ANTIBODIES TO IL-6 AND USE THEREOF

• US 20110293622A1
• Filed: 06/03/2011
• Published: 12/01/2011
• Est. Priority Date: 05/21/2007
• Status: Active Grant

• Current Assignee: Vitaeris Inc. (CSL Limited)
• Original Assignee: AlderBio Holdings, LLC (Lundbeck Seattle Biopharmaceuticals, Inc.)
• Inventors: Latham, John, Jensen, Anne Elisabeth Carvalho, Garcia-Martinez, Leon, Kovacevich, Brian, Dutzar, Ben, Olson, Katie, Ojala, Ethan, Smith, Jeffrey T.L.
• Granted Patent: US 9,758,579 B2
• Time in Patent Office: Days
• US Class Current: 424/139.1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07K 16/248 IL-6
• CPC Class Codes: C07K 2317/24 containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/34 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 2317/92 Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
• CPC Class Codes: C12N 15/81 for yeasts
• CPC Class Codes: C12N 9/60 from yeast
• CPC Class Codes: C12N 9/64 derived from animal tissue
• CPC Class Codes: C12P 21/02 having a known sequence of two or more amino acids, e.g. glutathione

Abstract

The present invention is directed to antibodies and fragments thereof and humanized versions thereof having binding specificity for IL-6. Another embodiment of this invention relates to the antibodies described herein, and binding fragments thereof, comprising the sequences of the V_H, V_L and CDR polypeptides described herein, and the polynucleotides encoding them. The invention also contemplates conjugates of anti-IL-6 antibodies and binding fragments thereof conjugated to one or more functional or detectable moieties. The invention also contemplates methods of making said anti-IL-6 antibodies and binding fragments thereof. Embodiments of the invention also pertain to the use of anti-IL-6 antibodies, and binding fragments thereof, for the diagnosis, assessment and treatment of diseases and disorders associated with IL-6. These antibodies may bind at least one of soluble IL-6, cell surface expressed IL-6, IL-6/IL-6R and/or prevent the association of IL-6 and IL-6R, the association of IL-6/IL-6R and gp130 and or the formation of IL-6/IL-6R/gp130 multimers and thereby inhibit a biological effect associated with any of the foregoing.

Claims

1-137. -137. (canceled)

138. An antibody or antibody fragment that specifically binds to human IL-6 wherein said antibody or fragment specifically competes for binding to the human IL-6 epitope specifically bound by the anti-IL-6 antibody comprising the variable light and heavy chain in SEQ ID NO:

3 and 2 respectively, wherein said competition can be detected in a competitive binding assay using said antibody or antibody fragment, the human IL-6 polypeptide in SEQ ID NO;

1, and an anti-IL-6 antibody comprising the variable light and heavy chain in SEQ ID NO;

3 and 2 respectively.

142. The antibody or antibody fragment of any of claims 138-141 wherein the antibody or antibody fragment blocks the interaction of human IL-6 with IL-6R1 and gp130.

143. The antibody or fragment of any one of claims 138-141 wherein the antibody or antibody fragment contains a humanized variable heavy chain selected from those in SEQ ID NO:

18, 19, 652, 653, 654, 655, 656, 657, 661, 664, 665, 657, 658, 704, and 708. and a humanized light chain region selected from those contained in SEQ ID NO;

2, 20, 647, 648, 649, 650, 651, 660, 666, 699, 702, 706, or 709.

144. The antibody or fragment of any one of claims 138-141 wherein the antibody or antibody fragment contains a humanized variable light region contained in SEQ ID NO:

709 and a humanized heavy chain region contained in SEQ ID NO;

656 or 657.

145. The antibody or fragment of any one of claims 138-141 wherein the antibody is selected from chimeric antibodies, human antibodies, humanized antibodies, rabbit antibodies, single chain antibodies selected from scFvs, camelbodies, nanobodies, IgNAR, and small-modular immunopharmaceuticals (SMIPs), and the antibody fragment is selected from Fab, Fab′

, and F(ab′

) fragments.

146. The antibody or fragment of any one of claims 138-141 wherein the antibody contains constant regions selected from the group consisting of IgG1, IgG2, IgG3, IgG4, IgG5, IgG6, IgG7, IgG8, IgG9, IgG10, IgG11, IgG12, IgG13, IgG14, IgG15, IgG16, IgG17, IgG18 or IgG19 constant regions.

147. The antibody or fragment of any one of claims 138-141 wherein the antibody is an IgG1.

148. The antibody or antibody fragment of any one of claims 138-141 that is non-glycosylated.

149. The antibody or antibody fragment of any one of claims 138-141 that contains an Fc region that has been modified to alter effector function, half-life, proteolysis, and/or glycosylation.

150. The antibody or antibody fragment of any one of claims 138-141 which is a human, humanized, single chain or chimeric antibody.

151. The anti-human IL-6 antibody or fragment of any one of claims 138-141 which is directly or indirectly attached to a detectable label or therapeutic agent.

152. A diagnostic composition comprising an antibody or antibody fragment according to any one of claims 138-141.

153. A therapeutic composition comprising a therapeutically effective amount of an antibody or antibody fragment according to any one of claims 138-141.

154. The antibody or antibody fragment according to any one of claims 138-141, wherein said antibody binds at least one of soluble IL-6, cell-surface expressed IL-6, IL-6/IL-6R, IL-6/IL-6R/gp130 complexes and or multimers thereof and/or antagonizes the biological effects of one or more of the foregoing.

155. The diagnostic composition of claim 152 which further comprises at least one stabilizer.

156. The pharmaceutical composition of claim 152 which further comprises at least one stabilizer.

157. The diagnostic composition of claim 152 which is lyophilized.

158. The therapeutic composition of claim 153 which is lyophilized.

139. An antibody or antibody fragment that specifically binds to human IL-6 wherein said antibody or fragment specifically competes for binding to the human IL-6 epitope specifically bound by the anti-IL-6 antibody comprising the variable light and heavy chain in SEQ ID NO:

3 and 2 respectively, and further wherein said anti-human IL-6 antibody, when used in a Western immunoblot assay that detects binding of the antibody or antibody fragment to peptides comprised in a library of 57 peptides which each are 15 amino acid fragments of human IL-6 polypeptide contained in SEQ ID NO;

590 through SEQ ID NO;

645 inclusive, specifically binds to the same peptides in said library as an anti-human IL-6 antibody comprising the variable heavy and variable light chain polypeptides in SEQ ID NO;

3 and 2 respectively, wherein specific binding of the antibody or antibody fragment is detected using a chemiluminescent label which emits a detectable chemiluminescent signal when specific binding of said antibody or antibody fragment to a peptide in said library occurs.

140. An anti-human IL-6 antibody or antibody fragment that specifically binds to human IL-6, wherein said antibody specifically competes for binding to the human IL-6 epitope specifically bound by the anti-IL-6 antibody comprising the variable light and heavy chain in SEQ ID NO:

3 and 2 respectively, and further wherein said anti-human IL-6 antibody or anti-human IL-6 antibody fragment, when used in a Western immunoblot assay specifically binds to the same 15 mer fragments of human IL-6 which are selected from the group consisting of amino acid residues 37-51, amino acid residues 70-84, amino acid residues 169-183, amino acid residues 31-45 and amino acid residues 58-72 of the human IL-6 polypeptide in SEQ ID NO;

1, as are specifically bound by the anti-human IL-6 antibody comprising the variable heavy and variable light chain polypeptides in SEQ ID NO;

3 and 2 respectively.

141. An antibody or antibody fragment that specifically binds to human IL-6, wherein said antibody or antibody fragment, when used in a Western immunoblot assay that detects binding of the antibody or antibody fragment to peptides comprised in a library of 57 peptides which each are 15 amino acid fragments of human IL-6 polypeptide contained in SEQ ID NO:

590 through SEQ ID NO;

645 inclusive, specifically binds to the same peptides in said library as an anti-human IL-6 antibody comprising the variable heavy and variable light chain polypeptides in SEQ ID NO;

3 and 2 respectively.