US2020231652A1PendingUtilityA1

Tgf-b-receptor ectodomain fusion molecules and uses thereof

44
Assignee: NAT RES COUNCIL CANADAPriority: Aug 31, 2015Filed: Aug 31, 2016Published: Jul 23, 2020
Est. expiryAug 31, 2035(~9.1 yrs left)· nominal 20-yr term from priority
Inventors:John C. ZwaagstraTraian SuleaMaria L. JaramilloMaureen D. O'ConnorAnne E. G. Lenferink
C07K 19/00C07K 2319/30A61K 2039/505A61P 35/00C07K 14/71C12N 15/62C07K 16/22C07K 16/30C07K 2317/94
44
PatentIndex Score
0
Cited by
0
References
0
Claims

Abstract

The present invention relates, in general, to polypeptides capable of binding and neutralizing transforming growth factor beta (TGF-beta) ligands, and uses of these polypeptides for treating disorders related to TGF-beta expression or activation (e.g. cancer and fibrotic diseases), and methods of making such molecules.

Claims

exact text as granted — not AI-modified
1 . A polypeptide construct comprising:
 a first portion comprising the second constant domain (C H2 ) and/or third constant domain (C H3 ) of an antibody heavy chain, and   a second portion comprising at least two TGF-β superfamily receptor ectodomains (TβSR-ED) linked in tandem,   wherein the N-terminus of the second portion is linked to the C-terminus of the first portion.   
     
     
         2 . A polypeptide construct comprising:
 a first portion comprising the second constant domain (CH2) and/or third constant domain (CH3) of an antibody heavy chain, and   a second portion comprising at least one TGF-β superfamily receptor ectodomains (TβSR-ED),   wherein the N-terminus of the second portion is linked to the C-terminus of the first portion,   and further wherein the first portion does not further comprise an antibody that binds to an antigen that is PD-L1, EGFR1, Her-2, CD4, CD6, CD20, CD25, MUC-1, IL-2, IL-6, or CTLA-4.   
     
     
         3 . A polypeptide construct comprising:
 a first portion comprising the second constant domain (C H2 ) and/or third constant domain (C H3 ) of an antibody heavy chain, and   a second portion comprising at least one TGF-β superfamily receptor ectodomain (TβSR-ED),   wherein the N-terminus of the second portion is directly fused to the C-terminus of the first portion.   
     
     
         4 . A polypeptide construct comprising
 a first portion comprising the second constant domain (C H2 ) and/or third constant domain (C H3 ) of an antibody heavy chain, and   a second portion comprising at least one TGF-β superfamily receptor ectodomain (TβSR-ED),   wherein the N-terminus of the second portion is linked to the C-terminus of the first portion, and wherein the polypeptide construct neutralizes TGF-β with at least 100-fold more potency than the TβSR-ED alone.   
     
     
         5 . The polypeptide construct of  claims 2 - 4 , wherein the second portion comprises one TβSR-ED. 
     
     
         6 . The polypeptide construct of  claim 5 , wherein the second portion comprises two TβSR-EDs. 
     
     
         7 . The polypeptide construct according to  claims 1 - 6 , wherein the TβSR-ED is a TGF-β receptor type II ectodomain (TβR-II-ED). 
     
     
         8 . The polypeptide construct of  claims 1 - 6 , wherein the TβSR-ED comprises a sequence selected from the group consisting of SEQ ID NO:35, SEQ ID NO:69, SEQ ID NO:75, SEQ ID NO:81, and a sequence substantially identical thereto. 
     
     
         9 . The polypeptide construct of  claims 1 - 8 , wherein the second portion comprises a sequence selected from the group consisting of SEQ ID NO:43-SEQ ID NO:51, SEQ ID NO:61-SEQ ID NO:68, SEQ ID NO:73, SEQ ID NO:74, SEQ ID NO:79, SEQ ID NO:80, SEQ ID NO:85, SEQ ID NO:86, SEQ ID NO:88, and a sequence substantially identical thereto. 
     
     
         10 . The polypeptide construct of any one of  claims 1 - 8 , wherein the first portion further comprises a C H1 , a C H1  and V H , or C H1  and scFv. 
     
     
         11 . The polypeptide construct of any one of  claims 1 - 10 , wherein the antibody heavy chain is of human origin. 
     
     
         12 . The polypeptide construct of any one of  claims 1 - 11 , wherein the antibody heavy chain is selected from the group consisting of a human IgG1, IgG2, IgG3, or IgG4 heavy chain. 
     
     
         13 . The polypeptide construct of any one of  claims 1 - 12 , wherein the antibody heavy chain is a human IgG1. 
     
     
         14 . The polypeptide construct of  claim 4 , wherein the polypeptide construct shows longer in vivo half-life compared to the half-life of the second portion alone. 
     
     
         15 . The polypeptide construct of any one of  claims 1 - 14 , wherein the polypeptide construct is a single chain polypeptide. 
     
     
         16 . The polypeptide construct of any one of  claims 1 - 15 , wherein the polypeptide construct forms a dimeric polypeptide. 
     
     
         17 . The polypeptide construct of  claims 1 - 16 , wherein the polypeptide construct is heterodimeric. 
     
     
         18 . A polypeptide construct selected from the group consisting of any one of SEQ ID NO:91 to SEQ ID NO:120, and a sequence substantially identical thereto. 
     
     
         19 . A polypeptide construct according to  claims 1 - 16 , wherein the construct comprises an antibody, antigen binding fragment thereof, or a targeting moiety. 
     
     
         20 . A polypeptide construct according to  claim 19 , comprising the antibody, antigen binding fragment, or targeting moiety at the N-terminus of the first portion. 
     
     
         21 . A polypeptide construct according to  claim 19 , wherein the antigen binding fragment may be selected from the group consisting of a Fv, scFv, Fab, or sdAb. 
     
     
         22 . A polypeptide construct according to  claim 19 , wherein the antigen binding fragment binds to an antigen that is not PD-L1, EGFR1, Her-2, CD4, CD6, CD20, CD25, MUC-1, IL-2, IL-6, or CTLA-4. 
     
     
         23 . A polypeptide construct according to  claim 19 , wherein the antibody is selected from the group consisting of Cetuximab, Avastin, Herceptin, Synagis, and FC5. 
     
     
         24 . A polypeptide construct according to  claim 23 , wherein the antibody is Cetuximab. 
     
     
         25 . A polypeptide construct according to  claim 19 , wherein the targeting moiety comprises a poly-aspartate sequence motif for bone targeting. 
     
     
         26 . A polypeptide construct according to  claim 25 , wherein the targeting moiety comprises D10. 
     
     
         27 . A polypeptide construct according to any preceding claim wherein the construct is a dimeric polypeptide. 
     
     
         28 . A polypeptide construct according to  claim 27 , wherein the dimeric polypeptide comprises:
 a first single chain polypeptide comprising a first portion comprising the second constant domain (C H2 ) and third constant domain (C H3 ) of an antibody heavy chain, and a heavy chain variable region of a given antibody;   a second portion comprising one or more TGF-β superfamily receptor ectodomains (TβSR-ED),   wherein the N-terminus of the second portion is linked to the C-terminus of the first portion, and   a second single chain polypeptide comprising a first portion comprising the second constant domain (C H2 ) and third constant domain (C H3 ) of an antibody heavy chain, and a light chain variable region of said given antibody;   a second portion comprising one or more TGF-β superfamily receptor ectodomain (TβSR-ED) which is the same or different from the ectodomain(s) in the first polypeptide, wherein the N-terminus of the second portion is linked to the C-terminus of the first portion.   
     
     
         29 . A nucleic acid molecule encoding the polypeptide construct of any preceding claim. 
     
     
         30 . A vector comprising the nucleic acid molecule of  claim 29 . 
     
     
         31 . A composition comprising one or more than one independently selected polypeptide construct of any one of  claims 1  to  30  and a pharmaceutically-acceptable carrier, diluent, or excipient. 
     
     
         32 . A transgenic cellular host comprising the nucleic acid molecule of  claim 29  or a vector of  claim 30 . 
     
     
         33 . The transgenic cellular host of  claim 32 , further comprising a second nucleic acid molecule or a second vector encoding a second polypeptide construct different from the first polypeptide construct. 
     
     
         34 . The use of a polypeptide construct according to any one of  claims 1 - 28 , for treatment of a medical condition, disease or disorder. 
     
     
         35 . The use according to  claim 34 , wherein the medical condition, disease or disorder comprises cancer, ocular diseases, fibrotic diseases, or genetic disorders of connective tissue.

Join the waitlist — get patent alerts

Track US2020231652A1 — get alerts on status changes and closely related new filings.

We store only your email — no account needed. See our privacy policy.