Recombinant anti-TNF-α antibodies

• US 7,179,893 B2
• Filed: 04/07/2006
• Issued: 02/20/2007
• Est. Priority Date: 03/18/1991
• Status: Expired due to Fees

• Current Assignee: Centocor Incorporated (Johnson & Johnson), New York University
• Original Assignee: Centocor Incorporated (Johnson & Johnson), New York University
• Inventors: Knight, David, Ghrayeb, John, Le, Junming, Vilcek, Jan, Siegel, Scott, Daddona, Peter
• Primary Examiner(s): Gambel; Phillip
• Application Number:
  US11/400,787
• Publication Number:
  US 20060240017A1
• Time in Patent Office: 319 Days
• Field of Search: None
• US Class Current: 530/388.23
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/167 having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
• CPC Class Codes: A61K 31/192 having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid cannabinoids A61K31/658
• CPC Class Codes: A61K 31/196 the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
• CPC Class Codes: A61K 31/405 Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
• CPC Class Codes: A61K 31/485 Morphinan derivatives, e.g. morphine, codeine
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 31/573 substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
• 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: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: A61K 45/00 Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: C07K 14/525 Tumour necrosis factor [TNF]
• CPC Class Codes: C07K 16/241 Tumor Necrosis Factors
• CPC Class Codes: C07K 16/30 from tumour cells
• CPC Class Codes: C07K 2317/24 containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/34 Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
• CPC Class Codes: C07K 2317/76 Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• CPC Class Codes: C07K 2317/92 : Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
• CPC Class Codes: C07K 2319/00 : Fusion polypeptide

Abstract

Anti-TNF antibodies, fragments and regions thereof which are specific for human tumor necrosis factor-α (TNFα) and are useful in vivo diagnosis and therapy of a number of TNFα-mediated pathologies and conditions, as well as polynucleotides coding for murine and chimeric antibodies, methods of producing the antibody, methods of use of the anti-TNF antibody, or fragment, region or derivative thereof, in immunoassays and immunotherapeutic approaches are provided.

Claims

1. An isolated recombinant anti-TNF-α

antibody or antigen-binding fragment thereof, said antibody comprising a human IgG4 constant region, wherein the antigen-binding fragment is a Fab′

fragment, and wherein said antibody or antigen binding fragment (i) competitively inhibits binding of A2 (ATCC Accession No. PTA-7045) to human TNF-α

, and (ii) binds to a neutralizing epitope of human TNF-α

with an affinity of at least 1×

10⁸ liter/mole, measured as an association constant (Ka), as determined by Scatchard analysis.

2. The antibody or antigen-binding fragment of claim 1, which comprises at least one human light chain and at least one human heavy chain.

3. The antibody or antigen-binding fragment of claim 1, wherein the antigen-binding regions are of murine origin.

4. A composition comprising the antibody or antigen-binding fragment of claim 1, and a pharmaceutically acceptable carrier.

5. The antibody or antigen-binding fragment of claim 1, which has specificity for a neutralizing epitope of human TNF-α

.

6. The antibody or antigen-binding fragment of claim 1, wherein said Scatchard analysis comprises labeling the anti-TNF-α

antibody or antigen-binding fragment thereof and measuring direct binding of ¹²⁵I labeled anti-TNF-α

antibody or antigen-binding fragment thereof to immobilized rhTNFα

, and wherein said antibodies are labelled to a specific activity of about 9.7 μ

Ci/μ

g by the iodogen method.

7. An isolated recombinant antibody light chain that specifically binds human TNFα

and competitively inhibits binding of A2 (ATCC Accession No. PTA-7045) to human TNF-α

, said light chain comprising a human IgG4 light chain constant region and a human light chain framework region, wherein said human light chain binds to a neutralizing epitope of human TNF-α

with an affinity of at least 1×

10⁸ liter/mole, measured as an association constant (Ka), as determined by Scatchard analysis.

8. An isolated recombinant anti-TNF-α

antibody or antigen-binding fragment thereof, said antibody comprising a human IgG4 constant region, wherein the antigen-binding fragment is a Fab fragment, and wherein said antibody or antigen binding fragment (i) competitively inhibits binding of A2 (ATCC Accession No. PTA-7045) to human TNF-α

, and (ii) binds to a neutralizing epitope of human TNF-α

with an affinity of at least 1×

10⁸ liter/mole, measured as an association constant (Ka), as determined by Scatchard analysis.

9. An isolated recombinant anti-TNF-α

antibody or antigen-binding fragment thereof, said antibody comprising a human IgG4 constant region, wherein the antigen-binding fragment is a F(ab′

)₂ fragment, and wherein said antibody or antigen binding fragment (i) competitively inhibits binding of A2 (ATCC Accession No. PTA-7045) to human TNF-α

, and (ii) binds to a neutralizing epitope of human TNF-α

with an affinity of at least 1×

10⁸ liter/mole, measured as an association constant (Ka), as determined by Scatchard analysis.