Actriib-fc polynucleotides, polypeptides, and compositions

Abstract

In certain aspects, the present invention provides compositions and methods for modulating (promoting or inhibiting) growth of a tissue, such as bone, cartilage, muscle, fat, and/or neuron. The present invention also provides methods of screening compounds that modulate activity of an ActRII protein and/or an ActRII ligand. The compositions and methods provided herein are useful in treating diseases associated with abnormal activity of an ActRII protein and/or an ActRII ligand.

1 - 14 . (canceled) 
     
     
         15 . An isolated polypeptide comprising an altered GDF11-binding domain of an ActRII receptor having a decreased selectivity for GDF11 versus activin relative to a GDF11-binding domain of a wild-type receptor, wherein the amino acid sequence of the altered GDF11-binding domain comprises: (i) the amino acid sequence of SEQ ID NO:1 wherein the amino acid residue at position 36 has been altered relative to the sequence of SEQ ID NO:1. 
     
     
         16 . The polypeptide of  claim 15 , wherein the altered binding domain has a ratio of K d  for activin binding to K d  for GDF11 binding that is at least 2 fold less for the altered binding domain relative to the ratio for the GDF11-binding domain of a wild-type receptor. 
     
     
         17 . The polypeptide of  claim 15 , wherein the altered binding domain has a ratio of K d  for activin binding to K d  for GDF11 binding that is at least 5 fold less for the altered binding domain relative to the ratio for the GDF11-binding domain of a wild-type receptor. 
     
     
         18 . The polypeptide of  claim 15 , wherein the altered binding domain has a ratio of K d  for activin binding to K d  for GDF11 binding that is at least 10 fold less for the altered binding domain relative to the ratio for the GDF11-binding domain of a wild-type receptor. 
     
     
         19 . The polypeptide of  claim 15 , wherein the altered binding domain has a ratio of K d  for activin binding to K d  for GDF11 binding that is at least 100 fold less for the altered binding domain relative to the ratio for the GDF11-binding domain of a wild-type receptor. 
     
     
         20 . The polypeptide of  claim 15 , wherein the altered binding domain has a ratio of IC 50  for inhibiting activin to IC 50  for inhibiting GDF11 that is at least 2 fold less for the altered binding domain than the GDF11-binding domain of a wild-type receptor. 
     
     
         21 . The polypeptide of  claim 15 , wherein the altered binding domain has a ratio of IC 50  for inhibiting activin to IC 50  for inhibiting GDF11 that is at least 5 fold less for the altered binding domain than the GDF11-binding domain of a wild-type receptor. 
     
     
         22 . The polypeptide of  claim 15 , wherein the altered binding domain has a ratio of IC 50  for inhibiting activin to IC 50  for inhibiting GDF11 that is at least 10 fold less for the altered binding domain than the GDF11-binding domain of a wild-type receptor. 
     
     
         23 . The polypeptide of  claim 15 , wherein the altered binding domain has a ratio of IC 50  for inhibiting activin to IC 50  for inhibiting GDF11 that is at least 100 fold less for the altered binding domain than the GDF11-binding domain of a wild-type receptor. 
     
     
         24 . The polypeptide of  claim 15 , which inhibits GDF11 with an IC 50  at least 2 times more than the IC 50  of the polypeptide for inhibiting activin. 
     
     
         25 . The polypeptide of  claim 15 , which inhibits GDF11 with an IC 50  at least 5 times more than the IC 50  of the polypeptide for inhibiting activin. 
     
     
         26 . The polypeptide of  claim 15 , which inhibits GDF11 with an IC 50  at least 10 times more than the IC 50  of the polypeptide for inhibiting activin. 
     
     
         27 . The polypeptide of  claim 15 , which inhibits GDF11 with an IC 50  at least 100 times more than the IC 50  of the polypeptide for inhibiting activin. 
     
     
         28 . The polypeptide of  claim 15 , wherein the GDF11 polypeptide is a fusion protein. 
     
     
         29 . The polypeptide of  claim 28 , wherein said altered GDF11-binding domain of an ActRII receptor is fused to an IgG Fc domain. 
     
     
         30 . The polypeptide of  claim 29 , wherein said IgG Fc domain comprises one or more mutations. 
     
     
         31 . The polypeptide of  claim 30 , wherein the Fc domain has reduced ability to bind to the Fc.gamma. receptor relative to a wild-type Fc domain. 
     
     
         32 . The polypeptide of  claim 30 , wherein the Fc domain has increase ability to bind to the MHC class I-related Fc-receptor (FcRN) relative to a wild-type Fc domain. 
     
     
         33 . The polypeptide of  claim 29 , wherein the Fc domain has a mutation at residues selected from the group consisting of: Asp-265, lysine 322, and Asn-434. 
     
     
         34 . The polypeptide of  claim 30 , wherein the mutation is shown in  FIG. 12 . 
     
     
         35 . The polypeptide of  claim 29 , wherein the IgG Fc domain has an amino acid sequence as set forth in SEQ ID NO: 13.