TNF-α binding proteins

1. A humanized binding protein or antigen binding fragment thereof comprising an antigen binding domain capable of binding human tumor necrosis factor-alpha (TNF-α), the antigen binding domain comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH region comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 29, 30, 31, 32, and 33, and the VL region comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 34, 35, and 36.

2. The humanized binding protein or antigen binding fragment thereof of claim 1 , wherein the binding protein or antigen binding fragment thereof inhibits a biological function of human TNF-α.

3. The humanized binding protein or antigen binding fragment thereof of claim 1 , wherein the binding protein or antigen binding fragment thereof neutralizes human TNF-α.

4. The humanized binding protein or antigen binding fragment thereof of claim 1 , wherein the binding protein or antigen binding fragment thereof diminishes the ability of human TNF-α to bind to its receptor.

5. The humanized binding protein or antigen binding fragment thereof of claim 4 , wherein the binding protein or antigen binding fragment thereof diminishes the ability of pro-human TNF-α, mature-human TNF-α, or truncated-human TNF-α to bind to its receptor.

6. The humanized binding protein or antigen binding fragment thereof of claim 1 , wherein the binding protein or antigen binding fragment thereof reduces one or more of an activity selected from the group consisting of TNF-α-dependent cytokine production; TNF-α-dependent cell killing; TNF-α-dependent inflammation; TNF-α-dependent bone erosion; and TNF-α-dependent cartilage damage.

7. The humanized binding protein or antigen binding fragment thereof of claim 1 , wherein the binding protein or antigen binding fragment thereof comprises a constant domain selected from the group consisting of a heavy chain immunoglobulin constant domain of a human IgM constant domain, a human IgG1 constant domain, a human IgG2 constant domain, a human IgG3 constant domain, a human IgG4 constant domain, a human IgA constant domain, or a human IgE constant domain.

8. The humanized binding protein or antigen binding fragment thereof of claim 7 , wherein the heavy chain immunoglobulin constant domain is a human IgG1 constant domain.

9. The humanized binding protein or antigen binding fragment thereof of claim 1 or 7 , wherein the binding protein or antigen binding fragment thereof further comprises a light chain immunoglobulin constant domain selected from the group consisting of a human Ig kappa constant domain and a human Ig lambda constant domain.

10. The humanized binding protein or antigen binding fragment thereof of claim 8 , wherein the human IgG1 constant domain comprises an amino acid sequence of selected from the group consisting of SEQ ID NO:2 Of and SEQ ID NO:3.

11. The humanized binding protein or antigen binding fragment thereof of claim 9 , wherein the human Ig kappa constant domain comprises an amino acid sequence of SEQ ID NO:4, or the human Ig lambda constant domain comprises an amino acid sequence of SEQ ID NO:5.

12. The humanized binding protein or antigen binding fragment thereof of claim 1 , wherein the humanized binding protein or antigen binding fragment further comprises: an immunoglobulin (Ig) constant heavy region comprising the amino acid sequence selected from the group consisting of SEQ ID NO: 2 and SEQ ID NO: 3; and an Ig constant light region comprising the amino acid sequence selected from the group consisting of SEQ ID NO: 4 and SEQ ID NO: 5.

13. The humanized binding protein or antigen binding fragment thereof of claim 1 , wherein the binding protein or antigen binding fragment thereof is selected from the group consisting of an immunoglobulin molecule, an Fv, a disulfide linked Fv, a monoclonal antibody, an scFv, a chimeric antibody, a single domain antibody, a CDR-grafted antibody, a diabody, a humanized antibody, a multispecific antibody, an Fab, a dual specific antibody, an Fab′ fragment, a bispecific antibody, an F(ab′)2 fragment, a DVD-Ig™ protein, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; a Fd fragment consisting of the VH and CH1 domains; an Fv fragment consisting of the VL and VH domains of a single arm of an antibody, a dAb fragment, and a single chain antibody.

14. A crystallized binding protein comprising the binding protein or antigen binding fragment thereof of claim 1 , wherein the binding protein or antigen binding fragment thereof is in the form of a crystal.

15. The crystallized binding protein of claim 14 , wherein the crystal is a carrier-free pharmaceutical controlled release crystal.

16. The crystallized binding protein of claim 14 , wherein the binding protein or antigen binding fragment thereof has a greater half life in vivo than the soluble counterpart of the binding protein or antigen binding fragment thereof.

17. A composition for the release of a TNF-α binding protein comprising: (a) a formulation, wherein the formulation comprises the binding protein or antigen binding fragment thereof of claim 1 or 14 , and an ingredient; and (b) at least one polymeric carrier.

18. The composition of claim 17 , wherein the ingredient is selected from the group consisting of albumin, sucrose, trehalose, lactitol, gelatin, hydroxypropyl-β-cyclodextrin, methoxypolyethylene glycol, and polyethylene glycol.

19. The composition of claim 17 , wherein the polymeric carrier is a polymer selected from the group consisting of poly acrylic acid, poly cyanoacrylate, a poly amino acid, a poly anhydride, a poly depsipeptide, a poly ester, poly lactic acid, poly lactic-co-glycolic acid, poly b-hydroxybutryate, poly caprolactone, poly dioxanone, poly ethylene glycol, poly hydroxypropyl methacrylamide, poly organophosphazene, poly ortho esters, poly vinyl alcohol, poly vinylpyrrolidone, maleic anhydride-alkyl vinyl ether copolymers, pluronic polyols, albumin, alginate, cellulose and cellulose derivatives, collagen, fibrin, gelatin, hyaluronic acid, oligosaccharides, glycaminoglycans, sulfated polysaccharides, and blends and copolymers thereof.

20. A tumor necrosis factor-alpha (TNF-α) binding protein construct comprising the humanized binding protein or antigen binding fragment thereof of claim 1 , and a linker or an immunoglobulin constant domain.

21. The TNF-α binding protein construct of claim 20 , wherein the binding protein or antigen binding fragment thereof is glycosylated.

22. The TNF-α binding protein construct of claim 20 , wherein the binding protein construct is a crystallized TNF-α binding protein construct.

23. The TNF-α binding protein construct of claim 22 , wherein the crystallized TNF-α binding protein construct is a carrier-free pharmaceutical controlled release crystallized TNF-α binding protein construct.

24. The TNF-α binding protein construct of claim 20 , wherein the binding protein construct has a greater half life in vivo than the soluble counterpart of the binding protein construct.

25. A tumor necrosis factor-alpha (TNF-α) binding protein conjugate comprising the TNF-α binding protein construct of claim 20 , and an agent selected from the group consisting of immunoadhesion molecule, an imaging agent, a therapeutic agent, or a cytotoxic agent.

26. The TNF-α binding protein conjugate of claim 25 , wherein the imaging agent is a radiolabel, an enzyme, a fluorescent label, a luminescent label, a bioluminescent label, a magnetic label, or biotin.

27. The TNF-α binding protein conjugate of claim 26 , wherein the radiolabel is selected from the group consisting of: 3 H, 14 C, 35 S, 90 Y, 99 Tc, 111 In, 125 I, 131 I, 177 Lu, 166 Ho, and 153 Sm.

28. The TNF-α binding protein conjugate of claim 25 , wherein the therapeutic agent or cytotoxic agent is selected from the group consisting of an anti-metabolite, an alkylating agent, an antibiotic, a growth factor, a cytokine, an anti-angiogenic agent, an anti-mitotic agent, an anthracycline, a toxin, or an apoptotic agent.

29. A pharmaceutical composition comprising the binding protein or antigen binding fragment thereof of claim 1 , and a pharmaceutically acceptable carrier.

30. The pharmaceutical composition of claim 29 , wherein the pharmaceutically acceptable carrier functions as an adjuvant.

31. The pharmaceutical composition of claim 30 , wherein the adjuvant is hyaluronidase.

32. The pharmaceutical composition of claim 29 , wherein the composition further comprises at least one additional agent for treating a disorder in which TNF-α activity is detrimental.

33. The pharmaceutical composition of claim 32 , wherein the additional agent is selected from the group consisting of a therapeutic agent, an imaging agent, a cytotoxic agent, an angiogenesis inhibitor, a kinase inhibitor, a co-stimulation molecule blocker, an adhesion molecule blocker, an anti-cytokine antibody or functional fragment thereof, methotrexate, cyclosporine, rapamycin, FK506, a detectable label, a detectable reporter, a TNF-α antagonist, an anti-rheumatic, a muscle relaxant, a narcotic, a non-steroid anti-inflammatory drug (NSAID), an analgesic, an anesthetic, a sedative, a local anesthetic, a neuromuscular blocker, an antimicrobial, an antipsoriatic, a corticosteroid, an anabolic steroid, an erythropoietin, an immunization, an immunoglobulin, an immunosuppressive agent, a growth hormone, a hormone replacement drug, a radiopharmaceutical, an antidepressant, an antipsychotic, a stimulant, an asthma medication, a beta agonist, an inhaled steroid, an oral steroid, an epinephrine or analog thereof, a cytokine, and a cytokine antagonist.