Methods of treating fgf21-associated disorders

Patent metadata

Field	Value
Publication number	US-2020087392-A1
Application number	US-201615749775-A
Country	US
Kind code	A1
Filing date	Aug 2, 2016
Priority date	Aug 3, 2015
Publication date	Mar 19, 2020
Grant date	—

Abstract

The present invention relates to monoclonal antibodies and antigen-binding fragments thereof that bind to human β-klotho, and pharmaceutical compositions and methods of treatment comprising the same.

First claim

1 . (canceled)

2 . An isolated antibody or antigen-binding fragment thereof that binds to an epitope of β-klotho, wherein the antibody or antigen-binding fragment thereof protects, as determined by hydrogen-deuterium exchange (HDx), one, two, three, four, five, or more of the following peptides of β-klotho (SEQ ID NO: 262): 245-266, 246-265, 343-349, 344-349, 421-429, 488-498, 509-524, 536-550, 568-576, 646-669, 646-670, 696-700, 773-804, 834-857, and 959-986 aa.

3 . The antibody or antigen-binding fragment thereof according to claim 2 , wherein said antibody or fragment (i) increases the activity of β-klotho and FGFR1c, and (ii) binds to a human β-klotho protein with a KD of less than or equal to 10 pM, as measured by solution equilibrium titration assay (SET).

4 . (canceled)

5 . The isolated antibody or antigen-binding fragment thereof according to claim 2 that binds to an epitope of β-klotho, wherein said epitope comprises one or more amino acids of residues 246-265, 536-550, 834-857 and 959-986 of the β-klotho sequence (SEQ ID NO:262), or (ii) one or more of amino acids of residues 646-670, 696-700, and 646-689 of the β-klotho sequence (SEQ ID NO:262).

6 . (canceled)

7 . (canceled)

8 . (canceled)

9 . (canceled)

10 . The isolated antibody or antigen-binding fragment of claim 2 , wherein said antibody or fragment protects, as determined by hydrogen-deuterium exchange (HDx), six, seven, eight, nine, ten, or more peptides from the following as set forth in Table 2: SEQ ID NOs: 109, 110, 111, 112, 113, 125, 126, 127, 128, 129, 141, 142, 143, 156, 157, 158, 159, 160, 161, 163, 164, 165, 167, 168, 169, 170, 171, 172, 184, 185, 186, 187, 188, 195, 196, 197, 198, 204, 212, 213, 214, 215, 216, 217, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 256, 257, 258, 259, 260, and 261.

11 . The isolated antibody or antigen-binding fragment of claim 2 , wherein said antibody or fragment comprises a heavy chain CDR1, heavy chain CDR2, and heavy chain CDR3 from Table 1, and a light chain CDR1, light chain CDR2, and light chain CDR3 from Table 1.

12 . The isolated antibody or antigen-binding fragment of claim 10 , wherein said antibody or fragment does not contact residues 701 (Tyr) or 703 (Arg) of human β-klotho (SEQ ID NO: 262).

13 . The isolated antibody or antigen-binding fragment of claim 2 , wherein the antibody or fragment comprises a heavy chain CDR1 selected from the group consisting of SEQ ID NO: 263 and 268; a heavy chain CDR2 selected from the group consisting of SEQ ID NO: 4, 24, 44, and 64; a heavy chain CDR3 selected from the group consisting of 5, 25, and 45; a light chain CDR1 selected from the group consisting of SEQ ID NO: 13, 33, 53, and 73; a light chain CDR2 selected from the group consisting of SEQ ID NO: 14, 34, 54, and 74; and a light chain CDR3 selected from the group consisting of SEQ ID NO: 15, 35, 55, and 75.

14 . The isolated antibody or antigen-binding fragment of claim 2 , wherein the antibody or fragment comprises a VH selected from the group consisting of SEQ ID NO: 9, 29, 49, 69 or an amino acid sequence with at least 80% or 90% or 95% or 97% identity thereof; and a VL selected from the group consisting of SEQ ID NO: 19, 39, 59, and 79 or an amino acid sequence with at least 80% or 90% or 95% or 97% identity thereof.

15 . (canceled)

16 . The isolated antibody or antigen-binding fragment of claim 11 , wherein the antibody or fragment comprises a heavy chain CDR1 of SEQ ID NO: 268; a heavy chain CDR2 of SEQ ID NO: 64; a heavy chain CDR3 of SEQ ID NO: 25; a light chain CDR1 of SEQ ID NO: 73; a light chain CDR2 of SEQ ID NO: 74; and a light chain CDR3 of SEQ ID NO: 75.

17 . (canceled)

18 . (canceled)

19 . The isolated antibody or antigen-binding fragment of claim 2 , wherein the antibody or fragment comprises a variable heavy chain selected from the group consisting of SEQ ID NO: 9, 29, 49, and 69; and variable light chain sequence selected from the group consisting of SEQ ID NO: 19, 39, 59, and 79.

20 . The isolated antibody or antigen-binding fragment of claim 2 , wherein the antibody or fragment is selected from the group consisting of: an antibody or fragment comprising a variable heavy chain sequence of SEQ ID NO: 9 and a variable light chain sequence of SEQ ID NO: 19, an antibody or fragment comprising a variable heavy chain sequence of SEQ ID NO: 29 and a variable light chain sequence of SEQ ID NO: 39; an antibody or fragment comprising a variable heavy chain sequence of SEQ ID NO: 49 and a variable light chain sequence of SEQ ID NO: 59; and an antibody or fragment comprising a variable heavy chain sequence of SEQ ID NO: 69 and a variable light chain sequence of SEQ ID NO: 79.

21 . The isolated antibody or antigen-binding fragment of claim 2 , wherein the antibody or fragment comprises a heavy chain CDR1 selected from the group consisting of SEQ ID NO: 3, 23, 43, and 63; a heavy chain CDR2 selected from the group consisting of SEQ ID NO: 4, 24, 44, and 64; a heavy chain CDR3 selected from the group consisting of 5, 25, 45, and 65; a light chain CDR1 selected from the group consisting of SEQ ID NO: 13, 33, 53, and 73; a light chain CDR2 selected from the group consisting of SEQ ID NO: 14, 34, 54, and 74; and a light chain CDR3 selected from the group consisting of SEQ ID NO: 15, 35, 55, and 75.

22 . The isolated antibody or antigen-binding fragment of claim 2 , wherein the antibody or fragment comprises a heavy chain CDR1 selected from the group consisting of SEQ ID NO: 6, 26, 46, and 66; a heavy chain CDR2 selected from the group consisting of SEQ ID NO: 7, 27, 47, and 67; a heavy chain CDR3 selected from the group consisting of 8, 28, 48, and 68; a light chain CDR1 selected from the group consisting of SEQ ID NO: 16, 36, 56, and 76; a light chain CDR2 selected from the group consisting of SEQ ID NO: 17, 37, 57, and 77; and a light chain CDR3 selected from the group consisting of SEQ ID NO: 18, 38, 58, and 78.

23 . The isolated antibody or antigen-binding fragment of claim 2 , wherein the antibody or fragment comprises:
(i) a heavy chain CDR1 of SEQ ID NO: 3; a heavy chain CDR2 of SEQ ID NO: 4; a heavy chain CDR3 of SEQ ID NO: 5; a light chain CDR1 of SEQ ID NO: 13; a light chain CDR2 of SEQ ID NO: 14; and a light chain CDR3 of SEQ ID NO: 15; (ii) a heavy chain CDR1 of SEQ ID NO: 23; a heavy chain CDR2 of SEQ ID NO: 24; a heavy chain CDR3 of SEQ ID NO: 25; a light chain CDR1 of SEQ ID NO: 33; a light chain CDR2 of SEQ ID NO: 34; and a light chain CDR3 of SEQ ID NO: 35; (iii) a heavy chain CDR1 of SEQ ID NO: 43; a heavy chain CDR2 of SEQ ID NO: 44; a heavy chain CDR3 of SEQ ID NO: 45; a light chain CDR1 of SEQ ID NO: 53; a light chain CDR2 of SEQ ID NO: 54; and a light chain CDR3 of SEQ ID NO: 55; (iv) a heavy chain CDR1 of SEQ ID NO: 63; a heavy chain CDR2 of SEQ ID NO: 64; a heavy chain CDR3 of SEQ ID NO: 65; a light chain CDR1 of SEQ ID NO: 73; a light chain CDR2 of SEQ ID NO: 74; and a light chain CDR3 of SEQ ID NO: 75; (v) a heavy chain CDR1 of SEQ ID NO: 6; a heavy chain CDR2 of SEQ ID NO: 7; a heavy chain CDR3 of SEQ ID NO: 8; a light chain CDR1 of SEQ ID NO: 16; a light chain CDR2 of SEQ ID NO: 17; and a light chain CDR3 of SEQ ID NO: 18; (vi) a heavy chain CDR1 of SEQ ID NO: 26; a heavy chain CDR2 of SEQ ID NO: 27; a heavy chain CDR3 of SEQ ID NO: 28; a light chain CDR1 of SEQ ID NO: 36; a light chain CDR2 of SEQ ID NO: 37; and a light chain CDR3 of SEQ ID NO: 38; (vii) a heavy chain CDR1 of SEQ ID NO: 46; a heavy ch

Assignees

• Novartis Ag

Inventors

• Boettcher Brian
• Caplan Shari Lynn
• Cebe Regis
• Li Guochun
• Taraszka John A
• Xu Fangmin
• Yowe David Langdon

Classifications

• C07K2317/90

  characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin · CPC title

• C07K2317/92

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

• C07K2317/94

  Stability, e.g. half-life, pH, temperature or enzyme-resistance · CPC title

• C07K2317/55

  Fab or Fab' · CPC title

• A61P3/00

  Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00) · CPC title