Thyroxin-binding HSA fragments

• US 5,698,517 A
• Filed: 03/21/1994
• Issued: 12/16/1997
• Est. Priority Date: 03/21/1994
• Status: Expired due to Fees

• Current Assignee: Office of The Governor of Ohio (State of Ohio)
• Original Assignee: Office of The Governor of Ohio (State of Ohio)
• Inventors: Bhagavan, Nadhipuram V., Petersen, Charles E., Mandel, Morton
• Primary Examiner(s): Wax, Robert A.
• Assistant Examiner(s): Lau, Kawai
• Application Number:
  US08/215,135
• Time in Patent Office: 1,366 Days
• Field of Search: 435/69.6, 530/363, 530/364, 514/12
• US Class Current: 514/15.2
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 25/26 Psychostimulants, e.g. nicotine, cocaine
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07K 14/765 Serum albumin, e.g. HSA

Abstract

Modified forms of human serum albumin (HSA) wherein the arginine at position 218 is substituted by a less basic amino acid show strong thyroxin-binding activity. These modified forms of HSA and fragments thereof are useful in binding thyroxin in standard assays for free thyroxin concentration and in treating conditions characterized by higher-than-desired levels of free thyroxin in animal subjects.

Claims

1. A compound which is a modified form of human serum albumin (HSA) wherein said modification comprises a substitution of an amino acid of lower basicity for arginine at position 218 of said HSA, wherein said HSA

(1) is a peptide fragment of HSA and is selected from a group consisting of peptides consisting of amino acid sequences found between positions 190-585, 190-487, 190-390, 190-292, 97-292 of HSA, and shorter versions of these peptides containing 1-10 fewer amino acids,

(2) contains said substitution at position 218, and

(3) exhibits thyroxin binding activity at least 10% of that of the corresponding full-length modified HSA,

wherein said compound is purified and isolated according to standard technology.

2. The compound of claim 1 wherein said amino acid of less basicity is selected from the group consisting of Gly, Ala, Ser, Cys, Thr, Gln, Ash and His.

3. The compound of claim 2 wherein said amino acid of less basicity is His.

5. A method to lower the free thyroxin level in an animal subject, which method comprises administering to a subject in need of said effect, an effective amount of the compound of claim 1 or a pharmaceutical or veterinary composition thereof.

4. A pharmaceutical composition effective to bind endogenous free thyroxin, which composition comprises a thyroxin-binding effective amount of a modified HSA wherein said modification comprises the substitution of an amino acid of lower basicity for arginine at position 218 of said HSA, wherein said HSA

(1) is a peptide fragment of HSA and is selected from a group consisting of peptides consisting of amino acid sequences found between positions 190-585, 190-487, 190-390, 190-292, 97-292 of HSA, and shorter versions of these peptides containing 1-10 fewer amino acids,

(2) contains said substitution at position 218, and

(3) exhibits thyroxin binding activity at least 10% of that of the corresponding full-length modified HSA,

wherein said compound is purified and isolated according to standard technology;

in admixture with a pharmaceutically acceptable carrier or diluent.