Drug – bio-affecting and body treating compositions – Lymphokine – Interleukin
Reexamination Certificate
2000-06-28
2004-02-10
Kunz, Gary (Department: 1647)
Drug, bio-affecting and body treating compositions
Lymphokine
Interleukin
C424S085100, C514S002600, C514S008100, C514S012200
Reexamination Certificate
active
06689353
ABSTRACT:
BACKGROUND OF THE INVENTION
FIELD
The invention is generally related to the field of pharmaceutical formulations. More specifically, the invention is directed to a stabilized, therapeutically active Interleukin-2 formulation capable of selectively activating T cells (PHA-blasts) and, very preferably, including an IL-2 mutein demonstrating reduced activation of Natural Killer (“NK”) cells. The stabilized compositions having the preferred properties include variants of IL-2 described below.
BACKGROUND
As discussed in a related application PCT/US 99/10643 published Nov. 25, 1999, Interleukin 2 (IL-2) is a potent immune stimulator, activating diverse cells of the immune system, including T cells, B cells, and monocytes. IL-2 is also a potent and critical growth factor of T cells. It was by virtue of these activities that IL-2 was tested for its ability to treat cancer. Human IL-2 is a FDA approved drug for the treatment of metastatic renal carcinoma and metastatic melanoma. The use of IL-2 in eligible patients is restricted due to the severe toxicity associated with IL-2 therapy; it is estimated that at best only 20% of eligible patients actually receive therapy. The toxicities associated with IL-2 therapy include severe fever, nausea, vomiting, vascular leak and serious hypotension. Despite these toxicities, however, IL-2 is effective for its approved indications. Variants of IL-2 having reduced toxicity are the subject matter of application WO 99/60128.
Significant information on stabilization of IL-2 and other therapeutic protein formulations is available. The currently approved Human IL-2 preparation (Proleukin® IL-2, Chiron Corporation) is a freeze-dried preparation which includes mannitol, sodium dodecyl sulfate (SDS) and a phosphate buffer. Other formulated therapeutic proteins, including IL-2, are described in the following references. Fernandes et al., 1986, Pharmaceutical compositions of microbially produced interleukin-2 (U.S. Pat. No. 4,604,377) describes a freeze-dried formulation containing a stabilizer (mannitol) and a solubilizing agent such as sodium dodecyl sulfate or sodium deoxycholate sulfate at about 100 to about 250 ug per mg of IL-2. The formulation for the currently available Proleukin® IL-2 product is believed to be described in this reference.
Patel, 1994 Stabilization of protein formulations (U.S. Pat. No. 5,358,708) describes aqueous formulations of an interferon, a granulocyte-macrophage colony-stimulating factor or an interleukin having extended storage lifetimes by incorporating methionine, histidine or mixtures thereof. Although reference is made to several interleukins, including IL-2, in work done with an IL-4 formulation the patentees found histidine to be less effective as a stabilizer than methionine, under conditions of the stabilizer test used.
Shaked, et al., 1991, Pharmaceutical compositions of recombinant interleuken-2 and formulation processes (U.S. Pat. No. 5,037,644) describes formulations which are either in freeze-dried or liquid form. The excipients of the formulation include a non-ionic polymeric detergent such as Triton X405, Triton X305, PEG (4000) monostearate, Tween 80 and Tween 20 at concentrations of about 0.001% to about 5%, a bulking/stabilizing agent such as sucrose, fructose, dextrose, maltose, glucose, dextran, mannitol, sorbitol, inositol, galactitol, xylitol, lactose, trehalose, human serum albumin and bovine serum albumin, and a buffering agent such as glycine, citrate, or phosphate in a concentration range from about 10 mM to about 50 mM with a pH ranging from about 3 to about 7. The concentration (wt/vol) of the polyol sugar bulking agent ranges from about 0.025% to about 10%.
Roskam et al., 1995, Drugs containing a glycosylated interleukin-2 (U.S. Pat. No. 5,417,970) describes a freeze-dried formulation containing hydrolyzed gelatin (or human serum albumin) and alanine with a pH 6.5.
Hora et al., 1992, Pharmaceutical composition for interleukin-2 containing physiologically compatible stabilizers (U.S. Pat. No. 5,078,997) describes formulations which are either liquid or freeze-dried. Formulations may contain one or a combination of stabilizers such as arginine, carnitine, betaine, pyridoxine polyvinylpyrrolidone, salts of capric acid, sugars, sugar alcohols, serum albumin, and citrate at pH 5.0-8.5 buffer. The concentration of stabilizers is between 0.2 and 3.0% (w/v) for arginine, between 0.2 and 3.0% (w/v) for carnitine, between 2 and 6% (w/v) for sucrose, and 0.01 and 0.3M for citrate.
Yasushi et al., 1987 Stable composition of interleukin-2 and albumin (U.S. Pat. No. 4,645,830) describes a stable aqueous formulation that contains human serum albumin (0.1-50 mg/ml) with or without a reducing excipient such as glutathione, thioctic acid, N-acetylcysteine, or ascorbic acid (concentration of 0.05-20 mg/ml) at pH between 3 to 5.5. The albumin formulation may contain a monoamino aliphatic amino acid, a cyclic amino acid, a monosaccharide, a sugar alcohol or monoamino aliphatic amino acid (concentration of 5 to 50 mg/ml).
Lee et al., 1989 Pharmaceutical plasma protein formulations in low ionic strength media; sodium chloride and/or potassium chloride, lysine hydrochloride, and histidine (U.S. Pat. No. 4,877,608) describes stable factor VIII and other plasma protein formulations in low ionic strength media which comprises: sodium chloride, potassium chloride or mixtures thereof; lysine hydrochloride; and histidine as the buffering agent.
Nayar, 1998 stabilized albumin-free recombinant Factor VIII preparation having a low sugar content (U.S. Pat. No. 5,763,401 and U.S. Pat. No. 5,874,408) describes an albumin free stabilized FVIII formulation including glycine, histidine, sucrose and NaCl.
In attempting to find a stable IL-2 formulation (especially for the preferred IL-2 mutein (N88R) of WO 99/60128), we have now found a very stable and pharmaceutically acceptable formulation for biologically active and useful Human IL-2. Our discovery is based on addressing what we believe is the basic mechanism responsible for stability, as described below.
REFERENCES:
patent: 4645830 (1987-02-01), Yasushi et al.
patent: 5358708 (1994-10-01), Patel
patent: 5656730 (1997-08-01), Lee
patent: 5763401 (1998-06-01), Nayar
patent: 6267958 (2001-07-01), Andya et al.
patent: WO-996018 (1999-11-01), None
Taneja et al., Increased thermal stability of proteins in the presence of amino acids, (1994) Biochem Journal, vol:303, 147-153.*
Rishi et al., Role of non-compatible osmolytes in the stabilization of proteins during heat stress, (1998) Biochem Journal, vol:329, 137-143.*
Pikal, M. J., Freeze-Drying of Proteins, PartII: Formulation Selection (1990), Biopharm, Vol 3, No. 9, pp 26-30.*
Chang, B. S. et al, Development of an Efficient Single Step Freeze-Drying Cycle for Protein Formulations, Pharm. Res., Vol 12, No. 6 pp 831-837 (1995), Plenum Publ. Corp.
Wang, W., Lyophilization and Development of Solid Protein Pharmaceuticals, International Journal of Pharmaceutics, 203:1-60, 2000.
Nayar Rajiv
Shearer Michael A.
Wang Wei
Bayer Pharmaceuticals Corporation
Mahoney John W.
Seharaseyon Jegatheesan
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