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Methods of reducing aggregation of il-1raRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Lymphokine, InterleukinMethods of reducing aggregation of il-1ra description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20070098684, Methods of reducing aggregation of il-1ra. Brief Patent Description - Full Patent Description - Patent Application Claims
[0001] This application claims the benefit of U.S. Provisional Application No. 60/558,879, filed Apr. 2, 2004, U.S. Provisional Application No. 60/559,161, filed Apr. 2, 2004, U.S. Provisional Application No. 60/601,216, filed Aug. 12, 2004, and U.S. Provisional Application No. 60/601,229, filed Aug. 12, 2004. U.S. Provisional Application Nos. 60/558,879, 60/559,161, 60/601,216, and 60/601,229 are incorporated by reference herein for any purpose. FIELD [0002] The present invention relates to methods of reducing aggregation of an aggregating interleukin-1 receptor antagonist (IL-1ra). The present invention also relates to methods of improving drug formulations comprising reducing aggregation of IL-1ra. The present invention also relates to methods of treating diseases using IL-1ra whose aggregation has been reduced. Finally, the present invention relates to compositions and kits comprising an IL-1ra whose aggregation has been reduced. BACKGROUND [0003] Interleukin-1 alpha (IL-1.alpha.), interleukin-1 beta (IL-1.beta.), and interleukin-1 receptor antagonist (IL-1ra) each binds to the type 1 IL-1 receptor (IL-1-RI), which is found on the surface of certain cell types. IL-1.alpha. and IL-1.beta. have physiological effects on a number of different target cells, including certain cells that are involved in the inflammatory and immune responses. IL-1ra, in contrast, binds to IL-1RI, but does not elicit comparable downstream biological responses. Rather, IL-1ra competitively inhibits IL-1.alpha.and IL-1.beta. binding to IL-1RI. Anakinra, an E. coli-produced version of IL-1ra, is marketed for treatment of rheumatoid arthritis. SUMMARY [0004] In certain embodiments, a method of reducing aggregation of an aggregating interleukin-1 receptor antagonist (IL-1ra) is provided. In certain embodiments, the method comprises incubating IL-1ra with at least one accessory molecule. [0005] In certain embodiments, a method of preparing an interleukin-1 receptor antagonist (IL-1ra) drug formulation is provided. In certain embodiments, the method comprises incubating the aggregating IL-1ra with at least one accessory molecule. In certain embodiments, aggregation is reduced. [0006] In certain embodiments, a method of treating a patient is provided. In certain embodiments, a method of treating a patient having arthritis is provided. In certain embodiments, a method of treating a patient having rheumatoid arthritis is provided. In certain embodiments, a method of treating a patient having osteoarthritis is provided. In certain embodiments, a method of treating a patient having at least one of Crohn's disease, ulcerative colitis, glomerulonephritis, or leukemia is provided. In certain embodiments, a method of treating a patient having an adverse effect of IL-1 is provided. In certain embodiments, the method of treating a patient comprises administering to the patient a composition comprising (i) a therapeutically effective amount of an aggregating interleukin-1 receptor antagonist (IL-1ra) and (ii) at least one accessory molecule. [0007] In certain embodiments, kits are provided. In certain embodiments, a kit comprises an aggregating interleukin-1 receptor antagonist (IL-1ra) and at least one accessory molecule. [0008] In certain embodiments, pharmaceutical compositions are provided. In certain embodiments, pharmaceutical compositions comprise an aggregating interleukin-1 receptor antagonist (IL-1ra) and at least one accessory molecule. [0009] In certain embodiments, at least one accessory molecule is at a concentration that reduces aggregation of an aggregating IL-1ra. In certain embodiments, at least one accessory molecule is at a concentration that reduces the rate of aggregation of an aggregating IL-1ra. In certain embodiments, at least one accessory molecule is selected from a sugar and a multiple-charge anion. In certain embodiments, at least one accessory molecule is a multiple-charge anion. In certain embodiments, at least one accessory molecule is 1 to 20 mM pyrophosphate. In certain embodiments, at least one accessory molecule is 1 to 20 mM citrate. In certain embodiments, at least one accessory molecule is at least one sugar. In certain embodiments, at least one of said sugars is glycerol, sorbitol, or sucrose. In certain embodiments, at least one of such sugars is at a concentration of from 1 to 3 percent. [0010] In certain embodiments, at least one accessory molecule is selected from a lysine-reactive accessory molecule and an arginine-reactive accessory molecule. In certain embodiments, at least one accessory molecule is selected from 6-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)hexanoic acid (NBD-X), methyl acetyl phosphate (MAP), and citraconic anhydride. BRIEF DESCRIPTION OF THE FIGURES [0011] FIG. 1 shows the IL-1ra wild-type protein aggregation profile over time in either PSE (10 mM phosphate, pH 6.5, 140 mM NaCl, 0.5 mM EDTA) or CSE (10 mM citrate, pH 6.5, 140 mM NaCl, 0.5 mM EDTA) discussed in Example 2. [0012] FIG. 2 shows the reverse-phase high performance liquid chromatography (RP-HPLC) of IL-1ra wild-type protein derivatized with NBD-X discussed in Example 3. The upper panel shows the absorbance of NBD-X labeled IL-1ra at 215 nm. The lower panel shows the fluorescent emission at 535 nm following excitation at 480 nm. [0013] FIG. 3 shows the rates of aggregation for IL-1ra wild-type protein in the presence of increasing concentrations of phosphate, pyrophosphate, and citrate anions discussed in Example 4. [0014] FIG. 4 shows the aggregation rates for IL-1ra wild-type protein in the presence of increasing concentrations of glycerol, sorbitol, or sucrose discussed in Example 5. [0015] FIG. 5 shows the nucleotide sequence (SEQ ID NO: 1) and amino acid sequence (SEQ ID NO: 2) of precursor human IL-1ra, which includes a secretory leader sequence. [0016] FIG. 6 shows the amino acid sequence of human IL-1ra lacking the secretory leader sequence (SEQ ID NO: 3). The dot (.cndot.) indicates the lysine at position 93. The plus (+) indicates the arginine at position 97. The locations of tryptophan-16 (.DELTA.) and tyrosine-34 (.largecircle.) are also indicated. [0017] FIG. 7 shows an exemplary x-ray crystal structure of IL-1ra. [0018] FIG. 8 shows a portion of the interface between the two subunits of the asymmetric IL-1ra dimer in the x-ray crystal structure described for FIG. 1. [0019] FIG. 9 shows the urea-induced equilibrium unfolding of IL-1ra detected by circular dichroism discussed in Example 6. [0020] FIG. 10 shows the urea-induced equilibrium unfolding of IL-1ra detected by intrinsic fluorescence discussed in Example 6. 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