US2010121039A1PendingUtilityA1

Methods and compositions for prolonging elimination half-times of bioactive compounds

64
Assignee: GENENTECH INCPriority: Dec 24, 1999Filed: Oct 26, 2009Published: May 13, 2010
Est. expiryDec 24, 2019(expired)· nominal 20-yr term from priority
Inventors:Mark S. DennisHenry B. LowmanWarren Delano
A61P 43/00C07K 14/001C07K 1/047A61K 47/65A61K 47/643A61K 47/62A61K 2039/505C07K 16/22A61K 47/68C07K 16/24C07K 2317/55C07K 16/461A61K 38/00C07K 7/08
64
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Claims

Abstract

Peptide ligands having affinity for IgG or for serum albumin are disclosed. Also disclosed are hybrid molecules comprising a peptide ligand domain and an active domain. The active domain may comprise any molecule having utility as a therapeutic or diagnostic agent. The hybrid molecules of the invention may be prepared using any of a number techniques including production in and purification from recombinant organisms transformed or transfected with an isolated nucleic acid encoding the hybrid molecule, or by chemical synthesis of the hybrid. The hybrid molecules have utility as agents to alter the elimination half-times of active domain molecules. Elimination half-time is altered by generating a hybrid molecule of the present invention wherein the peptide ligand has binding affinity for a plasma protein. In a preferred embodiment, a bioactive molecule having a short elimination half-time is incorporated as or into an active domain of the hybrid molecules of the invention, and the binding affinity of the peptide ligand domain prolongs the elimination half-time of the hybrid as compared to that of the bioactive molecule.

Claims

exact text as granted — not AI-modified
1 - 60 . (canceled) 
     
     
         61 . A method of prolonging the elimination half-time of an antibody or antibody fragment comprising conjugating the antibody or antibody fragment to a serum albumin binding amino acid sequence, wherein the elimination half time of the antibody or antibody fragment exceeds that of an antibody or antibody fragment lacking a serum albumin binding amino acid sequence. 
     
     
         62 . The method of  claim 61  wherein the antibody fragment comprises a Fab. 
     
     
         63 . The method of  claim 61  wherein the antibody fragment comprises a F(ab′) 2 . 
     
     
         64 . The method of any one of  claims 61 - 63  wherein the affinity of the serum albumin binding amino acid sequence for albumin is characterized by an equilibrium dissociation constant (K d ) that is less than about 1 μM. 
     
     
         65 . The method of any one of  claims 61 - 63  wherein the affinity of the serum albumin binding amino acid sequence for albumin is characterized by a K d  of less than about 500 nM. 
     
     
         66 . The method of any one of  claims 61 - 63  wherein the affinity of the serum albumin binding amino acid sequence for albumin is characterized by a K d  of less than about 50 nM. 
     
     
         67 . The method of any one of  claims 61 - 63  wherein the affinity of the serum albumin binding amino acid sequence for albumin is characterized by a K d  between about 1 μM and 1 nM. 
     
     
         68 . The method of  claim 61 , wherein the serum albumin binding amino acid sequence comprises the amino acid sequence (Xaa) x -Xaa-Xaa 1 -Cys-Xaa-Xaa-Xaa-Xaa-Xaa-Cys-Xaa-Xaa-(Xaa) z , wherein Xaa-Xaa 1 -Cys-Xaa-Xaa-Xaa-Xaa-Xaa-Cys-Xaa-Xaa is Asp-Xaa 1 -Cys-Leu-Pro-Xaa-Trp-Gly-Cys-Leu-Trp (SEQ ID NO:116), wherein Xaa or Xaa 1  is any amino acid, and x and z are 0 to 5 amino acids. 
     
     
         69 . The method of  claim 68  wherein x is 4 and z is 3. 
     
     
         70 . The method of  claim 68  wherein x is 5 and z is 4. 
     
     
         71 . The method of  claim 68  wherein Xaa 1  is Ile, Phe, Tyr or Val. 
     
     
         72 . The method of  claim 68  wherein Xaa-Xaa-Cys-Xaa-Xaa-Xaa-Xaa-Xaa-Cys-Xaa-Xaa is Asp-Ile-Cys-Leu-Pro-Arg-Trp-Gly-Cys-Leu-Trp (SEQ ID NO: 120). 
     
     
         73 . The method of  claim 68  wherein Xaa-Xaa-Cys-Xaa-Xaa-Xaa-Xaa-Xaa-Cys-Xaa-Xaa is Met-Glu-Asp-Ile-Cys-Leu-Pro-Arg-Trp-Gly-Cys-Leu-Trp-Glu-Asp (SEQ ID NO: 121). 
     
     
         74 . The method of  claim 68  wherein Xaa-Xaa-Cys-Xaa-Xaa-Xaa-Xaa-Xaa-Cys-Xaa-Xaa is Gln-Arg-Leu-Met-Glu-Asp-Ile-Cys-Leu-Pro-Arg-Trp-Gly-Cys-Leu-Trp-Glu-Asp-Asp-Phe (SEQ ID NO: 122). 
     
     
         75 . The hybrid molecule of  claim 68  wherein Xaa-Xaa-Cys-Xaa-Xaa-Xaa-Xaa-Xaa-Cys-Xaa-Xaa is Gln-Gly-Leu-Ile-Gly-Asp-Ile-Cys-Leu-Pro-Arg-Trp-Gly-Cys-Leu-Trp-Gly-Asp-Ser-Val (SEQ ID NO: 123). 
     
     
         76 . The method of  claim 68  wherein Xaa-Xaa-Cys-Xaa-Xaa-Xaa-Xaa-Xaa-Cys-Xaa-Xaa is Gln-Gly-Leu-Ile-Gly-Asp-Ile-Cys-Leu-Pro-Arg-Trp-Gly-Cys-Leu-Trp-Gly-Asp-Ser-Val-Lys (SEQ ID NO: 124). 
     
     
         77 . The method of  claim 68  wherein Xaa-Xaa-Cys-Xaa-Xaa-Xaa-Xaa-Xaa-Cys-Xaa-Xaa is Glu-Asp-Ile-Cys-Leu-Pro-Arg-Trp-Gly-Cys-Leu-Trp-Glu-Asp-Asp (SEQ ID NO: 125). 
     
     
         78 . The method of  claim 68  wherein Xaa-Xaa-Cys-Xaa-Xaa-Xaa-Xaa-Xaa-Cys-Xaa-Xaa is Arg-Leu-Met-Glu-Asp-Ile-Cys-Leu-Pro-Arg-Trp-Gly-Cys-Leu-Trp-Glu-Asp-Asp (SEQ ID NO: 126). 
     
     
         79 . The method of  claim 68  wherein Xaa-Xaa-Cys-Xaa-Xaa-Xaa-Xaa-Xaa-Cys-Xaa-Xaa is Met-Glu-Asp-Ile-Cys-Leu-Pro-Arg-Trp-Gly-Cys-Leu-Trp-Glu-Asp-Asp (SEQ ID NO: 127). 
     
     
         80 . The method of  claim 61  wherein the amino acid sequence is cyclized by the presence of disulfide-bonded Cys residues. 
     
     
         81 . The method of  claim 61  wherein the amino acid sequence is less than about 50 amino acid residues. 
     
     
         82 . The method of  claim 61  wherein the amino acid sequence is less than about 40 amino acid residues. 
     
     
         83 . The method of  claim 61  wherein the amino acid sequence is about 20 amino acid residues. 
     
     
         85 . The method of  claim 61  further comprising a bioactive compound.

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