ANTAGONISTS OF IL-6 TO RAISE ALBUMIN AND/OR LOWER CRP

• US 20120294852A1
• Filed: 11/24/2010
• Published: 11/22/2012
• Est. Priority Date: 11/24/2009
• Status: Abandoned Application

• Current Assignee: H. Lundbeck A/S (Lundbeck Foundation)
• Original Assignee: H. Lundbeck A/S (Lundbeck Foundation)
• Inventors: Smith, Jeffrey T.L.
• Application Number:
  US13/511,409
• Publication Number:
  US 20120294852A1
• Time in Patent Office: Days
• US Class Current: 424/133.1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 2039/545 characterised by the dose, timing or administration schedule
• CPC Class Codes: A61K 31/454 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
• CPC Class Codes: A61K 38/2013 IL-2
• CPC Class Codes: A61K 38/208 IL-12
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 49/0004 Screening or testing of compounds for diagnosis of disorders, assessment of conditions, e.g. renal clearance, gastric emptying, testing for diabetes, allergy, rheuma, pancreas functions
• CPC Class Codes: A61K 49/0058 Antibodies
• CPC Class Codes: A61K 51/1033 against receptors for cytokines, lymphokines or interferons
• CPC Class Codes: A61P 1/02 Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 15/06 Antiabortive agents; Labour repressants
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/06 : Antipsoriatics
• CPC Class Codes: A61P 17/14 : for baldness or alopecia
• CPC Class Codes: A61P 19/00 : Drugs for skeletal disorders
• CPC Class Codes: A61P 19/02 : for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/08 : for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 19/10 : for osteoporosis
• CPC Class Codes: A61P 21/00 : Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 25/00 : Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/24 : Antidepressants
• CPC Class Codes: A61P 25/28 : for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 29/00 : Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/04 : Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/04 : Antibacterial agents
• CPC Class Codes: A61P 31/12 : Antivirals
• CPC Class Codes: A61P 31/16 : for influenza or rhinoviruses
• CPC Class Codes: A61P 31/18 : for HIV
• CPC Class Codes: A61P 33/06 : Antimalarials
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 35/02 : specific for leukemia
• CPC Class Codes: A61P 37/02 : Immunomodulators
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/14 : of the thyroid hormones, e.g. T3, T4
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/02 : Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 7/04 : Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
• CPC Class Codes: A61P 7/06 : Antianaemics
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/02 : Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
• CPC Class Codes: A61P 9/04 : Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 : Antihypertensives
• CPC Class Codes: C07K 16/248 : IL-6
• CPC Class Codes: C07K 16/462 : Igs containing a variable region (Fv) from one specie and a constant region (Fc) from another
• CPC Class Codes: C07K 2317/24 : containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/33 : Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
• CPC Class Codes: C07K 2317/34 : Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
• CPC Class Codes: C07K 2317/41 : Glycosylation, sialylation, or fucosylation
• CPC Class Codes: C07K 2317/56 : variable (Fv) region, i.e. VH and/or VL
• CPC Class Codes: C07K 2317/565 : Complementarity determining region [CDR]
• CPC Class Codes: C07K 2317/76 : Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• CPC Class Codes: C07K 2317/90 : characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
• CPC Class Codes: C07K 2317/92 : Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
• CPC Class Codes: C07K 2317/94 : Stability, e.g. half-life, pH, temperature or enzyme-resistance
• CPC Class Codes: G01N 33/6863 : Cytokines, i.e. immune system proteins modifying a biological response such as cell growth proliferation or differentiation, e.g. TNF, CNF, GM-CSF, lymphotoxin, MIF or their receptors
• CPC Class Codes: Y02A 50/30 : Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The present invention is directed to therapeutic methods using antibodies and fragments thereof having binding specificity for IL-6 to prevent or treat cachexia, fever, weakness and/or fatigue in a patient in need thereof. In preferred embodiments, the anti-IL-6 antibodies will be humanized and/or will be aglycosylated. Also, in preferred embodiments these patients will comprise those exhibiting (or at risk of developing) an elevated serum C-reactive protein level. In another preferred embodiment, the patient'"'"'s survivability or quality of life will preferably be improved.

Claims

1-112. -112. (canceled)

113. A method of improving survivability or quality of life of a patient in need thereof, by increasing the patient'"'"'s serum albumin level, and decreasing the patient'"'"'s serum C reactive protein (“

CRP) level, comprising administering to the patient an effective amount of an anti-IL-6 antagonist that blocks the binding of human IL-6 to IL-6R1 and gp130, whereby the patient'"'"'s serum albumin level is reduced, and the patient'"'"'s serum C reactive protein (“

CRP) level is reduced.

114. The method of claim 113, wherein the IL-6 antagonist is an anti-human IL-6 antibody or antibody fragment.

115. The method of claim 114, wherein the anti-human IL-6 antibody or antibody fragment competes with and/or binds the same epitope as an anti human IL-6 antibody comprising the variable heavy and light sequences respectively in SEQ ID NO:

2 and 3.

116. The method of claim 113, which further includes monitoring the patient to assess the reduction in the patient'"'"'s serum CRP level.

117. The method of claim 113, which further includes monitoring the patient to assess the increase in the patient'"'"'s serum albumin level.

118. The method of claim 113, wherein said patient has an elevated serum CRP level prior to treatment and/or a reduced serum albumin level prior to treatment.

119. The method of claim 113, whereby the patient'"'"'s Glasgow Prognostic Score (GPS) is improved.

120. The method of claim 113, wherein the IL-6 antagonist comprises an anti-IL-6R, anti-gp130, anti-p38 MAP kinase, anti-JAK1, anti-JAK2, anti-JAK3, or anti-SYK antibody or antibody fragment or comprises a small molecule comprising thalidomide, lenalidomide, or any combination thereof.

121. The method of claim 113, wherein the anti-IL-6 antibody or fragment comprises the variable heavy chain in SEQ ID NO:

657 and the variable light chain in SEQ ID NO;

709 respectively or a antibody comprising variable heavy and/or light chain sequences comprising the same CDRs as the variable sequences in SEQ ID NO;

657 and 709.

122. The method of claim 121, wherein the anti-IL-6 antibody or fragment comprises the heavy chain and light chain constant regions comprised in SEQ ID NO:

588 and SEQ ID NO;

586 respectively.

123. The method of claim 114, wherein the anti-IL-6 antibody or antibody fragment specifically binds to the same epitope on an intact IL-6 polypeptide or fragment thereof that is specifically bound by an antibody containing the variable heavy and light sequences in SEQ ID NO:

3 and 2 respectively, and wherein said epitope(s) when ascertained by epitopic mapping using overlapping linear peptide fragments which span the full length of the native human IL-6 polypeptide includes one or more residues comprised in each of the IL-6 fragments selected from those respectively consisting of amino acid residues 37-51, amino acid residues 70-84, amino acid residues 169-183, amino acid residues 31-45 and/or amino acid residues 58-72 of SEQ ID NO;

1.

124. The method of claim 114, wherein the anti-IL-6 antibody or antibody fragment is aglycosylated and/or contains an Fc region that has been modified to alter effector function, half-life, proteolysis, and/or glycosylation.

125. The method of claim 114, wherein the anti-IL-6 antibody or antibody fragment is a human, humanized, single chain or chimeric antibody.

126. The method of claim 114, wherein the anti-IL-6 antibody or antibody fragment is administered to the patient with a frequency of about every four weeks or eight weeks.

127. The method of claim 114, wherein said antibody comprises a human Fc derived from IgG1, IgG2, IgG3, or IgG4.

128. The method of claim 114, wherein the anti-IL-6 antibody or antibody fragment has an elimination half-life of at least about 22 days, at least about 25 days or at least about 30 days.

129. The method of claim 113, wherein the IL-6 antagonist is coadministered with a chemotherapy.

130. The method of claim 114, wherein the anti-IL-6 antibody or antibody fragment which is directly or indirectly attached to a detectable label or therapeutic agent.

131. The method of claim 113, wherein the IL-6 antagonist is coupled to a half-life increasing moiety.

132. The method of claim 113, wherein 42, 49 or 56 days after IL-6 antagonist administration the patient'"'"'s serum albumin level remains above 35 g/L.

133. The method of claim 113, wherein the patient has been diagnosed with an autoimmune disorder or cancer.

134. The method of claim 114, wherein the antibody or fragment has variable heavy and light sequences contained at least 98% identical has the variable heavy and light sequences contained in SEQ ID NO:

19 or 20.

141. The method of claim 113, wherein said anti-IL-6 antibody is comprised in a composition formulated for subcutaneous or intravenous injection.

135. A method of increasing survivability or quality of life of a patient in need thereof, comprising administering to the patient an IL-6 antagonist, whereby the patient'"'"'s serum CRP level is reduced and/or the patient'"'"'s serum albumin level is increased, and monitoring the patient to assess the reduction in the patient'"'"'s serum CRP level and the increase in the patient'"'"'s serum albumin level comprising intravenously or subcutaneously administering an anti-IL-6 antibody or antibody fragment having the same epitopic specificity as art antibody containing the variable light and heavy sequences in SEQ ID NO:

2 and 3 respectively by intravenously administering a dosage of about (+1−

20%>

) 80, 160 or 320 mg of said antibody to a patient in need thereof.

136. The method of claim 135, wherein the patient is administered said dosage every 8 weeks or 2 months.

137. The method of claim 135, wherein said dosage is administered at least twice.

138. The method of claim 135, wherein the first dosage is on day one and the second dosage during week 8 (8th week after day 0).

139. The method of any one of claim 135, wherein said anti-IL-6 antibody contains variable heavy and light sequences which are at least 95% identical has the variable heavy and light sequences contained in SEQ ID NO:

19 or 20.

140. The method of claim 139, wherein said anti-IL-6 antibody or antibody fragment contains the variable heavy and light sequences contained in SEQ ID NO:

19 or 20.

142. The method of claim 135, wherein said anti-IL-6 antibody is comprised in a composition formulated for subcutaneous or intravenous injection.