Ciliary Neurotrophic Factor Receptor Ligands and Methods of Using the Same

Abstract

Provided are ciliary neurotrophic factor receptor (CNTFR) ligands. In certain aspects, a CNTFR ligand of the present disclosure exhibits increased affinity for CNTFR relative to the corresponding wild-type CNTFR ligand. In certain aspects, a CNTFR ligand of the present disclosure results in reduced binding affinity of glycoprotein 130 (gp130), leukemia inhibitory factor receptor (LIFR), or both, for a complex including the CNTFR ligand and CNTFR, relative to the binding affinity for a complex including the corresponding wild-type CNTFR ligand and CNTFR. In certain aspects, a CNTFR ligand of the present disclosure has both of the aforementioned properties. Also provided are pharmaceutical compositions including the CNTFR ligands, as well as methods of using the CNTFR ligands.

1 - 53 . (canceled) 
     
     
         54 . A method of treating a disorder associated with CNTFR signaling in an individual in need thereof, the method comprising:
 administering to the individual a therapeutically effective amount of a cardiotrophin-like cytokine factor 1 (CLCF1) polypeptide that exhibits increased binding affinity for ciliary neurotrophic factor receptor (CNTFR) relative to wild-type CLCF1, wherein the CLCF1 polypeptide comprises:
 an amino acid sequence having at least 85% sequence identity to the amino acid sequence set forth in SEQ ID NO:3, and 
 an amino acid substitution selected from the group consisting of: L86F, Q96R, H148R, and any combination thereof. 
   
     
     
         55 . The method according to  claim 54 , wherein the CLCF1 polypeptide comprises the amino acid substitution W169L, K180R, or both. 
     
     
         56 . The method according to  claim 54 , wherein the CLCF1 polypeptide comprises an amino acid substitution at position 22, 169, 180, or any combination thereof. 
     
     
         57 . The method according to  claim 54 , wherein the CLCF1 polypeptide comprises an amino acid substitution selected from the group consisting of: Y22C, W169L, K180R, and any combination thereof. 
     
     
         58 . The method according to  claim 54 , wherein the CLCF1 polypeptide comprises an amino acid substitution at position 151, 154, or both. 
     
     
         59 . The method according to  claim 54 , wherein the CLCF1 polypeptide comprises the amino acid substitution F151A, K154A, or both. 
     
     
         60 . The method according to  claim 54 , wherein the CLCF1 polypeptide comprises each of the amino acid substitutions L86F, Q96R, and H148R. 
     
     
         61 . The method according to  claim 54 , wherein the CLCF1 polypeptide comprises at least 95% sequence identity to the amino acid sequence set forth in SEQ ID NO:3 
     
     
         62 . The method according to  claim 54 , wherein the CLCF1 polypeptide is fused to a heterologous polypeptide. 
     
     
         63 . The method according to  claim 62 , wherein the heterologous polypeptide is an Fc domain, an albumin, a transferrin, XTEN, a homo-amino acid polymer, a proline-alanine-serine polymer, an elastin-like peptide, or any combination thereof. 
     
     
         64 . The method according to  claim 63 , wherein the heterologous polypeptide is an Fc domain. 
     
     
         65 . The method according to  claim 54 , wherein the disorder associated with CNTFR signaling is a cell proliferative disorder. 
     
     
         66 . The method according to  claim 65 , wherein the cell proliferative disorder is cancer. 
     
     
         67 . The method according to  claim 66 , wherein the cancer is lung cancer. 
     
     
         68 . The method according to  claim 67 , wherein the lung cancer is non-small cell lung cancer (NSCLC). 
     
     
         69 . The method according to  claim 54 , wherein the disorder associated with CNTFR signaling is a neurodegenerative disorder. 
     
     
         70 . The method according to  claim 69 , wherein the neurodegenerative disorder is selected from the group consisting of: Alzheimer's Disease (AD), Parkinson's Disease (PD), Lewy body dementia, frontotemporal dementia, amyotrophic lateral sclerosis (ALS), Huntington disease, and a prion disease. 
     
     
         71 . A pharmaceutical composition, comprising:
 a CLCF1 polypeptide that exhibits increased binding affinity for CNTFR relative to wild-type CLCF1, wherein the CLCF1 polypeptide comprises:
 an amino acid sequence having at least 90% sequence identity to the amino acid sequence set forth in SEQ ID NO:3, and 
 an amino acid substitution selected from the group consisting of: L86F, Q96R, H148R, and any combination thereof; and 
   a pharmaceutically acceptable carrier.   
     
     
         72 . The pharmaceutical composition of  claim 71 , wherein the CLCF1 polypeptide comprises at least 95% sequence identity to the amino acid sequence set forth in SEQ ID NO:3. 
     
     
         73 . The pharmaceutical composition of  claim 71 , wherein the CLCF1 polypeptide comprises each of the amino acid substitutions L86F, Q96R, and H148R.