Method of treating a localized fibrotic disorder using a tnf receptor 2 antagonist

Abstract

The subject invention provides a method of treating a patient suffering from a localized fibrotic condition which comprises administering to the patient an amount of an IL-33 antagonist effective to treat the patient. The subject invention also provides a method of treating a patient suffering from a localized fibrotic condition which comprises administering to the patient an amount of a TNF receptor 2 (TNFR2) antagonist effective to treat the patient. The invention additionally provides a method of treating a patient suffering from liver fibrosis of lung fibrosis which comprises administering to the patient an amount of a TNFR2 antagonist effective to treat the patient.

1 . A method of treating a patient suffering from a localized fibrotic condition which comprises administering to the patient an amount of selective antagonist of cell surface-bound TNF receptor 2 (TNFR2) effective to treat the patient, wherein the selective antagonist of cell surface-bound TNFR2 is not an antagonist of cell surface-bound TNF receptor 1 (TNFR1) and is
 a) an antibody, or antigen binding fragment of an antibody, that binds to, and selectively inhibits activation of, cell surface-bound TNFR2 on fibroblasts and myofibroblasts;   b) a soluble form of TNFR2 that binds to TNF-α and selectively inhibits activation of cell surface-bound TNFR2 on fibroblasts and myofibroblasts;   c) an antisense nucleic acid that selectively inhibits synthesis of cell surface-bound TNFR2; or   d) a siRNA that selectively inhibits synthesis of cell surface-bound TNFR2.   
     
     
         2 . A method of  claim 1 , wherein the localized fibrotic condition is selected from the group consisting of Dupuytren's disease, frozen shoulder (adhesive capsulitis), periarticular fibrosis, keloid or hypertrophic scars, endometriosis, abdominal adhesions, perineural fibrosis, Ledderhose disease, Peyronie's disease, peritendinous adhesions, and periarticular fibrosis. 
     
     
         3 . (canceled) 
     
     
         4 . The method of  claim 2 , wherein the localized fibrotic condition is Dupuytren's disease. 
     
     
         5 . The method of  claim 4 , wherein the localized fibrotic condition is early disease state Dupuytren's disease. 
     
     
         6 . The method of  claim 4 , wherein the localized fibrotic condition is established disease state Dupuytren's disease. 
     
     
         7 . The method of  claim 2 , wherein the localized fibrotic condition is frozen shoulder (adhesive capsulitis). 
     
     
         8 . The method of  claim 2 , wherein the localized fibrotic condition is periarticular fibrosis. 
     
     
         9 - 16 . (canceled) 
     
     
         17 . A method of treating a patient suffering from liver fibrosis or lung fibrosis which comprises administering to the patient an amount of a selective antagonist of cell surface-bound TNFR2 effective to treat the patient, wherein the selective antagonist is net an antagonist of cell-surface bound TNFR1. 
     
     
         18 . The method of  claim 36 , wherein the antibody is a bispecific antibody comprising at least one antigen binding domain which binds to and selectively Inhibits activation of, cell surface-bound TNFR2. 
     
     
         19 . The method of  claim 36 , wherein the antibody is selected from the group consisting of chimeric antibodies, humanized antibodies, human antibodies, and antigen binding fragments of chimeric humanized and human antibodies. 
     
     
         20 . The method of  claim 18 , wherein the bispecific antibody is selected from the group consisting of
 i) asymmetric IgG-like bispecific antibodies;   ii) symmetric IgG-like bispecific antibodies;   iii) IgG fusion bispecific antibodies;   iv) Fc fusion bispecific antibodies;   v) Fab fusion bispecific antibodies;   vi) ScFv- or diabody-based bispecific antibodies; and   vii) IgG/Non-IgG fusion bispecific antibodies.   
     
     
         21 . The method of  claim 1 , wherein the siRNA is an RNA interference (RNAi) selective antagonist of cell surface-bound TNFR2. 
     
     
         22 . (canceled) 
     
     
         23 . The method of  claim 1 , wherein the selective antagonist of cell surface-bound TNFR2 is administered orally, intralesionally, by intravenous therapy or by subcutaneous, intramuscular, intraarterial, intravenous, intracavitary, intracranial, or intraperitoneal injection. 
     
     
         24 - 25 . (canceled) 
     
     
         26 . The method of  claim 23  wherein the selective antagonist of cell surface-bound TNFR2 is injected directly into the affected tissue. 
     
     
         27 . The method of  claim 23  wherein the selective antagonist of cell surface-bound TNFR2 is injected to a site of maximal cellularity or maximal inflammation. 
     
     
         28 - 31 . (canceled) 
     
     
         32 . The method of  claim 1 , wherein the selective antagonist of cell surface-bound TNFR2 is administered in an amount between about 5 mg and about 300 mg. 
     
     
         33 . The method of  claim 1 , further comprising administering a therapeutically, prophylactically or progression-inhibiting amount of a damage-associated molecular pattern (DAMP) antagonist and/or an advanced glycation end product (AGE) inhibitor to the patient. 
     
     
         34 . The method of  claim 33 , wherein a DAMP antagonist is administered and the DAMP antagonist is an Alarmin antagonist. 
     
     
         35 . The method of  claim 34 , wherein the Alarmin antagonist is one or more of an antagonist of HMGB1, an antagonist of S100A8, an antagonist of S100A9, an antagonist of SI00A8/9, and a heat shock protein. 
     
     
         36 . The method of  claim 1 , wherein the selective antagonist of cell surface-bound TNFR2 is an antibody, or antigen binding fragment of an antibody, that binds to, and selectively inhibits activation of, cell surface-bound TNFR2 on fibroblasts and myofibroblasts. 
     
     
         37 . The method of  claim 1 , wherein the selective antagonist of cell surface-bound TNFR2 is a soluble form of TNFR2 that binds to TNF-α and selectively inhibits activation of cell surface-bound TNFR2 on fibroblasts and myofibroblasts.