WO2019169330A1 - Procédé de traitement de cancers exprimant le récepteur de la prolactine - Google Patents

Procédé de traitement de cancers exprimant le récepteur de la prolactine Download PDF

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Publication number
WO2019169330A1
WO2019169330A1 PCT/US2019/020402 US2019020402W WO2019169330A1 WO 2019169330 A1 WO2019169330 A1 WO 2019169330A1 US 2019020402 W US2019020402 W US 2019020402W WO 2019169330 A1 WO2019169330 A1 WO 2019169330A1
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WIPO (PCT)
Prior art keywords
prl
cancer cells
prolactin receptor
day
receptor antagonist
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Ceased
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PCT/US2019/020402
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English (en)
Inventor
James Donald PAYNE
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Oncolix Inc
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Oncolix Inc
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Publication of WO2019169330A1 publication Critical patent/WO2019169330A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/575—Hormones
    • C07K14/57554—Prolactin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/48—Ergoline derivatives, e.g. lysergic acid, ergotamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2869—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against hormone receptors

Definitions

  • a sequence listing is provided herewith as a text file“010464-5021- Sequence-Listing” created on March 1, 2019 and having a size of 4KB.
  • the contents of the text file are incorporated by reference herein in its entirety.
  • the present invention is directed to methods and compositions for simultaneous control of both pituitary and peripheral sources of PRL to improve the efficacy of PRLR antagonists in the treatment of cancers expressing PRLRs prolactin in receptors (PRLR).
  • PRLR prolactin in receptors
  • Prostate cancer is the most frequently diagnosed cancer in men.
  • PRL plays a key role in development of the prostate.
  • Inhibition of pituitary PRL production in rats during embryonic development results in severely limited prostate development, indicating that PRL plays a role in development of the prostate.
  • prostate cancer Treatment of prostate cancer frequently includes radical prostatectomy, radiation, and androgen deprivation therapy.
  • PRL resistance to hormone therapy is also common in prostate cancer, although both malignant and healthy prostates produce PRL. Tissues producing high PRL correlate strongly with high Gleason scores based on a microscopic analysis of cancer cells in prostate biopsy samples.
  • prostatic fluid from patients with prostate cancer has higher PRL levels than such fluids from control subjects.
  • PRL induces proliferation and inhibits apoptosis in some tumor cell lines.
  • PRLRs are expressed in the human prostate, and PRL expression is particularly elevated in prostate cancer patients and in prostate tumor cells.
  • Serum PRL in ovarian and endometrial cancer patients are also known to be elevated, indicating a role for PRL in gynecological cancers.
  • Expression of PRLR in ovarian and endometrial tumors, as well as in cases of endometrial hyperplasia is also significantly elevated, suggesting the importance of PRL signaling in malignant and premalignant conditions.
  • PRL mRNA transcripts are abundant in ovarian and endometrial tumors, indicating the presence of an autocrine loop in such cells.
  • Serum PRL levels are also significantly elevated in women with a strong family history of ovarian cancer.
  • PRL is thought to promote cancer via the JAK2/STAT5 pathway and may increase survival of cancer cells by stimulating the proliferation of cancer cells and interfering with apoptotic signals.
  • PRL has been shown to increase cell motility and promote the spread of cancer in both in vitro and in vivo studies.
  • PRL is also implicated in adaptive drug resistance to cytotoxic drugs such as cisplatin or paclitaxel.
  • PRL is not the only source of circulating PRL.
  • Many organs such as the mammary gland, prostate, skin, and brain tissue also express PRL.
  • PRL derived from such tissues is involved in development of breast tissue, the prostate, dermatological bio-regulation, and perception of pain. While peripheral extra-pituitary PRL secretion is also observed in animal models, it appears to be much more common in humans. Such extra-pituitary PRL secretion is dopamine independent. While only small amounts of PRL may be produced locally, relative to the amounts produced by the pituitary, such localized PRL production is important for tumor formation due to local availability.
  • PRL sensitive tumors express higher levels of PRLR when compared to healthy tissue.
  • PRLR comprises as many as six different isoforms. These six isoforms are variably expressed in different tissues and tumor types. Multiple studies suggest that low turnover of the PRLR in cancer cells increases invasive proliferation.
  • PRLR antagonists such as G129R, a human PRL variant in which the glycine at position 129 is replaced with arginine, reduce cancer cell proliferation and enhance the action of many anti-cancer drugs.
  • G129R sterically blocks the sequential dimerization and subsequent activation of PRLR, and induces cell death (either apoptosis or autophagy) of many different breast, prostate, and ovarian cancer cell lines. Although G129R disrupts autocrine production of PRL in such cancer cells it is not known to affect pituitary sources of PRL at all.
  • G129R Treatment of ovarian cancer patients with G129R results in an increase in circulating PRL similar to that observed when breast and prostate cancer patients are treated with LFA102. This indicates that G129R effectively blocks PRLR, but provokes increased expression of pituitary derived PRL. The ability to monitor the situation is further confused by the lack of simple clinical tests to differentiate endogenously produced PRL (whether from the pituitary or from peripheral sources) from G129R itself.
  • the present invention discloses that when administered in combination with G129R, dopamine agonists allow differentiation of exogenously administered G129R from pituitary derived PRL. Further, co-administration of PRLR antagonists, such as G129R, with a dopamine agonist provides a surprisingly synergistic improvement to existing cancer treatments relative to treatments based on
  • PLR refers to human prolactin with the amino acid sequence shown in SEQ ID NO. 1.
  • G129R refers to PRL in which the glycine at position 129 is replaced with arginine.
  • SIG ID NO. 2 The complete sequence of G129R is provided in SIG ID NO. 2.
  • PRLR antagonist refers to agents and compounds that block or dampen the biological response of the PRLR within a cell by binding to and blocking a receptor rather than activating it like an agonist.
  • PRLR antagonists There are several forms of PRLR antagonists that have been studied in animal models of cancer, including G129R. As used here, we include antibodies to regions of the PRLR which achieve a similar effect, such as the antibody LFA102.
  • Dopamine agonist refers to agents and compounds that activate dopamine receptors thereby reducing pituitary driven production of PRL.
  • Dopamine agonists as described herein include, without limitation, apomorphine, aripiprazole, bromocriptine (Parlodel® or Cycloset®), cabergoline (Dostinex®), ciladopa, dihedrexidine, dinapsoline, doxanthrine, epicriptine, lisuride. pergolide, phencyclidine, piribedil, pramipexole,
  • propylnorapomorphine quinagolide, quinpirole, ropinirole, rotigotine, roxindole, salvinorin A, sumanirole.
  • an effective dose of a PRLR antagonist and an effective dose of a dopamine agonist are co-administered to a human subject suffering from a cancer expressing PRLR.
  • the PRLR antagonist and the dopamine agonist may be administered to the subject simultaneously or separately.
  • an effective dose of G129R is co-administered with an effective amount of a dopamine agonist to a human subject suffering a cancer expressing PRLR.
  • the effective dose of G129R may be administered as a single injection or in multiple injections. Such injections may be any parenteral route such as, without limitation, intramuscular, intradermal, subcutaneous, intravenous, intrathecal, intracranial or intratumoral.
  • An effective dose of may be 50 mg of G129R per kg of patient body weight per day (50 mg/kg/day), 10 mg/kg/day, 5 mg/kg/day,
  • an effective dose of a monoclonal antibody that inhibits PRLR activity is coadministered with an effective amount of a dopamine agonist to a human subject suffering a cancer expressing PRLR.
  • the effective dose of the monoclonal antibody may be administered as a single injection or multiple injections. Such injections may be any parenteral route such as, without limitation, intramuscular, intradermal, intravenous, or intratumoral.
  • the monoclonal antibody is LFA102.
  • An effective dose of may be 10 mg of G129R per kg of patient body weight per day (10 mg/kg/day), 5 mg/kg/day, 2.5 mg/kg/day, 1 mg/kg/day, 0.5 mg/kg/day, 0.25 mg/kg/day, 0.1 mg/kg/day, 0.05 mg/kg/day, 0.025 mg/kg/day, 0.001 mg/kg/day.
  • an effective dose of a PRLR antagonist is co-administered with an effective amount of bromocriptine (a dopamine receptor agonist) to a human subject suffering a cancer expressing PRLR.
  • the effective dose of bromocriptine may be administered as singly or in multiple doses. Such administration may be any enteral or parenteral route.
  • An effective oral dose of bromocriptine may be 5 mg per kg of patient body weight per day (5 mg/kg/day), 1 mg/kg/day, 0.5 mg/kg/day, 0.25 mg/kg/day, 0.1 mg/kg/day, 0.05 mg/kg/day, 0.025 mg/kg/day, 0.01 mg/kg/day.
  • an effective dose of a PRLR antagonist is co administered with an effective amount of cabergobne (a dopamine receptor agonist) to a human subject suffering a cancer expressing PRLR.
  • the effective dose of cabergobne may be administered as singly or in multiple doses. Such administration may be any enteral or parenteral route.
  • An effective oral dose of cabergobne may be 50 pg per kg of patient body weight per week (50 pg/kg/wk), 25 pg/kg/wk, 10 pg/kg/wk, 5 pg/kg/wk, 1 pg/kg/wk, 0.5 pg/kg/wk, 0.25 pg/kg/day, 0.1 pg/kg/wk.
  • the cancer expressing PRLR may be breast cancer, prostate cancer, ovarian cancer or endometrial cancer.
  • Table 1 Circulating PRL (ng/ml) before and after administration of G129R in three subjects with ovarian cancer expressing PRLR.
  • Co-administration of PRL antagonist G129R with a dopamine agonist produces no increase in circulating PRL levels and improves the anti-tumor properties of G129R.
  • Tumor suppression markers as measured by RECIST (Response Evaluation Criteria In Solid Tumors) using imaging methods will indicate increased inhibition of growth and proliferation of the subject cancers relative to treatment with G129R alone.
  • the combination of G129R suppression of peripheral autocrine sources of PRL and suppression of pituitary sources of PRL by the dopamine agonist is a direct demonstration that G129R anti -tumor activity is enhanced by overall suppression of circulating PRL levels.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Immunology (AREA)
  • Engineering & Computer Science (AREA)
  • Endocrinology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Microbiology (AREA)
  • Mycology (AREA)
  • Toxicology (AREA)
  • Zoology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne des procédés et des compositions pour le contrôle des sources autocrines pituitaires et périphériques de la prolactine pour améliorer l'efficacité d'antagonistes du récepteur de la prolactine pour le traitement de cancers exprimant le récepteur de la prolactine.
PCT/US2019/020402 2018-03-02 2019-03-01 Procédé de traitement de cancers exprimant le récepteur de la prolactine Ceased WO2019169330A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201862637860P 2018-03-02 2018-03-02
US62/637,860 2018-03-02

Publications (1)

Publication Number Publication Date
WO2019169330A1 true WO2019169330A1 (fr) 2019-09-06

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PCT/US2019/020402 Ceased WO2019169330A1 (fr) 2018-03-02 2019-03-01 Procédé de traitement de cancers exprimant le récepteur de la prolactine

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080038369A1 (en) * 2003-12-11 2008-02-14 Clark Ross G Methods And Compositions For The Treatment Of Prolactin-Receptor Related Disorders
US20130022606A1 (en) * 2009-12-10 2013-01-24 Bayer Intellectual Property Gmbh Neutralizing prolactin receptor antibodies and their therapeutic use
US20130231286A1 (en) * 2010-11-17 2013-09-05 Oncolix, Inc. Use of Prolactin Receptor Antagonist and Chemotherapeutic Drug for Treating Ovarian Cancer
US20140227294A1 (en) * 2012-12-24 2014-08-14 Abbvie Inc. Prolactin receptor binding proteins and uses thereof
US20150133383A1 (en) * 2012-05-11 2015-05-14 Prorec Bio Ab Method for diagnosis and treatment of prolactin associated disorders

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080038369A1 (en) * 2003-12-11 2008-02-14 Clark Ross G Methods And Compositions For The Treatment Of Prolactin-Receptor Related Disorders
US20130022606A1 (en) * 2009-12-10 2013-01-24 Bayer Intellectual Property Gmbh Neutralizing prolactin receptor antibodies and their therapeutic use
US20130231286A1 (en) * 2010-11-17 2013-09-05 Oncolix, Inc. Use of Prolactin Receptor Antagonist and Chemotherapeutic Drug for Treating Ovarian Cancer
US20150133383A1 (en) * 2012-05-11 2015-05-14 Prorec Bio Ab Method for diagnosis and treatment of prolactin associated disorders
US20140227294A1 (en) * 2012-12-24 2014-08-14 Abbvie Inc. Prolactin receptor binding proteins and uses thereof

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