Methods for treating systemic sclerosis

1. A method for treating systemic sclerosis (SSc) in a human subject with SSc, the methods comprising administering about 200 mg of a dual-V-region bispecific antibody or antigen-binding fragment that specifically binds IL-4 and IL-13 subcutaneously to the subject, wherein a portion of human subjects treated have an improved modified Rodnan Skin Score (mRSS) of at least 20% at 24 weeks after initial administration of the bispecific antibody or antigen-binding fragment compared to baseline.

2. The method of claim 1 , wherein 200 mg of the bispecific antibody is administered to the subject about once per week or about every 5 to 9 days.

3. The method of claim 1 , wherein the treatment is given for at least about 24 weeks.

4. The method of claim 1 , wherein the bispecific antibody is in a pharmaceutical formulation.

5. The method of claim 4 , wherein the pharmaceutical formulation comprises about 100 mg/ml bispecific antibody, about 6.3 mM monobasic sodium phosphate, about 37 mM Tris, about 5% (w/v) sucrose, about 3% (w/v) proline, and about 0.2% (w/v) polysorbate 80, wherein the pH of the formulation is about 7.0.

6. The method of claim 5 , wherein the formulation is reconstituted from a lyophilized formulation.

7. The method of claim 1 , wherein the bispecific antibody is administered in combination with another agent.

8. The method of claim 7 , wherein the another agent is administered before, simultaneous with, or after administration of the bispecific antibody.

9. The method of claim 1 , wherein the systemic sclerosis is diffuse cutaneous systemic sclerosis.

10. The method of claim 1 , wherein the bispecific antibody or bispecific antibody fragment thereof comprises a light chain polypeptide comprising a light chain variable domain VL hB-B13 and a light chain variable domain VL hBD4-8 , and a heavy chain polypeptide comprising a heavy chain variable domain VH hB-B13 and a heavy chain variable domain VH hBD4-8 , wherein:

VL hB-B13 comprises the three CDRs comprising the amino acid sequences

(SEQ ID NO: 8)

RASESVDSYGQSYMH,

(SEQ ID NO: 9)

LASNLES,

and

(SEQ ID NO: 10)

QQNAEDSRT;

VL hBD4-8 comprises the three CDRs comprising the amino acid sequences

(SEQ ID NO: 14)

HASQNIDVWLS,

(SEQ ID NO: 15)

KASNLHTG,

and

(SEQ ID NO: 16)

QQAHSYPFT,

VH hB-B13 comprises the three CDRs comprising the amino acid sequences

(SEQ ID NO: 11)

GFSLTDSSIN,

(SEQ ID NO: 12)

DGRID,

and

(SEQ ID NO: 13)

DGYFPYAMDF,

VH hBD4-8 comprises the three CDRs comprising the amino acid sequences

(SEQ ID NO: 17)

GYSFTSYWIH,

(SEQ ID NO: 18)

IDPSDGETR

and

(SEQ ID NO: 19)

LKEYGNYDSFYFDV.

11. The method of claim 10 , wherein:

VL hB-B13 comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO:1,

VL hBD4-8 comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO:3,

VH hB-B13 comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO:2, and

VH hBD4-8 comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO:4.

12. The method of claim 10 , wherein:

VL hB-B13 comprises the amino acid sequence of SEQ ID NO:1,

VL hBD4-8 comprises the amino acid sequence of SEQ ID NO:3,

VH hB-B13 comprises the amino acid sequence of SEQ ID NO:2, and

VH hBD4-8 comprises the amino acid sequence of SEQ ID NO:4.

13. The method of claim 10 , wherein the light chain polypeptide comprises the structure N-VL hB-B13 -linker-VL hBD4-8 -CL-C and the heavy chain polypeptide comprises the structure N-VH hB-B13 -linker-V hBD4-8 -CH1-C.

14. The method of claim 10 , wherein the light chains comprise the structure N-VL hB-B13 -linker-VL hBD4-8 -CL-C and the heavy chains comprise the structure N-VH hB-B13 -linker-VH hBD4-8 -CH1-CH2-CH3-C.

15. The method of claim 14 , wherein the linker comprises the amino acid sequence of SEQ ID NO:6.

16. The method of claim 10 , wherein the bispecific antibody or bispecific antibody fragment thereof comprises two identical light chain polypeptides and two identical heavy chain polypeptides.

17. The method of claim 10 , wherein the light chain polypeptide comprises an amino acid sequence having at least about 90% identity to the amino acid sequence of SEQ ID NO:22 and the heavy chain polypeptide comprises an amino acid sequence having at least about 90% identity to the amino acid sequence of SEQ ID NO:23.

18. The method of claim 10 , wherein the light chain polypeptide comprises the amino acid sequence of SEQ ID NO:22 and the heavy chain polypeptide comprises the amino acid sequence of SEQ ID NO:23.

19. A method of reducing sclerotic plaques in a human subject with SSc, the method comprising administering an effective amount of an anti-IL4/anti-IL13 bispecific antibody to said subject; wherein a portion of human subjects treated have an improved modified Rodnan Skin Score (mRSS) of at least 20% at 24 weeks after initial administration of the bispecific antibody or antigen-binding fragment compared to baseline wherein the sclerotic plaques are reduced by at least about 20%, 40%, 60%, 80% or 100% at about 24 weeks after initial administration of the bispecific antibody compared to baseline.