious acid.
  • Bob cells (ECACC, #10021102) were cultured in keratinocyte-SFM (Invitrogen, #37010-022) supplemented with prequalified human recombinant epidermal growth factor 1-53, bovine pituitary extract and glutamine, 2 ng/ml leukemia inhibitory factor, 2 ng/ml stem cell factor, 100 ng/ml cholera toxin, and 1 ng/ml granulocyte macrophage colony stimulating factor.
  • keratinocyte-SFM Invitrogen, #37010-022
  • Shmac 4 (ECACC, #10112302), Shmac 5 (ECACC, #10112303) and P4E6 cells (ECACC, #10112301) were grown in Stemline Keratinocyte Medium II (Sigma, #S0196) with Stemline Keratinocyte Growth Supplement (Sigma, #S9945), 2 mM L-glutamine and 2% FCS.
  • the cells were maintained in 75 cm 2 tissue culture flasks (Nunc, #178905) at 37° C. in 5% CO 2 in a humidified atmosphere.
  • the following method was used to determine the inhibitory effect of IGF ligand-neutralizing mAbs and androgen signaling inhibitors on the growth of prostate cancer cell lines. Assays were performed in cell growth medium containing 10% serum.
  • Adherent cells were detached with trypsin/EDTA solution (GIBCO, #043-9031FU), resuspended in growth medium, centrifuged, resuspended in assay medium (supplemented with 10% heat inactivated FCS and 2 mM L-glutamine) and diluted to 5,000-40,000 cells per mL. 100 ⁇ L/well cell suspension was added to each well of a sterile flat-bottom white 96-well plate (PerkinElmer, #6005280) and plates were incubated overnight in a humidified incubator set at +37° C. and 5% CO 2 . On the next day supernatants were aspirated and 35 ⁇ L/well assay medium was added to all wells.
  • CellTiter-Glo is a bioluminescent assay (Promega, #G7571) designed to determine the number of viable cells in culture, in which the generation of a luminescent signal is proportional to the amount of ATP present in cells.
  • 100 ⁇ L of freshly mixed CellTiter-Glo reagent was added to each well. After 2 min on an orbital shaker (MTS 2/4, IKA) and 10 min incubation at RT, luminescence was recorded (luminescence reader (Genios Pro, Tecan or Victor X4, Perkin Elmer), integration time 1 sec).
  • One ⁇ 10 6 and 4 ⁇ 10 6 cells were plated in 6-well plates and 10 cm dishes, respectively, in medium containing 10% heat-inactivated FCS and after over night incubation the cells were treated with 1 ⁇ M of MDV-3100 and 100 nM of IGF mAb — 1 or a combination of antibody and AR signaling inhibitor. After 24 hours the cells were lyzed on the plates, total protein was isolated and protein concentration was determined by Bradford assay. Cell lysates were snap frozen and stored at ⁇ 80° C.
  • Cell cycle regulators and markers of proliferation and apoptosis were analyzed using the following antibodies: p21 Waf1/Cip1 (12D1; #2947, Cell Signaling; 1:1000), CDK2 (78B2; #2546, Cell Signaling; 1:1000), Cyclin E (C-19; sc-198, Santa Cruz; 1:1000), PCNA (#2586, Cell Signaling; 1:2000), and PARP (#9542, Cell Signaling; 1:1000).
  • Antibody dilutions were prepared in 5% BSA or 5% non-fat dry milk in TBS-0.5% Tween20 (TBS-T). Following washes in TBS-T membranes were incubated with a polyclonal HRP-conjugated goat anti-rabbit secondary antibody (DAKO, #P0448) for 1 hour and after further washes in TBS-T antibody reactivity was detected by means of ECL/Super ECL (GE Healthcare) and exposure on ImageQuant LAS4000. For the detection of total protein levels, membranes incubated with anti-phospho antibodies were stripped in Restore Western Blot Stripping Buffer (Thermo, #21059) for 15-20 min, blocked, and incubated with the antibody against the total protein before the membrane was processed as described above.
  • Restore Western Blot Stripping Buffer Thermo, #21059
  • 4 ⁇ 10 5 VCaP cells were treated with 1 ⁇ M of IGF mAb — 1 and 10 of MDV-3100, and the combination of both agents, and incubated in 6-well plates at 37° C. for 24 h, 48 h and 72 h. Subsequently, the supernatant was transferred to FACS tubes, adherent cells were detached with trypsin and collected in the respective FACS tubes. After centrifugation, the medium was discarded and the cell pellet was fixed in ice-cold 70% ethanol for a minimum of 2 h at 4° C.
  • VCaP cells were treated with 1 ⁇ M of IGF mAb — 1 and 10 ⁇ M of MDV-3100 and the combination of both agents and incubated as triplicates in flat-bottom 96-well plates for 96 hours at a density of 5 ⁇ 10 4 cells per well, in the absence of R1881,
  • 3 H-thymidine 0.4 ⁇ Ci/well; PerkinElmer, NET355001MC
  • the plates were frozen and incubated at ⁇ 20° C. for 24 h.
  • the plates were thawed and 40 ⁇ L Trypsin was added to each well to detach the cell fragments. The suspension was transferred to filter plates.
  • the plates were then washed three times with distilled water and dried at 60° C. for 3 h. 25 ⁇ L per well Microscint were added and the proliferation rate was determined by measuring thymidine incorporation (CPM; counts per minute) using a liquid scintillation counter (1450 Microbeta Wallac Trilux, PerkinElmer).
  • CPM thymidine incorporation
  • 3 ⁇ 10 5 cells/well VCaP cells were seeded in 2 mL cell culture medium per well. 24 hrs post seeding the cell culture medium was removed and replaced with DMEM+10% FCS without R1881. 24 hr following the medium change the pre-treatment wells were harvested and counted with the Beckman CoulterTM Vi-CELL XR 2.03, and 10 ⁇ M of MDV-3100 was added to the remaining cells. Four times every 24 hr VCaP cell number was determined in 3 wells for each time point. The mean value was calculated from these triplicates. To determine the generation time, following formula is used:
  • the CellPlayerTM 96-Well Kinetic Caspase-3/7 Reagent (Essen BioScience; #4440) was used. 50000 VCaP cells/100 ⁇ l/well were seeded and treated on the next day with the respective concentrations of both agents in growth medium in the absence of R1881.
  • the Caspase-3/7 reagent was diluted to a final concentration of 5 ⁇ M in 100 ⁇ l per well of growth medium and added to the medium.
  • the plate was placed within a microplate tray into the IncuCyteTM 2011A and 3 images per well were acquired every 4 hours for 7 days using the phase contrast and fluorescence channels.
  • VaP and DUCaP both cell lines were derived from the same prostate cancer patient from different sites of metastasis, and MDA PCa 2b
  • VaP and DUCaP both cell lines were derived from the same prostate cancer patient from different sites of metastasis
  • MDA PCa 2b showed single agent anti-proliferative response to both the AR and IGF signaling inhibition alone, and an enhanced effect when combined ( FIG. 1 ).
  • Treatment with abiraterone acetate implies autocrine androgen production by the tumor cells for abiraterone acetate to show anti-proliferative effects. This might limit the number of cells sensitive to abiraterone acetate treatment.
  • Results of 2D and 3D proliferation assays for VCaP and 2D assays of MDA PCa 2b and DUCaP cells are shown in FIG. 2 . These data suggest that the single agent effects of abiraterone acetate on cell proliferation can be enhanced by the combination with antibodies neutralizing IGF ligands.
  • FIG. 3 shows signaling protein expression in the VCaP, MDA PCa 2b, and DUCaP cell lines, which are sensitive to AR and IGF signaling inhibition, in comparison to the insensitive cell line PC-3.
  • Cells were treated with MDV-3100 and IGF mAb — 1 as single agents, or in combination, for 24 hours and protein lysates were compared to untreated controls for protein expression of IGF-1R, AR, PTEN and AKT, and for phosphorylation of AKT-Ser473.
  • Responsive cell lines expressed wt AR, IGF-1R, and PTEN. These characteristics were not present in PC-3 or the other tested cell lines which did not show an anti-proliferative response to either one of the single agent treatments or the combination of both agents (Table 1).
  • IGF mAb — 1 The effects of MDV-3100 and IGF ligand mAb (IGF mAb — 1) as single agents, and combined treatment, on the inhibition of AKT phosphorylation were analyzed by Western blot from 4 h until 120 h of treatment. The combination of both agents resulted in a more complete and longer lasting inhibition of AKT phosphorylation than the antibody treatment alone ( FIG. 4 ).
  • results from tritiated thymidine incorporation assays shown in FIG. 5 demonstrates that both MDV-3100 and IGF mAb — 1 alone have an inhibitory effect on cell proliferation (approximately 50%), however, the combination of both agents was much more effective.
  • Treatment of VCaP cells with IGF mAb 1 alone led to a modest increase in apoptosis as assessed by phase contrast microscopy ( FIG. 6A ), caspase 3 activity ( FIG. 7 ), FACS-based cell cycle analysis ( FIG. 8 ), and PARP cleavage ( FIG. 9 ).
  • the reduced cell number seen after treatment with MDV-3100 alone FIG.
  • FIG. 6A was due to prolonged cellular doubling time ( FIG. 6B ).
  • MDV-3100 did not induce caspase 3 activity ( FIG. 7 ), sub-G1 apoptosis cell population ( FIG. 8 ), or PARP cleavage ( FIG. 9 ).
  • IGF mAb — 1 and MDV-3100 were combined a synergistic effect on caspase 3 activity was observed ( FIG. 7 ), in addition to enhanced sub-G1 apoptotic cell population ( FIG. 8 ) and cleaved PARP ( FIG. 9 ).
  • IGF mAb — 1 will be administered weekly in 28 day cycles of treatment by a one hour intravenous infusion at the start of each treatment cycle.
  • Enzalutamide will be administered daily by continuous oral dosing during each treatment cycle.
  • IGF mAb — 1 is a fully human monoclonal antibody (HumAb) of the IgG1 isotype.
  • the Ab binds with high affinity to IGF-1 and IGF-2, and potently neutralizes the proliferative and prosurvival cellular signaling triggered by both proteins.
  • Enzalutamide is an androgen receptor antagonist that acts on different steps in the androgen receptor signalling pathway.
  • the chemical name is 4- ⁇ 3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-sulfanylideneimidazolidin-1-yl ⁇ -2-fluoro-N-methylbenzamide.
  • the molecular weight is 464.44 and molecular formula is C21H16F4N4O2S.
  • Enzalutamide is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC)
  • IGF mAb — 1 will be administered weekly in 28 day cycles of treatment, by a one hour intravenous infusion at the start of each treatment cycle.
  • Enzalutamide will be administered daily by continuous oral dosing during each treatment cycle.
  • Part I of the study will be performed in 3 or more centres. Part II of the study will be performed in 10 or more centres globally.
  • Patients to be included in this study must have diagnosed and histologically, or cytologically, confirmed metastatic CRPC and have received and progressed after one line of docetaxol treatment. Patients may, or may not, have received and failed prior abiraterone, or cabazitaxel treatment, in any setting.
  • the patient has histologically, or cytologically, confirmed adenocarcinoma of the prostate.
  • Patients with radiographic evidence of metastatic prostate cancer (stage M1 or D2). Distant metastases evaluable by radionuclide bone scan, CT scan, or MRI within 28 days of start of study treatment.
  • Patients with a history of diabetes are allowed to participate, provided that their blood glucose is within normal range (fasting ⁇ 160 mg/dL or below ULN) and that they are on a stable dietary or therapeutic regimen for this condition.
  • Known human immunodeficiency virus infection or acquired immunodeficiency syndrome-related illness 15.
  • Patients with epilepsy, seizures, or predisposing factors for seizure as judged by the investigator. 15.
  • Active alcohol or active drug abuse as judged by the investigator.
  • a history of allergy to human monoclonal antibodies 19.
  • Prior therapy with agents targeting IGF and/or IGFR pathway. 20. Patients who are sexually active and unwilling to use a medically acceptable method of contraception (e.g.
  • Table 1 gives an overview of the mutations, protein expression and effects of androgen and IGF signaling inhibition observed in the 15 different tested prostate cancer cell lines.
  • AR androgen receptor
  • IGF-1R Insulin-like growth factor 1 receptor
  • mut mutated
  • n.d. not determined
  • wt wild type

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