Anti-tenascin-c a2 antibodies and methods of use

Patent metadata

Field	Value
Publication number	US-2016264651-A1
Application number	US-201514843112-A
Country	US
Kind code	A1
Filing date	Sep 2, 2015
Priority date	Aug 13, 2010
Publication date	Sep 15, 2016
Grant date	—

Abstract

The invention provides antibodies against the A2 domain of tenascin-C and methods of using the same.

First claim

1 . An isolated antibody that specifically binds to the A2 domain of tenascin A2 (TNC A2), wherein the antibody comprises three heavy chain complementarity determining regions (HCDRs) HCDR1, HCDR2, HCDR3 and three light chain CDRs (LCDRs) LCDR1, LCDR2, LCDR3, having the amino acid sequences as follows:
(a) a heavy chain CDR1 selected from the group of SEQ ID NO: 3, SEQ ID NO: 5, and SEQ ID NO: 7; (b) a heavy chain CDR2 selected from the group of SEQ ID NO: 9, SEQ ID NO: 11, SEQ ID NO: 13, SEQ ID NO: 15, SEQ ID NO: 17, SEQ ID NO: 19, SEQ ID NO:21, SEQ ID NO: 23, and SEQ ID NO: 25; (c) a heavy chain CDR3 of SEQ ID NO: 27; (d) a light chain CDR1 selected from the group of SEQ ID NO: 29, SEQ ID NO: 31, and SEQ ID NO: 33; (e) a light chain CDR2 selected from the group of SEQ ID NO: 35, SEQ ID NO: 37, SEQ ID NO: 39, SEQ ID NO: 41, SEQ ID NO: 43, and SEQ ID NO: 45; and (f) a light chain CDR3 of SEQ ID NO:47, wherein said antibody does not comprise the combination of a heavy chain CDR1 (HCDR1) selected from the group of SEQ ID NO: 3, SEQ ID NO: 5, SEQ ID NO: 7, and a heavy chain CDR2 (HCDR2) selected from the group of SEQ ID NO: 9, SEQ ID NO: 15, and SEQ ID NO: 21, and the heavy chain CDR3 (HCDR3) of SEQ ID NO: 27, and the light chain CDR1 (LCDR1) of SEQ ID NO: 29, and the light chain CDR2 (LCDR2) of SEQ ID NO: 35, and the light chain CDR3 (LCDR3) of SEQ ID NO:47.

2 . The antibody of claim 1 , which is a monoclonal antibody.

3 . The antibody of claim 1 , which is a human, a humanized, or a chimeric antibody.

4 . The antibody of claim 1 , which is an antibody fragment that binds to the A2 domain of TNC A2.

5 . The antibody of claim 1 , wherein said antibody binds to human TNC A2 with a KD value lower than about 1 μM.

6 . An isolated antibody that specifically binds to the A2 domain of tenascin A2 (TNC A2), wherein the antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein said VH has an amino acid sequence having at least 95% sequence identity to an amino acid sequence selected from the group of SEQ ID NOs: 59, 63 and 67, wherein the antibody does not comprise the combination of the VH sequence of SEQ ID NO: 59 and the VL sequence of SEQ ID NO: 55 or SEQ ID NO: 57.

7 . The isolated antibody of claim 6 , wherein the VL has an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NOs: 55, 57, 69, 73, 77, 81, 85 and 89.

8 . The antibody of claim 6 , comprising a VH sequence selected from the group of SEQ ID NOs: 59, 63 and 67, wherein the antibody does not comprise the combination of the VH sequence of SEQ ID NO: 59 and the VL sequence of SEQ ID NO: 55 or SEQ ID NO: 57.

9 . The antibody of claim 8 , comprising a VL sequence selected from the group of SEQ ID NOs: 55, 57, 69, 73, 77, 81, 85 and 89.

10 . The antibody of claim 1 , wherein said antibody is a full-length IgG class antibody having a human constant region comprising a glycoengineered Fc region, wherein said antibody has an increased proportion of non-fucosylated oligosaccharides in said Fc region, as compared to a non-glycoengineered antibody.

11 . The antibody of claim 10 , wherein said antibody has increased ADCC effector function and/or increased Fc receptor binding affinity as compared to a non-glycoengineered antibody.

12 . An isolated nucleic acid encoding the antibody of claim 1 .

13 . A host cell comprising the nucleic acid of claim 12 .

14 . A method of producing an antibody that specifically binds to the A2 domain of tenascin A2, said method comprising a) culturing the host cell of claim 13 in a medium under conditions allowing the expression of the antibody, and b) recovering the antibody.

15 . The host cell of claim 13 , wherein said host cell has been manipulated to express increased levels of one or more polypeptides having GnTIII activity.

16 . A method of producing an antibody that specifically binds to the A2 domain of tenascin A2, said method comprising: a) culturing the host cell of claim 15 in a medium under conditions allowing the expression of the antibody and the modification of the oligosaccharides present on the Fc region of said antibody by said polypeptide having GnTIII activity, and b) recovering the antibody.

17 . An immunoconjugate comprising the antibody of claim 1 and a cytotoxic agent.

18 . A pharmaceutical formulation comprising the antibody of claim 1 and a pharmaceutically acceptable carrier.

19 . A method of treating an individual having cancer characterized by TNC A2 expression, comprising administering to the individual an effective amount of the antibody of claim 1 .

20 . A method of inducing cell lysis of a tumor cell or a stromal cell of a tumor in an individual comprising administering to the individual an effective amount of the antibody of claim 1 , wherein the cell lysis is induced by antibody dependent cell-mediated cytotoxicity of the antibody.

21 . A method of diagnosing disease in an individual, said method comprising administering to the individual an effective amount of a diagnostic agent, wherein said diagnostic agent comprises the antibody of claim 1 and a label that allows detection of a complex of said diagnostic agent and TNC A2.

22 . An isolated antibody that specifically binds to TNC A2, wherein the antibody comprises three heavy chain complementarity determining regions (HCDRs) HCDR1, HCDR2, HCDR3 and three light chain CDRs (LCDRs) LCDR1, LCDR2, LCDR3 comprising the combination of a heavy chain CDR1 (HCDR1) selected from the group of SEQ ID NO: 3, SEQ ID NO: 5, SEQ ID NO: 7, and a heavy chain CDR2 (HCDR2) selected from the group of SEQ ID NO: 9, SEQ ID NO: 15, and SEQ ID NO: 21, and the heavy chain CDR3 (HCDR3) of SEQ ID NO: 27, and the light chain CDR1 (LCDR1) of SEQ ID NO: 29, and the light chain CDR2 (LCDR2) of SEQ ID NO: 35, and the light chain CDR3 (LCDR3) of SEQ ID NO:47, wherein said antibody is a full length IgG class antibody having a human constant region.

23 . The antibody of claim 22 , wherein said human constant region comprises a glycoengineered Fc region having an increased proportion of non-fucosylated oligosaccharides in said Fc region, as compared to a non-glycoengineered antibody.

24 . The antibody of claim 23 , wherein said antibody has increased ADCC effector function and/or increased Fc receptor binding affinity as compared to a non-glycoengineered antibody.

25 . An isolated nucleic acid encoding the antibody of claim 22 .

26 . A host cell comprising the nucleic acid of claim 25 .

27 . A method of producing an antibody that specifically binds to the A2 domain of tenascin A2, said method comprising a) culturing the host cell of claim 26 in a medium under conditions allowing the expression of the antibody, and b) recovering the antibody.

28 . The host cell of claim 26 , wherein said host cell has been manipulated to express increased levels of one or more polypeptides having GnTIII activity.

29 . A method of producing an antibody that specifically binds to the A2 domain of tenascin A2, said method comprising: a) culturing the host cell of claim 28 in a medium under conditions allowing the expression of the antibody and the modification of the oligosaccharides present on the Fc region of said antibody by said polypeptide having GnTIII activity, and b) recovering the antibody.

Assignees

• Roche Glycart Ag

Inventors

• Freimoser-Grundschober Anne
• Hosse Ralf
• Klein Christian
• Moessner Ekkehard
• Nicolini Valeria G
• Umaña Pablo

Classifications

• A61K47/6843

  the antibody targeting a material from animals or humans · CPC title

• A61K39/39558

  against tumor tissues, cells, antigens · CPC title

• C07K2317/565

  Complementarity determining region [CDR] · CPC title

• C07K2317/92

  Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value · CPC title

• C07K2317/55

  Fab or Fab' · CPC title