Treatment of dermal fibrosis
The present invention relates to RSPO and LGR antagonists, and methods of using the RSPO and LGR antagonists for treating or preventing fibrotic diseases.
1. A method of treating dermal fibrosis in a subject, comprising administering to the subject a therapeutically effective amount of a human R-spondin 3 (RSPO3) antagonist antibody that specifically binds human RSPO3, wherein the antibody comprises:
(a) a heavy chain CDR1 comprising DYSIH (SEQ ID NO:37), a heavy chain CDR2 comprising YIYPSNGDSGYNQKFK (SEQ ID NO:38), and a heavy chain CDR3 comprising TYFANNFD (SEQ ID NO:39), and a light chain CDR1 comprising KASQSVDYDGDSYMN (SEQ ID NO:41), a light chain CDR2 comprising AASNLES (SEQ ID NO:42), and a light chain CDR3 comprising QQSNEDPLT (SEQ ID NO:44); or
(b) a heavy chain variable region having at least 97% sequence identity to SEQ ID NO: 46 and a light chain variable region having at least 97% sequence identity to SEQ ID NO: 47, wherein the heavy chain variable region comprises a heavy chain CDR3 comprising TYFANNFD (SEQ ID NO: 39) and the light chain variable region comprises a light chain CDR3 comprising QQSNEDPLT (SEQ ID NO: 44).
2. The method of claim 1 , wherein the antibody of (a) comprises a heavy chain variable region having at least 97% sequence identity to SEQ ID NO: 46 and a light chain variable region having at least 97% sequence identity to SEQ ID NO: 47.
3. The method of claim 2 , wherein the antibody comprises a heavy chain variable region of SEQ ID NO: 46 and a light chain variable region of SEQ ID NO: 47.
4. The method of claim 1 , wherein the antibody is a recombinant antibody, a monoclonal antibody, a chimeric antibody, a monospecific antibody, a bispecific antibody, a humanized antibody, a human antibody, an IgG1 antibody, an IgG2 antibody, or an antibody fragment comprising an antigen binding site.
5. The method of claim 1 , comprising administration of at least one additional therapeutic agent.
6. The method of claim 5 , wherein the additional therapeutic agent is a second antibody.
7. The method of claim 6 , wherein the second antibody is an antibody which specifically binds a second RSPO protein.
8. The method of claim 5 , wherein the additional therapeutic agent is an anti-inflammatory agent.
9. The method of claim 1 , wherein the dermal fibrosis is scleroderma, systemic sclerosis, scleroderma-like disease, sine scleroderma, keloid formation, or hypertrophic scarring.
10. The method of claim 1 further comprising determining the expression level of RSPO1, RSPO2, RSPO3, and/or RSPO4 in a sample from the subject.
11. A method of treating dermal fibrosis in a human subject, comprising:
(a) selecting a subject for treatment based, at least in part, on the subject having a tissue sample that has an elevated level of RSPO3 expression compared to a pre-determined level of RSPO3 expression in normal tissue, and
(b) administering to the subject a therapeutically effective amount of a human R-spondin 3 (RSPO3) antagonist antibody that specifically binds human RSPO3, wherein the antibody comprises:
(i) a heavy chain CDR1 comprising DYSIH (SEQ ID NO:37), a heavy chain CDR2 comprising YIYPSNGDSGYNQKFK (SEQ ID NO:38), and a heavy chain CDR3 comprising TYFANNFD (SEQ ID NO:39), and a light chain CDR1 comprising KASQSVDYDGDSYMN (SEQ ID NO:41), a light chain CDR2 comprising AASNLES (SEQ ID NO:42), and a light chain CDR3 comprising QQSNEDPLT (SEQ ID NO:44); or
(ii) a heavy chain variable region having at least 97% sequence identity to SEQ ID NO: 46 and a light chain variable region having at least 97% sequence identity to SEQ ID NO: 47, wherein the heavy chain variable region comprises a heavy chain CDR3 comprising TYFANNFD (SEQ ID NO: 39) and the light chain variable region comprises a light chain CDR comprising QQSNEDPLT (SEQ ID NO: 44).
12. The method of claim 11 , wherein the antibody of (i) comprises a heavy chain variable region having at least 97% sequence identity to SEQ ID NO: 46 and a light chain variable region having at least 97% sequence identity to SEQ ID NO: 47.
13. The method of claim 12 , wherein the antibody comprises a heavy chain variable region of SEQ ID NO: 46 and a light chain variable region of SEQ ID NO: 47.