US2022220172A1PendingUtilityA1

Progranulin variants

69
Assignee: DENALI THERAPEUTICS INCPriority: Dec 23, 2019Filed: Mar 18, 2022Published: Jul 14, 2022
Est. expiryDec 23, 2039(~13.4 yrs left)· nominal 20-yr term from priority
Inventors:Gerald Maxwell CherfGunasekaran KannanKatrina W. LexaRay L.Y. LowRachel ProrokAnkita Srivastava
C07K 2319/30C07K 14/47A61P 25/28A61K 38/00C07K 14/705C07K 14/475
69
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Claims

Abstract

Provided herein are progranulin variants and fusion proteins that comprise a progranulin variant and an Fc polypeptide. Methods of using such proteins to treat progranulin-associated disorders (e.g., a neurodegenerative disease, such as frontotemporal dementia (FTD)) are also provided herein.

Claims

exact text as granted — not AI-modified
What is claimed is: 
     
         1 . A fusion protein comprising:
 (a) a progranulin variant comprising a sequence having at least 90% identity to SEQ ID NO:2 and a sequence defined by X 1 X 2 X 3  at the positions corresponding to residues 574 to 576 of SEQ ID NO:2, wherein X 1 , X 2 , and X 3  together are PIL, PFL, PPL, PYL, QRL, or QHL;   (b) a first Fc polypeptide that is linked to the progranulin variant of (a); and   (c) a second Fc polypeptide that forms an Fc polypeptide dimer with the first Fc polypeptide.   
     
     
         2 . The fusion protein of  claim 1 , wherein the first Fc polypeptide or the second Fc polypeptide specifically binds to a transferrin receptor. 
     
     
         3 . The fusion protein of  claim 1 , wherein the first Fc polypeptide is linked to the progranulin variant by a polypeptide linker comprising G 4 S (SEQ ID NO:90) or (G 4 S) 2  (SEQ ID NO:91). 
     
     
         4 . The fusion protein of  claim 1 , wherein the C-terminus of the first Fc polypeptide is linked to the N-terminus of the progranulin variant. 
     
     
         5 . The fusion protein of  claim 1 , wherein:
 (i) the first Fc polypeptide comprises a W at position 366 and the second Fc polypeptide comprises an S at position 366, an A at position 368, and a V at position 407, according to EU numbering; or   (ii) the first Fc polypeptide comprises an S at position 366, an A at position 368, and a V at position 407 and the second Fc polypeptide comprises a W at position 366, according to EU numbering.   
     
     
         6 . The fusion protein of  claim 1 , wherein the first Fc polypeptide and/or the second Fc polypeptide independently comprises an A at position 234 and an A at position 235, according to EU numbering. 
     
     
         7 . The fusion protein of  claim 1 , wherein the second Fc polypeptide comprises a sequence selected from the group consisting of SEQ ID NOS:70, 75, 80, 85, and 129-132. 
     
     
         8 . The fusion protein of  claim 1 , wherein X 1 X 2 X 3  is PIL. 
     
     
         9 . The fusion protein of  claim 1 , wherein the progranulin variant comprises the sequence of any one of SEQ ID NOS: 13, 15, and 17-20. 
     
     
         10 . The fusion protein of  claim 1 , wherein the first Fc polypeptide linked to the progranulin variant comprises the sequence of SEQ ID NO:98, and the second Fc polypeptide comprises the sequence of SEQ ID NO:75 or 130. 
     
     
         11 . The fusion protein of  claim 1 , wherein the first Fc polypeptide linked to the progranulin variant comprises the sequence of SEQ ID NO:99, and the second Fc polypeptide the sequence of SEQ ID NO:75 or 130. 
     
     
         12 . The fusion protein of  claim 1 , wherein the first Fc polypeptide linked to the progranulin variant comprises the sequence of SEQ ID NO:126, and the second Fc polypeptide comprises the sequence of SEQ ID NO:75 or 130. 
     
     
         13 . The fusion protein of  claim 1 , wherein the first Fc polypeptide linked to the progranulin variant comprises the sequence of SEQ ID NO:98, and the second Fc polypeptide comprises the sequence of SEQ ID NO:85 or 132. 
     
     
         14 . The fusion protein of  claim 1 , wherein the first Fc polypeptide linked to the progranulin variant comprises the sequence of SEQ ID NO:99, and the second Fc polypeptide the sequence of SEQ ID NO:85 or 132. 
     
     
         15 . A pharmaceutical composition comprising the fusion protein of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         16 . A pharmaceutical composition comprising a plurality of the fusion protein of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         17 . The pharmaceutical composition of  claim 16 , wherein more than 50% of the plurality of the fusion protein comprises an intact C-terminus in the progranulin variant of the fusion protein. 
     
     
         18 . The pharmaceutical composition of  claim 16 , wherein the K D  value for sortilin binding of the fusion protein plurality is less than about 100 nM. 
     
     
         19 . The pharmaceutical composition of  claim 16 , wherein the EC50 value for sortilin binding of the fusion protein plurality is less than about 25 nM. 
     
     
         20 . A method of treating a subject having a neurodegenerative disease, atherosclerosis, a disorder associated with TDP-43, age-related macular degeneration (AMD), or a progranulin-associated disorder, the method comprising administering the fusion protein of  claim 1  to the subject. 
     
     
         21 . The method of  claim 20 , wherein the subject has a neurodegenerative disease selected from the group consisting of frontotemporal dementia (FTD), neuronal ceroid lipofuscinosis (NCL), Niemann-Pick disease type A (NPA), Niemann-Pick disease type B (NPB), Niemann-Pick disease type C (NPC), C9ORF72-associated amyotrophic lateral sclerosis (ALS)/FTD, sporadic ALS, Alzheimer's disease (AD), Gaucher's disease, and Parkinson's disease. 
     
     
         22 . A fusion protein comprising:
 (a) a progranulin variant comprising a sequence having at least 90% identity to SEQ ID NO:2 and a sequence defined by X 1 X 2 X 3  at the positions corresponding to residues 574 to 576 of SEQ ID NO:2, wherein X 1 , X 2 , and X 3  together are PIL;   (b) a first Fc polypeptide that is linked to the progranulin variant of (a); and   (c) a second Fc polypeptide that forms an Fc polypeptide dimer with the first Fc polypeptide;   wherein the first Fc polypeptide or the second Fc polypeptide specifically binds to a transferrin receptor.   
     
     
         23 . A protein comprising:
 (a) a fusion polypeptide comprising a progranulin variant linked to a first Fc polypeptide, wherein the fusion polypeptide sequence comprises SEQ ID NO:98; and   (b) a second Fc polypeptide comprising a sequence that is at least 95% identical to SEQ ID NO:75.   
     
     
         24 . The protein of  claim 23 , wherein the second Fc polypeptide comprises a sequence that is SEQ ID NO:75. 
     
     
         25 . The protein of  claim 23 , wherein the second Fc polypeptide comprises a sequence that is SEQ ID NO:130. 
     
     
         26 . A pharmaceutical composition comprising the protein of  claim 23  and a pharmaceutically acceptable carrier. 
     
     
         27 . A protein comprising:
 (a) a fusion polypeptide comprising a progranulin variant linked to a first Fc polypeptide, wherein the fusion polypeptide sequence comprises SEQ ID NO:98; and   (b) a second Fc polypeptide comprising a sequence that is at least 95% identical to SEQ ID NO:85.   
     
     
         28 . The protein of  claim 27 , wherein the second Fc polypeptide comprises a sequence that is SEQ ID NO:85. 
     
     
         29 . The protein of  claim 27 , wherein the second Fc polypeptide comprises a sequence that is SEQ ID NO:132. 
     
     
         30 . A pharmaceutical composition comprising the protein of  claim 27  and a pharmaceutically acceptable carrier.

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