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1. (WO2006138181) SELF-BUFFERING PROTEIN FORMULATIONS
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What is claimed:
1. A composition comprising a pharmaceutical protein, wherein at the pH of the composition, 21° C, one atmosphere, and equilibrium with ambient atmosphere, the protein has a buffer capacity per unit volume of at least that of approximately 4.0 niM sodium acetate buffer in pure water in the range of pH 5.0 to 4.0 or pH 5.0 to 5.5 under the same conditions, wherein further, exclusive of the buffer capacity of said protein, the buffer capacity per unit volume of the composition under the same conditions is no more than that of 2.0 mM sodium acetate buffer in pure water in the range of pH 5.0 to 4.0 or pH 5.0 to 5.5 under the same conditions, wherein the composition has been approved for pharmaceutical use by an authority legally empowered to grant such approval.
2. A composition comprising a pharmaceutical protein, wherein at the pH of the composition, 21° C, one atmosphere, and equilibrium with ambient atmosphere, the protein has a buffer capacity per unit volume of at least 1.50 mEq/liter-pH unit, wherein further, exclusive thereof, the buffer capacity per unit volume of the composition is less than 0.5 mEq/liter-pH unit, wherein the composition has been approved for pharmaceutical use by an authority legally empowered to grant such approval.
3. A composition according to claim 1 , wherein the protein provides at least 80% of the buffer capacity of the composition.
4. A composition according to claim 3, wherein the concentration of the protein is between approximately 20 and 400 mg/ml.
5. A composition according to claim 4, wherein the pH maintained by the buffering action of the protein is between approximately 3.5 and 8.0.
6. A composition according to claim 5, wherein the pH maintained by the buffering action of the protein is between approximately 4 and 6.
7. A composition according to claim 5, further comprising one or more pharmaceutically acceptable salts, wherein the total salt concentration is less than 150 mM.
8. A composition according to claim 7, further comprising one or more pharmaceutically acceptable salts, wherein the total salt concentration is less than 100 mM.
9. A composition according to claim 5, further comprising one or more pharmaceutically acceptable polyols.

10. A composition according to claim 9, wherein the polyol is one or more of sorbitol, mannitol, sucrose, trehalose, or glycerol.
11. A composition according to claim 5, further comprising one or more pharmaceutically acceptable surfactants.
12. A composition according to claim 11, wherein the surfactant is one or more of polysorbate 20, polysorbate 80, other fatty acid esters of sorbitan,
polyethoxylates, and poloxamer 188.
13. A composition according to claim 9, further comprising one or more pharmaceutically acceptable surfactants.
14. A composition according to claim 1, further comprising one or more pharmaceutically acceptable: osmotic balancing agents; anti-oxidants; antibiotics; antimycotics; bulking agents; lyoprotectants; anti-foaming agents; chelating agents; preservatives; colorants; analgesics; or additional pharmaceutical agents.
15. A composition according to claim 5, further comprising one or more pharmaceutically acceptable: osmotic balancing agents; anti-oxidants; antibiotics; antimycotics; bulking agents; lyoprotectants; anti-foaming agents; chelating agents; preservatives; colorants; analgesics; or additional pharmaceutical agents.
16. A composition according to claim 7, further comprising one or more pharmaceutically acceptable: osmotic balancing agents; anti-oxidants; antibiotics; antimycotics; bulking agents; lyoprotectants; anti-foaming agents; chelating agents; preservatives; colorants; analgesics; or additional pharmaceutical agents.
17. A composition according to any of claims 1, 5, 7, 9, 11, 13, or 14, wherein the protein is or comprises: an antibody, Fab fragment, Fab2 fragment, Fab3 fragment, Fc fragment, scFv fragment, bis-scFv(s) fragment, minibody, diabody, triabody tetrabody, VhH domain, V-NAR domain, VH domain, VL domain, camel Ig, Ig NAR, receptibody, peptibody, or a variant or a derivative thereof or a protein related thereto, or a modification thereof.
18. A composition according to claim 17, wherein the protein comprises an Fc fragment or a part thereof, or a variant or a derivative of an Fc fragment or a part thereof or a protein related to an Fc fragment or part thereof, or a modification of any thereof.
19. A composition according to claim 18, wherein the protein further comprises a first binding moiety of a pair of cognate binding moieties.

20. A composition according to any of claims 1, 5, 7, 9, 11, 13, or 14, wherein the protein is selected from the group consisting of proteins that bind specifically to one or more CD proteins, HER receptor family proteins, cell adhesion molecules, growth factors, nerve growth factors, fibroblast growth factors, transforming growth factors (TGF), insulin-like growth factors, osteoinductive factors, insulins and insulin-related proteins, coagulation and coagulation-related proteins, colony stimulating factors (CSFs), other blood and serum proteins blood group antigens;
receptors, receptor-associated proteins, growth hormone receptors, T-cell receptors; neurotrophic factors, neurotrophins, relaxins, interferons, interleukins, viral antigens, lipoproteins, integrins, rheumatoid factors, immunotoxins, surface membrane proteins, transport proteins, homing receptors, addressins, regulatory proteins, and
immunoadhesins,
21. A composition according to any of claims 1, 5, 7, 9, 11, 13, or 14, wherein the protein is selected from the group consisting of: OPGL specific binding proteins, myostatin specific binding proteins, IL-4 receptor specific binding proteins, ILl-Rl specific binding proteins, Ang2 specific binding proteins, NGF-specific binding proteins, CD22 specific binding proteins, IGF-I receptor specific binding proteins, B7RP-1 specific binding proteins, IFN gamma specific binding proteins, TALL-I specific binding proteins, stem cell factors, Flt-3 ligands, and IL-17 receptors.
22. A composition according to any of claims 1, 5, 7, 9, 11, 13 or 14, wherein the protein is selected from the group consisting of proteins that bind specifically to one ormore of: CD3, CD4, CD8, CD19, CD20, CD34; HER2, HER3, HER4, the EGF receptor; LFA-I, MoI, pl50,95, VLA-4, ICAM-I, VCAM, alpha v/beta 3 integrin; vascular endothelial growth factor ("VEGF"); growth hormone, thyroid stimulating hormone, follicle stimulating hormone, luteinizing hormone, growth hormone releasing factor, parathyroid hormone, mullerian-inhibiting substance, human macrophage inflammatory protein (MIP-I -alpha), erythropoietin (EPO), NGF-beta, platelet-derived growth factor (PDGF), aFGF, bFGF, epidermal growth factor (EGF), TGF-alpha, TGF-betal, TGF-beta2, TGF-beta3, TGF-beta4, TGF-beta5, IGF-I, IGF-II, des(l -3)-IGF-I (brain IGF-I), insulin, insulin A-chain, insulin B-chain, proinsulin, insulin-like growth factor binding proteins;, such as, among others, factor VIII, tissue factor, von Willebrands factor, protein C, alpha- 1 -antitrypsin, plasminogen activators, such as urokinase and tissue plasminogen activator ("t-P A"), bombazine, thrombin, and thrombopoietin; M-CSF, GM-CSF, G-CSF, albumin, IgE, flk2/flt3 receptor, obesity (OB) receptor, bone-derived neurotrophic factor (BDNF), NT-3, NT-4, NT-5, NT-6); relaxin A-chain, relaxin B-chain, prorelaxin; interferon-alpha, -beta, and -gamma;IL-l to IL-IO; AIDS envelope viral antigen; calcitonin, glucagon, atrial natriuretic factor, lung surfactant, tumor necrosis factor-alpha and -beta, enkephalinase, RANTES, mouse gonadotropin-associated peptide, Dnase, inhibin, and activin; protein A or D, bone morphogenetic protein (BMP), superoxide dismutase, decay accelerating factor (DAF).
23. A composition according to any of claims 1, 5, 7, 9, 11, 13 or 14, wherein the protein is selected from the group consisting of: Actimmune (Interferon-gamma- Ib), Activase (Alteplase), Aldurazme (Laronidase), Amevive (Alefacept), Avonex (Interferon beta- Ia), BeneFIX (Nonacog alfa), Beromun (Tasonermin), Beatseron (Interferon-beta-lb), BEXXAR (Tositumomab), Tev-Tropin (Somatropin), Bioclate or RECOMBINATE (Recombinant), CEREZME (Imiglucerase), ENBREL (Etanercept), Eprex (epoetin alpha), EPOGEN/Procit (Epoetin alfa), FABRAZYME (Agalsidase beta), Fasturtec/Elitek ELITEK (Rasburicase), FORTEO (Teriparatide), GENOTROPIN (Somatropin), GlucaGen (Glucagon), Glucagon (Glucagon, rDNA origin), GONAL-F (follitropin alfa), KOGENATE FS (Octocog alfa), HERCEPTIN (Trastuzumab), HUMATROPE (SOMATROPIN), HUMIRA (Adalimumab), Insulin in Solution, INFERGEN® (Interferon alfacon-1), KINERET® (anakinra), Kogenate FS (Antihemophilic Factor), LEUKIN (SARGRAMOSTIM Recombinant human granulocyte-macrophage colony stimulating factor (rhuGM-CSF)), CAMPATH (Alemtuzumab), RITUXAN® (Rituximab), TNKase (Tenecteplase), MYLOTARG (gemtuzumab ozogamicin), NATRECOR (nesiritide), ARANESP (darbepoetm alfa), NEULASTA (pegfilgrastim), NEUMEGA (oprelvekin), NEUPOGEN (Filgrastim), NORDITROPIN CARTRIDGES (Somatropin), NOVOSEVEN (Eptacog alfa), NUTROPIN AQ (somatropin), Oncaspar (pegaspargase), ONTAK (denileukin diftitox), ORTHOCLONE OKT (muromonab-CD3), OVIDREL (choriogonadotropin alfa), PEGASYS (peginterferon alfa-2a), PROLEUKIN (Aldesleukin), PULMOZYME (dornase alfa), Retavase (Reteplase), REBETRON Combination Therapy containing REBETOL® (Ribavirin) and INTRON® A (Interferon alfa-2b), REBIF (interferon beta-la), REFACTO (Antihemophilic Factor), REFLUDAN (lepirudin), REMICADE (infliximab), REOPRO (abciximab)ROFERON®-A (Interferon alfa-2a), SIMULECT (baasiliximab), SOMAVERT (Pegivisomant), SYNAGIS® (palivizumab), Stemben

(Ancestim, Stem cell factor), THYROGEN, INTRON® A (Interferon alfa-2b), PEG- INTRON® (Peginterferon alfa-2b), XIGRIS® (Drotrecogin alfa activated), XOLAIR® (Omalizumab), ZENAP AX® (daclizumab), and ZEVALIN® (Ibritumomab Tiuxetan).

24. A composition according to any of claims 1, 5, 7, 9, 11, 13, or 14, wherein the protein is Ab-hOPGL or a fragment thereof, or a variant or derivative of Ab-hOPGL or of a fragment thereof, or an Ab-hOPGL related protein or fragment thereof, or a modification of any thereof.
25. A composition according to any of claims 1, 5, 7, 9, 11, 13, or 14, wherein the protein is Ab-hOPGL.
26. A composition according to any of claims 1, 5, 7, 9, 11, 13, or 14, wherein the protein is Ab-hIL4R or a fragment thereof, or a variant or derivative of Ab-hIL4R or of a fragment thereof, or an Ab-hIL4R related protein or fragment thereof, or a modification of any thereof.
27. A composition according to any of claims 1, 5, 7, 9, 11, 13, or 14, wherein the protein is Ab-hIL4R.
28. A composition according to any of claims 1, 5, 7, 9, 11, 13, or 14, wherein the protein is Ab-hB7RPl or a fragment thereof, or a variant or derivative of Ab-hB7RPl or of a fragment thereof, or an Ab-hB7RPl related protein or fragment thereof, or a modification of any thereof.
29. A composition according to any of claims 1, 5, 7, 9, 11, 13, or 14, wherein the protein is Ab-hB7RP 1.
30. A lyophilate which upon reconstitution provides a composition according to any of claim 1, 5, 7, 9, 11, 13 or 14.
31. A kit comprising in one or more containers a composition according to any of claim 1, 5, 7, 9, 11, 13 or 14 and instructions regarding the use thereof.
32. A kit comprising in one or more containers a lyophilate according to claim 31, and instructions regarding the use thereof.
33. A method for treating a subject, comprising administering to a subject in an amount and by a route effective for treatment, a composition according to any of claim 1, 5, 7, 9, 11, 13 or 14.
34. A process for preparing a composition according to any of claim 1, 5, 7,

9, 11, 13 or 14, comprising removing residual buffer using a counter ion.
35. A process for preparing a composition according to claim 34, comprising removing residual buffer using any one or more of the following in the presence of a counter ion: size exclusion chromatography, dialysis, and/or tangential flow filtration.
36. A process for preparing a composition according to claim 35, comprising removing residual buffer using ion exchange chromatography.
37. A process for preparing a composition according to any of claim 1, 5, 7,

9, 11, 13 or 14, comprising removing residual buffer by diafiltration against a bufferless solution having a pH below the desired pH.
38. A process for preparing a composition according to claim 37, wherein following diafiltration the pH is adjusted to a desired pH by addition of dilute acid and/or dilute base.
39. A lyophilate which upon reconstitution provides a composition according to claim 20.
40. A kit comprising in one or more containers a composition according to claim 20 and instructions regarding the use thereof.
41. A kit comprising in one or more containers a lyophilate according to claim 40, and instructions regarding the use thereof.
42. A method for treating a subject, comprising administering to a subject in an amount and by a route effective for treatment, a composition according to claim 20.

43. A process for preparing a composition according to claim 20, comprising removing residual buffer using a counter ion.
44. A process for preparing a composition according to claim 43, comprising removing residual buffer using any one or more of the following in the presence of a counter ion: size exclusion chromatography, dialysis, and/or tangential flow filtration.
45. A process for preparing a composition according to claim 43, comprising removing residual buffer using ion exchange chromatography.
46. A process for preparing a composition according to claim 20, comprising removing residual buffer by diafiltration against a bufferless solution having a pH below the desired pH.
47. A process for preparing a composition according to claim 46, wherein following diafiltration the pH is adjusted to a desired pH by addition of dilute acid and/or dilute base.
48. A lyophilate which upon reconstitution provides a composition according to claim 21.

49. A kit comprising in one or more containers a composition according claim 21 and instructions regarding the use thereof.
50. A kit comprising in one or more containers a lyophilate according to claim 49, and instructions regarding the use thereof.
51. A method for treating a subject, comprising administering to a subject in an amount and by a route effective for treatment, a composition according to claim 21.

52. A process for preparing a composition according to claim 21, comprising removing residual buffer using a counter ion.
53. A process for preparing a composition according to claim 52, comprising removing residual buffer using any one or more of the following in the presence of a counter ion: size exclusion chromatography, dialysis, and/or tangential flow filtration.
54. A process for preparing a composition according to claim 52, comprising removing residual buffer using ion exchange chromatography.
55. A process for preparing a composition according to claim 21 , comprising removing residual buffer by diafiltration against a bufferless solution having a pH below the desired pH.
56. A process for preparing a composition according to claim 55, wherein following diafiltration the pH is adjusted to a desired pH by addition of dilute acid and/or dilute base.
57. A lyophilate which upon reconstitution provides a composition according to claim 23.
58. A kit comprising in one or more containers a composition according claim 23 and instructions regarding the use thereof.
59. A kit comprising in one or more containers a lyophilate according to claim 57, and instructions regarding the use thereof.
60. A method for treating a subject, comprising administering to a subject in an amount and by a route effective for treatment, a composition according to claim 23.

61. A process for preparing a composition according to claim 23, comprising removing residual buffer using a counter ion.
62. A process for preparing a composition according to claim 61, comprising removing residual buffer using any one or more of the following in the presence of a counter ion: size exclusion chromatography, dialysis, and/or tangential flow filtration.
63. A process for preparing a composition according to claim 61 , comprising removing residual buffer using ion exchange chromatography.
64. A process for preparing a composition according to claim 21 , comprising removing residual buffer by diafiltration against a bufferless solution having a pH below the desired pH.
65. A process for preparing a composition according to claim 62, wherein following diafiltration the pH is adjusted to a desired pH by addition of dilute acid and/or dilute base.