Antigen Binding Molecules That Bind LIGHT

• US 20190315876A1
• Filed: 01/24/2019
• Published: 10/17/2019
• Est. Priority Date: 01/24/2018
• Status: Active Grant

• Current Assignee: Centessa Pharmaceuticals Limited
• Original Assignee: Capella Bioscience Ltd. (Centessa Pharmaceuticals Plc)
• Inventors: Holmes, Steve
• Granted Patent: US 11,312,781 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 39/001136 Cytokines
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: C07K 16/2875 against the NGF/TNF superfamily, e.g. CD70, CD95L, CD153, CD154 against NGF C07K16/22, against TNF C07K16/241
• 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 2317/51 Complete heavy chain or Fd fragment, i.e. VH + CH1
• CPC Class Codes: C07K 2317/55 Fab or Fab'
• 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

Abstract

The present invention relates to antigen binding molecules, including antibodies, fragments, and variants thereof, that bind to the TNF-related cytokine LIGHT (TNFSF14). The present invention also relates to methods of use of such antigen binding molecules in treating and/or preventing inflammatory disorders and immune disorders.

Claims

1. An anti-LIGHT antigen binding molecule or an affinity matured mutant, wherein the antigen binding molecule or an affinity matured mutant has a higher affinity for membrane-bound LIGHT compared to soluble LIGHT.

2. The anti-LIGHT antigen binding molecule or an affinity matured mutant of claim 1, wherein the antigen binding molecule or an affinity matured mutant specifically binds to membrane-bound human LIGHT.

3. The anti-LIGHT antigen binding molecule or an affinity matured mutant of claim 1, wherein the antigen binding molecule or an affinity matured mutant has from about 10 times to about 100 times higher affinity for membrane bound LIGHT compared to soluble LIGHT.

6. The anti-LIGHT antigen binding molecule of claim 1 wherein the anti-LIGHT antigen binding molecule is an antibody selected from the group consisting of 2E08, 3A07, 3B04, 3C10, 3D12, 3E09, 2B11, 3B04_var1, 3B04_var2, 3B04_var3, 3B04_var4, 3B04_var5, 3B04_var6, 3B04_var7, 3B04_var8, 3B04_var9, 3B04_var10, 3B04_var11, 3B04_var12, 3B04_var13, 3B04_var14, 3B04_var15, 3B04_var16, 3D12_var1, 3D12_var2, 3D12_var3, 3D12_var4, 3D12_var5, 3D12_var6, 3D12_var7, 3D12_var8, 3D12_var9, 3D12_var10, 3D12_var11, 3D12_var12, 3D12_var13, 3D12_var14, 3D12_var15 and 3D12_var16.

7. An affinity matured mutant antibody derived from the antigen binding molecule of claim 6.

8. The anti-LIGHT antigen binding molecule or affinity matured mutant of claim 1 comprising:

a heavy chain variable region having at least 80% identity to the amino acid sequence selected from the group consisting of SEQ ID NO;

5, SEQ ID NO;

13, SEQ ID NO;

21, SEQ ID NO;

29, SEQ ID NO;

37, SEQ ID NO;

45, SEQ ID NO;

53, SEQ ID NO;

61, SEQ ID NO;

69, SEQ ID NO;

77, SEQ ID NO;

85, SEQ ID NO;

93, SEQ ID NO;

101, SEQ ID NO;

109, SEQ ID NO;

117;

and/or

a light chain variable region having at least 80% identity to the amino acid sequence selected from the group consisting of consisting SEQ ID NO;

1, SEQ ID NO;

9, SEQ ID NO;

17, SEQ ID NO;

25, SEQ ID NO;

33, SEQ ID NO;

41, SEQ ID NO;

49, SEQ ID NO;

57, SEQ ID NO;

65, SEQ ID NO;

73, SEQ ID NO;

81, SEQ ID NO;

89, SEQ ID NO;

97, SEQ ID NO;

105, SEQ ID NO;

113.

9. The anti-LIGHT antigen binding or affinity matured mutant molecule of claim 8 comprising:

a heavy chain variable region having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the amino acid sequence selected from the group consisting of SEQ ID NO;

5, SEQ ID NO;

13, SEQ ID NO;

21, SEQ ID NO;

29, SEQ ID NO;

37, SEQ ID NO;

45, SEQ ID NO;

53, SEQ ID NO;

61, SEQ ID NO;

69, SEQ ID NO;

77, SEQ ID NO;

85, SEQ ID NO;

93, SEQ ID NO;

101, SEQ ID NO;

109, SEQ ID NO;

117;

and/or

a light chain variable region having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the amino acid sequence selected from the group consisting of consisting SEQ ID NO;

1, SEQ ID NO;

9, SEQ ID NO;

17, SEQ ID NO;

25, SEQ ID NO;

33, SEQ ID NO;

41, SEQ ID NO;

49, SEQ ID NO;

57, SEQ ID NO;

65, SEQ ID NO;

73, SEQ ID NO;

81, SEQ ID NO;

89, SEQ ID NO;

97, SEQ ID NO;

105, SEQ ID NO;

113.

10. The anti-LIGHT antigen binding molecule or affinity matured mutant of claim 1, wherein the antigen binding molecule or affinity matured mutant comprises:

a VHCDR1 having at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of any one of SEQ ID NOs 38, 125, 6, 46, 127, 14, 22, 30, 54, 62, 70, 78, 86, 94, 102, 110, 118;

a VHCDR2 having at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of any one of SEQ ID NOs 39, 126, 7, 47, 128, 15, 23, 31, 55, 63, 71, 79, 87, 95, 103, 111, 119; and

a VHCDR3 having at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of any one of SEQ ID NOs 40, 8, 48, 16, 24, 32, 56, 64, 72, 80, 88, 96, 104, 112 and 120;

and/or

a VLCDR1 having at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of any one of SEQ ID NOs 34, 2, 42, 10, 18, 26, 50, 58, 66, 74, 82, 90, 98, 106, 114;

a VLCDR2 having at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of any one of SEQ ID NOs;

35, 3, 43, 11, 19, 27, 51, 59, 67, 75, 83, 91, 99, 107, 115; and

a VLCDR3 having at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of any one of SEQ ID NOs 36, 4, 44, 12, 20, 28, 52, 60, 68, 76, 84, 92, 100, 108, and 116.

11. The anti-LIGHT antigen binding molecule or affinity matured mutant of claim 1, wherein the antigen binding molecule or affinity matured mutant is selected from the group consisting of:

(a) an anti-LIGHT antigen binding molecule comprising a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence DYEMH (SEQ ID NO;

     38), a VHCDR2 comprising the amino acid sequence EIDPETGDTAYSQKFQG (SEQ ID NO;

     39) and a VHCDR3 comprising the amino acid sequence ETDYFFDY (SEQ ID NO;

     40); and

a light chain variable region comprising a VLCDR1 comprising the amino acid sequence RASENIYGALN (SEQ ID NO;

     34), a VLCDR2 comprising the amino acid sequence GATNLAE (SEQ ID NO;

     35) and a VLCDR3 comprising the amino acid sequence QNVLTTPWT (SEQ ID NO;

     36);

(b) an anti-LIGHT antigen binding molecule comprising a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence DYEMH (SEQ ID NO;

     6), a VHCDR2 comprising the amino acid sequence EIDPETGDTAYSQKFKG (SEQ ID NO;

     7), a VHCDR3 comprising the amino acid sequence ETDYFFDY (SEQ ID NO;

     8); and

a light chain variable region comprising a VLCDR1 comprising the amino acid sequence GASENIYGALN (SEQ ID NO;

     2), a VLCDR2 comprising the amino acid sequence GATNLAD (SEQ ID NO;

     3) and a VLCDR3 comprising the amino acid sequence QNVLTTPWT (SEQ ID NO;

     4);

(c) an anti-LIGHT antigen binding molecule comprising a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence DSEIH (SEQ ID NO;

     46), a VHCDR2 comprising the amino acid sequence EIDPETGGTAYNQKFKG (SEQ ID NO;

     47), a VHCDR3 comprising the amino acid sequence ETDYFFDY (SEQ ID NO;

     48); and

a light chain variable region comprising a VLCDR1 comprising the amino acid sequence GASENIYGALN (SEQ ID NO;

     42), a VLCDR2 comprising the amino acid sequence GATNLAD (SEQ ID NO;

     43) and a VLCDR3 comprising the amino acid sequence QNVLSTPWT (SEQ ID NO;

     44);

(d) an anti-LIGHT antigen binding molecule comprising a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence DYAIH (SEQ ID NO;

     86), a VHCDR2 comprising the amino acid sequence VISTYYGDASYNQKFKG (SEQ ID NO;

     87), a VHCDR3 comprising the amino acid SRGEYGNYDAMDY sequence (SEQ ID NO;

     88); and

a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KASQSVDYDGDSYMN (SEQ ID NO;

     82), a VLCDR2 comprising the amino acid sequence AASNLES (SEQ ID NO;

     83) and a VLCDR3 comprising the amino acid sequence QQSNEDPLT (SEQ ID NO;

     84);

(e) an anti-LIGHT antigen binding molecule comprising a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence DSEIH (SEQ ID NO;

     94), a VHCDR2 comprising the amino acid sequence EIDPETGGTAYNQKFKG (SEQ ID NO;

     95), a VHCDR3 comprising the amino acid sequence ETDYFFDY (SEQ ID NO;

     96); and

a light chain variable region comprising a VLCDR1 comprising the amino acid sequence SASSSVSYMY (SEQ ID NO;

     90), a VLCDR2 comprising the amino acid sequence DTSNLAS (SEQ ID NO;

     91) and a VLCDR3 comprising the amino acid sequence QQWSSYPLT (SEQ ID NO;

     92);

(f) an anti-LIGHT antigen binding molecule comprising heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence DSEIH (SEQ ID NO;

     102), a VHCDR2 comprising the amino acid sequence EIDPETGGTAYNQKFKG (SEQ ID NO;

     103), a VHCDR3 comprising the amino acid sequence ETDYFFDY (SEQ ID NO;

     104); and

a light chain variable region comprising a VLCDR1 comprising the amino acid sequence SASSSVSYMY (SEQ ID NO;

     98), a VLCDR2 comprising the amino acid sequence DTSNLAS (SEQ ID NO;

     99) and a VLCDR3 comprising the amino acid sequence QQWSSYPLT (SEQ ID NO;

     100);

(g) an anti-LIGHT antigen binding molecule comprising a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence DYYMY (SEQ ID NO;

     110), a VHCDR2 comprising the amino acid sequence AIGDGGIYTYYADTVKG (SEQ ID NO;

     111), a VHCDR3 comprising the amino acid sequence GTGDGFAY (SEQ ID NO;

     112); and

a light chain variable region comprising a VLCDR1 comprising the amino acid sequence RASESVDSYGNSFMH (SEQ ID NO;

     106), a VLCDR2 comprising the amino acid sequence LASNLES (SEQ ID NO;

     107) and a VLCDR3 comprising the amino acid sequence QQNNEDPYT (SEQ ID NO;

     108);

(h) an anti-LIGHT antigen binding molecule comprising a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence DYAIH (SEQ ID NO;

     118), a VHCDR2 comprising the amino acid sequence VISTYYGDASYNQKFKG (SEQ ID NO;

     119), a VHCDR3 comprising the amino acid sequence SRGEYGNYDAMDY (SEQ ID NO;

     120); and

a light chain variable region comprising a VLCDR1 comprising the amino acid sequence RASESVDSYGNSFMH (SEQ ID NO;

     114), a VLCDR2 comprising the amino acid sequence RASNLES (SEQ ID NO;

     115) and a VLCDR3 comprising the amino acid sequence QQSNEDPYT (SEQ ID NO;

     116);

(i) an anti-LIGHT antigen binding molecule comprising a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence GYTFTDY (SEQ ID NO;

     125), a VHCDR2 comprising the amino acid sequence DPETGDTA (SEQ ID NO;

     126), a VHCDR3 comprising the amino acid sequence ETDYFFDY (SEQ ID NO;

     8); and

a light chain variable region comprising a VLCDR1 comprising the amino acid sequence GASENIYGALN (SEQ ID NO;

     2), a VLCDR2 comprising the amino acid sequence GATNLAD (SEQ ID NO;

     3) and a VLCDR3 comprising the amino acid sequence QNVLTTPWT (SEQ ID NO;

     4); and

(j) an anti-LIGHT antigen binding molecule comprising a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence DYTFTDS (SEQ ID NO;

     127), a VHCDR2 comprising the amino acid sequence DPETGGTA (SEQ ID NO;

     128), a VHCDR3 comprising the amino acid sequence ETDYFFDY (SEQ ID NO;

     48); and

a light chain variable region comprising a VLCDR1 comprising the amino acid sequence GASENIYGALN (SEQ ID NO;

     42), a VLCDR2 comprising the amino acid sequence GATNLAD (SEQ ID NO;

     43) and a VLCDR3 comprising the amino acid sequence QNVLSTPWT (SEQ ID NO;

     44).

13. A nucleic acid encoding the antigen binding molecule or affinity matured mutant of claim 1.

14. A plasmid comprising the nucleic acid of claim 13.

15. A vector comprising the nucleic acid of claim 13.

16. A pharmaceutical composition comprising an antigen binding molecule of claim 1 and a pharmaceutically acceptable excipient.

17. A method of treating or preventing a LIGHT-mediated disease or disorder comprising administering to a patient an antigen binding molecule or affinity matured mutant of claim 1.

18. A method of treating or preventing an inflammatory disorder or disease or an autoimmune disorder or disease comprising administering to a patient an antigen binding molecule or affinity matured mutant of claim 1.

19. A method of inhibiting interferon-gamma release by administering to a patient an antigen binding molecule or affinity matured mutant of claim 1.

20. The method of claim 17, wherein the antigen binding molecule or affinity matured mutant is 3B04, 3D12 or variants thereof.

4. An anti-LIGHT antigen binding molecule comprising:

a VHCDR3 having at least 80% identity to the amino acid sequence of any one of SEQ ID NOs 8, 16, 24, 32, 40, 48, 56, 64, 72, 80, 88, 96, 104, 112 and 120; and

/or

a VLCDR3 having at least 80% identity to the amino acid sequence of any one of SEQ ID NOs 4, 12, 20, 28, 36, 44, 52, 60, 68, 76, 84, 92, 100, 108, and 116.

5. The anti-LIGHT antigen binding molecule of claim 4 comprising:

a VHCDR3 having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the amino acid sequence of any one of SEQ ID NOs 8, 16, 24, 32, 40, 48, 56, 64, 72, 80, 88, 96, 104, 112 and 120; and

/or

a VLCDR3 having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the amino acid sequence of any one of SEQ ID NOs 4, 12, 20, 28, 36, 44, 52, 60, 68, 76, 84, 92, 100, 108, and 116.

12. An antigen-binding molecule that specifically binds to an epitope of human LIGHT wherein the epitope comprises the amino acids GRATSSSRVW (SEQ ID NO:

124).