Anti-stem cell factor (SCF) and Anti-thymic stromal lymphopoietin (TSLP) antibodies and bispecific constructs

Abstract

Provided herein are novel anti-TSLP and anti-SCF antibodies, and binding domains thereof, as well as bispecific constructs comprising such antibodies and binding domains. Also provided herein are methods of treating disorders associated with an immune response (e.g., immune cell migration, activation, and / or proliferation) via interaction (e.g., binding) of TSLP and / or SCF with its receptor (TSLPR and / or c-Kit, respectively) on immune cells (such as disorders of the immune system) by administering the antibodies (or antigen binding fragments thereof), bispecific constructs, or compositions described herein to a patient in need thereof.

Description

This application provides novel anti-TSLP and anti-SCF antibodies and their binding domains, as well as bispecific constructs comprising such antibodies and binding domains. This application also provides a method of treating conditions (such as immune system disorders) associated with immune responses (e.g., immune cell migration, activation, and / or proliferation) through the interaction (e.g., binding) of TSLP and / or SCF with their receptors (TSLPR and / or c-Kit, respectively) on immune cells to a patient in need. Abstract

Claims

CLAIMS:

1. A bispecific construct comprising an anti-TSLP antibody, or binding domain thereof, linked to an anti-SCF antibody, or binding domain thereof,, wherein:(a) the anti-TSLP antibody, or binding domain thereof, comprises heavy chain variable region CDR1, CDR2 and CDR3 domains having the amino acid sequences respectively set forth in (i) SEQ ID NOs: 6, 7, and 8, (ii) SEQ ID NOs: 2, 3, and 4, (hi) SEQ ID NOs: 10, 11, and 12, (iv) SEQ ID NOs: 14, 15, and 16, or conservative sequence modifications thereof, and light chain variable region CDR1, CDR2 and CDR3 domains having the amino acid sequences respectively set forth in (v) SEQ ID NOs: 18, 19, and 20, (vi) SEQ ID NOs: 22, 23, and 24, (vii) SEQ ID NOs: 26, 27, and 28, (viii) SEQ ID NOs: 30, 31, and 32, or conservative sequence modifications thereof; and(b) the anti-SCF antibody, or binding domain thereof, comprises heavy chain variable region CDR1, CDR2 and CDR3 domains having the amino acid sequences respectively set forth in (i) SEQ ID NOs: 46, 47, and 48, (ii) SEQ ID NOs: 38, 39, and40, (hi) SEQ ID NOs: 42, 43, and 44, (iv) SEQ ID NOs: 34, 35, and 36, or conservative sequence modifications thereof, and light chain variable region CDR1, CDR2 and CDR3 domains having the amino acid sequences respectively set forth in (v) SEQ ID NOs: 58, 59, and 60, (vi) SEQ ID NOs: 54, 55, and 56, (vii) SEQ ID NOs: 50, 51, and 52, (viii) SEQ ID NOs: 62, 63, and 64, or conservative sequence modifications thereof.

2. A bispecific construct comprising an anti-TSLP antibody, or binding domain thereof, linked to an anti-SCF antibody, or binding domain thereof,, wherein:(a) the anti-TSLP antibody, or binding domain thereof, comprises a heavy chain variable region having the amino acid sequences set forth in SEQ ID NOs: 5, 1, 9, 13, or a sequence at least 90% identical thereto, and a light chain variable region having the amino acid sequences set forth in SEQ ID NOs: 17, 21, 25, 29, or a sequence at least 90% identical thereto; and(b) the anti-SCF antibody, or binding domain thereof, comprises a heavy chain variable region having the amino acid sequences set forth in SEQ ID NOs:45, 33, 37,41, or a sequence at least 90% identical thereto, and a light chain variable regionhaving the amino acid sequences set forth in SEQ ID NOs: 57, 49, 53, 61, or a sequence at least 90% identical thereto.

3. The bispecific construct of claim 1 or 2, wherein the anti-TSLP antibody, or binding domain thereof, comprises heavy and light chain variable regions respectively comprising the amino acid sequences set forth in (a) SEQ ID NOs: 5 and 17, (b) SEQ ID NOs: 1 and 21, (c) SEQ ID NOs: 1 and 25, (d) SEQ ID NOs: 1 and 29, (e) SEQ ID NOs: 1 and 17, (f) SEQ ID NOs: 5 and 21, (g) SEQ ID NOs: 5 and 25, (h) SEQ ID NOs: 5 and 29, (i) SEQ ID NOs: 9 and 17, (j) SEQ ID NOs: 9 and 21, (k) SEQ ID NOs: 9 and 25, (1) SEQ ID NOs: 9 and 29, (m) SEQ ID NOs: 13 and 17, (n) SEQ ID NOs: 13 and 21, (o) SEQ ID NOs: 13 and 25, or (p) SEQ ID NOs: 13 and 29.

4. The bispecific construct of claim 1 or 2, wherein the anti-TSLP antibody, or binding domain thereof, comprises heavy and light chain variable regions respectively comprising the amino acid sequences set forth in (a) SEQ ID NOs: 5 and 17, (b) SEQ ID NOs: 1 and 21, (c) SEQ ID NOs: 1 and 25, (d) SEQ ID NOs: 1 and 17, (e) SEQ ID NOs: 5 and 21, (f) SEQ ID NOs: 5 and 25, (g) SEQ ID NOs: 9 and 17, (h) SEQ ID NOs: 9 and 21, or (i) SEQ ID NOs: 9 and 25.

5. The bispecific construct of any one of claims 1-4, wherein the anti-SCF antibody, or binding domain thereof, comprises heavy and light chain variable regions respectively comprising the amino acid sequences set forth in (a) SEQ ID NOs: 45 and 57, (b) SEQ ID NOs: 33 and 53, (c) SEQ ID NOs: 33 and 57, (d) SEQ ID NOs: 33 and 61, (e) SEQ ID NOs: 37 and 49, (f) SEQ ID NOs: 37 and 53, (g) SEQ ID NOs: 37 and 57, (h) SEQ ID NOs: 33 and 61, (i) SEQ ID NOs: 41 and 49, (j) SEQ ID NOs: 41 and 53, (k) SEQ ID NOs: 41 and 57, (1) SEQ ID NOs: 41 and 61, (m) SEQ ID NOs: 45 and 49, (n) SEQ ID NOs: 45 and 53, (o) SEQ ID NOs: 33 and 49, or (p) SEQ ID NOs: 45 and 61.

6. The bispecific construct of any one of claims 1-4, wherein the anti-SCF antibody, or binding domain thereof, comprises heavy and light chain variable regions respectively comprising the amino acid sequences set forth in (a) SEQ ID NOs: 45 and 57, (b) SEQ ID NOs: 33 and 61, (c) SEQ ID NOs: 37 and 57, (d) SEQ ID NOs: 37 and 61, (e) SEQ ID NOs:41 and 57, (f) SEQ ID NOs: 41 and 61, (g) SEQ ID NOs: 33 and 57, or (h) SEQ ID NOs: 45 and 61.

7. The bispecific construct of any one of claims 1-6, wherein (a) the anti-TSLP antibody, or binding domain thereof, further comprises a human IgGl constant domain or (b) the anti- SCF antibody, or binding domain thereof, further comprises a human IgGl constant domain.

8. The bispecific construct of any one of claims 1-7, wherein (a) the anti-SCF antibody, or binding domain thereof, is linked to the C-terminus of the heavy chain of the anti-TSLP antibody, or binding domain thereof, or (b) the anti-TSLP antibody, or binding domain thereof, is linked to the C-terminus of the heavy chain of the anti-SCF antibody, or binding domain thereof,.

9. The bispecific construct of any one of claims 1 -8, wherein the anti-SCF binding domain is a scFv or (b) the anti-TSLP binding domain is a scFv.

10. The bispecific construct of any one of claims 1-9, wherein the anti-TSLP antibody, or binding domain thereof, and the anti-SCF antibody, or binding domain thereof, are genetically fused.

11. The bispecific construct of any one of claims 1-9, wherein the anti-TSLP antibody, or binding domain thereof, and the anti-SCF antibody, or binding domain thereof, are chemically conjugated.

12. A bispecific construct comprising an anti-TSLP antibody linked to an anti-SCF scFv, wherein:(a) the anti-SCF scFv comprises heavy chain variable region CDR1, CDR2 and CDR3 domains comprising the amino acid sequences as set forth in SEQ ID NOs: 34, 35, and 36, respectively, and light chain variable region CDR1, CDR2 and CDR3 domains comprising the amino acid sequences as set forth in SEQ ID NOs: 62, 63, and 64, respectively; and(b) the anti-TSLP antibody comprises heavy chain variable region CDR1, CDR2 and CDR3 domains comprising the amino acid sequences as set forth in SEQ ID NOs:2, 3, and 4, respectively, and light chain variable region CDR1, CDR2 and CDR3 domains comprising the amino acid sequences as set forth in SEQ ID NOs: 18, 19, and 20, respectively, and a human IgGl constant domain.

13. The bispecific construct of claim 12, wherein:(a) the anti-SCF scFv comprises heavy and light chain variable regions respectively comprising the amino acid sequences set forth in SEQ ID NOs: 33 and 61; and(b) the anti-TSLP antibody comprises heavy and light chain variable regions respectively comprising the amino acid sequences set forth in SEQ ID NOs: 1 and 17, and a human IgGl constant domain.

14. A bispecific construct comprising an anti-TSLP antibody linked to an anti-SCF scFv, wherein:(a) the anti-SCF scFv comprises heavy chain variable region CDR1, CDR2 and CDR3 domains comprising the amino acid sequences as set forth in SEQ ID NOs: 38, 39, and 40, respectively, and light chain variable region CDR1, CDR2 and CDR3 domains comprising the amino acid sequences as set forth in SEQ ID NOs: 62, 63, and 64, respectively; and(b) the anti-TSLP antibody comprises heavy chain variable region CDR1, CDR2 and CDR3 domains comprising the amino acid sequences as set forth in SEQ ID NOs: 2, 3, and 4, respectively, and light chain variable region CDR1, CDR2 and CDR3 domains comprising the amino acid sequences as set forth in SEQ ID NOs: 18, 19, and 20, respectively, and a human IgGl constant domain.

15. The bispecific construct of claim 14, wherein:(a) the anti-SCF scFv comprises heavy and light chain variable regions respectively comprising the amino acid sequences set forth in SEQ ID NOs: 37 and 61; and(b) the anti-TSLP antibody comprises heavy and light chain variable regions respectively comprising the amino acid sequences set forth in SEQ ID NOs: 1 and 17, and a human IgGl constant domain.

16. A bispecific construct comprising an anti-TSLP antibody linked to an anti-SCF scFv, wherein:(a) the anti-SCF scFv comprises heavy chain variable region CDR1, CDR2 and CDR3 domains comprising the amino acid sequences as set forth in SEQ ID NOs: 46, 47, and 48, respectively, and light chain variable region CDR1, CDR2 and CDR3 domains comprising the amino acid sequences as set forth in SEQ ID NOs: 58, 59, and 60, respectively; and(b) the anti-TSLP antibody comprises heavy chain variable region CDR1, CDR2 and CDR3 domains comprising the amino acid sequences as set forth in SEQ ID NOs: 2, 3, and 4, respectively, and light chain variable region CDR1, CDR2 and CDR3 domains comprising the amino acid sequences as set forth in SEQ ID NOs: 18, 19, and 20, respectively, and a human IgGl constant domain.

17. The bispecific construct of claim 16, wherein:(a) the anti-SCF scFv comprises heavy and light chain variable regions respectively comprising the amino acid sequences set forth in SEQ ID NOs: 45 and 57; and(b) the anti-TSLP antibody comprises heavy and light chain variable regions respectively comprising the amino acid sequences set forth in SEQ ID NOs: 1 and 17, and a human IgGl constant domain.

18. A bispecific construct comprising an anti-TSLP antibody linked to an anti-SCF scFv, wherein:(a) the anti-SCF scFv comprises heavy chain variable region CDR1, CDR2 and CDR3 domains comprising the amino acid sequences as set forth in SEQ ID NOs: 34, 35, and 36, respectively, and light chain variable region CDR1, CDR2 and CDR3 domains comprising the amino acid sequences as set forth in SEQ ID NOs: 62, 63, and 64, respectively; and(b) the anti-TSLP antibody comprises heavy chain variable region CDR1, CDR2 and CDR3 domains comprising the amino acid sequences as set forth in SEQ ID NOs: 6, 7, and 8, respectively, and light chain variable region CDR1, CDR2 and CDR3 domains comprising the amino acid sequences as set forth in SEQ ID NOs: 18, 19, and 20, respectively, and a human IgGl constant domain.

19. The bispecific construct of claim 18, wherein(a) the anti-SCF scFv comprises heavy and light chain variable regions respectively comprising the amino acid sequences set forth in SEQ ID NOs: 33 and 61; and(b) the anti-TSLP antibody comprises heavy and light chain variable regions respectively comprising the amino acid sequences set forth in SEQ ID NOs: 5 and 17, and a human IgGl constant domain.

20. A bispecific construct comprising an anti-TSLP antibody linked to an anti-SCF scFv, wherein:(a) the anti-SCF scFv comprises heavy chain variable region CDR1, CDR2 and CDR3 domains comprising the amino acid sequences as set forth in SEQ ID NOs: 38, 39, and 40, respectively, and light chain variable region CDR1 , CDR2 and CDR3 domains comprising the amino acid sequences as set forth in SEQ ID NOs: 62, 63, and 64, respectively; and(b) the anti-TSLP antibody comprises heavy chain variable region CDR1, CDR2 and CDR3 domains comprising the amino acid sequences as set forth in SEQ ID NOs: 6, 7, and 8, respectively, and light chain variable region CDR1, CDR2 and CDR3 domains comprising the amino acid sequences as set forth in SEQ ID NOs: 18, 19, and 20, respectively, and a human IgGl constant domain.

21. The bispecific construct of claim 20, wherein:(a) the anti-SCF scFv comprises heavy and light chain variable regions respectively comprising the amino acid sequences set forth in SEQ ID NOs: 37 and 61; and(b) the anti-TSLP antibody comprises heavy and light chain variable regions respectively comprising the amino acid sequences set forth in SEQ ID NOs: 5 and 17, and a human IgGl constant domain.

22. A bispecific construct comprising an anti-TSLP antibody linked to an anti-SCF scFv, wherein:(a) the anti-SCF scFv comprises heavy chain variable region CDR1, CDR2 and CDR3 domains comprising the amino acid sequences as set forth in SEQ ID NOs: 46, 47, and 48, respectively, and light chain variable region CDR1, CDR2 and CDR3 domains comprising the amino acid sequences as set forth in SEQ ID NOs: 58, 59, and 60, respectively; and(b) the anti-TSLP antibody comprises heavy chain variable region CDR1, CDR2 and CDR3 domains comprising the amino acid sequences as set forth in SEQ ID NOs: 6, 7, and 8, respectively, and light chain variable region CDR1, CDR2 and CDR3 domains comprising the amino acid sequences as set forth in SEQ ID NOs: 18, 19, and 20, respectively, and a human IgGl constant domain.

23. The bispecific construct of claim 22, wherein:(a) the anti-SCF scFv comprises heavy and light chain variable regions respectively comprising the amino acid sequences set forth in SEQ ID NOs: 45 and 57 ; and(b) the anti-TSLP antibody comprises heavy and light chain variable regions respectively comprising the amino acid sequences set forth in SEQ ID NOs: 5 and 17, and a human IgGl constant domain.

24. A bispecific construct comprising an anti-SCF antibody linked to an anti-TSLP scFv, wherein:(a) the anti-SCF antibody comprises heavy chain variable region CDR1, CDR2 and CDR3 domains comprising the amino acid sequences as set forth in SEQ ID NOs: 34, 35, and 36, respectively, and light chain variable region CDR1, CDR2 and CDR3 domains comprising the amino acid sequences as set forth in SEQ ID NOs: 62, 63, and 64, respectively, and a human IgGl constant domain; and(b) the anti-TSLP scFv comprises heavy chain variable region CDR1, CDR2 and CDR3 domains comprising the amino acid sequences as set forth in SEQ ID NOs: 2, 3, and 4, respectively, and light chain variable region CDR1, CDR2 and CDR3 domains comprising the amino acid sequences as set forth in SEQ ID NOs: 18, 19, and 20, respectively.

25. The bispecific construct of claim 24, wherein:(a) the anti-SCF antibody comprises heavy and light chain variable regions respectively comprising the amino acid sequences set forth in SEQ ID NOs: 33 and 61, and a human IgGl constant domain; and(b) the anti-TSLP scFv comprises heavy and light chain variable regions respectively comprising the amino acid sequences set forth in SEQ ID NOs: 1 and 17.

26. A bispecific construct comprising an anti-SCF antibody linked to an anti-TSLP scFv, wherein:(a) the anti-SCF antibody comprises heavy chain variable region CDR1, CDR2 and CDR3 domains comprising the amino acid sequences as set forth in SEQ ID NOs: 38, 39, and 40, respectively, and light chain variable region CDR1, CDR2 and CDR3 domains comprising the amino acid sequences as set forth in SEQ ID NOs: 62, 63, and 64, respectively, and a human IgGl constant domain; and(b) the anti-TSLP scFv comprises heavy chain variable region CDR1 , CDR2 and CDR3 domains comprising the amino acid sequences as set forth in SEQ ID NOs: 2, 3, and 4, respectively, and light chain variable region CDR1, CDR2 and CDR3 domains comprising the amino acid sequences as set forth in SEQ ID NOs: 18, 19, and 20, respectively.

27. The bispecific construct of claim 26, wherein:(a) the anti-SCF antibody comprises heavy and light chain variable regions respectively comprising the amino acid sequences set forth in SEQ ID NOs: 37 and 61, and a human IgGl constant domain; and(b) the anti-TSLP scFv comprises heavy and light chain variable regions respectively comprising the amino acid sequences set forth in SEQ ID NOs: 1 and 17.

28. A bispecific construct comprising an anti-SCF antibody linked to an anti-TSLP scFv, wherein:(a) the anti-SCF antibody comprises heavy chain variable region CDR1, CDR2 and CDR3 domains comprising the amino acid sequences as set forth in SEQ ID NOs: 46, 47, and 48, respectively, and light chain variable region CDR1, CDR2 and CDR3 domains comprising the amino acid sequences as set forth in SEQ ID NOs: 58, 59, and 60, respectively, and a human IgGl constant domain; and(b) the anti-TSLP scFv comprises heavy chain variable region CDR1, CDR2 and CDR3 domains comprising the amino acid sequences as set forth in SEQ ID NOs: 2, 3, and 4, respectively, and light chain variable region CDR1, CDR2 and CDR3 domains comprising the amino acid sequences as set forth in SEQ ID NOs: 18, 19, and 20, respectively.

29. The bispecific construct of claim 28, wherein:(a) the anti-SCF antibody comprises heavy and light chain variable regions respectively comprising the amino acid sequences set forth in SEQ ID NOs: 45 and 57, and a human IgGl constant domain; and(b) the anti-TSLP antibody comprises heavy and light chain variable regions respectively comprising the amino acid sequences set forth in SEQ ID NOs: 1 and 17.

30. A bispecific construct comprising an anti-SCF antibody linked to an anti-TSLP scFv, wherein:(a) the anti-SCF antibody comprises heavy chain variable region CDR1, CDR2 and CDR3 domains comprising the amino acid sequences as set forth in SEQ ID NOs: 34, 35, and 36, respectively, and light chain variable region CDR1, CDR2 and CDR3 domains comprising the amino acid sequences as set forth in SEQ ID NOs: 62, 63, and 64, respectively, and a human IgGl constant domain; and(b) the anti-TSLP scFv comprises heavy chain variable region CDR1, CDR2 and CDR3 domains comprising the amino acid sequences as set forth in SEQ ID NOs: 6, 7, and 8, respectively, and light chain variable region CDR1, CDR2 and CDR3 domains comprising the amino acid sequences as set forth in SEQ ID NOs: 18, 19, and 20, respectively.

31. The bispecific construct of claim 30, wherein:(a) the anti-SCF antibody comprises heavy and light chain variable regions respectively comprising the amino acid sequences set forth in SEQ ID NOs: 33 and 61, and a human IgGl constant domain; and(b) the anti-TSLP scFv comprises heavy and light chain variable regions respectively comprising the amino acid sequences set forth in SEQ ID NOs: 5 and 17.

32. A bispecific construct comprising an anti-SCF antibody linked to an anti-TSLP scFv, wherein:(a) the anti-SCF antibody comprises heavy chain variable region CDR1, CDR2 and CDR3 domains comprising the amino acid sequences as set forth in SEQ ID NOs: 38, 39, and 40, respectively, and light chain variable region CDR1, CDR2 and CDR3 domains comprising the amino acid sequences as set forth in SEQ ID NOs: 62, 63, and 64, respectively, and a human IgGl constant domain; and(b) the anti-TSLP scFv comprises heavy chain variable region CDR1, CDR2 and CDR3 domains comprising the amino acid sequences as set forth in SEQ ID NOs: 6, 7, and 8, respectively, and light chain variable region CDR1, CDR2 and CDR3 domains comprising the amino acid sequences as set forth in SEQ ID NOs: 18, 19, and 20, respectively.

33. The bispecific construct of claim 32, wherein:(a) the anti-SCF antibody comprises heavy and light chain variable regions respectively comprising the amino acid sequences set forth in SEQ ID NOs: 37 and 61, and a human IgGl constant domain; and(b) the anti-TSLP scFv comprises heavy and light chain variable regions respectively comprising the amino acid sequences set forth in SEQ ID NOs: 5 and 17.

34. A bispecific construct comprising an anti-SCF antibody linked to an anti-TSLP scFv, wherein:(a) the anti-SCF antibody comprises heavy chain variable region CDR1, CDR2 and CDR3 domains comprising the amino acid sequences as set forth in SEQ ID NOs: 46, 47, and 48, respectively, and light chain variable region CDR1, CDR2 and CDR3 domains comprising the amino acid sequences as set forth in SEQ ID NOs: 58, 59, and 60, respectively, and a human IgGl constant domain; and(b) the anti-TSLP scFv comprises heavy chain variable region CDR1, CDR2 and CDR3 domains comprising the amino acid sequences as set forth in SEQ ID NOs: 6, 7, and 8, respectively, and light chain variable region CDR1, CDR2 and CDR3 domains comprising the amino acid sequences as set forth in SEQ ID NOs: 18, 19, and 20, respectively.

35. The bispecific construct of claim 34, wherein:(a) the anti-SCF antibody comprises heavy and light chain variable regions respectively comprising the amino acid sequences set forth in SEQ ID NOs: 45 and 57, and a human IgGl constant domain; and(b) the anti-TSLP scFv comprises heavy and light chain variable regions respectively comprising the amino acid sequences set forth in SEQ ID NOs: 5 and 17.

36. A bispecific construct comprising an anti-SCF antibody linked to an anti-TSLP scFv, comprising the amino acid sequence set forth in SEQ ID NO: 65 or encoded by the nucleotide sequence set forth in SEQ ID NO: 66.

37. A bispecific construct comprising an anti-SCF antibody linked to an anti-TSLP scFv, comprising the amino acid sequence set forth in SEQ ID NO: 67 or encoded by the nucleotide sequence set forth in SEQ ID NO: 68.

38. The bispecific construct of any one of claims 12-23, wherein the anti-SCF scFv is linked to the C-terminus of the heavy chain of the anti-TSLP antibody.

39. The bispecific construct of any one of claims 24-35, wherein the anti-TSLP scFv is linked to the C-terminus of the heavy chain of the anti-SCF antibody.

40. The bispecific construct of any one of claims 12-35, wherein the antibody and scFv are genetically fused.

41. The bispecific construct of any one of claims 12-35, wherein the antibody and scFv are chemically conjugated.

42. An anti-TSLP antibody, or antigen-binding fragment thereof, comprising heavy chain variable region CDR1, CDR2 and CDR3 domains having the amino acid sequences respectively set forth in (i) SEQ ID NOs: 2, 3, and 4, (ii) SEQ ID NOs: 6, 7, and 8, (hi) SEQ ID NOs: 10, 11, and 12, (iv) SEQ ID NOs: 14, 15, and 16, or conservative sequence modifications thereof, and light chain variable region CDR1, CDR2 and CDR3 domains having the amino acid sequences respectively set forth in (v) SEQ ID NOs: 18, 19, and 20,(vi) SEQ ID NOs: 22, 23, and 24, (vii) SEQ ID NOs: 26, 27, and 28, (viii) SEQ ID NOs: 30, 31, and 32, or conservative sequence modifications thereof.

43. The anti-TSLP antibody, or antigen-binding fragment thereof, of claim 42, comprising a heavy chain variable region having the amino acid sequences set forth in SEQ ID NOs: 1, 5, 9, 13, or a sequence at least 90% identical thereto, and a light chain variable region having the amino acid sequences set forth in SEQ ID NOs: 17, 21, 25, 29, or a sequence at least 90% identical thereto.

44. The anti-TSLP antibody, or antigen-binding fragment thereof, of claim 42 or 43, wherein the anti-TSLP antibody, or antigen-binding fragment thereof, comprises heavy and light chain variable regions respectively comprising the amino acid sequences set forth in (a) SEQ ID NOs: 1 and 17, (b) SEQ ID NOs: 1 and 21, (c) SEQ ID NOs: 1 and 25, (d) SEQ ID NOs: 1 and 29, (e) SEQ ID NOs: 5 and 17, (f) SEQ ID NOs: 5 and 21 , (g) SEQ ID NOs: 5 and 25, (h) SEQ ID NOs: 5 and 29, (i) SEQ ID NOs: 9 and 17, (j) SEQ ID NOs: 9 and 21, (k) SEQ ID NOs: 9 and 25, (1) SEQ ID NOs: 9 and 29, (m) SEQ ID NOs: 13 and 17, (n) SEQ ID NOs: 13 and 21, (o) SEQ ID NOs: 13 and 25, or (p) SEQ ID NOs: 13 and 29.

45. The anti-TSLP antibody, or antigen-binding fragment thereof, of claim 42 or 43, wherein the anti-TSLP antibody, or antigen-binding fragment thereof, comprises heavy and light chain variable regions respectively comprising the amino acid sequences set forth in (a) SEQ ID NOs: 1 and 17, (b) SEQ ID NOs: 1 and 21, (c) SEQ ID NOs: 1 and 25, (d) SEQ ID NOs: 5 and 17, (e) SEQ ID NOs: 5 and 21, (f) SEQ ID NOs: 5 and 25, (g) SEQ ID NOs: 9 and 17, (h) SEQ ID NOs: 9 and 21, or (i) SEQ ID NOs: 9 and 25.

46. A bispecific construct comprising the anti-TSLP antibody, or antigen binding fragment thereof, of any one of claims 42-45 linked to a second antibody, or antigen binding fragment thereof.

47. The bispecific construct of claim 46, wherein the second antibody, or antigen binding fragment thereof, binds to (a) a member of the TNF superfamily (e.g., TNFa), (b) a tumor necrosis factor (TNF) receptor (e.g., TNFRSF4), (c) an interleukin (e.g., IL-23, IL-17A, or IL-13), (d) an immunoglobulin (e.g., IgE), or (e) an integrin (e.g., integrin a4p7).48.. The bispecific construct of claim 47, further comprising one or more additional binding agents.

49. An anti-SCF antibody, or antigen-binding fragment thereof, comprising heavy chain variable region CDR1, CDR2 and CDR3 domains having the amino acid sequences respectively set forth in (i) SEQ ID NOs: 34, 35, and 36, (ii) SEQ ID NOs: 38, 39, and 40, (iii) SEQ ID NOs: 42, 43, and 44, (iv) SEQ ID NOs: 46, 47, and 48, or conservative sequence modifications thereof, and light chain variable region CDR1, CDR2 and CDR3 domains having the amino acid sequences respectively set forth in (v) SEQ ID NOs: 50, 51, and 52, (vi) SEQ ID NOs: 54, 55, and 56, (vii) SEQ ID NOs: 58, 59, and 60, (viii) SEQ ID NOs: 62, 63, and 64, or conservative sequence modifications thereof.

50. The anti-SCF antibody, or antigen-binding fragment thereof, of claim 49, comprising a heavy chain variable region having the amino acid sequences set forth in SEQ ID NOs: 33, 37, 41, 45, or a sequence at least 90% identical thereto, and a light chain variable region having the amino acid sequences set forth in SEQ ID NOs: 49, 53, 57, 61, or a sequence at least 90% identical thereto.

51. The anti-SCF antibody, or antigen-binding fragment thereof, of claim 49 or 50, wherein the anti-SCF antibody, or antigen-binding fragment thereof, comprises heavy and light chain variable regions respectively comprising the amino acid sequences set forth in (a) SEQ ID NOs: 33 and 49, (b) SEQ ID NOs: 33 and 53, (c) SEQ ID NOs: 33 and 57, (d) SEQ ID NOs: 33 and 61, (e) SEQ ID NOs: 37 and 49, (f) SEQ ID NOs: 37 and 53, (g) SEQ ID NOs: 37 and 57, (h) SEQ ID NOs: 33 and 61, (i) SEQ ID NOs: 41 and 49, (j) SEQ ID NOs: 41 and 53, (k) SEQ ID NOs: 41 and 57, (1) SEQ ID NOs: 41 and 61, (m) SEQ ID NOs: 45 and 49, (n) SEQ ID NOs: 45 and 53, (o) SEQ ID NOs: 45 and 57, or (p) SEQ ID NOs: 45 and 61.

52. The anti-SCF antibody, or antigen-binding fragment thereof, of claim 49 or 50, wherein the anti-SCF antibody, or antigen-binding fragment thereof, comprises heavy and light chain variable regions respectively comprising the amino acid sequences set forth in (a) SEQ ID NOs: 33 and 57, (b) SEQ ID NOs: 33 and 61, (c) SEQ ID NOs: 37 and 57, (d) SEQID NOs: 37 and 61, (e) SEQ ID NOs: 41 and 57, (f) SEQ ID NOs: 41 and 61, (g) SEQ ID NOs: 45 and 57, or (h) SEQ ID NOs: 45 and 61.

53. A bispecific construct comprising the anti-SCF antibody, or antigen binding fragment thereof, of any one of claims 49-52 linked to a second antibody, or antigen binding fragment thereof.

54. The bispecific construct of claim 53, wherein the second antibody, or antigen binding fragment thereof, binds to (a) a member of the TNF superfamily (e.g., TNFa), (b) a tumor necrosis factor (TNF) receptor (e.g., TNFRSF4), (c) an interleukin (e.g., IL-23, IL-17A, or IL-13), (d) an immunoglobulin (e.g., IgE), or (e) an integrin (e.g., integrin a4p7).

55. The bispecific construct of claim 54, further comprising one or more additional binding agents.

56. A composition comprising the bispecific construct of any one of claims 1-41, 46-48, 53-55, or the antibody, or antigen binding fragment thereof, of any one of claims 42-45 and 47-50 and a pharmaceutically acceptable carrier.

57. A kit comprising the bispecific construct of any one of claims 1-41, 46-48, 53-55, or the antibody, or antigen binding fragment thereof, of any one of claims 42-45 and 47-50 and instructions for use.

58. An isolated nucleic acid molecule comprising a nucleotide sequence encoding an antibody variable region, wherein the antibody variable region comprises the amino acid sequence as set forth in SEQ ID NO: 1, 5, 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49, 53, 57, or 61.

59. An isolated nucleic acid molecule comprising a nucleotide sequence encoding heavy and light chain variable regions of an antibody, wherein the heavy and light chain variable regions respectively comprise the amino acid sequences depicted in (a) SEQ ID NOs: 1 and 17, (b) SEQ ID NOs: 1 and 21, (c) SEQ ID NOs: 1 and 25, (d) SEQ ID NOs: 1 and 29, (e) SEQ ID NOs: 5 and 17, (f) SEQ ID NOs: 5 and 21, (g) SEQ ID NOs: 5 and 25, (h) SEQ IDNOs: 5 and 29, (i) SEQ ID NOs: 9 and 17, (j) SEQ ID NOs: 9 and 21, (k) SEQ ID NOs: 9 and 25, (1) SEQ ID NOs: 9 and 29, (m) SEQ ID NOs: 13 and 17, (n) SEQ ID NOs: 13 and 21, (o) SEQ ID NOs: 13 and 25, (p) SEQ ID NOs: 13 and 29, (q) SEQ ID NOs: 33 and 49, (r) SEQ ID NOs: 33 and 53, (s) SEQ ID NOs: 33 and 57, (t) SEQ ID NOs: 33 and 61, (u) SEQ ID NOs: 37 and 49, (v) SEQ ID NOs: 37 and 53, (w) SEQ ID NOs: 37 and 57, (x) SEQ ID NOs: 33 and 61, (y) SEQ ID NOs: 41 and 49, (z) SEQ ID NOs: 41 and 53, (aa) SEQ ID NOs: 41 and 57, (bb) SEQ ID NOs: 41 and 61, (cc) SEQ ID NOs: 45 and 49, (dd) SEQ ID NOs: 45 and 53, (ee) SEQ ID NOs: 45 and 57, or (ff) SEQ ID NOs: 45 and 61.

60. A nucleic acid molecule coding for the bispecific construct as set forth in any one of claims 1-41, 46-48, and 55-55, e.g., an isolated nucleic acid molecule comprising the nucleotide sequence as set forth in SEQ ID NO: 65-69, 269-272, 274-277, 281-284, 286-289, or 350.

61. A nucleic acid molecule as set forth in any one of claims 58-60 in the form of an expression vector.

62. A method of blocking TSLP from binding to TLSPR expressed on immune cells in a subject, comprising administering to the subject the bispecific construct of any one of claims 1-41, 46-48, 53-55, or the antibody, or antigen binding fragment thereof, of any one of claims 42-45 and 47-50, or the composition of claim 56, in an amount effective to block TSLP from binding to TSLPR.

63. A method of blocking SCF from binding to c-Kit expressed on immune cells in a subject, comprising administering to the subject the bispecific construct of any one of claims 1-41, 46-48, 53-55, or the antibody, or antigen binding fragment thereof, of any one of claims 42-45 and 47-50, or the composition of claim 56, in an amount effective to block SCF from binding to c-Kit.

64. A method for inhibiting activation of immune cells in a subject, comprising administering to the subject the bispecific construct of any one of claims 1-41, 46-48, 53-55, or the antibody, or antigen binding fragment thereof, of any one of claims 42-45 and 47-50,or the composition of claim 56, in an amount effective to inhibit activation of immune cells in the subject.

65. A method for reducing the accumulation of immune cells within organs or tissues in a subject, comprising administering to the subject the bispecific construct of any one of claims 1-41, 46-48, 53-55, or the antibody, or antigen binding fragment thereof, of any one of claims 42-45 and 47-50, or the composition of claim 56, in an amount effective to reduce the accumulation of immune cells within organs or tissues in the subject.

66. A method for reducing inflammation in a subject, comprising administering to the subject the bispecific construct of any one of claims 1-41, 46-48, 53-55, or the antibody, or antigen binding fragment thereof, of any one of claims 42-45 and 47-50, or the composition of claim 56, in an amount effective to reduce inflammation in the subject.

67. A method for treating an inflammatory disease in a subject, comprising administering to the subject the bispecific construct of any one of claims 1-41, 46-48, 53-55, or the antibody, or antigen binding fragment thereof, of any one of claims 42-45 and 47-50, or the composition of claim 56, in an amount effective to treat the subject.

68. The method of any one of claims 63-67, wherein the method results in at least one of the following biological activities in the subject: (a) inhibition of TSLP-induced activation and / or proliferation of mast cells, dendritic cells (DC), and / or natural killer T cells (NKT); (b) inhibition of TSLP-induced osteoprotegerin (OPG) secretion; (c) inhibition of TSLP-induced secretion of Th2 cytokines (such as TARC, CCL22, IL-4, IL-13 or IL-5); or (d) inhibition of SCF-induced secretion of mast cells, eosinophils, type 2 innate lymphoid (ILC2) cells, and / or type 3 innate lymphoid (ILC3) cells.

69. The method of any one of claims 64-67, wherein the subject is diagnosed with a disorder of the immune system, allergic inflammation, allergic airway inflammation, DC- mediated inflammatory Th2 responses, atopic dermatitis, atopic eczema, asthma, obstructive airways disease, chronic obstructive pulmonary disease, a food allergy, inflammatory arthritis, rheumatoid arthritis, psoriasis, an IgE-mediated disorder, rhino-conjunctivitis, a fibrotic disease, a disease associated with tissue remodeling, idiopathic pulmonary fibrosis,chronic obstructive pulmonary disease, acute respiratory distress syndrome, cystic fibrosis, peribronchial fibrosis, hypersensitivity pneumonitis, asthma, sclerodoma, inflammation, liver cirrhosis, renal fibrosis, parenchymal fibrosis, endomyocardial fibrosis, mediastinal fibrosis, nodular subepidermal fibrosis, fibrous histiocytoma, fibrothorax, hepatic fibrosis, fibromyalgia, gingival fibrosis, radiation-induced fibrosis, a cardiovascular disease, a gastrointestinal disease, lung disease, a metabolic disease (such as Type 2 diabetes), a neurodegenerative disease (such as Parkinson’s disease), or colon cancer.

70. The method of any one of claims 63-69, further comprising administration of one or more additional therapeutics.

71. The method of claim 70, wherein the additional therapeutic is selected from, but not limited to: immunosuppressants (for example, corticosteroids, non-steroidal glucocorticoid receptor agonists, leukotriene D4 antagonists, leukotriene B4 antagonists, A2A agonists, A2B antagonists, dopamine receptor agonists, pirfenidone, nintedanib, or avB6 antagonists), bronchodilators (for example, P-2 adrenergic receptor agonists, muscarinic antagonists, shortacting 2 receptor agonists, long-acting 2 receptor agonists, short-acting anticholinergic drugs, methyl xanthine drugs, long-acting anticholinergic drugs), other cytokine or cytokine receptor antagonists or antibodies (for example, IL-13 antagonists, IL-6 antagonists, antagonists of IL-1, IL-33, IL-25 or TNF-a, anti-IgE antibodies, anti-IL31 antibodies, anti- IL31R antibodies, anti-IL13 antibodies, anti-endoglin antibodies, anti-ILlb antibodies, another anti-TSLP antibody or anti-hTSLPR antibodies), antibiotics, radiotherapy, leukotriene antagonists (for example, montelukast, zafirlukast or pranlukast), PDE4 inhibitors (for example, roflumilast, xanthene), antihistamines or antitussive drugs.

72. An in vitro method of blocking TSLP from binding to TLSPR, comprising contacting cells expressing TSLPR with the bispecific construct of any one of claims 1-41, 46-48, 53-55, or the antibody, or antigen binding fragment thereof, of any one of claims 42-45 and 47-50, or the composition of claim 56, in an amount effective to block TSLP from binding to TSLPR.

73. An in vitro method of blocking SCF from binding to c-Kit, comprising contacting cells expressing c-Kit with the bispecific construct of any one of claims 1-41, 46-48, 53-55,or the antibody, or antigen binding fragment thereof, of any one of claims 42-45 and 47-50, or the composition of claim 56, in an amount effective to block SCF from binding to c-Kit.

74. A human, humanized or chimeric antibody or bispecific construct thereof which binds to soluble human SCF (hSCF165) with greater affinity than to membrane bound human SCF (hSCF222).

75. A human, humanized or chimeric antibody or bispecific construct thereof which binds to an epitope comprising residue K100 of human SCF.

76. A bispecific construct comprising an anti-TSLP antibody, or binding domain thereof, linked to an anti-SCF antibody, or binding domain thereof.

77. A method for reducing mast cell activity by administering an antibody or bispecific construct as claimed in any of claims 74-76 to a patient in need thereof.

78. A method for treating an inflammatory disorder by administering an antibody or bispecific construct as claimed in any of claims 74-76 to a patient in need thereof.

79. A construct comprising an anti-SCF antibody (or binding domain) linked to a second antibody (or binding domain) that binds to TSLP.

80. A construct comprising an anti-SCF antibody (or binding domain) linked to a second antibody (or binding domain) that binds to a member of the TNF superfamily.

81. A construct comprising an anti-SCF antibody (or binding domain) linked to a second antibody (or binding domain) that binds to a tumor necrosis factor (TNF) receptor.

82. A construct comprising an anti-SCF antibody (or binding domain) linked to a second antibody (or binding domain) that binds to IL- 12 and / or IL-23.

83. A construct comprising an anti-SCF antibody (or binding domain) linked to a second antibody (or binding domain) that binds to IL-23 A.

84. A construct comprising an anti-SCF antibody (or binding domain) linked to a second antibody (or binding domain) that binds to IL-17A.

85. A construct comprising an anti-SCF antibody (or binding domain) linked to a second antibody (or binding domain) that binds to IL- 13.

86. A construct comprising an anti-SCF antibody (or binding domain) linked to a second antibody (or binding domain) that binds to IgE.

87. A construct comprising an anti-SCF antibody (or binding domain) linked to a second antibody (or binding domain) that binds to an integrin.

88. A construct comprising an anti-TSLP antibody (or binding domain) linked to a second antibody (or binding domain) that binds to a member of the TNF superfamily.

89. A construct comprising an anti-TSLP antibody (or binding domain) linked to a second antibody (or binding domain) that binds to IL- 12 and / or IL-23.

90. A construct comprising an anti-TSLP antibody (or binding domain) linked to a second antibody (or binding domain) that binds to IL-23 A.

91. A construct comprising an anti-TSLP antibody (or binding domain) linked to a second antibody (or binding domain) that binds to IL-17A.

92. A construct comprising an anti-TSLP antibody (or binding domain) linked to a second antibody (or binding domain) that binds to IL- 13.

93. A construct comprising an anti-TSLP antibody (or binding domain) linked to a second antibody (or binding domain) that binds to IgE.

94. A construct comprising an anti-TSLP antibody (or binding domain) linked to a second antibody (or binding domain) that binds to an integrin.

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