Humanized Anti-acth antibodies and use thereof

Abstract

The present invention is directed to antibodies and fragments thereof having binding specificity for ACTH. Embodiments of this invention relate to the binding fragments of antibodies described herein, comprising the sequences of the VH, VL and / or CDR polypeptides described herein, and the polynucleotides encoding them. The invention also contemplates anti-ACTH antibodies and binding fragments thereof conjugated to one or more functional or detectable moieties. The invention further contemplates methods of making said anti-ACTH antibodies and binding fragments thereof. Embodiments of the invention also pertain to the use of anti-ACTH antibodies and binding fragments thereof for the diagnosis, assessment, prevention and treatment of diseases and disorders associated with ACTH, such as CAH, FGD, Cushing's Disease, Cushing's Syndrome, Parkinson's disease, obesity, diabetes, sleep disorders, depression, anxiety disorders, cancer, muscle atrophy, hypertension, hyperinsulinemia, cognitive dysfunction, Alzheimer's disease, galactorrhea, stress related conditions, cardiac conditions, metabolic syndrome, hyperaldosteronism, Conn's syndrome and familial hyperaldosteronism.

Description

Abstract This invention relates to antibodies and fragments thereof having ACTH binding specificity. Embodiments of the invention relate to binding fragments of the antibodies described herein, including sequences of the VH, VL, and / or CDR polypeptides, and the polynucleotides encoding them. The invention also contemplates anti-ACTH antibodies and binding fragments thereof coupled to one or more functional or detectable groups. The invention further relates to methods for manufacturing the anti-ACTH antibodies and binding fragments thereof. Embodiments of the invention also relate to the use of anti-ACTH antibodies and binding fragments thereof for the diagnosis, assessment, prevention, and treatment of ACTH-related diseases and conditions, such as congenital adrenal hyperplasia (CAH), familial adrenal insufficiency (FGD), Cushing's disease, Cushing's syndrome, Parkinson's disease, obesity, diabetes, sleep disorders, depression, anxiety disorders, cancer, muscular dystrophy, hypertension, hyperinsulinemia, cognitive impairment, Alzheimer's disease, galactorrhea, stress-related conditions, heart disease, metabolic syndrome, hyperaldosteronism, Klinefelter syndrome, and familial hyperaldosteronism.

Claims

1. An anti-human ACTH antibody or fragment thereof comprising the heavy chain CDR1, CDR2, and CDR3 polypeptides of SEQ ID NO: 564; SEQ ID NO: 566; and SEQ ID NO: 568, and the light chain CDR1, CDR2, and CDR3 of SEQ ID NO: 584; SEQ ID NO: 586; and SEQ ID NO: 588; and which comprises or consists of the variable heavy chain of SEQ ID NO: 562 and the variable light chain of SEQ ID NO: 582, for use in blocking, inhibiting or neutralizing one or more biological effects associated with ACTH.

2. An anti-human ACTH antibody or fragment thereof comprising the heavy chain CDR1, CDR2, and CDR3 polypeptides of SEQ ID NO: 564; SEQ ID NO: 566; and SEQ ID NO: 568, and the light chain CDR1, CDR2, and CDR3 of SEQ ID NO: 584; SEQ ID NO: 586; and SEQ ID NO: 588; and which comprises or consists of the variable heavy chain of SEQ ID NO: 562 and the variable light chain of SEQ ID NO: 582, for use in ameliorating or reducing the symptoms of or treating or preventing a condition associated with ACTH.

3. The use of claim 2, wherein said condition associated with ACTH comprises congenital adrenal hyperplasia (CAH), Classical CAH, Nonclassical CAH, familial glucocorticoid deficiency (FGD), Cushing's disease, Cushing's syndrome, hypertension, hyperaldosteronism, familial hyperaldosteronism, primary hyperaldosteronism, or secondary hyperaldosteronism, or comprises Allgrove syndrome, bilateral adrenalectomy, or Nelson's Syndrome.

4. The use of claim 2 or claim 3, wherein said condition associated with ACTH comprises congenital adrenal hyperplasia (CAH), Classical CAH, Nonclassical CAH, Cushing's disease or Cushing's syndrome.

5. An anti-human ACTH antibody or fragment thereof comprising the heavy chain CDR1, CDR2, and CDR3 polypeptides of SEQ ID NO: 564; SEQ ID NO: 566; and SEQ ID NO: 568, and the light chain CDR1, CDR2, and CDR3 of SEQ ID NO: 584; SEQ ID NO: 586; and SEQ ID NO: 588; and which comprises or consists of the variable heavy chain of SEQ ID NO: 562 and the variable light chain of SEQ ID NO: 582, for use in ameliorating or reducing the symptoms of or treating or preventing a condition associated with elevated ACTH, cortisol, aldosterone, and / or corticosterone wherein said anti-human ACTH antibody or fragment thereof is optionally administered with another therapeutic agent or therapeutic regimen, wherein the condition is selected from the group consisting of: congenital adrenal hyperplasia (CAH), Classical CAH, Nonclassical CAH, familial glucocorticoid deficiency (FGD), ACTH-driven hypercortisolism, acute coronary syndrome, acute heart failure, atherosclerosis, atrial fibrillation, cachexia, cancer, Cushing's Syndrome resulting from ectopic ACTH expression, Cushing's Syndrome resulting from ectopic ACTH expression associated with small cell lung cancer, Cushing's Syndrome resulting from ectopic ACTH expression associated with non-small cell lung cancer (NSCLC), Cushing's Syndrome resulting from ectopic ACTH expression associated with pancreatic carcinoma, Cushing's Syndrome resulting from ectopic ACTH expression associated with neural tumors, Cushing's Syndrome resulting from ectopic ACTH expression associated with thymoma, cardiac conditions, cardiac fibrosis, cardiovascular disorders, chronic renal failure, chronic stress syndrome, cognitive dysfunction, Alzheimer's disease, congestive heart failure, Conn's syndrome, coronary heart diseases, Cushing's Disease, Cushing's Syndrome, depression, anxiety disorders, diabetes, endothelial dysfunction, exercise intolerance, familial hyperaldosteronism, fibrosis, galactorrhea, heart failure, hyperaldosteronism, hypercortisolemia, hypertension, hyperinsulinemia, hypokalemia, impaired cardiac function, increased formation of collagen, inflammation, metabolic syndrome, muscle atrophy, conditions associated with muscle atrophy, myocardiac fibrosis, nephropathy, obesity, post-myocardial infarction, primary hyperaldosteronism, remodeling following hypertension, renal failure, restenosis, secondary hyperaldosteronism, sleep apnea, sleep disorders, stress related conditions, and syndrome X, or comprising Allgrove syndrome, bilateral adrenalectomy, or Nelson's syndrome.

6. The use of claim 5, wherein (i) said other therapeutic agent or regimen comprises: Accupril (quinapril), Aceon (perindopril), Adalat, Adalat CC, Aldactone (spironolactone), aldosterone receptor blockers, alpha-adrenergic receptor blockers, alpha-glucosidase inhibitors, Altace (ramipril), Alteplase, aminoglutethimide (Cytadren®), amiodarone, angiotensin converting enzyme (ACE) Inhibitors, angiotensin II receptor antagonists, Angiotensin II receptor blockers (ARBs), antiarrhythmics, anti-cholesterol drugs, anti-clotting agents, antidiabetogenic drugs, anti-hypertensive agents, antiplatelet drugs, ApoA-I mimics, aspirin, Atacand (candesartan), Avapro (irbesartan), beta blockers, beta-adrenergic receptor blockers, Betapace (sotalol), BiDil (hydralazine with isosorbide dinitrate), biguanides, blood thinners, Brevibloc (esmolol), Bumex (bumetanide), cabergoline (Dostinex®), Caduet (a combination of a statin cholesterol drug and amlodipine), Calan, Calan SR, Calcium channel blockers, Capoten (captopril), Cardene, Cardene SR (nicardipine), Cardizem, Cardizem CD, Cardizem SR, CETP inhibitors, conivaptan (Vaprisol®), Cordarone (amiodarone), Coreg (carvedilol), Covera-HS, Cozaar (losartan), cyproheptadine (Periactin® or Peritol®), Demadex (torsemide), digoxin, Dilacor XR, Dilatrate-SR, Diltia XT, Diovan (valsartan), dipeptidyl peptidase-4 inhibitors, diuretics, Dobutrex (dobutamine), drugs that suppress ACTH secretion, drugs that suppress cortisol secretion, dual angiotensin converting enzyme / neutral endopeptidase (ACE / NEP) inhibitors, endothelin antagonists, endothelin receptor blockers, Esidrix (hydrochlorothiazide), etomidate (Amidate®), Fragmin, gemfibrozil (Lopid, Gemcor), glucocorticoid receptor antagonists, heart failure drugs, Heparin, HMG-Co-A reductase inhibitors, holestyramine (Questran), IMDUR (isosorbide mononitrate), Inderal (propranolol), inhibitors of a Na-K-ATPase membrane pump, inhibitors of steroidogenesis, insulin therapies, Iso-Bid, Isonate, Isoptin, Isoptin SR, Isorbid (isosorbide dinitrate), Isordil, Isotrate, ketoconazole (Nizoral®), Lasix (furosemide), lixivaptan (VPA-985), Lopressor, Lotensin (benazepril), Lovenox, Mavik (trandolapril), meglitinides, metyrapone (Metopirone®), Micardis (telmisartan), mifepristone (Korlym®), mitotane (Lysodren®), Monopril (fosinopril), neutral endopeptidase (NEP) inhibitors, Normodyne, Norvasc (amlodipine), obesity-reducing agents, Omacor, pantethine, pasireotide (Signifor®), Plendil (felodipine), PPAR-gamma agonists, Primacor (milrinone), Prinivil, Procanbid (procainamide), Procardia, Procardia XL (nifedipine), renin inhibitors, Reteplase, rosiglitazone (Avandia®), satavaptan (SR121463, planned trade name Aquilda®), Sectral (acebutolol), somatostatin analogs, Sorbitrate (isosorbide dinitrate), statins, Streptokinase, Sular (nisoldipine), sulfonylurea, Tambocor (flecainide), Tenecteplase, Tenormin (atenolol), thiazolidinediones, Tiazac (diltiazem), Tissue plasminogen activator (TPA), tolvaptan (OPC-41061), Toprol-XL (metoprolol), Trandate (labetalol), Univasc (moexipril), Urokinase, valproic acid (Depakote®), vaptans, Vascor (bepridil), vasodilators, Vasodilators, vasopressin antagonists, Vasotec (enalapril), Verelan, Verelan PM (verapamil), warfarin (Coumadin), Zaroxolyn (metolazone), Zebeta (bisoprolol), or Zestril (lisinopril), and / or (ii) the other active agent comprises one or more corticosteroids, glucocorticoids, mineralocorticoids, cortisol (hydrocortisone), dexamethasone, cortisone, prednisone, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, beclometasone, fludrocortisone, fludrocortisone acetate, deoxycorticosterone, deoxycorticosterone acetate (DOCA), or aldosterone, and / or (iii) the other active agent comprises one or more of antiandrogens, flutamide, gonadotropin-releasing hormone analogs, leuprolide, cyproterone, cyproterone acetate, enzalutamide, galeterone, abiraterone, abiraterone acetate, orteronel, steroidal antiandrogens, flutamide, VT-464, aminoglutethimide, enzalutamide, an androgen receptor antagonist, an androgen biosynthesis inhibitor, an aromatase inhibitor, a long-acting gonadotropin-releasing hormone (GnRH) agonists, growth hormone, testosterone, dihydrotestosterone (DHT), androstenedione, and / or estrogen.

7. The anti-human ACTH antibody or fragment thereof for use according to any one of claims 1-6, wherein said anti-human ACTH antibody or fragment thereof comprises or consists of the heavy chain of SEQ ID NO: 561 and the light chain of SEQ ID NO: 581.

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