Recombinant A2-specific TNFα specific antibodies

• US 7,070,775 B2
• Filed: 07/18/2002
• Issued: 07/04/2006
• 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:
  US10/198,845
• Publication Number:
  US 20030144484A1
• Time in Patent Office: 1,447 Days
• Field of Search: 464/130.1, 464/145.1, 530/387.1, 530/388.23
• US Class Current: 424/145.1
• 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 constant region, 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

in vivo 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, wherein the antibody or antigen-binding fragment comprises a human constant region and a human variable region.

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

4. The antibody or antigen-binding fragment of claim 3, wherein the light chain comprises all antigen-binding regions of the light chain of A2 (ATCC Accession No. PTA-7045).

5. The antibody or antigen-binding fragment of claim 3, wherein the heavy chain comprises all antigen-binding regions of the heavy chain of A2 (ATCC Accession No. PTA-7045).

6. The antibody or antigen-binding fragment of claim 3, wherein the light chain comprises all antigen-binding regions of the light chain of A2 (ATCC Accession No. PTA-7045) and the heavy chain comprises all antigen-binding regions of the heavy chain of A2 (ATCC Accession No. PTA-7045).

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

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

.

10. 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.

11. The antibody or antigen-binding fragment of claim 1, which is of immunoglobulin class IgG1, IgG2, IgG3, IgG4 or IgM.

12. The antigen-binding fragment of claim 1, wherein said fragment is selected from the group consisting of Fab, Fab′

, F(ab′

)₂ and Fv.

7. An isolated recombinant anti-TNF-α

antibody or antigen-binding fragment thereof, said antibody comprising a human constant region, wherein said antibody or antigen-binding fragment (i) comprises the antigen-binding regions of A2 (ATCC Accession No. PTA-7045), and (ii) binds to a neutralizing epitope of human TNF-α

in vivo with an affinity of at least 1×

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

13. An isolated recombinant anti-TNF-α

antibody or antigen-binding fragment thereof, said antibody comprising a human IgG1 constant region, 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

in vivo with an affinity of at least 10⁸ liter/mole, measured as an association constant (Ka), as determined by Scatchard analysis.

14. The antibody or antigen-binding fragment of claim 13, wherein the antibody or antigen-binding fragment comprises a human constant region and a human variable region.

15. The antibody or antigen-binding fragment of claim 13, which comprises at least one human light chain and at least one human heavy chain.

16. The antibody or antigen-binding fragment of claim 15, wherein the light chain comprises all antigen-binding regions of the light chain of A2 (ATCC Accession No. PTA-7045).

17. The antibody or antigen-binding fragment of claim 15, wherein the heavy chain comprises all antigen-binding regions of the heavy chain of A2 (ATCC Accession No. PTA-7045).

18. The antibody or antigen-binding fragment of claim 15, wherein the light chain comprises all antigen-binding regions of the light chain of A2 (ATCC Accession No. PTA-7045) and the heavy chain comprises all antigen-binding regions of the heavy chain of A2 (ATCC Accession No. PTA-7045).

20. A composition comprising the antibody or antigen-binding fragment of claim 13 and a pharmaceutically acceptable carrier.

19. An isolated recombinant anti-TNF-α

antibody or antigen-binding fragment thereof, said antibody comprising a human IgGi constant region, wherein said antibody or antigen-binding fragment (i) comprises the antigen-binding regions of A2 (ATCC Accession No. PTA-7045), and (ii) binds to a neutralizing epitope of human TNF-α

in vivo with an affinity of at least 1×

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

21. 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 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

in vivo with an affinity of at least 1×

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

22. An isolated recombinant antibody heavy chain that specifically binds human TNTα

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

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

in vivo with an affinity of at least 1×

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