US2006147444A1PendingUtilityA1

Biosynthetic binding proteins for immuno-targeting

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Individually held — no corporate assignee on recordPriority: Feb 6, 1992Filed: Oct 10, 2003Published: Jul 6, 2006
Est. expiryFeb 6, 2012(expired)· nominal 20-yr term from priority
Inventors:James S. HustonLou L. HoustonDavid B. RingHermann Oppermann
C07K 2317/622C07K 2317/565C07K 2319/33C07K 16/30C07K 16/22A61P 35/00C07K 2319/02C07K 2317/567A61K 2039/505C07K 2319/00C07K 16/32C07K 16/3069C07K 2319/55C07K 16/3015
62
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Claims

Abstract

Disclosed is a formulation for targeting an epitope on an antigen expressed in a mammal. The formulation comprises a pharmaceutically acceptable carrier together with a dimeric biosynthetic construct for binding at least one preselected antigen. The biosynthetic construct contains two polypeptide chains, each of which define single-chain Fv (sFv) binding proteins and have C-terminal tails that facilitate the crosslinking of two sFv polypeptides. The resulting dimeric constructs have a conformation permitting binding of a said preselected antigen by the binding site of each said polypeptide chain when administered to said mammal. The formulation has particular utility in in vivo imaging and drug targeting experiments.

Claims

exact text as granted — not AI-modified
1 . A formulation for targeting an epitope on an antigen expressed in a mammal, the formulation comprising a pharmaceutically acceptable carrier in combination with, 
 a dimeric biosynthetic construct for binding at least one preselected antigen, the construct comprising: 
 (a) two polypeptide chains, each of which have:  
   an amino acid sequence defining at least two polypeptide domains, connected by a polypeptide linker spanning the distance between the C-terminus of one domain and the N-terminus of the other, the amino acid sequence of each said domain comprising complementarity determining regions (CDRs) interposed between framework regions (FRs), the CDRs and FRs of each polypeptide chain together defining a binding site immunologically reactive with a said preselected antigen, and 
 and a C-terminal tail having a non-self-associating structure under physiological conditions and comprising at least a crosslinking means, and  
   (b) a linkage coupling said crosslinking means on said two polypeptide chains,    said dimeric construct having a conformation permitting binding of a said preselected antigen by the binding site of each said polypeptide chain when administered to said mammal.    
     
     
         2 . A formulation for targeting an epitope on an antigen expressed in a mammal, the formulation comprising a pharmaceutically acceptable carrier in combination with, 
 a dimeric biosynthetic construct for binding preferentially to a preselected antigen, the construct comprising: 
 (a) two polypeptide chains, each of which have:  
   an amino acid sequence defining at least two polypeptide domains, connected by a polypeptide linker spanning the distance between the C-terminus of one domain and the N-terminus of the other, the amino acid sequence of each said domain comprising complementarity determining regions (CDRs) interposed between framework regions.(FRs), the CDRs and FRs of each polypeptide chain together defining a binding site immunologically reactive with a said preselected antigen, and 
 a C-terminal tail having a non-self-associating structure under physiological conditions and comprising at least a crosslinking means, and  
   (b) a linkage coupling said crosslinking means to form a homodimeric construct,    said homodimeric construct having a conformation permitting binding to said preselected antigen in said mammal with an avidity greater than the avidity of either of said polypeptide chains individually.    
     
     
         3 . A polypeptide chain for binding preferentially to a preselected antigen, the polypeptide chain comprising: 
 an amino acid sequence defining at least two polypeptide domains, connected by a polypeptide linker spanning the distance between the C-terminus of one domain and the N-terminus of the other, the amino acid sequence of each said domain comprising complementarity determining regions (CDRS) interposed between framework regions (FRs), the CDRs and FRs of each polypeptide chain together defining a binding site immunologically reactive with said preselected antigen, and    a C-terminal tail having a non-self-associating structure under physiological conditions and comprising at least a crosslinking means.    
     
     
         4 . The polypeptide chain of  claim 1 ,  2  or  3  wherein said C-terminal tail comprises the amino acid sequence Ser-Cys.  
     
     
         5 . The polypeptide chain of  claim 1 ,  2  or  3  wherein said C-terminal tail comprises the amino acid sequence (Gly) 4 -Cys.  
     
     
         6 . The polypeptide chain of  claim 1 ,  2  or  3  wherein said C-terminal tail comprises the amino acid sequence (His) 6 -(Gly) 4 -Cys.  
     
     
         7 . The polypeptide chain of  claim 1 ,  2  or  3  wherein said C-terminal tail can chelate one or more ions.  
     
     
         8 . The polypeptide chain of  claim 7  wherein said ion is a metal ion.  
     
     
         9 . The polypeptide chain of  claim 1 ,  2  or  3  wherein said crosslinking means is a derivatizable amino acid side chain.  
     
     
         10 . The polypeptide chain of  claim 9  wherein said derivatizable amino acid is selected from the group consisting of lysine, arginine and histidine.  
     
     
         11 . The polypeptide chain of  claim 9  wherein said derivatizable amino acid is a cysteine amino acid.  
     
     
         12 . The polypeptide chain of  claim 1 ,  2  or  3  wherein said crosslinking means comprises a posttranslationally modified amino acid.  
     
     
         13 . The polypeptide chain of  claim 12  wherein said posttranslationally modified amino acid is the Asn residue located in the amino acid sequence selected form group of Asn-Xaa-Ser and Asn-Xaa-Thr.  
     
     
         14 . The formulation of  claim 1  or  2  wherein said linkage is a chemical bridge.  
     
     
         15 . The formulation of  claim 1  or  2  wherein said linkage comprises a disulfide bond.  
     
     
         16 . The formulation of  claim 1  or  2  wherein said linkage comprises a bismaleimidohexane cross-linker.  
     
     
         17 . The formulation of  claim 1  or  2  wherein said linkage comprises a bismaleimidocaproyl amino acid linker.  
     
     
         18 . The formulation of  claim 1  or  2  wherein said linkage comprises a peptidyl linker.  
     
     
         19 . The formulation of  claim 1  or  2  wherein said linkage forms a substantially inflexible structure under physiological conditions.  
     
     
         20 . The formulation of  claim 1  or  2  wherein said linkage has a length and composition optimized for binding of two preselected antigens expressed on a tissue surface in a mammal.  
     
     
         21 . The formulation of  claim 1  or  2  wherein said linkage comprises a detectable moiety.  
     
     
         22 . The formulation of  claim 21  wherein said detectable moiety comprises Technetium −99m .  
     
     
         23 . The formulation of  claim 21  wherein said detectable moiety comprises means for inducing proton relaxation in vivo.  
     
     
         24 . The formulation of  claim 1  or  2  wherein said dimeric biosynthetic construct targets said epitope on said antigen with an avidity greater than that of a monoclonal antibody having the same antigenic determinant as said construct, or a fragment thereof.  
     
     
         25 . The formulation of  claim 1  or  2  wherein said dimeric biosynthetic construct targets said epitope on said antigen with an avidity greater than that of either of said polypeptide chains individually.  
     
     
         26 . The formulation of  claim 1  or  2  wherein said preselected antigen is expressed on the surface of a cell.  
     
     
         27 . The formulation of  claim 1  or  2  wherein said antigen is an intracellular component exposed upon cell lysis.  
     
     
         28 . The formulation of  claim 1  or  2  wherein said dimeric construct binds two different epitopes.  
     
     
         29 . The formulation of  claim 1  or  2  wherein one of said binding sites further comprises a catalytic site.  
     
     
         30 . The formulation of  claim 1  or  2  wherein one of said binding sites binds an epitope on a therapeutic agent to be targeted to a cell surface.  
     
     
         31 . The formulation of  claim 30  wherein said therapeutic agent is a cytotoxic agent.  
     
     
         32 . The formulation of  claim 1 ,  2  or  3  wherein said construct has improved in vivo imaging characteristics.  
     
     
         33 - 49 . (canceled)

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