Fn14 Binding Proteins and Uses Thereof

Abstract

The present disclosure provides proteins comprising antibody antigen binding domains that bind to Fn14 and uses thereof. The present disclosure also provides methods for treating wasting disorders, such as cachexia.

We claim: 
     
         1 . A method of treating or preventing a wasting disorder which is associated with a condition, the method comprising administering to a subject an Fn14-binding protein comprising an antigen binding domain of an anti-Fn14 antibody. 
     
     
         2 . The method of  claim 1 , wherein the wasting disorder is cachexia. 
     
     
         3 . The method of  claim 2 , wherein the wasting disorder is cachexia associated with cancer or diabetes. 
     
     
         4 . The method of  claim 1 , wherein the condition is cancer cachexia and the method additionally comprises selecting a subject suffering from cancer cachexia, wherein the subject suffers from a cancer expressing Fn14. 
     
     
         5 . The method of  claim 1 , wherein the Fn14-binding protein comprises an antigen binding domain of an anti-Fn14 antibody, wherein the antigen binding domain binds specifically to Fn14 and wherein the protein reduces Tweak-induced NFκB-signaling in a HEK293T cell expressing Fn14 and a nucleic acid encoding fluorescent protein operably linked to a promoter that facilitates gene expression as a result of NFκB signaling, and wherein the protein does not detectably induce NFκB-signaling when contacted to a cell expressing Fn14 and a nucleic acid encoding fluorescent protein operably linked to a promoter that facilitates gene expression as a result of NFκB signaling in the absence of Tweak. 
     
     
         6 . The method of  claim 1 , wherein the Fn14-binding protein has one or more of the following characteristics:
 (i) binds to recombinant human Fn14 with a K D  of 1 nM or less;   (ii) binds to recombinant human Fn14 with a Kd of about 8×10 −4 s −1  or less;   (iii) binds to a mutant of an extracellular domain of Fn14 comprising the sequence set forth in SEQ ID NO: 52 or SEQ ID NO: 54;   (iv) binds to a mutant of an extracellular domain of Fn14 comprising the sequence set forth in SEQ ID NO: 56; and/or   (v) binds to a mutant of an extracellular domain of Fn14 comprising the sequence set forth in SEQ ID NO: 63 at a similar or substantially the same level as it binds to an extracellular domain of Fn14.   
     
     
         7 . The method  claim 1 , wherein the Fn14-binding protein is an antibody comprising one or more of the following:
 (i) a V H  comprising the sequence set forth in SEQ ID NO: 15 or a humanized, synhumanized or deimmunized version thereof and a V L  comprising the sequence set forth in SEQ ID NO: 22 or a humanized, synhumanized or deimmunized version thereof; or   (ii) a V H  comprising the sequence set forth in SEQ ID NO: 16 or a humanized, synhumanized or deimmunized version thereof and a V L  comprising the sequence set forth in SEQ ID NO: 23 or a humanized, synhumanized or deimmunized version thereof.