US2020339694A1PendingUtilityA1

Activatable antibodies that bind interleukin-6 receptor and methods of use thereof

64
Assignee: CYTOMX THERAPEUTICS INCPriority: Sep 25, 2012Filed: Feb 20, 2020Published: Oct 29, 2020
Est. expirySep 25, 2032(~6.2 yrs left)· nominal 20-yr term from priority
Inventors:James William WestJason Gary SagertDaniel Robert HostetterStephen MooreMargaret Thy Luu NguyenOlga VasiljevaJeanne Grace Flandez
C07K 2317/515C07K 2317/94C07K 16/2866C07K 2317/56C07K 2319/50C07K 2317/51C07K 2317/565C07K 2317/55A61K 47/65A61K 2039/505C07K 2317/90C07K 2317/92
64
PatentIndex Score
0
Cited by
0
References
0
Claims

Abstract

The invention relates generally to activatable antibodies that include a masking moiety (MM), a cleavable moiety (CM), and an antibody (AB) that specifically binds to interleukin-6 receptor (IL-6R), and to methods of making and using these anti-IL-6R activatable antibodies in a variety of therapeutic, diagnostic and prophylactic indications.

Claims

exact text as granted — not AI-modified
1 - 39 . (canceled) 
     
     
         40 . A method of preventing, delaying the progression of,
 treating, alleviating a symptom of, or otherwise ameliorating inflammation or an inflammatory disorder comprising:   administering a therapeutically effective amount of an activatable antibody to a subject in need thereof, wherein the activatable antibody comprises:   an antibody or an antigen binding fragment thereof (AB) that specifically binds to IL-6R;   a masking moiety (MM) that inhibits the binding of the AB to IL-6R in an uncleaved state; and   a cleavable moiety (CM) coupled to the AB, wherein the CM is a polypeptide that functions as a substrate for a protease.   
     
     
         41 . (canceled) 
     
     
         42 . A method of treating, preventing, delaying the progression of, alleviating a symptom of, or otherwise ameliorating an IL-6R-mediated disorder or disease comprising:
 administering a therapeutically effective amount of an activatable antibody to a subject in need thereof, wherein the activatable antibody comprises:   an antibody or an antigen binding fragment thereof (AB) that specifically binds to IL-6R;   a masking moiety (MM) that inhibits the binding of the AB to IL-6R in an uncleaved state; and   a cleavable moiety (CM) coupled to the AB, wherein the CM is a polypeptide that functions as a substrate for a protease.   
     
     
         43 . A method of preventing, delaying the progression of, treating, alleviating a symptom of, or otherwise ameliorating an autoimmune disease or disorder in a subject comprising:
 administering a therapeutically effective amount of an activatable antibody to a subject in need thereof, wherein the activatable antibody comprises:   an antibody or an antigen binding fragment thereof (AB) that specifically binds to IL-6R;   a masking moiety (MM) that inhibits the binding of the AB to IL-6R in an uncleaved state; and   a cleavable moiety (CM) coupled to the AB, wherein the CM is a polypeptide that functions as a substrate for a protease.   
     
     
         44 . The activatable antibody of  claim 40 , wherein the AB comprises
 a VH CDR1 sequence that comprises the VH CDR1 sequence of SEQ ID NO: 1,   a VH CDR2 sequence that comprises the VH CDR2 sequence of SEQ ID NO: 1,   a VH CDR3 sequence that comprises the VH CDR3 sequence of SEQ ID NO: 1,   a VL CDR1 sequence that comprises the VL CDR1 sequence of SEQ ID NO: 2,   a VL CDR2 sequence that comprises the VL CDR2 sequence of SEQ ID NO: 2, and   a VL CDR3 sequence that comprises the VL CDR3 sequence of SEQ ID NO: 2.   
     
     
         45 . The method of  claim 40 , wherein the AB comprises
 a VH CDR1 sequence that comprises the amino acid sequence SDHAWS (SEQ ID NO: 175);   a VH CDR2 sequence that comprises the amino acid sequence YISYSGITTYNPSLKSRVT (SEQ ID NO: 176);   a VH CDR3 sequence that comprises the amino acid sequence SLARTTAMDY (SEQ ID NO: 177);   a VL CDR1 sequence that comprises the amino acid sequence RASQDISS (SEQ ID NO: 178);   a VL CDR2 sequence that comprises the amino acid sequence TISSLQP (SEQ ID NO: 179); and   a VL CDR3 sequence that comprises the amino acid sequence QQGNTLPY (SEQ ID NO: 180).   
     
     
         46 . The method of  claim 40 , wherein the activatable antibody has the structural arrangement from N-terminus to C-terminus as follows in the uncleaved state: MM-CM-AB or AB-CM-MM. 
     
     
         47 . The method of  claim 40 , wherein the activatable antibody comprises a linking peptide between the MM and the CM. 
     
     
         48 . The method of  claim 40 , wherein the activatable antibody comprises a linking peptide between the CM and the AB. 
     
     
         49 . The method of  claim 40 , wherein the activatable antibody comprises a first linking peptide (LP1) and a second linking peptide (LP2), and wherein the activatable antibody has the structural arrangement from N-terminus to C-terminus as follows in the uncleaved state: MM-LP1-CM-LP2-AB or AB-LP2-CM-LP1-MM. 
     
     
         50 . The method of  claim 49 , wherein the two linking peptides need not be identical to each other. 
     
     
         51 . The method of  claim 49 , wherein at least one of LP1 or LP2 comprises an amino acid sequence selected from the group consisting of (GS) n , (GGS) n , (GSGGS) n  (SEQ ID NO: 93) and (GGGS) n  (SEQ ID NO: 94), where n is an integer of at least one. 
     
     
         52 . The method of  claim 49 , wherein at least one of LP1 or LP2 comprises an amino acid sequence selected from the group consisting of GGSG (SEQ ID NO: 95), GGSGG (SEQ ID NO: 96), GSGSG (SEQ ID NO: 97), GSGGG (SEQ ID NO: 98), GGGSG (SEQ ID NO: 99), and GSSSG (SEQ ID NO: 100). 
     
     
         53 . The method of  claim 49 , wherein LP1 comprises the amino acid sequence GSSGGSGGSGGSG (SEQ ID NO: 101), GSSGGSGGSGG (SEQ ID NO: 112), GSSGGSGGSGGS (SEQ ID NO: 113), GSSGGSGGSGGSGGGS (SEQ ID NO: 169), GSSGGSGGSG (SEQ ID NO: 170), or GSSGGSGGSGS (SEQ ID NO: 171). 
     
     
         54 . The method of  claim 49 , wherein LP2 comprises the amino acid sequence GSS, GGS, GGGS (SEQ ID NO: 172), GSSGT (SEQ ID NO: 102) or GSSG (SEQ ID NO: 103). 
     
     
         55 . The method of  claim 49 , wherein the AB has an equilibrium dissociation constant of about 100 nM or less for binding to IL-6R. 
     
     
         56 . The method of  claim 40 , wherein the antigen binding fragment thereof is selected from the group consisting of a Fab fragment, a F(ab′)2 fragment, a scFv, a scAb, a dAb, a single domain heavy chain antibody, and a single domain light chain antibody. 
     
     
         57 . The method of  claim 40 , wherein the AB comprises a heavy chain variable region comprising the variable region of the heavy chain amino acid sequence SEQ ID NO: 1. 
     
     
         58 . The method of  claim 40 , wherein the AB comprises a light chain variable region comprising the variable region of the light chain amino acid sequence SEQ ID NO: 2. 
     
     
         59 . The method of  claim 40 , wherein the AB comprises a heavy chain variable region comprising the variable region of the heavy chain amino acid sequence SEQ ID NO: 1 and a light chain variable region comprising the variable region of the light chain amino acid sequence SEQ ID NO: 2. 
     
     
         60 . The method of  claim 40 , wherein the AB comprises a heavy chain amino acid sequence comprising SEQ ID NO: 1 and a light chain amino acid sequence comprising SEQ ID NO: 2. 
     
     
         61 . The method of  claim 40 , wherein the activatable antibody comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 6-32, 109-111, 163-168, 181, and 182. 
     
     
         62 . The method of  claim 40 , wherein the activatable antibody comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 6-32, and 163-168. 
     
     
         63 . The method of  claim 40 , wherein the MM has an equilibrium dissociation constant for binding to the AB which is greater than the equilibrium dissociation constant of the AB to IL-6R. 
     
     
         64 . The method of  claim 40 , wherein the MM does not interfere or compete with the AB for binding to IL-6R in a cleaved state. 
     
     
         65 . The method of  claim 40 , wherein the MM is a polypeptide of up to 40 amino acids in length. 
     
     
         66 . The method of  claim 40 , wherein the MM polypeptide sequence is different from that of IL-6R. 
     
     
         67 . The method of  claim 40 , wherein the MM polypeptide sequence is no more than 50% identical to any natural binding partner of the AB. 
     
     
         68 . The method of  claim 40 , wherein the MM comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 33-89. 
     
     
         69 . The method of  claim 40 , wherein the protease is co-localized with IL-6R in a tissue, and wherein the protease cleaves the CM in the activatable antibody when the activatable antibody is exposed to the protease. 
     
     
         70 . The method of  claim 40 , wherein the CM is a polypeptide of up to 15 amino acids in length. 
     
     
         71 . The method of  claim 40 , wherein the CM is a substrate for an enzyme selected from the group consisting of a matrix metalloprotease (MMP), thrombin, a neutrophil elastase, a cysteine protease, legumain, matriptase, and uPA. 
     
     
         72 . The method of  claim 40 , wherein the CM comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 90-92, 104, 105, 107, 116-128, 157-162, 173, 174, and 183-193. 
     
     
         73 . The method of  claim 40 , wherein the activatable antibody comprises a spacer, wherein the spacer is joined directly to the MM and has the structural arrangement from N-terminus to C-terminus of spacer-MM-CM-AB. 
     
     
         74 . The method of  claim 40  comprising an agent conjugated to the AB. 
     
     
         75 . The method of  claim 74 , wherein the agent is a therapeutic agent, an antineoplastic agent, or a toxin or fragment thereof. 
     
     
         76 . The method of  claim 74 , wherein the agent is conjugated to the AB via a linker. 
     
     
         77 . The method of  claim 76 , wherein the linker is a cleavable linker. 
     
     
         78 . The method of  claim 40 , wherein the activatable antibody comprises a detectable moiety. 
     
     
         79 . The method of  claim 78 , wherein the detectable moiety is a diagnostic agent.

Join the waitlist — get patent alerts

Track US2020339694A1 — get alerts on status changes and closely related new filings.

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