US2016152711A1PendingUtilityA1

Design and development of masked therapeutic antibodies to limit off-target effects: application to anti-egfr antibodies

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Assignee: HOPE CITYPriority: Dec 8, 2008Filed: Oct 30, 2014Published: Jun 2, 2016
Est. expiryDec 8, 2028(~2.4 yrs left)· nominal 20-yr term from priority
Inventors:John C. WilliamsUlrich RodeckJoshua M. DonaldsonCsaba Kari
C07K 2319/50C07K 2319/30C07K 16/32C07K 2319/33C07K 2317/622C07K 16/2863C07K 2317/34C07K 2317/92C07K 2317/73C07K 2317/33C07K 2317/76C07K 16/30C07K 2319/32C07K 2317/31
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Claims

Abstract

In one embodiment, a masked monoclonal antibody (mAb) is provided, the mAb, encoded by a nucleic acid sequence or an amino acid sequence molecule comprising a signal sequence, a masking epitope sequence, a linker sequence that is cleavable by a protease specific to a target tissue; and an antibody or a functional fragment thereof. In another embodiment, a cross-masked mAb heterodimer complex is provided, comprising a first masked mAb, comprising a first signal sequence, a first masking epitope sequence, a first linker that is cleavable by a protease specific to a target tissue, and a first antibody or fragment thereof; and a second masked mAb, comprising a second signal sequence, a second masking epitope sequence, a second linker that is cleavable by a protease specific to a target tissue, and a second antibody or fragment thereof.

Claims

exact text as granted — not AI-modified
What is claimed is: 
     
         1 . A recombinant nucleic acid molecule comprising:
 (a) a signal nucleic acid sequence;   (b) a nucleic acid sequence which encodes a masking epitope;   (c) a nucleic acid sequence which encodes a linker that is cleavable by a protease specific to a target tissue; and   (d) a nucleic acid sequence which encodes an antibody or an antigen binding fragment thereof.   
     
     
         2 . The recombinant nucleic acid molecule of  claim 1 , wherein the masking epitope comprises an epitope specific to an antigenic recognition site of the antibody or functional fragment thereof. 
     
     
         3 . The recombinant nucleic acid molecule of  claim 2 , wherein the antigenic recognition site is one or more complementary determining regions (CDRs). 
     
     
         4 . The recombinant nucleic acid molecule of  claim 1 , wherein the protease is matrix metalloproteinase-9 (MMP-9). 
     
     
         5 . The recombinant nucleic acid molecule of  claim 1 , wherein the antibody or antigen binding fragment thereof is specific to EGFR. 
     
     
         6 . The recombinant nucleic acid molecule of  claim 1 , wherein the antibody or antigen binding fragment thereof is an IgG. 
     
     
         7 . The recombinant nucleic acid molecule of  claim 1 , wherein the antibody or antigen binding fragment thereof is an scFv. 
     
     
         8 . The recombinant nucleic acid molecule of  claim 1 , comprising SEQ ID NO:1 or SEQ ID NO:2. 
     
     
         9 . A masked monoclonal antibody (mAb) which comprises an amino acid sequence, the amino acid sequence comprising:
 (a) a masking epitope sequence;   (b) a linker sequence that is cleavable by a protease specific to a target tissue; and   (c) an antibody sequence or an antigen binding fragment thereof.   
     
     
         10 . The masked mAb of  claim 9 , wherein the nucleic acid molecule which encodes the masking epitope sequence comprises a nucleic acid molecule which encodes an epitope specific to an antigenic recognition site of the antibody or functional fragment thereof. 
     
     
         11 . The masked mAb of  claim 10 , wherein the antigenic recognition site is one or more complementary determining regions (CDRs). 
     
     
         12 . The masked mAb of  claim 9 , wherein the protease is matrix metalloproteinase-9 (MMP-9). 
     
     
         13 . The masked mAb of  claim 9 , wherein the linker sequence comprises SEQ ID NO:3. 
     
     
         14 . The masked mAb of  claim 9 , wherein the linker sequence comprises SEQ ID NO:4. 
     
     
         15 . The masked mAb of  claim 9 , wherein the antibody or antigen binding fragment thereof is specific to EGFR. 
     
     
         16 . The masked mAb of  claim 9 , wherein the antibody or antigen binding fragment thereof comprises an IgG. 
     
     
         17 . The masked mAb of  claim 9 , wherein the antibody sequence or antigen binding fragment thereof is an scFv. 
     
     
         18 . The masked mAb of  claim 9 , wherein the amino acid sequence of the masked mAb comprises SEQ ID NO:5 or SEQ ID NO:6. 
     
     
         19 . A masked monoclonal antibody (mAb) comprising:
 (a) a masking epitope amino acid sequence;   (b) a linker sequence comprising SEQ ID NO:3; and   (c) an antibody amino acid sequence or an antigen binding fragment thereof.   
     
     
         20 . The masked mAb of  claim 19 , wherein the linker sequence further comprises SEQ ID NO:4.

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