Antibody fragment-polymer conjugates and uses of same
First Claim
1. A method of therapeutic treatment of a tumor necrosis factor α
- -mediated (TNF-α
-mediated) disorder in a mammal comprising administering to the mammal an effective amount of a conjugate consisting essentially of an antibody fragment covalently modified by one or two nonproteinaceous polymer molecules at a free sulfhydryl group of a cysteine residue within the hinge region of the antibody fragment,wherein said antibody fragment is engineered to both (1) provide an unpaired cysteine within the hinge region, so as to provide said free sulfhydryl group, and (2) to avoid disulfide bridge formation between said cysteine and an amino acid in the opposite chain of said antibody fragment,wherein (a) the average actual molecular weight of each nonproteinaceous polymer molecule is at least 20 kD, (b) the conjugate binds the same antigen as the parental molecule that is not covalently modified by one or two nonproteinaceous polymer molecules, wherein the antibody fragment comprises an antigen binding site that binds to a human tumor necrosis factor-α
(TNF-α
) polypeptide, and wherein the TNF-α
-mediated disorder is selected from the group consisting of Crohn'"'"'s disease and rheumatoid arthritis.
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Accused Products
Abstract
Described are conjugates formed by an antibody fragment covalently attached to a non-proteinaceous polymer, wherein the apparent size of the conjugate is at least about 500 kD. The conjugates exhibit substantially improved half-life, mean residence time, and/or clearance rate in circulation as compared to the underivatized parental antibody fragment. Also described are conjugates directed against human vascular endothelial growth factor (VEGF), human p185 receptor-like tyrosine kinase (HER2), human CD20, human CD18, human CD11a, human IgE, human apoptosis receptor-2 (Apo-2), human tumor necrosis factor-α (TNF-α), human tissue factor (TF), human α4β7 integrin, human GPIIb-IIIa integrin, human epidermal growth factor receptor (EGFR), human CD3, and human interleukin-2 receptor α-chain (TAC) for diagnostic and therapeutic applications.
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Citations
3 Claims
-
1. A method of therapeutic treatment of a tumor necrosis factor α
- -mediated (TNF-α
-mediated) disorder in a mammal comprising administering to the mammal an effective amount of a conjugate consisting essentially of an antibody fragment covalently modified by one or two nonproteinaceous polymer molecules at a free sulfhydryl group of a cysteine residue within the hinge region of the antibody fragment,wherein said antibody fragment is engineered to both (1) provide an unpaired cysteine within the hinge region, so as to provide said free sulfhydryl group, and (2) to avoid disulfide bridge formation between said cysteine and an amino acid in the opposite chain of said antibody fragment, wherein (a) the average actual molecular weight of each nonproteinaceous polymer molecule is at least 20 kD, (b) the conjugate binds the same antigen as the parental molecule that is not covalently modified by one or two nonproteinaceous polymer molecules, wherein the antibody fragment comprises an antigen binding site that binds to a human tumor necrosis factor-α
(TNF-α
) polypeptide, and wherein the TNF-α
-mediated disorder is selected from the group consisting of Crohn'"'"'s disease and rheumatoid arthritis. - View Dependent Claims (2, 3)
- -mediated (TNF-α
Specification