JPWO2021156170A5

JPWO2021156170A5 -

Info

Publication number: JPWO2021156170A5
Application number: JP2022547167A
Authority: JP
Publication date: 2024-02-07

Claims

An antibody that binds to kallikrein 5 (KLK5), the antibody comprising a variable light chain and a variable heavy chain,
a. The variable light chain comprises a CDR-L1 comprising SEQ ID NO: 1 or SEQ ID NO: 62 or SEQ ID NO: 63, a CDR-L2 comprising SEQ ID NO: 2, and a CDR-L3 comprising SEQ ID NO: 3; and b. The variable heavy chain comprises CDR-H1 comprising SEQ ID NO: 4, CDR-H2 comprising SEQ ID NO: 5, and CDR-H3 comprising SEQ ID NO: 6.
The above antibody.

a. The variable light chain comprises CDR-L1 comprising SEQ ID NO: 1, CDR-L2 comprising SEQ ID NO: 2, and CDR-L3 comprising SEQ ID NO: 3; and b. The variable heavy chain comprises CDR-H1 comprising SEQ ID NO: 4, CDR-H2 comprising SEQ ID NO: 5, and CDR-H3 comprising SEQ ID NO: 6.
The antibody according to claim 1.

An antibody that binds to kallikrein 5 (KLK5), comprising amino acid residues Arg87, Ala107, Arg110, Lys111, Lys112, Val113, Val137, Lys138, Ser139, Ile140, Pro141, His142, Pro143, The above antibody binds to an epitope of human KLK5 including Tyr145, Ser146, and His147.

4. The antibody of claim 3, wherein the epitope is characterized by X-ray crystallography.

The antibody according to any one of claims 1 to 4, which inhibits or reduces the protease activity of KLK5.

6. The antibody according to any one of claims 1 to 5, which binds to KLK5 when KLK5 is bound to LEKTI or a fragment of LEKTI.

7. The antibody of any one of claims 1 to 6, wherein the antibody does not compete with LEKTI or a fragment of LEKTI for binding to KLK5.

8. An antibody according to any one of claims 1 to 7, wherein the antibody forms a complex with KLK5 bound to LEKTI or a fragment of LEKTI.

9. The fragment of LEKTI according to any one of claims 6 to 8, wherein the fragment of LEKTI is human LEKTI domain 5 comprising amino acids 1 to 64 of SEQ ID NO: 54, or LEKTI domain 8 comprising amino acids 1 to 71 of SEQ ID NO: 61. antibody.

Antibody according to any one of claims 1 to 9, wherein the antibody binds to human KLK5, preferably human KLK5 comprising SEQ ID NO:53, and to cynomolgus (cyno) KLK5, preferably cynoKLK5 comprising SEQ ID NO:60.

11. The antibody of any one of claims 1 to 10, wherein the antibody does not bind to human or cyno kallikrein 2 (KLK2); or human or cyno kallikrein 4 (KLK4); or human or cyno kallikrein 7 (KLK7).

the antibody comprises a variable light chain and a variable heavy chain;
a. The variable light chain comprises a CDR-L1 comprising SEQ ID NO: 1 or SEQ ID NO: 62 or SEQ ID NO: 63, preferably a CDR-L1 comprising SEQ ID NO: 1, a CDR-L2 comprising SEQ ID NO: 2, and a CDR-L1 comprising SEQ ID NO: 3. comprising L3; and b. The variable heavy chain comprises CDR-H1 comprising SEQ ID NO: 4, CDR-H2 comprising SEQ ID NO: 5, and CDR-H3 comprising SEQ ID NO: 6.
Antibody according to any one of claims 3 to 11

The antibody according to any one of claims 1 to 12, wherein the antibody is a chimeric antibody or a humanized antibody.

The antibody according to any one of claims 1 to 13, wherein the antibody is a full-length antibody.

15. An antibody according to claim 14, wherein the full-length antibody is selected from IgG1, IgG4 or IgG4P.

Antibody according to any one of claims 1 to 13, wherein the antibody is selected from Fab, Fab', F(ab') ₂ , scFv, dAb or VHH.

The antibody is
a. a light chain variable region comprising SEQ ID NO: 7 or 11 or 15 or 19 or 23; and/or b. Heavy chain variable region comprising SEQ ID NO: 9 or 27 or 31 or 35 or 39 or 43
The antibody according to any one of claims 1 to 16, comprising:

The antibody is
a. a light chain variable region comprising SEQ ID NO: 15; and
b. Heavy chain variable region comprising SEQ ID NO: 39
The antibody according to any one of claims 1 to 16, comprising:

The antibody is
a. a light chain comprising SEQ ID NO: 13 or 17 or 21 or 25; and b. 18. An antibody according to any one of claims 1 to 15 or 17, comprising a heavy chain comprising SEQ ID NO: 29 or 33 or 37 or 41 or 45.

The antibody is
a. a light chain comprising SEQ ID NO: 17; and
b. Heavy chain comprising SEQ ID NO: 41
The antibody according to any one of claims 1 to 15 or 17 to 19, comprising:

Claim 17, wherein the amino acid residue glutamine (Gln; Q) in L-CDR1 at position 24 is substituted with arginine (Arg; R) or lysine (Lys; K) with reference to SEQ ID NO: 15 or 17. The antibody according to any one of 1 to 20 .

22. The antibody according to any one of claims 1 to 21 , wherein KLK5 is human KLK5 comprising SEQ ID NO: 51 or 52 or 53, or cynoKLK5 comprising SEQ ID NO: 60.

a. competes with an antibody according to any one of claims 1 to 22 for binding to KLK5; and/or b. cross-blocks or is cross-blocked with an antibody according to any one of claims 1 to 22 for binding to KLK5; and/or c. binds KLK5 to the same epitope as an antibody according to any one of claims 1 to 22 ; and/or d. a heavy chain variable region having at least 90% identity or similarity to a sequence according to SEQ ID NO: 29 or 33 or 37 or 41 or 45; and/or e. comprising a light chain variable region having at least 90% identity or similarity to a sequence according to SEQ ID NO: 13 or 17 or 21 or 25;
antibody.

An isolated polynucleotide encoding an antibody according to any one of claims 1 to 22 .

25. The isolated polynucleotide of claim 24 , wherein the polynucleotide encodes:
a. a light chain variable region, wherein the polynucleotide comprises i. at least 90% identical to SEQ ID NO: 8 (or nucleotides 1-330 of SEQ ID NO: 8) or 12 (or nucleotides 1-330 of SEQ ID NO: 12) or 16 or 20 or 24 or 64 or 66; or ii. or iii. or b. a heavy chain variable region, wherein the polynucleotide comprises i. at least 90% identical to SEQ ID NO: 10 or 28 or 32 or 36 or 40 or 44; or ii. comprises SEQ ID NO: 10 or 28 or 32 or 36 or 40 or 44; or iii. consisting essentially of SEQ ID NO: 10 or 28 or 32 or 36 or 40 or 44; or c. a light chain, where the polynucleotide is i. at least 90% identical to SEQ ID NO: 14 or 18 or 22 or 26 or 65 or 67 or 100 or 101 or 102 or 103 or 104; or ii. or iii. consisting essentially of SEQ ID NO: 14 or 18 or 22 or 26 or 65 or 67 or 100 or 101 or 102 or 103 or 104; or d. a heavy chain, where the polynucleotide is i. at least 90% identical to SEQ ID NO: 30 or 34 or 38 or 42 or 46; or ii. comprises SEQ ID NO: 30 or 34 or 38 or 42 or 46; or iii. Consisting essentially of SEQ ID NO: 30 or 34 or 38 or 42 or 46.

26. A cloning or expression vector comprising one or more polynucleotides according to any one of claims 24 or 25 .

a. one or more polynucleotides according to any one of claims 24 or 25 , or b. 27. A host cell comprising one or more expression vectors according to claim 26 .

The method according to any one of claims 1 to 22 , comprising culturing the host cell according to claim 27 under conditions suitable for producing antibodies, and isolating the antibody produced by the host cell. A method for producing antibodies.

A pharmaceutical composition comprising an antibody according to any one of claims 1 to 22 and one or more pharmaceutically acceptable carriers, excipients, or diluents.

30. A pharmaceutical composition according to claim 29 for use in therapy.

30. A pharmaceutical composition according to claim 29 for use in the treatment of a disease characterized by dysregulation of KLK5 or dysregulation of inhibition of KLK5.

32. A pharmaceutical composition according to claim 31 , wherein the disease is selected from Netherton syndrome, atopic dermatitis, ichthyosis, rosacea, asthma, or cancer, such as ovarian cancer or bladder cancer, or a combination thereof.

33. The pharmaceutical composition according to claim 32 , wherein the disease is Netherton syndrome.

33. The pharmaceutical composition according to claim 32 , wherein the disease is atopic dermatitis.