MXPA06001332A - Crystalline tumor necrosis factor receptor 2 polypeptides - Google Patents
Crystalline tumor necrosis factor receptor 2 polypeptidesInfo
- Publication number
- MXPA06001332A MXPA06001332A MXPA/A/2006/001332A MXPA06001332A MXPA06001332A MX PA06001332 A MXPA06001332 A MX PA06001332A MX PA06001332 A MXPA06001332 A MX PA06001332A MX PA06001332 A MXPA06001332 A MX PA06001332A
- Authority
- MX
- Mexico
- Prior art keywords
- tnfr2
- polypeptide
- crystalline
- polypeptides
- etanercept
- Prior art date
Links
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Abstract
The present invention relates to crystalline polypeptides and to methods of making them;to pharmaceutical compositions comprising crystalline polypeptides;and to therapeutic uses of such polypeptides and compositions.
Description
Published: For • two-letter codes and other bbreviations, referto the "Guid¬
- with intemational search report ance Notes on Codes and Abbreviations "appearing at the beginning - before the expiration of the time limit for amending the no regular issue of the PCT Gazette.
CRYSTALLINE POLYPEPTIDQS OF TUMOR NECROSIS FACTOR RECEIVER 2
This application claims the benefit under provisional application 35 C.F.R 119 (e) of the United States series No.60 / 491, 827, filed on August 1, 2003, which is incorporated herein by reference in its entirety.
BACKGROUND OF THE INVENTION
Many therapeutic molecules are polypeptides, some of which are prone to denaturation, degradation and / or aggregation. Aggregation of the polypeptides is undesirable insofar as this can result in immunogenicity (Clean et al., Crit Rev Therapeutic Drugs Carrier Systems, 10: 307-377; and Robbins et al., 1987, Diabetes, 36: 838 -845). The polypeptides are also subjected to catalysis or conversion to inactive forms by natural biological processes of the organisms to which they are administered. Additionally, therapeutic polypeptides can be produced as a heterogeneous mixture of forms, which vary in the proportion of glycosylation or in other aspects of their three-dimensional conformation. The crystallization of the therapeutic polypeptides provides an advantage to produce a stable and homogeneous formulation of such polypeptides. Certain advantages of the crystals include easier handling of the therapeutic compound to prepare the pharmaceutical products; reduced degradation, denaturation and / or aggregation; the potential to create a sustained release form of the therapeutic polypeptide to reduce the frequency of dosing; and the ability to use crystalline therapeutic polypeptides to form a pharmaceutical composition having a very high concentration of the therapeutic polypeptide. In addition, crystallization methods can produce a more homogeneous population of polypeptides in the formulation, because only the addition of similarly configured polypeptide molecules will add sustained crystal growth-when a limiting amount of polypeptides of varying structure have been incorporated into the crystal network, the resulting structural weakness in the crystal will prevent its further growth. Because the incorporation into the crystalline form can ensure that a greater percentage of the polypeptide is in an active form, administration of a smaller amount of the crystalline therapeutic peptides can produce a therapeutic effect equivalent to the administration of a larger amount of a more heterogeneous polypeptide formulation. Therefore, there is a need for a crystalline formulation of therapeutic polypeptides.
SUMMARY OF THE INVENTION
The present invention provides crystalline forms of the TNFR2 polypeptides, which include the TNFR2: Fc polypeptides and the crystalline etanercept. One embodiment of the invention is a crystal of etanercept; In certain modalities the etanercept crystal is in the shape of a bar, and / or has a maximum length of between 0.5 mm and 1.5 mm between 0.05 mm and 0.3 mm. The invention also provides methods for making crystals of TNFR2 polypeptides such as a TNFR2-lg fusion polypeptide or etanercept. In certain embodiments, the TNFR2 polypeptides of monomers; in further embodiments TNFR2 polypeptides of multimers such as dimers, trimers or oligomers. In additional embodiments, the TNFR2 polypeptide shares at least 90% of the amino acid identity along the length of amino acids 39 to 162 of SEQ ID. No .: 1. The present invention also relates to the use of the TNFR2 polypeptides or the TNFR2 crystal polypeptides described, such as the crystalline polypeptides TNFR2: Fc or crystalline etanercept, in the preparation of a medicament for the prevention or treatment therapeutic of each medical disorder described here.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is a photograph of etanercept crystals formed of a polypeptide solution containing 50.96 mg of etanercept per milliliter, as further described in Example 1 below. The crystallization reservoir buffer was HEPES 0.1M pH 7.0, PEG 6000 30%, lithium chloride 0.7M; after 7 days at room temperature the crystals were harvested manually, washed profusely in the anterior reservoir buffer, and the photograph was taken. The crystals in this group were subjected to N-terminal amino acid sequence analysis.
DETAILED DESCRIPTION OF THE INVENTION
The invention is directed to TNFR2 polypeptides in crystalline form, and to methods for making and using such TNFR2 crystal polypeptides. The polypeptide crystals are advantageous because the crystalline polypeptides can be stored for longer periods and may exhibit greater physical stability and retention of biological activity, under a wider range of storage and handling conditions than polypeptides not found in crystalline form. Definitions "Polypeptide" is defined herein as synthetic or recombinant proteins or peptides that generally have more than 10 amino acids. "Polypeptide linker" can be a polypeptide formed by a series of amino acids as short as one amino acid in length. "Isolated", as used herein, refers to a polypeptide or other molecule that has been removed from its environment in which it occurs naturally. "Substantially purified", as used herein, refers to a polypeptide that is substantially free of other polypeptides present in the environment in which it occurs naturally or in which it was produced; a preparation of a polypeptide that has been substantially purified contains at least 90% by weight (or at least 95%, at least 98%, or at least 99% by weight) of that polypeptide, wherein the weight of the polypeptide includes any carbohydrate , lipid, or other residues covalently bound to the polypeptide. A substantially purified polypeptide preparation can contain variation between the polypeptide molecules within the preparation, with respect to the proportion and type of glycosylation or other post-translational modification, or with respect to the conformation or proportion of the multimerization. "Purified polypeptide" as used herein, refers to an essentially homogeneous polypeptide preparation; however, an essentially homogeneous polypeptide preparation can contain the variation between the polypeptide molecules within the preparation, with respect to the proportion and type of glycosylation, other post-translational modification with respect to the conformation or proportion of the multimerization. The "full length" polypeptides are those that have a complete primary amino acid sequence of the polypeptide as originally translated; for example, the full-length form of human TNFR2 is shown in SEQ ID. No.:1. The "mature form" of a polypeptide refers to a polypeptide that has undergone post-translational processing steps such as cleavage of the signal sequence or proteolytic cleavage to remove a prodomain. Multiple mature forms of a full-length polypeptide can be produced, for example, by cleavage of the signal sequence to multiple sites, or by differential regulation of proteases that clone the polypeptide. Mature forms of such a polypeptide can be obtained by expressing, in a suitable mammalian cell or in another host cell, a nucleic acid molecule encoding the full-length polypeptide. The sequence of the mature form of the polypeptide can also be determined in the amino acid sequence of the full-length form, through the identification of the signal sequences or the protease cleavage sites. In certain modalities, the mature form of the human TNFR2 polypeptide has an N-terminal amino acid residue selected from the group consisting of amino acids 23, 27, and 28 of the SEC ID. No.:1, or an N-terminal amino acid selected from the group consisting of each amino acid between amino acid 1 and amino acid 39 of the SEC ID. No.:1. The "percentage identity" of two amino acid sequences can be determined by visual inspection and mathematical calculation, and comparison can also be made by comparing sequence information using a computer program. The first stage to determine the percentage identity is to align the amino acid sequences in order to maximize the overlap and identities, although minimizing the spaces of the alignment. The second stage to determine the percentage identity is the calculation of the number of identities between the aligned sequences, divided by the total number of amino acids in the alignment. When determining the percentage identity that an amino acid sequence has "along the length of" a target amino acid sequence, or a target amino acid sequence, the length of the target amino acid sequence is the minimum value for the number of amino acids. Total bases in the alignment. For example, when determining the percent identity of a first amino acid sequence of 50 amino acids "along the length of" a second amino acid sequence of amino acids 1 to 100 of the SEQ ID. No.:X, if the first amino acid sequence is identical to amino acids 1 to 50 of the SEC ID. No.:X, the percentage identity would be 50%. The identities of the 50 amino acids divided by the total length of the alignment (100 amino acids). An example computer program to align the amino acid sequence and compute the percentage identity is the BLASTP program available for use via the website of the
National Library of Medicine ncbi.nlm.nih.gov/Gora/wblast2.cgi, or the UW-BLAST 2.0 algorithm. The default standard parameter settings for UW-BLAST 2.0 are described on the following Internet site: sapiens.wustl.edu/blast/README.html. In addition, the algorithm
BLAST uses an amino acid qualification matrix BLOSUM62, and the optional parameters that can be used are as follows: (A) inclusion of a filter to mask segments of the query sequence that have low compositional complexity (determined by the program
SEG by Wootton and Federhen (Computers and Chemistry, 1993); and see also Wootton and Federhen, 1996, Analysis of compositionally biased regions in SECuence databases, Methods Enzymol. 266: 554-71) or the elements that consist of short-term internal repetitions (determined through the XNU program of Claverie and States (Computers and Chemistry, 1993)), and (B) a threshold of statistical significance to report matches against sequences of the database, or an E-score (the expected probability of coincidences found simply by chance, according to the stochastic model of Karlin and Altschul (1990)), if the statistical significance ascribed to a parity is greater than the E-score rating threshold, parity will not be reported); The E-score rating threshold values are 0.5, 0.25, 0.1, 0.05, 0.01, 0.001, 0.0001, 1e-5, 1 e-10, 1e-15, 1e-20, 1e-25, 1e-30, 1e -40, 1e-50, 1e-75, or 1e-100. Other programs used by those skilled in the sequence comparison art can also be used to align the amino acid sequences, such as, the Genetics Computer Group (GCG; Madison, Wl) program 10.0 Wisconsin package version "GAP" (Devereux et al., 1984, Nucí Acids Res. 12: 387). The default parameters of the "GAP" program include: (1) The GCG implementation of a unary comparison matrix (containing a value of 1 for identities and 0 for non-identities) for nucleotides, and the amino acid comparison matrix heavy of Gribskov and Burgess, Nucí. Acids Res. 14: 6745, 1986, as described by Schwartz and Dayhoff, eds., Atlas of Polypeptide SECuence and Structure, National Biomedical Research Foundation, p. 353-358, 1979; or other comparable comparison nuances: (2) a penalty of 30 for each space and an additional penalty of 1 for each symbol in each space for the amino acid sequences, or a penalty of 50 for space and an additional penalty of 3 for each symbol in each space for the nucleotide sequences; (3) no penalty for final spaces; and (4) no maximum penalty for long spaces.
"Soluble forms" of the TNFR2 polypeptides of the invention comprise certain fragments or domains of these polypeptides. Soluble polypeptides are polypeptides that are capable of being secreted from the cells in which they are expressed. The secreted soluble polypeptide can be identified (and distinguished from its non-soluble membrane-bound counterparts) by separating the intact cells expressing the desired polypeptide from the culture medium, for example, by centrifugation, and assaying the medium (supernatant) for the presence of the desired polypeptide. The presence of the desired polypeptide in the medium indicates that the polypeptide was secreted from the cells and thus is a soluble form of the polypeptide. The use of the soluble forms of cytosine polypeptide of the invention is advantageous for many applications. Purification of polypeptides from recombinant host cells is facilitated, because the soluble polypeptides are secreted from the cells. Moreover, soluble polypeptides are generally more suitable in membrane-bound forms for parenteral administration and for many enzymatic procedures. In certain embodiments of the invention, mature soluble forms of TNFR2 polypeptides do not contain a transmembrane or a membrane anchoring domain such as amino acids 258 to 87 of SEQ ID. No .: 1, or contains an insufficient portion of such a domain (eg 10 amino acids or less) which results in retention of the polypeptide in a membrane bound form.
"An isolated polypeptide consisting essentially of an amino acid sequence" means that the polypeptide may optionally have, in addition to said amino acid sequence, additional material covalently linked to either or both ends of the polypeptide, said additional material between 1 and 10,000 additional covalently linked amino acids to either or both ends of the polypeptide; or between 1 and 1,000 additional amino acids covalently linked to either or both ends of the polypeptide; or between 1 and 100 additional amino acids covalently linked to either or both ends of the polypeptide. The covalent linkage of additional amino acids to either or both ends of the polypeptide according to the invention results in a combined amino acid sequence that is not naturally occurring.
TNFR2 polypeptides for crystallization
TNFR2 polypeptides are polypeptides that comprise at least a portion of a TNFR2 polypeptide (tumor necrosis factor receptor 2), or at least a portion of a variant thereof. The TNFR2 polypeptide includes the TNFR2-Ig fusion polypeptides described below, as well as TNFR2 polypeptides: Fc, etanercept, and variants, monomeric and multimeric forms, modified and conjugated versions thereof.
The TNFR2 polypeptide has also been called TNFRSF1B (member of the tumor necrosis factor receptor 1B superfamily), p75, and CD120b; the full-length amino acid sequence of the TNFR2 polypeptide is shown in SEQ ID NO. No .: 1 (see also the access number of the Swiss-Prot database P20333). Another related but distinct tumor necrosis factor receptor is TNFR1, also called TNFRSF1A and p55 (see also Accession Number of Swiss-Prot Database P19438). TNFR2 and TNFR1 are known to bind to the alpha factor of pleiotropic cytosine tumor necrosis (TNF-alpha or simply "TNF"), which is associated with inflammation. In addition to binding to TNF-alpha, the TNFR2 and TNFR1 polypeptides mediate the binding to homotimer cells of TNF-beta (more commonly termed "limfotoxin-alpha," or LT-alpha), which is another cytosine associated with inflammation and which shares structural similarities with TNF-alpha (for example, see Cosman, Blood Cell Biochem 7: 51-77, 1996). As used herein, "TNFR'O polypeptide" TNFR refers to a polypeptide that is capable of binding to TNF-alpha or LT-alpha; Specific examples of the TNFR polypeptides are TNFR2 and TNFR1. As used herein, "binding", or "ligand binding", or "having ligand binding activity" means binding a ligand such as TNF-alpha or LT-alpha with an affinity (ie, with a constant of K1 inhibition) of at least 1x107 M "1 when in a monomeric form, or in an additional mode, with an affinity of at least 1x109 M" 1 when in a multimeric form such as a dimer or trimer, or with an affinity of at least 8X109 M-1 when in the form of a multimer such as a dimer or trimer. The TNF-alpha binding affinity (inhibition constant) of a TNFR2 polypeptide or a variant thereof can be determined using a binding assay such as that described in Example 6 below (see also Mohier er al., 1993, J). Inimunol 151: 1548-1561 and Peppel et al., 1991, J Exp Med 174: 1483-1489). Similarly, analogous assays can be used to determine the binding affinity of the TNFR2 polypeptide or a variant thereof for LT-alpha or any other potential ligand. In "related to TNFR", as used herein, it refers to polypeptides that are related by means of amino acid sequence similarity or three-dimensional structural similarity to TNFR polypeptides, but which do not necessarily bind to TNF-alpha or LT-alpha. Examples of TNFR-related polypeptides are the CD40 (Swiss-Prot Dasease Accession Number P25942) and OX40 (Swiss-Prot Dasease Accession Number P43489) polypeptides. The three-dimensional structures for TNFR1 and for some TNFR-related polypeptides have been determined; for example, the extracellular domain of p55 TNFR1 has been crystallized and submitted to the Protein Data Bank (PDB, www.rcsb.org/pdb/) under the access number 1EXT, and the p55 TNFR1 polypeptide in association with its LT-alpha ligand has been submitted to PDB as 1TNR. Also, in the source of Structural Protein Classification (SCOP, scop.erkeke.edu) the TNFR and related TNFR polypeptides that define the protein fold similar to the SCOP TNF receptor are structurally related in that they share an extracellular domain that has at least three similar domains rich in disulfide. For example, TNFR2 as shown in SEQ ID. No.:1, it has four such domains, with the majority of the three N-terminal domains sharing a characteristic pattern of conserved cysteine residues that are involved in disulfide bond formation. The four disulfide-rich domains are at amino acids 39 to 76, at amino acids 77 to 118, at amino acids 119 to 162, and at amino acids 163 to 201 of SEC. No.:1. Disulfide bonds are formed between the cysteine residue pairs in the following amino acid assumptions: 40 and 53.54 and 67.57 and 75.78 and 93.96 and 110.100 and 118.120 and 126.134 and 143.137 and 161, and ( in the fourth domain) 164 and 179; the fourth disulfide-binding domain also contains another pair of cysteine residues at amino acids 184 and 200 of the SEC ID. No.:1. TNFR2 polypeptides and variants thereof can be analyzed by three-dimensional similarity with structurally characterized TNFR polypeptides and with TNFR-related polypeptides when using computer programs such as GeneFold (Tripos, Inc., St. Louis, MO; Jaroszewski et al. , 1998, Prot Sci 7: 1431-1440), a spinning protein program that overlays a query protein sequence on structural derivatives within the Protein Data Bank (PDB) (Berman et al., 2000, Nucleic Acids Res 28: 235 -242). To use the GeneFold to evaluate the structure of a TNFR2 polypeptide or a variant of this, the polypeptide sequence is entered into the program, which assigns it a probability rating that is reflected in that it is also doubled over known protein structures ( structures "molds") that are present in the GeneFold database. For qualification, GeneFold relies on the similarity of the primary amino acid sequence, "burial" residue patterns, local interactions, and secondary structure comparisons. The GeneFold program folds (or spins) the amino acid sequence on all template structures in the protein folding database, which includes the resolved structures for several human TNFR polypeptides such as p55 TNFR1 (the "1tnrR" template) and also the TNFR-related polypeptide CD40 (the "1cdf_" template). For each comparison, three different grades are calculated, based on (i) only the sequence; (ii) the sequence plus the local conformation preferences plus the terms "burial"; and (iii) the sequence plus the local conformation preferences plus the terms "burial" plus the secondary structure. In each case, the program determines the optimal alignment, calculates the probability (P value) that this degree of alignment occurs by chance, and reports the inverse of the P value as the rating. These ratings therefore reflect the extent to which the query polypeptide sequence matches the various reference structures such as the TNFR polypeptide structures. When GeneFold is used to compare a TNFR2 polypeptide or a variant of this (the polypeptide of consultation) or other TNFR or TNFR-related polypeptides, the polypeptide of consultation will coincide with 1cdf_, 1tnrR, and another TNFR or TNFR-related template as the highest blow in one of the three rating categories, and / or will match a TNFR mold with any rating of at least 500, or at least 700, or at least 900, or at least 990, or 999.9 (the maximum rating). Another method for the analysis of a TNFR2 polypeptide or a variant thereof is the alignment of the structure of that polypeptide with those of the TNFR or TNFR-related proteins through the well-known process of homology modeling. A useful software program that can be used for modeling homology in the "Modeler" program available Acceírys, a subsidiary of Pharmacopeia Inc. (Princeton, NJ). The TNFR2 polypeptide for crystallization comprises at least a portion of the extracellular region of the TNFR2 polypeptide of SEQ ID. No.:1, or a variant of this. In certain embodiments, the complete extracellular region of the TNFR2 polypeptide is included in the TNFR2. As certain examples, the TNRF2 polypeptide can comprise amino acids 28 to 257, or amino acids 27 to 257, or amino acids 23 to 257 of SEQ ID. No.:1. In additional embodiments, the extracellular region of the TNFR2 polypeptide is truncated to suppress at least one potential N-linked glycosylation site (eg, amino acids 171 and 193 of SEQ ID NO: 1) and / or a region rich in proline (for example amino acids 24 to 36 of SEQ ID No.:1 or amino acids 217 to 261 of SEQ ID No.:1) while leaving intact the three most N-terminal domains having bridges of intramolecular sulfide. For example, in one embodiment, the TNFR2 polypeptide comprises amino acids 39 to 162 of the SEQ ID. No .: I, or amino acids 39 to 179 of the SEC ID. No.:1, or amino acids 39 to 200 of the SEC ID. No.:1, or a variant of any of the above. TNFR2 polypeptides for crystallization according to the present invention include polypeptides with amino acid sequence lengths that are at least 20% (or at least 25%, or at least 30%, or at least 35%, or at least 40%, or at least 50%) of the length of the TNFR2 polypeptide of SEQ ID. No.:1 and have at least 60% sequence identity (or at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97.5% , at least 99%, or at least 99.5%) with that TNFR2 polypeptide. Also included in the present invention are TNFR2 polypeptides and polypeptide fragments that contain a segment comprising at least 80, or at least 90, or at least 100, or at least 110, or at least 120, or at least 130 amino acids contiguous of the SEC ID. No.:1, or a variant of these. Such polypeptides and polypeptide fragments may also contain a segment that shares at least 70% sequence identity (or at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97.5%, at least 99%, or at least 99.5%) with the TNFR2 polypeptide of SEC ID. No.:1. When such variants of TNFR2 polypeptides are made to be crystallized, various considerations can be used to guide those skilled in the art in the development of variants that retain biological activity such as TNF-alpha binding activity. In certain embodiments, it will be desirable to retain at least the N-terminal sulfide binding regions, or at least all of the four disulfide bonding regions described above for the TNFR2 polypeptide of SEQ ID. No.:1. Additionally, portions of the extracellular domain TNFR2 comprising the three N-terminal disulfide regions can be extended to include all of a portion of the fourth disulfide linking region, and in particular modalities in which none of the the fourth disulfull junction region that includes the first cistern pair (at amino acids 164 and 179 of SEQ ID NO: 1) that is included, and / or a region of the fourth disulfide bond region that includes the second pair of cysteine (at amino acids 185 and 200 of SEQ ID No.:1) which is included. Therefore, the variants comprised within the scope of the invention retain the cistern residues involved in the formation of the disulfide bonds of these domains, and also retain the approximate spacing (ie the number of residues of the primary amino acid sequence) between those cysteines. For example, variants that do not insert or delete more than five amino acids between the pairs of cisterns forming the disulfide linkages are within the scope of the invention, as are variants that do not insert or delete more than four amino acids between such cysteines, and the variants that do not insert or delete more than three amino acids between such cysteines, and the variants that do not insert or delete more than two amino acids between such cysteines, and the variants that do not insert or delete more than one amino acid between such cysteines. Other considerations that will guide those skilled in the art to make variants of TNFR2 polypeptides is the nature of the amino acid substitutions that are made; such substitutions may be conservative, which means that the amino acid present in the variant in a certain position has the same chemical and / or size properties as the amino acid in the corresponding position in the undisturbed TNFR2 polypeptide. Table 2 summarizes the groups of amino acids that are considered to have similar properties, such that replacement of any amino acid with another from the same row of Table 2 would be a conservative substitution. In certain embodiments, the TNFR2 polypeptide variants have 20% fewer amino acid substitutions (or 15% or less, or 10% or less, or 7.5% or less, or 5% or less, or 2.5% or less, or 1% or less) along the length of amino acids 39 to 162 of the SEC ID. No.:1, or from amino acids 39 to 179 of the SEC ID. No.:1, or amino acids 39 to 200 of the SEC ID. No.:1. In certain embodiments, TNFR2 polypeptide variants have 20% or less conservative amino acid substitutions (or 15% or less, or 10% or less, or 7.5% or less, or 5% or less, or 2.5% or less, or 1% or less) along the length of amino acids 39 to 162 of the SEC ID. No.:1, or from amino acids 39 to 179 of the SEC ID. No.:1, or amino acids 39 to 200 of the SEC ID. No.:1. In certain embodiments, TNFR2 polypeptides or variants thereof to be crystallized have a TNF-alpha binding activity and / or LT-alpha binding activity. Table 2 Conservative Amino Acid Substitutions
TNFR2 Fusion Proteins In certain embodiments, the TNFR2 polypeptides are used in the crystallization methods of the invention that include TNFR2 polypeptides fused to a portion of an Ig polypeptide (immunoglobulin), or a variant thereof with an optional polypeptide linker between the portion TNFR2 and the Ig portion of the TNFR2-Ig fusion fusion polypeptide. (The optional polypeptide linker may be so short an amino acid in length, when present in a TNFR2 fusion polypeptide). The immunoglobulin (Ig) polypeptides are related by amino acid sequence and also by the three-dimensional structure. The Ig polypeptide superfamily, as defined by SCOP, is a subset of proteins that have the "sandwich immunoglobulin-like beta" fold, which is described as having generally seven strands arranged in two sheets, although some members of double folds have additional strands . The Ig superfamily is subdivided into four protein domain families: the domains of the V set (similar to antibody variable domain); the domains of the C1 set (similar to antibody constant domains); the domains of set C2; and the set I. domains. The TNFR2-Ig fusion polypeptide comprises at least a portion of an Ig polypeptide, for example, at least 10 contiguous amino acids of a constant region of an Ig polypeptide or a polypeptide of at least 14 amino acids in length which shares at least 70% amino acid identity with at least 20 contiguous amino acids of a constant region of an Ig polypeptide. A TNFR2-Ig fusion polypeptide of the present invention can preferably comprise at least one heavy chain constant region and, in certain embodiments, at least one light chain constant region. In certain embodiments, the Ig polypeptide comprises a constant region of an IgG class heavy chain or a fragment and / or variant thereof, and in other embodiments the constant region of other immunoglobulin isotypes can be used to generate such TNFR2-Ig fusions. . For example, a TNFR2-lg fusion polypeptide comprising the constant region of an IgM class heavy chain or a fragment and / or variant thereof can be used to generate a covalent form of the TNFR2-lg fusion polypeptide. The constant region of the immunoglobulin heavy chains, with a specific example of a human lgG1 class heavy chain constant domain by SEQ ID NO. No.:2, comprises a CH1 domain (amino acids 1 to 98 of SEQ ID NO: 2), a joint region (amino acids 99 to 110 of SEQ ID NO: 2), a CH2 domain (amino acids 111 to 223 of SEQ ID NO: 2), and a CH3 domain (amino acids 224 to 330 of SEQ ID NO: 2). The SEC ID. No.:3 provides a specific example of a variant of a heavy chain constant domain class IgG 1, in which two amino acid substitutions have been made (Glu has been replaced by Asp at position 239, and the Met has been replaced by Leu in position 241). Certain embodiments of the invention include TNFR2-lg fusion polypeptides that comprise all of a portion of the extracellular domain of TNFR2 polypeptide (SEQ ID NO: 1) fused to all or a portion of the SEQ ID. No.:2 or SEC ID. No.:3, optionally with a linker polypeptide between the TNFR2 portion and the Ig portion of the TNFR2-Ig fusion fusion polypeptide. In further embodiments of the invention, a heavy chain constant region comprising at least a portion of CH1 is the Ig portion of the TNFR2-Ig fusion fusion polypeptide. Certain embodiments may also include, for example, the C-terminal half of the articulation region to provide a disulfide bridge between heavy chains. In certain embodiments of this invention, the TNFR2 polypeptide is covalently linked, optionally through a polypeptide linker, to the N-terminus of at least a portion of the C ^ region of the heavy chain constant domain to form a TNFR2-Ig fusion polypeptide. In certain additional modalities, at least a portion of the articulation region is attached to the CHT region. As an example, CH1 and CH2 are present in the molecule, and the entire joint region is also present. As another example CH! it is present together with the first seven amino acids of the joint (amino acids 99 to 105 of SEQ ID No.:2 or 3). It will be understood by one skilled in the art that the TNFR2-lg fusion polypeptides of the invention may be, for example, monomeric or dimeric, and that if the TNFR2-lg dimeric fusion polypeptide is desired, it is important to include the joint portion. of the region involved in the disulfide bond formation between the heavy chains (eg, a portion of amino acids 99 to 110 of SEQ ID No.:2 or 3 which includes amino acids 109 of SEQ ID No. .:2 or 3). In further embodiments of the invention, the TNFR2-lg fusion polypeptide may comprise portions of the CH3 domain that does not include the C-terminal licheus residue (amino acid 330 of SEQ ID NO: 2 or 3), as or by reason that this residue has been observed to be removed in post-translational processing of Ig heavy chain polypeptides.
Fc domains
As used herein an Fc domain may contain one or all of the heavy chain CH1, joint, CH2, and CH3 domains described above, or fragments or variants thereof, and may be monomeric, dimeric, or multimeric determined by the constituents of the TNFR2-lg fusion comprising the Fc domain. Certain polypeptides specifically contemplated by crystallization according to the invention include TNFR2-lg fusion polypeptides comprising at least a portion of an Fc domain. A preferred preferred TNFR2 polypeptide for treating diseases in humans and other mammals is TNFR2: Fc, which is used herein to refer to all or a portion of an extracellular domain of a TNFR2 polypeptide or a variant thereof, fused to the Fc portion of an immunoglobulin polypeptide, optionally with a polypeptide linker between the TNFR2 portion and the Fc portion of the TNFR2: Fc polypeptide.
Other multimerizing domains
The multimers of the invention include the TNFR2 polypeptides for crystallization, wherein the TNFR2 polypeptides are in dimeric, trimeric, decameric, or other multimeric forms. Another method for preparing the multimers of the invention involves the use of a leucine zipper. The leucine zipper domains are peptides that promote the oligomerization of the polypeptides in which they are found. Leucine zippers were originally identified in several DNA binding polypeptides (Landschulz et al., Science 240: 1759, 1988), and have been found in a variety of different polypeptides. Among the known leucine zippers are the naturally occurring peptides and derivatives thereof which are dimerized or trimerized. The domain between the known leucine zippers are the naturally occurring peptides and the derivatives thereof that are dimerized or trimerized. The zipper domain (also referred to herein as a multimerizing or multimeric formation domain) comprises a repeating heptad repeat, often with four or five leucine residues interspersed with other amino acids distributed at intervals. The use of leucine zippers and multimeric preparations using leucine zippers are well known in the art. Other multimerization domains include the trimerization domain found in the lung surfactant protein (Kovacs et al., 2002, J Biomol NMR 24: 89-102) and other such domains known in the art.
Etanercept
In one embodiment, the TNFR2 polypeptide that is crystallized is "etanercept", which is a dimero of two polypeptides each consisting of 235 amino acids derived from the extracellular portion of the TNFR2 polypeptide, fused to a 232 amino acid portion of human IgG1. The amino acid sequence of the monomeric component of etanercept is shown as SEC ID. No.:4 The dimeric form of this molecule, two of these fusion polypeptides (or "monomers") are held together by three disulfide linkages that are formed between the immunoglobulin portions of the two monomers. The etanercept dimer thus consists of 934 amino acids, and they have an apparent molecular weight of approximately 150 kilodaltons (Physicians Desk Reference, 2002, Medical Economics Company Inc., pp. 1752-1755). Etanercept is usually sold under the trade name ENBREL® (Amgen Inc., Thousand Oaks, CA).
Giicosilation and Conjugates
The invention includes the TNFR2 polypeptides of the invention with and without associated native pattern glycosylation. Polypeptides expressed in yeast or mammalian expression systems (e.g., COS-1 or CHO cells) may be similar to or significantly different from a native human polypeptide in molecular weight and glycosylation pattern, depending on the choice of expression system . The expression of the polypeptides of the invention in bacterial expression systems, such as E. coli, do not supply glycosylated molecules. In addition, a given preparation can differentially include multiple glycosylated species of the polypeptide. The glycosylated groups can be removed by conventional methods, in particular those using glycopeptidase. In general, the glycosylated polypeptides of the invention can be incubated with a molar excess of glycopeptidase (Boehringer Mannheim). The TNFR2 polypeptide for crystallization and use in the therapies described herein can be conjugated with polyethylene glycol (pegylated) to prolong its serum half-life or to improve protein delivery. As an example of a pegylated TNFR polypeptide derived from p55 TNFR is the soluble p55 TNFR conjugated polyethylene glycol (PEG-sTNFR type I), which contains the extracellular domain TNFR p55; TNFR2 polypeptides and fragments thereof can be conjugated with polyethylene glycol in a similar manner. Reagents and methods for pegylation of polypeptides are described, for example, in WO 92/16221; WO 99/102330; and U.S. Patent No. 6,420,339; 6,433,158; 6,441,136; 6,451,986; 6,548,644; and 6,552,170; all of which are incorporated here as a reference. The invention also comprises crystalline forms of the TNFR2 polypeptides conjugated with a cytotoxic or luminescent substance. Such substances include: maytansino derivatives (such as DM1); enterotoxins (such as Staphylococcal enterotoxins); other proteins and compounds (such as Ricin-A, Pseudomonas toxin, Diphtheria toxin, daunorubicin, doxorubicin, methotrexate, and Mitomycin C); isotopes of iodine (such as iodine-125); isotopes of technetium (such as Tc-99m); other isotopes (212Bi, 131l, 186Re, and 90Y); cyanine fluorochromes (such as Cy5.5.18); and ribosome inactivating polypeptides (such as bouganin, gelonin, or saporin-S6).
Production and Purification of Polypeptides for Crystallization
The TNFR2 polypeptide can be produced from living host cells expressing the polypeptide, such as host cells that have been genetically engineered to produce the polypeptide. Methods of cells genetically engineered to produce polypeptides are well known in the art. See, for example, Ausubel et al., Eds. (1990), Current Protocols in Molecular Biology (Wiley, New York). Such methods include introducing nucleic acid encoding and allowing expression of the polypeptide in living host cells. These host cells can be bacterial cells, fungal cells, insect cells, or animal cells growing in culture. Bacterial host cells include, but are not limited to, Escherichia coli cells. Examples of suitable E. coli strains include: HB101, DHSA, GM2929, JM109, KW251, NM538, NM539, and any strain of E. that fails to clivar foreign DNA. The fungal host cells that can be used include, but are not limited to, Saccharomyces cerevisiae, Pichia pastors, and Aspergillus cells. A few examples of animal cell lines that can be used are CHO, VERO, BHK, HeLa, Cos, MDCK, 293, 3T3, and WI38. New animal cell lines can be established using methods well known to those skilled in the art (e.g., by transformation, viral infection, and / or selection). Optionally, the polypeptide can be secreted by host cells in the medium. The purification of the expressed TNFR2 polypeptide can be developed by any standard method. When the TNFR2 polypeptide is produced intracellularly, the particulate debris is removed, for example, by centrifugation or ultrafiltration. When the polypeptide is secreted into the medium, the supernatants of such expression systems can be first concentrated using filters of standard polypeptide concentration. Protease inhibitors may also be added to inhibit proteolysis and antibiotics may be included to prevent the growth of microorganisms. TNFR2 polypeptides may be produced in the presence of chaperone or accessory proteins in order to obtain a desired polypeptide conformation, or may be subjected to conditions such as oxidation and / or reduction conditions after production in order to induce redoubling or changes in the polypeptide conformation (see, for example, WO 02/068455). The TNFR2 polypeptide can be purified using, for example, hydroxyapatite chromatography, gel electrophoresis, dialysis, and affinity chromatography, and any combination of known or as yet undiscovered purification techniques. For example, protein A can be used to purify TNFR2-Ig polypeptides that are based on human 1, 2, or 4 gamut heavy chains (Lindmark et al., 1983, J. Immunol, Meth. 13), where the Ig portion of the TNFR2-lg fusion polypeptide contains the portion of the constant domain involved in protein A binding. The G protein is recommended for all mouse isotypes and for the human gamma 3 (Guss et al. ., 1986, EMBO J. 5: 1567-1575). Other techniques can be used for the purification of the TNFR2 polypeptide, depending on the need, including but not limited to fractionation on an ion exchange column, precipitation with ethanol or other alcohols, reverse FACE HPLC, FPLC, chromatography on silica, chromatography on heparin SEPHAROSET ™, chromatography on an anion or cation exchange resin (such as a piliaspartic acid column), hydrophobic interaction chromatography, chromatofocusing, SDS-PAGE, and ammonium sulfate precipitation can also be used depending of necessity.
Production of Crystals, Crystal Formulations, and Compositions:
Polypeptide crystals grow by controlled crystallization of polypeptides from aqueous solutions or other solutions containing organic solvents or additives. The solution conditions that can be controlled include, for example, the evaporation rate of the solvent, organic solvents or additives, the presence of suitable co-solutes and buffers, pH, and temperature. A comprehensive review of several factors affecting the crystallization of proteins has been published by McPherson, 1985, Methods Enzymol 114: 112-120. In addition, McPherson and Gilliland, 1988, J Crystal Growtlz, 90: 51-59 have compiled comprehensive lists of polypeptides that have been crystallized, as well as the conditions under which they were crystallized. A compendium of crystals and recipes of crystallization, as well as a deposit of protein structure coordinates resolved, is maintained in the Protein Data Bank at the Brookhaven National Laboratory (www.rcsb.org/pdb/; Bernstein et al., 1977, J Mol Biol 112: 535-542). These references can be used to determine the conditions necessary for the crystallization of a polypeptide, as a prelude to the formation of the appropriate polypeptide crystals and can guide the crystallization strategy for another polypeptide. It should be noted, however, that the conditions reported in most of the aforementioned references have been optimized to produce, in most cases, a few large crystals with diffraction quality. Accordingly, it will be appreciated by those skilled in the art that some degree of adjustment of these conditions to provide a high production process for large scale production of the polypeptide crystals may be necessary. In general, crystals are produced by combining the polypeptide to be crystallized with an appropriate aqueous solvent or an aqueous solvent containing appropriate crystallization agents, such as salts or solvents or organic additives. The solvent is combined with the polypeptide and can be subjected to agitation at a temperature determined experimentally to be suitable for the induction of crystallization and acceptable for the maintenance of the activity and stability of the polypeptide. The solvent may optionally include co-solutes, such as divalent cations, co-factors, or chaotropes, as well as buffer species to control pH. "Co-solute means" for crystallization include compounds that can deliver a co-solute to facilitate the crystallization of a polypeptide. Examples of co-solute media include ammonium acetate, ammonium chloride, ammonium fluoride, ammonium formate, ammonium nitrate, ammonium phosphate, ammonium sulfate, cadmium chloride, cadmium sulfate, calcium acetate, cadmium, cesium chloride, cobalt chloride, CH3 (CH2) i5N (CH3) 3 + Br "(C ), diammonium citrate, diammonium hydrogen phosphate, diammonium phosphate, diammonium tartrate, dipotassium phosphate, disodium phosphate, disodium tartrate, DL-malic acid, ferric chloride, L-proline, lithium acetate, lithium chloride, lithium nitrate, lithium sulfate, magnesium acetate, magnesium chloride, magnesium formate, magnesium nitrate, sulphate magnesium nickel chloride, potassium acetate, potassium bromide, potassium chloride, potassium citrate, potassium fluoride, potassium format, potassium nitrate, potassium phosphate, potassium solid tartrate, potassium sulfate, potassium thiocyanate, potassium acetate, sodium bromide, chloride sodium, sodium citrate, sodium fluoride, sodium format, sodium malonate, sodium nitrate, sodium phosphate, sodium sulfate, sodium thiocyanate, succinic acid, tacsimate, triammonium citrate, trilithium citrate, N-oxide trimethylamine, tripotassium citrate, trisodium citrate, zinc acetate, zinc sulfate, and other compounds that function to supply co-solutes. "Crystallization buffer" includes compounds that maintain the pH of a solution in a desired range to facilitate crystallization of a polypeptide. Examples of crystallization buffer media include acid ACES (N- (2-acetamido) -2-aminoethanesulfonic acid), BES (N, N-bis (2-hydroxyethyl) -2-aminoethanesulfonic acid), Bicine (N, N-Bis (2-hydroxyethyl) glycine), BIS-TRIS (2,2-bis- (hydroxymethyl) - 2 , 2 ', 2"-nitrilotrietanol), boric acid, (3- [cyclohexylamino] -1-propane-sulfonic acid) CAPS, (HEPPS, 4- (2-Hydroxyethyl) piperazine-l-propanesulfonic acid) EPPS, Gly- Gly
(NH2CH2CONHCH2COOH, glycyl-glycine), (4- (2-hydroxyethyl) piperazine-1-ethanesulfonic acid) HEPES, imidazole, (2-morpholinoethanesulfonic acid) MES, (3- (N-morpholino) -propanesulfonic acid) MOPS , (piperazine-1,4-bis (2-ethanesulfonic acid) PIPES), sodium acetate, sodium bicarbonate, monobasic sodium phosphate (higrogen sodium phosphate), (N- [tris- (hydroxymethyl) methyl] - 3-aminopropanesulfonic) TAPS,
(N- [tris (hydroxymethyl) methyl] -3-amino-2-hydroxypropanesulfonic acid) TAPSO, (N- [tris (hydroxymethyl) methyl] -2-aminoethane-sulfonic acid) TES, Tricine (N- [tris (hydroxymethyl ) methyl] glycine), Tris-HCl, TRIZMA (2-amino-2- (hydroxymethyl) -l, 3-propanediol), and other compounds that function to maintain a solution at a pH close to that specified.
The need for co-solutes, shock absorbers, etc. and their concentrations are determined experimentally to facilitate crystallization. Some examples of suitable crystallization conditions for a polypeptide are described in Examples 1, 2, and 3 below. In an industrial-scale process, the controlled precipitation leading to crystallization can best be carried out by the simple combination of polypeptide, precipitant, co-solutes and, optionally, buffers in a batch process. As another potion, the polypeptides can be crystallized by using polypeptide precipitates as the starting material ("seed"). In this case, the polypeptide precipitates are added to a crystallization solution and incubated until the crystal is formed. Crystallization methods of alternative laboratories, such as dialysis or steam diffusion, can also be adopted, McPherson, supra and Gilliland, supra, include a comprehensive list of suitable conditions in their reviews of the crystallization literature. Occasionally, in cases in which the crystallized polypeptide is going to be cross-linked, incompatibly between a targeted cross-linking agent and the crystallization medium may require exchanging the crystals in a more suitable solvent system. According to one embodiment of this invention, the polypeptide crystals, the crystal formulations and the compositions are prepared by the following process: first, the polypeptide is crystallized. Then, the excipients or ingredients as described herein are added directly to the mother liquor. Alternatively, the crystals are suspended in an excipient solution or other formulation ingredients, after the mother liquor is removed, for a minimum of 1 hour to a maximum of 24 hours. The concentration of excipients is typically between about 0.01 to 30% W / W, which corresponds to a polypeptide crystal concentration of 99.99 to 70% W / W, respectively. In one embodiment, the excipient concentration is between about 0.1 to 10%, which corresponds to the crystal concentration of 99.9 to 90% W / W, respectively. The mother liquor can be removed from the glass suspension either by filtration or by centrifugation. Subsequently, the crystals are optionally washed with solutions of 50 to 100% one or more organic solvents or additives such as, for example, ethanol, methanol, isopropanol, or ethyl acetate, or at room temperature or at temperatures between 20 ° C to 25 ° C. The crystals are dried by passing the stream of nitrogen, air, or inert gas over the crystals. Alternatively, the crystals are dried by air drying or by lyophilization or by vacuum drying. Drying is carried out for a minimum of 1 hour to a maximum of 72 hours after washing, until the moisture content of the product ends below 10% by weight, more preferably below 5%. Finally, the micronization of the crystals can be developed if necessary. The drying of the polypeptide crystals is the removal of water, the organic solvent or additive, or the liquid polymer by means including drying with N2, air, or inert gases; drying with vacuum oven; lyophilization; washing with a volatile organic solvent or additive followed by evaporation of the solvent; or evaporation in a smoke hood. Typically, drying is achieved when the crystals become a free-flowing powder. The drying can be carried out by passing a stream of gas over wet crystals. The gas can be selected from the group consisting of: nitrogen, argon, helium, carbon dioxide, air or a combination thereof. The polypeptide crystals of the invention can be further processed to achieve a desired particle size distribution upon micronization in a suitable mill, such as a jet mill, and the components of the particle or powder formulation can be mixed before or after of micronization. The diameter of the particles achieved can be in the range of 0.1 to 100 micrometers, or in the range of 0.2 to 10 micrometers, or in the range of 10 to 50 micrometers, or in the range of 0.5 to 2 micrometers. For the formulations to be administered by inhalation in one embodiment the particles formed from the polypeptide crystals are in the range of 0.5 to 1 microns. In accordance with one embodiment of this invention, when preparing protein crystals, protein formulations or crystal compositions, enhancers, such as surfactants, are not added during crystallization. The excipients or ingredients are added to the mother liquor after crystallization, at a concentration of between about 1-10% W / W, alternately at a concentration of 0.1-25% W / W, alternatively at a concentration of between about 0.1-50. % P / P. These concentrations correspond to crystal concentrations of 99-90% P / P, 99.9-75% P / P and 99.9-50% P / P, respectively. The excipient or ingredient is incubated with the crystals in the mother liquor for approximately 0.1-3 hours, alternatively the incubation is carried out for 0.1-12 hours, alternatively the incubation is carried out for 0.1-24 hours. In another embodiment of this invention, the ingredient or excipient is dissolved in a solution different from the mother liquor, and the protein crystals are removed from the mother liquor and suspended in the excipient or solution of ingredients. The ingredient or excipient concentrations and incubation times are the same as those described above.
Polypeptide crystals
As used herein, "crystal" or "crystalline" refers to a solid state form of matter, which is distinct from a second form - the amorphous solid state. The crystals display characteristic features that include a network structure, characteristic shapes, and optical properties such as refractive index and birefringence. A crystal consists of atoms arranged in a pattern that is periodically repeated in three dimensions (C. S. Barrett, Structure of Metals, 2nd ed., McGraw-Hill, New York, 1952, p.1). In contrast, the amorphous material is a solid, non-crystalline form of matter, sometimes referred to as an amorphous precipitate. Such precipitates do not have a network molecular structure characteristic of the crystalline solid state and do not display birefringence or other typical spectroscopic characteristics of the crystalline forms of matter. Polypeptide crystals are polypeptide molecules arranged in a crystal lattice. The polypeptide crystals contain an interaction pattern of specific polypeptides-polypeptides that are periodically repeated in three dimensions. The polypeptide crystals of this invention should be distinguished from amorphous solid forms or polypeptide precipitates, such as those obtained by lyophilization or by lyophilizing a polypeptide solution. In polypeptide crystals, the molecules of the polypeptide form asymmetric units that are arranged together to form symmetric units. The geometric structure of the symmetric units of the polypeptide crystals can be cubic, hexagonal, monoclinic, orthorhombic, tetragonal, triclinic, or trigonal. The total structure of the crystals as a whole may be in the form of bipyramids, cubes, needles, plates, prisms, rhomboids, bars or spheres, or combinations of these. Crystals that are of the "cubic" structural class can more specifically have octadecahedral or dodecahedron crystalline forms. The diameter of the crystals is defined as the diameter of Martin. This is measured as the length of the line, parallel to the ocular scale, which divides the randomly oriented crystals into two equal projected areas. The crystals in the forms such as needles or bars will also have a maximum dimension which is referred to herein as the length of the crystal.
Formulations for Therapeutic Administration
As used herein, a "composition" is understood to mean a mixture comprising at least two components. In particular, the invention provides compositions comprising a crystalline TNFR2 polypeptide, or prepared using a crystalline TNFR2 polypeptide. In one embodiment of the invention, the composition or formulation comprising or prepared using a crystalline TNFR2 polypeptide is prepared in such a way that it is suitable for injection and / or administration to a patient in need thereof. The compositions when administered for pharmaceutical purposes to patients are substantially sterile and do not contain any agents that are unduly toxic or infectious to the recipient.
In one embodiment of the invention, the crystalline TNFR2 polypeptides such as etanercept are administered in the form of a physiologically acceptable composition (also referred to herein as a pharmaceutical composition or as a pharmaceutical formulation) comprising a polypeptide
TNFR2 which is formulated with one or more of the following: physiologically acceptable carriers, excipients, or diluents. Such carriers, excipients, or diluents are non-toxic to the receptors in doses and concentrations employed. Ordinarily, the preparation of such compositions involves combining the crystalline TNFR2 polypeptide with one or more of the following: buffers, antioxidants such as ascorbic acid, low molecular weight polypeptides (such as those having less than 10 amino acids) proteins, amino acids, carbohydrates such as glucose, sucrose dextrins, chelating agents such as DTA, glutathione or other stabilizers and excipients. In liquid formulations, neutral buffered saline or saline mixed with conespecific serum albumin are examples of suitable diluents according to appropriate industry standards, condoms, such as benzyl alcohol, can also be added. Additional examples of components that can be employed in pharmaceutical formulations are presented in Remington's Pharmaceutical Sciences, 16th Ed, Mack Publishing Company, Easton, PA, 1980, and in the Handbook of Pharmaceutical Excipients, published jointly with the American Pharmaceutical Association and the Pharmaceutical Society From great britain. In one embodiment, it is contemplated that the formulation of the invention is prepared in bulk formulation and as such, the components of the pharmaceutical composition are adjusted in such a way that they are greater than would be required for administration, and are properly diluted before of administration. The polypeptide crystals of the present invention can be formulated as a solid or powder crystalline formulation in suitable forms for storage and handling, and in forms suitable for inhalation or pulmonary administration, for example in the form of powders for the precipitation of formulations of aerosol. In a further embodiment, the polypeptide crystals can be formulated in a liquid solution of such crystals, or in a suspension of such crystals. In another embodiment, the polypeptide crystals are used to prepare a liquid formulation, such as an aqueous formulation, for therapeutic administration.
Solid crystalline formulations
Solid crystal formulations are ideally suited for pulmonary administration, which is particularly useful for biological macromolecules that are difficult to deliver by other routes of administration (see, for example, PCT patent applications WO 96/32152, WO 95/24183 and WO 97/41833). Solid formulations of polypeptide crystals include crystals that have been substantially isolated from the liquid solution or dried and are present as free crystals or as particles in, for example, powder form. In the present context the expression "powder" refers to a connection of essentially dry particles, ie, the moisture content is below 10% by weight, or below 6% by weight, or below 4% in weigh. In one embodiment the invention provides a method for aerosolizing a dose of crystalline TNFR2 polypeptide comprising delivering the crystalline TNFR2 polypeptide as a dry powder, dispersing a quantity of dry powder in a gas stream and forming an aerosol, and capturing the aerosol in a camera for the subsequent inhalation. The polypeptide crystals or powders may optionally be combined with carriers and surfactants. Suitable carrier agents include 1) carbohydrates, for example monosaccharides such as fructose, galactose, glucose, sorbose, and the like; 2) disaccharides, such as lactose, trehalose and the like; 3) polysaccharides, such as raffinose, maltodextrins, dextrans, and the like; 4) alditols, such as mannitol, xylitol, and the like; 5) inorganic salts, such as sodium chloride, and the like; and 6) organic salts, such as sodium citrate, sodium ascorbate, and the like. In certain embodiments, the carrier selected from the group consisting of trehalose, raffinose, mannitol, sorbitol, xylitol, inositol, sucrose, sodium chloride, and sodium citrate. The surfactants can be selected from a group consisting of salts of fatty acids, bile salts and phospholipids. The fatty acid salts include salts of C 1 -C 14 fatty acids, such as, sodium caprate, sodium laurate, and sodium myristate. The salts of bile include salts of use of oxicolate, taurocholate, glycocholate, and taurodihydrofusidate. In one embodiment, the surfactant is a taurocholate salt such as sodium taurocholate. Phospholipids that can be used as surfactants include lysophosphatidylcholine. The molar ratio of the crystalline polypeptide to surfactant in a powder formulation of the present invention is for example 9: 1 to 1: 9, or between 5: 1 to 1: 5, or between 3: 1 to 1: 3.
Crystals in Solution or Suspension
In one embodiment, this invention provides a method for making polypeptide crystals suitable for storage and suspensions comprising replacing the crystallization buffer (the mother liquor) with a non-aqueous solvent. In yet another embodiment, the crystalline suspension can be produced solid by spinning the first solvent and washing the remaining crystalline solid using a second organic solvent or additive to remove the water, followed by evaporation of the non-aqueous solvent. The non-aqueous suspension of crystalline therapeutic proteins is used especially for subcutaneous delivery. In one such embodiment, the polypeptide crystals of the invention are combined with liquid organic additives in order to stabilize the polypeptide crystals. Such a mixture can be characterized as an organic aqueous mixture comprising n% organic additive, where n is between 1 and 99 and m% aqueous solution, in m is 100-n. Examples of organic additives include phenolic compounds, such as m-cresol or phenol or a mixture thereof, and acetone, methyl alcohol, methyl isobutyl ketone, chloroform, 1-propanol, isopropanol, 2-propanol, acetonitrile, 1-butanol, -butanol, ethyl alcohol, cyclohexane, dioxane, ethyl acetate, dimethylformamide, dichloroethane, hexane, isooctane, methylene chloride, tert-butyl alcohol, toluene, carbon tetrachloride, or combinations thereof.
Liquid Formulations
One embodiment of the present invention is directed to an aqueous formulation that allows stable long-term storage of a pharmaceutical composition wherein a crystalline TNFR2 polypeptide is the active ingredient used in the preparation of the pharmaceutical composition. This formulation is useful, in part, because it is more convenient to use it for the patient, because this formulation does not require any extra step such as rehydration. As used herein, a liquid solution or formulation is intended to mean a liquid preparation containing one or more chemicals dissolved in a suitable solvent or mixture of mutually visible solvent. The reconstitution of the dissolution of the polypeptide crystals of the crystal formulations of the compositions in an appropriate buffer or pharmaceutical formulation.
Components of Pharmaceutical Formulations
The present pharmaceutical composition is prepared by combining, in addition to a crystalline TNFR2 polypeptide as described above, one or more of the following types of ingredients or excipients listed in the paragraphs below, many or all of which are available from commercial suppliers. It will be understood by one skilled in the art that by combining the various components when being included in the composition can be done in an appropriate order, namely, the shock absorber can be added first, in the middle or at the end and the tone modifier can be added first, in the middle or at the end. It should also be understood by one skilled in the art that some of these chemicals may be incompatible in certain combinations, and accordingly, they are easily substituted with different chemicals that have similar properties but are compatible in the relevant mixture. There is knowledge in the art regarding the suitability of various combinations of excipients and other ingredients or materials present in, for example, the containers used to store the pharmaceutical composition and / or the devices used for therapeutic administration (see, for example, Akers, 2002, JPharm Sci 91: 2283-2300).
Acidifying agents ("acidifying media"): acetic acid, glacial acetic acid, citric acid, fumaric acid, hydrochloric acid, dilute hydrochloric acid, malic acid, nitric acid, phosphoric acid, diluted phosphoric acid, sulfuric acid, tartaric acid, and others suitable acids.
Active ingredients: additional active ingredients can also be included in the composition currently described, for example, to reduce the discomfort of the injection site. Such active ingredients include, but are not limited to, non-steroidal anti-inflammatory drugs such as, for example, tromethamine, in an appropriate dose.
Aerosol propellants ("propellant media"): butane, dichlorodifluoromethane, dichloro-tetrafluoroethane, isobutane, propane, tri-chloromonof luoro methane.
Aggregation inhibitors ("means of inhibition"): reduce the tendency of the polypeptides to associate in ternary or quaternary complexes in appropriate or undesired. Suitable aggregation inhibitors include the amino acids L-arginine and / or L-cysteine, which can act to reduce the aggregation of polypeptides containing an Fc domain for long periods, for example, two years or more. The concentration of aggregation inhibitor of the formulation can be between about 1 mM to 1M, or about 10mM to about 200mM, or about 10mM to about 100mM, to about 15mM to about 75mM, to about 25mM.
Denaturing alcohol ("denaturing media"): denatonium benzoate, methyl isobutyl ketone, sucrose octacetate.
Alkalising agents ("alkalizing media"): strong ammonium solution, ammonium carbonate, diethanolamine, diisopropanolamine, potassium hydroxide, sodium bicarbonate, sodium borate, sodium carbonate, sodium hydroxide, trolamine.
Antitorta agents ("antitorta media"): calcium silicate, magnesium silicate, colloidal silicon dioxide, talc.
Anti-foaming agents ("antifoaming agents"): dimethicone, simethicone.
Antioxidants ("antioxidant media") can be included in the formulations of the present invention. Antioxidants contemplated for use in the preparation of the formulations include amino acids such as glycine and licina, chelating agents such as EDTA and DTPA, and free radical absorbers such as sorbitol and marital. Additional antioxidants include ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorous acid, monothio-glycerol, propyl gallate, sodium bisulfite, sodium formaldehyde sulfoxylate, sodium metabisulfite, sodium thiosulfate, sulfur dioxide, tocopherol, and excipient of tocopherols. Also contemplated for use in the inhibition of oxidation is nitrogen or carbon dioxide superimposed. The nitrogen or carbon dioxide superimposed can be introduced into the upper space of a prefilled bottle or syringe during the filling process.
Buffering agents ("buffering formulation") maintain the pH of the pharmaceutical formulation in a desired range. With the pH of the pharmaceutical composition being established at or near physiological levels, patient comfort is maximized after administration. In particular, in certain embodiments the pH of a pharmaceutical composition is given within the pH range of about 4.0 to 8.4, at a pH range of about 5.0 to 8.0, at a pH range of about 5.8 to 7.0 at a pH range. from approximately 5.8 to 7.4, or approximately 6.2 to 7.0. It should be understood that the pH can be adjusted as necessary to maximize the stability and solubility of the polypeptide in a particular formulation and as such, a pH outside the physiological ranges, still tolerable by the patient, is within the scope of the invention. . Various buffers suitable for use in the pharmaceutical composition of the composition of the invention include histidine, alkaline salts (sodium or potassium phosphate or its hydrogen or dihydrogen salts), sodium citrate / citric acid, sodium acetate / acetic acid, citrate potassium, maleic acid, ammonium citrate, ammonium acetate, tris- (hydroxymethyl) -aminomethane (tris), various forms of acetate and diethanolamine, ammonium carbonate, ammonium phosphate, boric acid, lactic acid, phosphoric acid, metaphosphate of potassium, potassium monobasic phosphate, sodium lactate solution, and any other buffering agent with pharmaceutically acceptable pH known in the art. Agents for pH use such as hydrochloric acid, sodium hydroxide, or a salt thereof, may also be included in order to obtain the desired pH. A suitable buffer is sodium phosphate for maintaining the pharmaceutical compositions at or near pH 6.2. In another example, acetate is a buffer more efficient at pH 5 than pH 6 so that less acetate can be used in a solution at pH 5 than at pH 6. The concentration of the buffer in the formulation can be between about 1 mM to about 1M, or about 10mM to about 200mM.
Guelantes agents ("guelantes means", also called sequestering agents): sodium edetate, ethylenediaminetetraacetic acid and salts, edetic acid.
Coating agents ("coating means"): sodium carboxymethylcellulose, cellulose acetate, cellulose acetate ethacrylate, ethylcellulose, gelatin, pharmaceutical enamel, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose, ethacrylic acid, methacrylic acid copolymer, ethylcellulose, polyethylene glycol, polyvinylacetate, phthalate, shellac, sucrose, titanium dioxide, carnauba wax, microcrystalline wax, zein.
Colors ("coloring means"): caramel; erythrosine (FD &C Red No. 3); FD &C No. 40; FD &C Yellow No. 5; FD &C Yellow No. 6; FD &C Blue No. 1; red, yellow, black, blue or mixtures; ferric oxide.
Complexing agents ("complexing means"): ethylenediaminetetraacetic acid and salts (EDTA), acetic acid, ethnolmidogenistic acid, oxyquinoline sulfate.
Dissecting agents ("desiccant media"): calcium chloride, calcium sulfate, silicon dioxide.
Filtration aids ("filtration media"): Cellulose powder, purified siliceous earth.
Flavors and perfumes ("flavoring means"): anethole, anise oil, benzaldehyde, cinnamon oil, cocoa, ethylvaniline, menthol, methyl salicylate, monosodium glutamate, orange flower oil, orange oil, pepper, pepper oil, pepper spirit , rose oil, strong rose water, thymol, tincture of tolu balsam, vanilla, vanilla tincture, vanillin.
Moisturizers ("moisture retention means"): glycerin, hexylene glycol, propylene glycol, sorbitol.
Ointment bases ("ointment means"): Lanolin, anhydrous lanolin, hydrophilic ointment, white ointment, yellow ointment, polyethylene glycol ointment, petrolatum, hydrophilic petrolatum, white petrolatum, rose water ointment, squalene.
Plasticizers ("plasticizing media"): castor oil, diacetylated monoglycerides, diethylphthalate, glycerin, mono- and diacetylated monoglycerides, polyethylene glycol, propylene glycol, triacetin, triethyl citrate.
Membranes of polymer: cellulose acetate.
Polymer carriers ("carrier media") are polymers used for the encapsulation of polypeptide crystals for delivery of the polypeptide, which includes the biological delivery, such polymers include biocompatible and biodegradable polymers. The polymeric carrier can be a simple polymer type or can be a composite of a mixture of polymer types. Polymers useful as the polymer carrier include, for example, poly (acrylic acid), poly (cyanoacrylate), poly (amino acid), poly (anhydride), poly (depsipeptide), poly (esters), such as poly (lactic acid) or PLA poly (lactic acid-co-glycolic acid) or PLGA, poly (B-hydroxybutyrate), poly (caprolactone), and poly (dioxanone); poly (ethylene glycol), poly (hydroxypropyl) methacrylamide, poly [(organo) phosphazene), poly (orthoesters), poly (vinylalcohol), poly (vinylpyrrolidoin), maleic anhydride-alkyl vinyl ether copolymers, pluronic polyols, albumin, polypeptides natural and synthetic, alginate, cellulose and cellulose derivatives, collagen, fibrin, gelatin, mieluronic acid, oligosaccharides, glycolino glycans, sulfated polysaccharides or any conventional material that will encapsulate the polypeptide crystals.
Preservatives (or "preservative media"), such as antimicrobial preservatives, contemplated for use in the formulations of the present invention, such as multidose formulations, include benzalkonium chloride, benzalkonium chloride solution, benzyltonium chloride, benzoic acid, benzyl alcohol, butylparaben, cetylpyrimidine chloride, chlorobutanol, chlorocresol, créeselo, dehydroacetic acid, ethylparaben, methylparaben, methylparaben, sodium methylparaben, phenol, phenylethyl alcohol, phenylmercuric acetate, phenylmercuric nitrate, potassium benzoate, potassium solvate, propylparaben, propylparaben sodium, sodium benzoate , sodium dihydroacetate, sodium propionate, sorbic acid, thimerosal, and thymol. The amount of condom included will be in the range of 0% to 2% p / v) or approximately 1% (p / v).
Solubilizing and stabilizing agents ("solubilizing means" or "stabilizing media", also referred to as emulsifying agents, co-solutes, or co-solvents) that increase the solubility of the peptide and / or stabilize the polypeptide while it is in solution (or in dry or frozen form) can also be added to a pharmaceutical composition. Examples of solubilizing and stabilizing agents include but are not limited to sugars / polyols such as: sucrose, lactose, glycerol, silitol, sorbitol, mannitol, maltose, inositol, trehalose, glucose; polymers such as: serum albumin (bovine serum albumin (BSA), human SA (HSA), or recombinant HA), dextran, PVA, hydroxypropylmethylcellulose (HPMC), polyethyleneimine, gelatin, polyvinylpyrrolidone, (PVP), hydroxyethylcellulose (HEC); non-aqueous solvents such as: polyhydric alcohols (for example PEG, ethylene glycol and glycerol), methylsulfoxide (DMSO), and dimethylformamide (DMF); amino acids such as: proline, L-methionine, L-serine, glutamic acid sodium, alanite, glycine, lysine hydrochloride, sarcosine, and gamma-aminobutyric acid, surfactants such as: Tween-80, Tween-20, SDS, polysorbate , polyoxyethylene copolymer; and miscellaneous stabilizing excipients such as: potassium phosphate, sodium acetate, ammonium sulfate, magnesium sulfate, sodium sulfate, trimethylamine N-oxide, betaine, metal ions (eg zinc, copper, calcium, manganese and magnesium) , CHAPS, monolaurate, 2-O-beta-manglicerate; or any of the following: acacia, cholesterol, diethanolamine (adjunct), glycerol monostearate, lanolin alcohols, lecithin, mono- and diglycerides, monoethanolamine (adjunct), oleic acid (adjunct), oleyl alcohol (stabilizer), poloxamer , polyoxyethylene 50 stearate, castor oxyoxyl agent 35, polyoxyl 40 hydrogenated castor oil, polyoxyl 10 oleyl ether, polyoxyol 20 ketostearyl ether, polyoxyl 40 stearate, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, propylene glycol diacetate, polypropylene glycol monostearate , sodium lauryl sulfate, sodium stearate, sorbitan monolaurate, sorbitan monooateate, sorbitan monopalmitate, sorbitan monostearate, stearic acid, trolamine, emulsifying wax; wetting and / or solubilizing agents such as benzalkonium chloride, benzethonium chloride, cetyl pyridinium chloride, docusate sodium, monoxinol 9, nonoxynol 10, octoxinol 9, polyoxyl 50 stearate, tyloxapol; or any combination of the above. The concentration of the solubilizers / stabilizers in the formulation can be between about 0.001 and 5% by weight, or about 0.1 to 2% by weight. In one embodiment, the stabilizer is selected from sorbitan derivatives mono-9-octadecenoate poly (oxy-1,2-ethanediyl), which includes but is not limited to, polysorbate 80 or polysorbate 20. The amount of polysorbate 20 or 80 a to be used in this modality is in the range of 0.001% to 0.1% (w / v), such as 0.005% (w / v), in simple use or in multidose derivations. In another embodiment, free L-methionine in the range of 0.05 mM to 50 mM is included in the formulation: the amount of free L-methionine is 0.05 mM at 5 mM for single use formulations, and 1 mM at 10 mM for multi-dose formulations
Solvents ("means to dissolve"): acetone, alcohol, diluted alcohol, amylene hydrate, benzyl benzoate, butyl alcohol, carbon tetrachloride, chloroform, corn oil, cottonseed oil, ethyl acetate, glycerin, hexylene glycol, isopropyl alcohol, methylalcohol , methylene chloride, methyl isobutyl ketone, mineral oil, peanut oil, polyethylene glycol, propylene carbonate, propylene glycol, sesame oil, water for injection, sterile water for injection, sterile water for irrigation, purified water.
Sorbents (also referred to as adsorbents, "adsorption media"): powdered cellulose, mineral coal, purified siliceous earth; and carbon dioxide solvents: barium hydroxide lime, lime soda.
Aging agents ("enriguecedores means"): hydrogenated castor oil, cetostearil alcohol, cetil alcohol, cetil esters wax, hard fat, paraffin, polyethylene excipient, stearyl alcohol, emulsifying wax, white wax, yellow wax.
Suppository bases ("suppository media"): cocoa butter, hard wax, polyethylene glycol.
Suspension and / or viscosity increase agents ("viscosity increase media"): acacia, agar, alginic acid, aluminum monostearate, bentonite, purified bentonite, magma bentonite, carbomer 934p carboxymethylcellulose calcium, carboxymethylcellulose sodium, sodium carboxymethylcellulose 12 , carrageenan, microcrystalline sodium cellulose and carboxymethylcellulose, dextrin, gelatin, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, magnesium aluminum silicate, methylcellulose, pectin, polyethylene oxide, polyvinyl alcohol, povidone, propenylglycol alginate, silicon dioxide , colloidal silicon dioxide, sodium alginate, tragacanth, xanthan gum.
Sweetening agents ("sweetening media"): aspartame, dextrose, dextrose, dextrose excipient, fructose, mannitol, saccharin, calcium saccharin, sodium saccharin, sorbitol, sorbitol solution, sucrose, understandable sugar, sugar confection, molasses.
Tablet ligations ("tablet binding media"): acacia, alginic acid, sodium carboxymethylcellulose, microcrystalline cellulose, dextrin, ethylcellulose, gelatin, liquid glucose, guar gum, hydroxypropyl methylcellulose, methylcellulose, polyethylene oxide, povidone, pregelatinized starch , molasses.
Tablet and / or capsule diluents ("diluent media"): calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, microcrystalline cellulose, cellulose powder, dextrates, dextrin, dextrose excipient, fructose, kaolin , lactose, mannitol, sorbitol, starch, pregelatinized starch, sucrose, understandable sugar, confectionery sugar.
Tablet disintegrants ("tablet disintegrating media"): alginic acid, microcrystalline cellulose, croscarmellose sodium, corspovidone, potassium polacrilin, sodium starch glycolate, starch, pregelatinized starch.
Tablet and / or capsule lubricants ("means of lubrication"): calcium stearate, glyceryl behenate, magnesium stearate, light mineral oil, polyethylene glycol, sodium stearyl fumarate, stearic acid, purified stearic acid, talc, hydrogenated vegetable acid, zinc stearate.
Tonicity modifiers ("means that modify tonicity"): they are understood to be molecules that contribute to the osmolality of a solution. The osmolality of a pharmaceutical composition is preferably regulated in order to maximize the stability of the active ingredients and also to minimize patient discomfort after administration. The serum is approximately 300 +/- 50 milliosmolales per kilogram. It is generally preferred that the pharmaceutical composition is isotonic with serum, ie having the same or similar osmolality, which is achieved by the addition of a tonicity modifier, thus it is contemplated that the osmolality is from about 180 to about 420 milliosmolales, however, it must be understood that the osmolality may be either greater or less than the specific conditions required. Examples of suitable tonicity modifiers for modifying osmolality include, but are not limited to amino acids (eg, arginine, cysteine, histidine, and glycine), salts (eg, sodium chloride, potassium chloride, and sodium citrate) and / or saccharides (eg, sucrose, glucose, dextrose, glycerin and mannitol). The concentration of the tonicity modifier of a formulation may be between about 1mM to 1M, or about 10mM to about 200mM. In one embodiment, the tonicity modifier is sodium chloride within a concentration range of OmM at 200mM. In another embodiment, the tonicity modifier is sorbitol or trehalose and is not present in sodium chloride.
Vehicles ("vehicle means"): flavored and / or sweetened (aromatic elixir, elixir of benzaldehyde compound, elixir, so-alcoholic, pepper water, sorbitol solution, molasses, thallus balsam molasses); oilseed (almond oil, corn oil, corn seed oil, ethyl oleate, isopropyl myristate, isopropyl palmitate, mineral oil, light mineral oil, myristyl alcohol, octyldodecanol, olive oil, peanut oil, persian oil, sesame oil , soybean oil, squalene); solid carriers such as sugar esters; (bacteriostatic water for injection, bacteriostatic sodium chloride injection) sterile.
Water repellent agent ("water repellent means"): cyclomethicone, dimethicone, cimethicone.
In certain embodiments, the pharmaceutical composition comprises a compound selected from the following, or any combination thereof: salts of 1) amino acids such as glycine, arginine, aspartic acid, glutamic acid, lysine, asparigin, glutamine, proline; 2) carbohydrates, for example monosaccharides such as glucose, fructose, galactose, mannose, arabinose, xylose, ribose; 3) disaccharides, such as, trihalosa, maltose sucrose; 4) polysaccharides, such as maltodextrins, dextrans, starch, glycogen; 5) alditols, such as, mannitol, xylitol, lacticol, sorbitol; 6) glucuronic acid, galacturonic acid; 7) cyclodextrins, such as methyl cyclodextrin, hydroxypropyl-β-cyclodextrin and the like; 8) inorganic salts, such as sodium chloride, potassium chloride, magnesium chloride, sodium and potassium phosphates, ammonium carbonate of boric acid and ammonium phosphate; 9) organic salts, such as acetates, citrate, ascorbate, lactate; 10) emulsifying or solubilizing agents such as acacia, diethanolamine, glyceryl monostearate, lecithin, monoetalonamine, oleic acid oil, oleyl alcohol, poloxamer, polysorbates, sodium lauryl sulfate, stearic acid, sorbitan monolaurate, sorbitan monostearate and other sorbitan derivatives, polyexyl derivatives, wax, polyoxyethylene derivative, sorbitan derivatives; 11) reagents that increase viscosity such as agar, alginic acid and its salts, guar gum, pectin, polyvinyl alcohol, polyethylene oxide, cellulose and its propylene carbonate derivatives, polyethylene glycol, hexylene glycol, tyloxapol; and 12) particular ingredients such as sucrose, trehalose, lactose, sorbitol, lactitol, inositol, sodium and potassium salts such as acetate, phosphates, citrates, borate, glycine arginine, polyethylene oxide, polyvinyl alcohol, polyethylene glycol, hexylene glycol, methoxy polyethylene glycol , gelatin, hydroxypropyl-β-cyclodextrin.
Ways of sustained liberation
In a preferred embodiment of the invention, sustained release forms (also referred to as "controlled release" forms) of crystalline TNFR2 polypeptides are used, including sustained release forms of TNFR2: Crystalline Fc; Sustained or controlled release forms comprise crystalline polypeptide and a substance (the "sustained release means") for extending the physical release or biological availability of the crystalline polypeptide for a desired period of time. Sustained release forms suitable for use in the disclosed methods include, but are not limited to, crystalline TNFR2 polypeptides that are encapsulated in sustained release media such as slow dissolving biocompatible polymers (eg, the polymeric carriers described herein, the microparticles of alginate described in the US
6,036,978, or the polyethylene-vinyl acetate and the poly (lactic-glycolic acid) compositions described in the U.S. 6,083,534), mixed with such a polymer (including topically applied hydrogels), and stored in a biocompatible semipermeable implant. Additional embodiments of the invention include additional sustained release forms such as polymeric microparticles, wherein once the active ingredient and sustained release media such as polymers (eg, PLGA) are dispersed within a continuous phase, and the resulting dispersion it is directly lyophil to remove water and organic solvents or additives and form said microparticles (US Pat. No. 6,020,004); injectable gel compositions include a biodegradable anionic polysaccharide such as an alginate ester, a polypeptide and at least one bound polyvalent metal ion (U.S. Patent No. 6,432,449); injectable biodegradable polymeric shades having reverse thermal gelation properties and optionally gelling that responds to pH / degelification properties (U.S. Patent No. 6,541,0333 and 6,451,346); bicompable polyol: oil suspensions such as those wherein the suspension comprises polyol in the range of from about 15% to about 30% by weight (U.S. Patent No. 6,245,740). Such release forms are suitable for continuous delivery of polypeptides through administration in the form of a reservoir, wherein the reservoir can be an implant, or it can be in the form of injectable microspheres, nanospheres, or gels. The above list of U.S. patents (U.S. Patent No. 6,036,978, 6,083,534, 6,020,004, 6,432,449, 6,541,033, 6,451,346 and 6,245,740) are incorporated herein by reference in their entirety. In addition, sustained or controlled release forms of crystalline polypeptides of the invention comprise types of sustained release media such as those described in Kim, C, 2000, "Controlled Relay Dosage Form Desing," Techonomic Publishing Co., Lancaster PA, which includes the following natural polymers (gelatine, sodium alginic acid, xanthan gum, gum arabic, or chitosan), semi-synthetic polymers or cellulose derivatives (methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, cellulose acetate, cellulose acetate butyrate, cellulose acetate propionate, cellulose acetate phthalate, or hydroxypropylmethyl cellulose phthalate), and synthetic polymers (ion exchange resins (methacrylic acid, sulfonated polystyrene / divinylbenzene) polyacrylic acid (Carbopol), poly (MMA / MAA pol
(MMA / DEAMA), poly (MMA / EA), poly (vinyl acetate phthalate) poly (vinyl alcohol), poly (vinyl pyrrolidone), poly (lactic acid) poly (glycolic acid), poly (lactic acid / glycolic acid) polyethylene glycol, polyethylene oxide, poly (dimethyl silicone), poly (hydroxyethyl methacrylate), poly (ethylene / vinyl acetate), poly (ethylene- / vinyl alcohol), polybutadiene, poly (anhydride), poly (orthoester), and poly ( glutamic acid)). Additional embodiments of the invention include crystals of TNFR2 polypeptides encapsulated in at least one polymeric carrier to form microspheres by virtue of encapsulation within the matrix of the polymeric carrier to preserve their native biologically active tertiary structure, as described in U.S. Pat. No. 6,541,606, which is incorporated herein by reference in its entirety. The TNFR2 polypeptide crystals or formulations thereof for making encapsulates are suspended in a polymeric carrier such as PLGA which is dissolved in a solvent or organic additive. Such encapsulated TNFR2 polypeptide crystals maintain the biological activity of the TNFR2 polypeptide for a longer period of time than the TNFR2 polypeptides in solution when stored under comparable conditions.
Illustrative Modalities
The formulation may comprise about 25 to 50 mg of TNFR2 or etanercept polypeptides, wherein the TNRF2 or etanercept polypeptide is reconstituted in crystalline forms, about 10 mM to about 100 mM L-arginine, about 10 mM to about 500 mM phosphate. sodium about 0.75% to about 1.25% sucrose, about 50 mM to about 150 mM NaCl, at about pH 6.0 to about pH 7.0. In another embodiment, L-arginine can be replaced with L-cysteine (at about 1 to about 500 micromolar) in the formulation. In another embodiment, the pH may be about pH 7.0. In another embodiment, the pharmaceutical composition comprises 25 mg / ml crystalline TNFR2, approximately 25 mM L-arginine, approximately 25 mM sodium phosphate, approximately 98 mM sodium chloride, and approximately 1% sucrose or pH 6.2 . In another embodiment, wherein the crystalline etanercept or the reconstituted etanercept of the crystalline form has a higher biological level per unit of etanercept than the non-crystallized etanercept preparations, the formulation may comprise about 10 to about 50 mg of crystalline etanercept or reconstituted etanercept in crystalline form or approximately 15 to approximately 25 mg of crystalline etanercept or etanercept reconstituted in crystalline form.
Test Formulations for Polypeptide Stability and Biological Activity
In yet another embodiment, the invention provides a method for testing the accelerated stability of the stability of a crystalline TNFR2 polypeptide in a pharmaceutical composition of the invention comprising the steps of assaying the activity of the polypeptide formulated according to the invention prior to storage, that is, time zero; storing the composition at 37 ° C for one month and measuring the stability of the polypeptide; and compare the stability form of time zero with that of the monthly time point. This information is helpful for the early elimination of batches or batches that seem to have good stability initially, but that are not stored well for longer periods. Moreover, the present pharmaceutical composition provides improved long-term storage in such a way that the active ingredient, for example, a crystalline TNFR2 polypeptide is stable during the course of storage or in a liquid or frozen state. As used herein, the phrase "long term" storage is meant to mean that the pharmaceutical composition can be stored for three months or more, for six months or more, and preferably for a year or more. Long-term storage is also understood to mean that the pharmaceutical composition is stored as a liquid at 2-89 C or frozen, for example, at -20a C or colder. It can also be contemplated that the composition can be frozen and thawed more than once. The term "stable" with respect to long-term storage is understood to mean that the active polypeptide of the pharmaceutical composition loses no more than 20%, or more preferably 15%, or even more preferably 10%, and more preferably the 5% of its activity relative to the activity of the composition at the beginning of storage. TNFR2 polypeptide activity can be assayed by any one of a number of assays, including ligand binding assays such as ELISA assays, wherein the ligand is bound to a solid support, assay preparations and control of TNFR2 polypeptides are add, and binding of the TNFR2 polypeptide to the ligand is detected using labeled anti-Ig antibodies directed to the Ig component of the TNFR2 polypeptide. In addition, assays such as those described in Example 6 can be used to detect biological activity of TNFR2 polypeptides that bind to TNF, or can be modified for assay activity of TNFR2 polypeptides that bind to other ligands.
Administration and Dosage
As used herein, "administration of crystalline TNFR2" or "administration of crystalline TNFR2 polypeptides" means administration of a pharmaceutical composition comprising crystalline TNFR2 polypeptides, or preparations using crystalline TNFR2 polypeptides. Any effective route of administration can be used to therapeutically administer crystalline TNFR2. If the crystalline TNFR2 is injected, it can be administered, for example, intra-articularly, intravenously, intramuscularly, intralesionally, intraperitoneally, or subcutaneously by bolus injection or by continuous infusion. Other suitable means of administration include sustained release of implants, deposits (implanted or injected), suppositories, aerosol inhalation, eye drops, oral repairs, including pills, molasses, trochesco, or chewing gum, and topical preparations such as lotions, gels, powders, ointments, or other suitable techniques. When the crystalline TNFR2 in combination with one or more other biologically active compounds these can be administered by the same or different routes, and can be administered simultaneously, separately or sequentially. Appropriate doses can be determined in standard dosing assays, and can vary according to the chosen route of administration. The amount and frequency of administration will depend on such factors as the nature and severity of the indication being treated, the desired response, the age and condition of the patient, and so on. In the following dosing regimens, the amount of crystalline TNFR2 administered is understood to be the amount of crystalline TNFR2 for pharmaceutical compositions comprising crystalline TNFR2, or the amount of TNFR2 polypeptide for pharmaceutical compositions prepared using crystalline TNFR2. In one embodiment of the invention, the crystalline TNFR2 is administered once a week to treat a medical disorder or conditions described herein, in another modality it is administered at least twice a week, and in another modality it is administered at least three times a week . An adult patient is a person who is 18 years of age or older. If the effective amount of crystalline TNFR2 is injected per adult dose it varies from 1-20 mg / m2 of body surface area, and preferably is about 5-12 mg / m2. Alternatively, an exact dose can be administered, the amount of which varies from 5-100 mg / dose. The ranges of example doses for an exact dose to be administered by subcutaneous injection are 5-25 mg / dose, 25-50 mg / dose and 50-100 mg / dose. In one embodiment of the invention, the various indications described below are treated by administering an acceptable preparation for injection containing or being prepared from crystalline TNFR2 at 25 mg TNFR2 per dose, or alternatively, containing 50 mg per dose. The dose of 25 mg or 50 mg can be administered repeatedly, particularly for chronic conditions. If a route of administration other than injection is used, the dose is appropriately adjusted in accordance with standard medical practices. In several cases, an improvement in the patient's condition will be obtained by injecting a dose of about 25 mg of crystalline TNFR2 one to three times a week for a period of at least three weeks, or a dose of 50 mg of crystalline TNFR2 a or twice a week for at least three weeks, although longer periods of treatment may be necessary to induce the desired degree of improvement. For incurable chronic conditions, the regimen can be continued indefinitely, with adjustments made to the dose and frequency if deemed necessary by the patient's physician.
For pediatric patients (age 4-17), an adequate regimen involves subcutaneous injection of 0.4 mg / kg body weight, up to a maximum of 25 mg per dose of crystalline TNFR2, administered by subcutaneous injection one or more times per week. In addition to human patients, the crystalline TNFR2 polypeptides are useful in the treatment of medical conditions as described herein that afflict non-human animals, such as pets (dogs, cats, birds, primates, etc.), domestic farm animals (herds of horses, sheep , pigs, birds, etc.) or any animal that suffers from a condition comparable to one of the conditions described here. In such instances, an appropriate dose can be determined according to the body weight of the animal. For example, a dose of 0.2-1 mg / kg can be used. Alternatively, the dose is determined according to the surface area of the animal, an example dose varies from 0.1-20 mg / m2 body surface area, or more preferably 5-12 mg / m2 body surface area. For small animals, such as dogs or cats, a suitable dose is 0.4 mg / kg of body weight. In another embodiment, crystalline TNFR2 (wherein the TNFR2 polypeptide is preferably expressed from genes derived from the same species according to the patient) is administered by injection or other suitable route one or more times per week until the condition of the animal is improve, or these can be administered indefinitely.
In another embodiment, wherein the crystalline TNFR2 polypeptide or the reconstituted TNFR2 polypeptide of the crystalline form have a higher level of biological activity per TNFR2 polypeptide unit than the non-crystallized TNFR2 polypeptide preparations, the doses given above can be appropriately reduced, based on the degree of increase in the biological activity of the crystalline TNFR2 polypeptide. For example, the above doses can be reduced to 50% of the above doses and the doses vary if the crystallization increases the biological activity twice per unit of TNFR2 polypeptide; in other modalities, the doses are reduced from 10 to 95% of the higher dose, or from 25 to 75% of the higher dose, or 60% or 70% or 80% of the higher dose. The invention further includes the administration of crystalline TNFR2 concurrently with one or more other drugs that are administered to the same patient in combination with the pharmaceutical composition comprising crystalline TNFR2 polypeptides, or prepared using crystalline TNFR2 polypeptides, each drug is administered in accordance with an adequate regimen for such medication. "Concurrent administration" encompasses simultaneous or sequential treatment with the components of the combination, as well as regimens in which the drugs alternate, or where a long-term component is administered and the others are administered intermittently. Components can be administered in the same composition or in separate compositions, and by the same or different routes of administration.
Therapeutic Uses
The invention pertains to methods for treating various medical disorders by administering crystalline TNFR2 polypeptides. The crystalline TNFR2 polypeptides can be administered in combination with other biologically active molecules, by way exemplified by, but not limited to, the combination and / or concurrent therapies described herein. This invention provides compounds, compositions, and methods for treating a mammalian patient that includes a human patient, suffering from a medical disorder. For the purposes of this description, the terms "bad", "disease", "medical condition", "abnormal condition" and the like are used interchangeably with the term "medical disorder". In accordance with this invention, patients having medical disorders are administered a therapeutically effective amount of a crystalline TNFR2 polypeptide. The crystalline TNFR2 polypeptide may be the crystalline form of a soluble TNF-alpha receptor that binds to TNF-alpha such as TNFR2: Crystalline Fc. As used herein, the phrase "administering a therapeutically effective amount" of a therapeutic agent means that the patient is treated with the agent in an amount and for a time sufficient to induce a sustained improvement over a baseline in at least one indicator that reflects the severity of the disorder. An improvement is considered "sustained" if the patient exhibits improvement on at least two separate occasions for one or more weeks. The degree of improvement is determined based on signs or symptoms and questionnaires of determinations that are administered to the patient, such as quality of life questionnaires, can also be used. Several indicators that reflect the extent of the patient's illness can be evaluated to determine if the amount and time of treatment are sufficient. The baseline value for the chosen indicator or indicators is established by examining the patient before administration of the first dose of crystalline etanercept or another crystalline TNFR2 polypeptide. Preferably, the baseline examination is done within about 60 days of the administration of the first dose. If the crystalline TNFR2 polypeptide is being administered to treat acute symptoms, such as for example treating a traumatic knee injury, the first dose is administered as soon as practically possible after the injury has occurred. Improvement was induced by administering the crystalline TNFR2 polypeptide until the patient manifests an improvement over the baseline for the chosen indicator or indicators. In the treatment of chronic conditions, this degree of improvement is obtained by repeatedly administering this medication for a period of at least one month or more, for example during one, two, or three months, or indefinitely. A period of one to six weeks, or even a single dose, is often enough to treat acute conditions. For injuries or acute conditions, a single dose may be sufficient. Although the extent of the patient's disease after treatment may appear to improve according to one or more indicators, the treatment may be continued indefinitely at the same level or at a reduced dose or frequency. Once the treatment has been reduced or discontinued, it can be resumed to the original level if the symptoms reappear. In one embodiment, the medical disorders to be treated with crystalline TNFR2 polypeptides are characterized by excessive or abnormal TNFR-alpha levels. It has been proposed that a localized or systemic excess of TNF-alpha contributes to the progression of numerous medical disorders. For example, patients with chronic heart failure have elevated serum TNF-alpha levels that have been shown to increase with disease progression (see, for example, Levine et al., N Eng J Med 323: 236-241, 1990 ). A variety of other diseases are associated with elevated levels of TNF-alpha (see, for example, Feldman et al., Transplantation Proceedings 30: 4126-4127, 1998). It has been suggested that the suppression of TNF-alpha may be beneficial in patients suffering from disorders characterized by excessive or abnormal expression of TNF-alpha.
However, although progress has been made in devising effective treatments for such diseases, medications and improved methods of treatment are needed. Methods are here provided to treat a number of medical disorders characterized by abnormal TNF-alpha expression by administering crystalline TNFR2 polypeptides, such as the crystalline form of a soluble TNF-alpha receptor such as TNFR2: Fc, for a sufficient period of time to induce a sustained improvement in the patient's condition. The subject methods involve administering to the patient a formulation comprising or being prepared upon use, a crystalline TNFR2 polypeptide that is capable of reducing the effective amount of biologically active endogenous TNF-alpha, such as to prevent binding of TNF-alpha to its receptor of cell surface (TNFR).
Cardiovascular Disorders
Cardiovascular disorders are treatable with described crystalline TNFR2 polypeptides, pharmaceutical compositions thereof, and / or combination therapies. Examples of cardiovascular disorders treatable with a crystalline TNFR2 polypeptide, such as TNFR2: Crystalline Fc include: aortic aneurysms; arteritis; vascular occlusion, which includes cerebral arterial occlusion. Complications of coronary bypass surgery; ischemia / repercussion; heart attack, which includes atherosclerotic heart disease, myocarditis, which includes chronic autoimmune myocarditis and viral myocarditis, heart failure, including heart failure (CHF), heart failure cachexia; myocardial infarction; restenosis after heart surgery; silent myocardial ischemia; postimplantation complications of left ventricular assist devices; Raynaud's phenomenon; thrombophlebitis; vasculitis, which includes Kawasaki vasculitis, giant cell arthritis, Wegener granulomatosis; and purple Schoenlein-Henoch. Additionally, TNFR2: Fc or other crystalline TNFR2 polypeptides described herein may be used in combination with angiogenic or myeloid stem cell therapies for the treatment of cardiovascular disease, including cardiomyopathy of ischemic or non-ischemic origin, angiogenic post-myocardial infarction therapy or treatment of peripheral arterial disease. Stem cells useful for this purpose include mesenchymal stem cells and endothelial precursor cells, such as those found in spleen, fetal liver, bone marrow (U.S. Patent No. 5,486,359, Deisher T, Drugs 3 (6): 649-53 (2000); Huss R, Stem Cells 18: 1-9 (2000), Huss et al., Stem Cells 18: 252-60 (2000) .The crystalline TNFR2 polypeptides can be given concurrently with stem cell transplants as well as with factor treatments. of differentiated or proliferative stem cell growth TNF-alpha and I L-8 have been implicated as chemotactic factors in arteriosclerotic abdominal aortic aneurysm (Szekanecz et al., Pathobiol 62: 134-139 (1994)). Abdominal can be treated in human patients by administering a crystalline TNFR2 polypeptide, such as TNFR2: Crystalline Fc, which can be administered in combination with an inhibitor of I L-8, such treatment has the effect of reducing the neurovascu pathological larisation associated with this condition. Studies have shown that metalloproteinases (MMPs) are a key element in myocardial remodeling and fibrosis. Thus, administering crystalline TNFR2 polypeptides to inhibit TNF-alpha and the inflammatory response in conjunction with direct inhibition of MMP will reduce, prevent, or reverse, disorders such as left ventricular pump dysfunction. This is accompanied by a coadministration of a crystalline TNFR2 polypeptide, such as TNFR2: Crystalline Fc, together with an MMP inhibitor. Alternatively, treatment of left ventricular pump dysfunction may involve administering a crystalline TNFR2 polypeptide without the concurrent use of an MMP inhibitor. Any of the described TNFR2 crystalline polypeptides or combination treatments described herein can also be used to treat combined familial hyperlipidemia (FCH). The FHC is a dyslipidemia characterized by premature coronary heart disease. Patients with FCH are genetically defective in their TNFRII genehave low levels of TNFRII levels in their bodies and seem to respond to the deleterious effects of endogenous TNF-alpha (van Greevenbroek et al., 2000, Atherosclerosis 153: 1-8). Coronary heart disease, insulin resistance and obesity associated with FCH can be reduced or avoided when administering to patients with FCH any of the crystalline TNFR2 polypeptides described herein, such as crystalline etanercept or TNFR2: crystalline Fc. Additionally, treatment with crystalline TNFR2 polypeptide for FCH can be administered concurrently with reduction of dietary fat and cholesterol and / or with one or more other drugs used to treat this condition, including bile acid sequestering resins (cholestyramine and colestipol) , nicotinic acid, niacin, a cholesterol-lowering drug, such as gengefibrosil or probucol, or one of the HMG-CoA reductase inhibitors or "statin", such as lovastatin or pravastatin. In another aspect of the invention, the crystalline TNFR2 polypeptides are used to treat patients who have elevated serum levels of C-reactive protein (CRP) and who are at risk for heart attack even when their cholesterol can be reduced (Ridker et al. al., 2001, New Eng J Med 344: 1959-1965).
Infections and Injuries
The described TNFR2 crystalline polypeptides, compositions and / or combination of combination therapies described herein are useful in medicine for treating bacterial, viral or protozoal infections, and complications resulting therefrom. One such disease is Mycoplasma pneumonia. Additionally, the use of crystalline TNFR2 polypeptides to treat AIDS and related conditions, such as AIDS dementia complex, emanations associated with AIDS, and isotropy due to antiretroviral therapy; and Kaposi's sarcoma. The use of crystalline TNFR2 polypeptides to treat protozoan diseases is included herein, includes. malaria (which includes cerebral malaria) and e'squistosomiasisi. HE.'. additionally provides the use: of crystalline TNFR2 polypeptides to treat leprosum nodosum erythema; "Acterial" or viral meningitis- tuberculosis, which includes pulmonary tuberculosis, and secondary pneumonitis for a bacterial or viral infection.The use of crystalline TNFR2 polypeptides is also provided here to prepare drugs to treat fevers or relapse of louse birth, such as Those originated by Borrelia recurrentis The crystalline TNFR2 polypeptides can also be used to prepare a medicament for treating conditions caused by herpes viruses, such as herpetic stromal keratitis, corneal lesions, and virus-induced cornea disorders, In addition, polypeptides can be used. Crystalline TNFR2 in the treatment of human papillomavirus infections, as well as in the treatment of infectious mononucleosis Crystalline TNFR2 polypeptides are also used to prepare drugs to treat influenza, as well as to treat critical disease myopathy and polyneuropathy (CIPNM),an inflammatory syndrome that occasionally occurs in conjunction with prolonged septic disease. The subject crystal TNFR2 polypeptides are also used to treat transmissible spongiform encephalopathy, which is believed to be prion mediated. Another disorder that can be treated with any of the described TNFR2 crystalline polypeptides, pharmaceutical compositions of these methods, or combination therapies is myelopathy (TSP / H.AM) .. -...-associated with paraparesis. Tropical spastic HTLV-1 This disease is caused by infection with the human retrovirus rHT.LV-1 ... Recent studies have suggested that TNF-alpha may play a role in the reduced glutamate uptake exhibited by cells infected with HTLV (Szymocha et al., 2000, J Virol 74: 6433-6441) TSP / HAM is a slowly progressive condition of the spine that causes weakness and muscle stiffness in the legs, often accompanied by a loss of sensation. In the feet, known treatments for this condition include corticosteroids and plasmapheresis.The TSP / HAM can be treated with any of the crystalline TNFR2 polypeptides described herein, either of which can be administered concurrently with a corticosteroid. roide, plamapheresis or both. A crystalline TNFR2 polypeptide for treating TSP / HAM is TNFR2: Crystalline Fc. Sufficiency of treatment is determined by monitoring the patient for improvement of leg strength, or stopping the patient's deterioration or by any other means deemed appropriate by the patient's physician. Other conditions treatable by the described TNFR2 crystalline polypeptides, compositions and / or combination therapies include those resulting from injuries to the head or spine and include subdural hematoma due to head trauma.
Of s or r e n e n u u r g e s, D or I o r,. Y . Fever • •-; v '' -
The: migraine cervicogéni.ca - is a common form of migraine that arises from the dysfunction in the neck area, and that is associated with high levels of TNF-alpha, which is believed to mediate an inflammatory condition that does not contribute to the comfort of the patient (Martelleti, Clin Exp Rheumatol 18 (2 Supp 19): S33-8 (Mar-Apr, 2000)). The cervicogenic migraine can be treated by administering crystalline TNFR2 polypeptides as described herein, thereby reducing the inflammatory response and the associated migraine pain. Additionally, the object crystalline TNFR2 polypeptides, compositions and / or combination therapies are used to treat conditions of chronic pain, such as chronic pelvic pain, which includes chronic prostatitis / pelvic pain syndrome. As a further example, the crystalline TNFR2 polypeptides, compositions and / or combination therapies of the invention are used to treat post-herpetic pain.
The crystalline TNFR2 polypeptides, compositions and / or combination therapies are useful for treating primary amyloidosis. Additionally, secondary amyloidosis that is characteristic of various conditions is also treatable with crystalline TNFR2 polypeptides such as TNFR2: Crystalline Fc, and the compositions, and / or combination therapies described herein. Such conditions include: Alzheimer's disease, secondary reactive amyloidosis, Down syndrome; - and amyloidosis associated with dialysis. Compounding the compounds, compositions and / or combination therapies of the invention are the inherited periodic fever syndromes, which include familial Mediterranean fever, periodic fever syndrome. Hyperimmunoglobulin D and periodic syndrome associated with TNF receptor (TRAPS) The described TNFR2 crystalline polypeptides, compositions, and / or combination therapies are additionally useful for treating acute polyneuropathy, anorexia nervosa, Bell's palsy, chronic fatigue syndrome, transmissible dementia, which includes Creutzfeld-Jacob disease, neuropathy • demyeliation, Guillain-Barre syndrome, vertebral disc disease, Gulf war syndrome, myasthenia gravis, silent cerebral ischemia, sleep disorders, including narcolepsy and sleep apnea, chronic neuronal degeneration and stroke, which includes cerebral ischemic diseases.
Oncological and Hematological Disorders
Methods for using crystalline TNFR2 polypeptides, compositions and / or combination therapies to treat various hematological and oncological disorders are provided herein. For example, the crystalline TNFR2 polypeptides are used to treat various forms of cancer, including acute myelogenous leukemia, Epstein-Barr positive virus nasopharyngeal carcinoma, vesicle bladder carcinoma, glioma, colon, stomach, prostate, renal cell, cancers of ovarian and cervical, lung cancer (SCLC and NSCLC), which includes nausea associated with cancer, cachexia associated with cancer, fatigue, asthenia, paraneoplastic syndrome of cachexia and hypercalcemia. Additional diseases treatable with subject crystalline TNFR2 polypeptides, compositions and / or combination therapies are solid tumors including sarcoma, osteosarcoma, and carcinoma, such as adenocarcinoma (breast cancer) and squamous cell carcinoma. Additionally, the subject compounds, compositions and / or combination therapies are useful for treating leukemia, including acute chronic myelogenous leukemia, acute or chronic lymphoblastic leukemia, and tricholeucite leukemia. Other malignancies with invasive metastatic potential can be treated with the subject compounds, compositions, and / or combination therapies that include multiple myeloma. When crystalline TNFR2 polypeptides are used to treat a tumor, this treatment can be administered in combination with target antibodies for membrane proteins that are expressed at a high level in the particular tumor to be treated. For example, tumors such as breast tumor, ovarian, and prostate carcinoma and other Her2-positive tumors, can be administered with TNFRC2: Crystalline Fc or other crystalline TNFR2 polypeptides in combination with antibodies against Her2 / neu, such as HERCEPTIN® ( Known generically as "trastuzumab;" Genentech, Inc.). The cancer, for example ovarian cancer or prostate cancer, can be treated by concurrent administration of a crystalline TNFR2 polypeptide, such as TNFR2: crystalline Fc, and interferon-? (Windbichler et al., 2000, British J Cancer 82: 1138-1144). Several limfoproliferative disorders are also treatable with the crystalline TNFR2 polypeptides, compositions, and / or combination therapies. These include, but are not limited to, autoimmune limfoproliferative syndrome (ALPS), chronic lymphoblastic leukemia, tricholeucite leukemia, chronic lymphatic leukemia, peripheral T cell lymphoma, small lymphocytic lymphoma, mantle cell lymphoma, follicular lymphoma, Burkitt's lymphoma, Epstein-Barr positive virus T cell lymphoma, histiocytic lymphoma, Hodgkin's disease, diffuse aggressive lymphoma, acute lymphatic leukemia, T-cell lymphoproliferative disease, cutaneous B-cell lymphoma, cutaneous T-cell lymphoma (i.e., mycosis fungoides) and Sézary syndrome.
Additionally, the described crystalline TNFR2 polypeptides, compositions and / or combination therapies can be used to treat anemias and hematological disorders including anemia of chronic disease, aplastic anemia, including Fanconi aplastic anemia; idiomatic thrombocytopenic purpura (ITP); myelodysplastic syndromes (including refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation); myelofibrosis / myeloid metaplasia; and vasoclusive crisis of the cell and calciform cell vasoclusive crisis. Additionally, crystalline TNFR2 polypeptides, such as crystalline TNFR2: Fc, are useful for treating chronic idiomatic neutropenia. A combination of crystalline TNFR2 polypeptide and one or more anti-angiogenesis factors can be used to treat solid tumors, thereby reducing the vascularity that nourishes the tumor tissue. Suitable anti-angiogenic factors for such combination therapies include inhibitors IL-8, angiostatin, endostatin, kringle 5, inhibitors of vascular endothelial growth factor (VEGA), angiopoietin-2 or other angiopoietin-1 antagonists, activating factor antagonists platelets, and basic fibroblast growth factor antagonists. Antibodies against vascular endothelial growth factor, such as anti-VEGF (AVASTIN ™, generically known as "bevacizumab;" Genentech, Inc.), are useful for combination treatments with crystalline TNFR2 polypeptides such as TNFR2: Fc. In one embodiment of the invention, the crystalline TNFR2 polypeptide, such as TNFR2: Crystalline Fc, is administered to cancer patients in combination with a proteasome inhibitor, which includes administration to patients suffering from hematologic cancers or solid tumors. The proteosome controls the stability of several proteins involved in the cell cycle and apoptosis, such as cyclins and NF-KappaB (see, for example, Schenkeim, 2002, Clin Lymphoma 3: 49-55 and Adams, 2002, Curr Opin Oncol 14: 628-634). Proteasome inhibitors can induce apoptosis, and can thus synthesize cancer cells for other anticancer agents. Exemplary proteasome inhibitors for the subject combinations include, for example, carbobenzoxy-L-Leucyl-L-Leucyl-L-Leucinal (MG132), clasto-lactacystin beta-lactone (AG-Scientific, Inc.), carbobenzoxy-L- isoleucyl- (gamma) -t-butyl-L-glutamyl-L-alanyl-L-leucinal (PSI), N-acetyl-leu-leu-noleucinal (ALLN), MLN519 (Millennium Pharmaceuticals), acid [(1R) - 3-methyl-1 - [[(2S) -1-oxo-3-phenyl-2 - [(pyrazinylcarbonyl) amino] propyl] -aminojbutyl] boronic acid (PS-341, known generically as "bortezomib;" trade name VELCADE® Millennium Pharmaceutical), and carbobenzoxy-L-leucyl-L-leucyl-L-norvalinal (MG115; Affiniti Research Products). For example, multiple myeloma, ovarian cancer, prostate cancer, breast cancer, hematologic malignancies, such as lymphoma or leukemia, or other tumors may be treated concurrently with a proteasome inhibitor, such as PS-341, and a TNFR2 polypeptide. crystalline, such as TNFR2: crystalline Fc or crystalline etanercept. Unwanted side effects of certain therapies can be treated with crystalline TNFR2 polypeptides, such as TNFR2: Crystalline Fc. Such side effects in some cases are mediated by high levels of TNF-alpha, so such patients will benefit from treatment with an agent that reduces TNF-alpha levels. For example, crystalline TNFR2 polypeptides such as TNFR2: Crystalline Fc can be administered to help combat nausea associated with chemotherapy and other drug-induced nausea. Additionally, the crystalline TNFR2 polypeptides are used to treat brain damage induced by radiation associated with radiation treatment for brain tumors. Additionally, crystalline TNFR2 polypeptides are used to treat the toxicity associated with the administration of monoclonal antibodies directed against antigens present on the surface of particular classes of cancer cells. For example, the crystalline TNFR2 polypeptides described herein can be used to treat the toxicity associated with the CAMPATH 1-H® infusion (Known generically as "alemtuzumab")."Berlex Laboratories, see also EP 0328404A1), which is used to treat chronic lymphocytic leukemia." CAMPATH -H is a humanized antibody specific for CD52, a cell surface antigen found in monocytes, B cells and T cells. of the invention, the described crystalline TNFR2 polypeptides, such as TNFR2: crystalline Fc or crystalline etanercept, can be administered to ameliorate the autoimmune response disorder related to long-term interferon treatment.A crystalline TNFR2 polypeptide can be administered to cancer patients to reduce unwanted side effects associated with long-term administration of interferon, which may include fever, fatigue, neutropemia, rash, migraine, digestive disorders, liver enzyme imbalance, and so on, eg, interferon (IFN? ) has been shown to be active in ovarian cancer, so a patient with ovarian cancer can be to treat through the concurrent administration of IFN? and a crystalline TNFR2 polypeptide, such as TNFR2: Crystalline Fc, or crystalline etanercept. In a similar way IFN is often used? to treat chronic myelogenous leukemia, basal cell carcinoma, tricholeucite leukemia, bladder cancer, childhood and childhood hemangiomas, multiple myeloma, kaposi's sarcoma, mycosis fungoides, non-Hodgkin's lymphoma and renal cell carcinoma and can be administered concurrently with a crystalline TNFR2 polypeptide, such as TNFR2: Crystalline Fc, to reduce the side effects induced by interferon.
Additionally, the crystalline TNFR2 polypeptides can be used to prevent the development of or alleviate resistance to the drug for agents that are linked by alpha-1-acid glycoprotein (AGP), a protein that is capable of binding to small molecules and that preferentially they join basic molecules. AGP is an acute phase protein that is increased in a variety of pathological conditions, including chronic inflammation, myocardial infarction. STI 571 (Glivec®, generically known as "imatinib;" Novartis) is an active inhibitor of C-kit kinase activity, and is useful for treating chronic myelogenous leukemia (CML). A mouse model study of CML has shown that AGP binds and inactivates imatinib, resulting in resistance to this drug (Gambacorti-passerini et al., 2000, J Nati Can Inst 92: 1641-1650). The level of AGP in a patient can be reduced by administration of pentoxifylline (Voisin et al., 1998, Am J Physiol 275: R1412-R1419). The subject invention provides methods for preventing or reducing resistance to imatinil by concurrent administration of a crystalline TNFR2 polypeptide, such as TNFR2: crystalline Fc or crystalline etanercept to a CML patient who is undergoing treatment with imatinib. UCN-01 (7-hydroxistaurosporin), an agent used to treat gastrointestinal tumors and other solid tumors, also has a propensity to bind to AGP (Senderowicz et al., 2000, J Nati Cancer Inst 92 (5): 376-387 ); Noriaki et al., 2000, Biol Pharmac Bull 23 (79: 893-895, Fuse et al., 1999, Cancer Res 59 (5): 1054-1060, Tamura et al., 1999, Proc Annu Mee Am Soc Clin Oncol 18: A611). A method for preventing or reducing UCN-01 binding to AGP is provided herein by administering a crystalline TNFR2 polypeptide, such as TNFR2: Crystalline Fc, to a patient with gastrointestinal cancer who is being treated concurrently with UCN-01 thereby improving the effectiveness of the UCN-01 treatment. Alternatively, patients receiving imatinib or UCN-01 can be treated by concurrent administration of an IL-1 inhibitor or a crystalline TNFR2 polypeptide together with an IL-1 inhibitor, such as one of the inhibitors I L-1 described in WO 01/87328, which is incorporated herein by reference in its entirety. By these methods the crystalline TNFR2 polypeptide can be administered one or more times per week, for example, one, two or three times per week. A suitable mode of administration for the crystalline TNFR2 polypeptide is by subcutaneous injection. When the patient is an adult, the appropriate dose for the crystalline TNFR2 polypeptide injected includes 5-12 mg / m2 of body surface area, or 25 mg or 50 mg per dose. If the patient is a pediatric patient, the crystalline TNFR2 polypeptide can be administered by subcutaneous injection one or more times per week in a dose of 0.4 / kg of body weight, up to a maximum of 25 mg per dose.
Pulmonary Disorders A number of lung disorders can also be treated with the crystalline TNFR2 polypeptides, compositions and / or combination therapies. One such condition is adult respiratory distress syndrome (ARDS), which is associated with elevated TNF-alpha and can be activated by a variety of causes, including exposure to toxic chemicals, pancreatitis, trauma or other causes. The disclosed compounds, compositions and / or combination therapies of the invention are also useful for treating bronchopulmonary dysplasia (BPD); lymphangio-leiomyomatosis; pulmonary hypertension; chronic fibrotic lung disease of premature infants; and idiopathic bronchiectasis. Idiopathic bronchiectasis is a disease in which neutrophils mediate the degradation of the proteoglycan component of the bronchial matrix. Proinflammatory mediators in the bronchial secretions of patients with bronchiectasis, particularly TNF-alpha, are suspected to improve the degradative action of these neutrophils (Shum et al., Am J Respir Crit Care med 162: 1925-31 (2000). The present invention provides treatment for idiopathic bronchiectasis which comprises administering a crystalline TNFR2 polypeptide, such as a TNFR2: Crystalline Fc. Additionally, the compounds, compositions and / or combination therapies of the invention are used to treat occupational lung disease, which includes asbestosis, coal worker pneumoconiosis, silicosis, or similar conditions associated with long-term exposure of fine particles. In other aspects of the invention, the disclosed compounds, compositions, and / or combination therapies are used to treat pulmonary disorders, including chronic obstructive pulmonary disease (COPD) associated with chronic bronchitis or emphysema.; fibrotic lung disease, such as cystic fibrosis, idiopathic pulmonary fibrosis and radiation-induced pulmonary fibrosis; sarcoidosis, which includes pulmonary sarcoidosis; and allergies that include allergic rhinitis, contact dermatitis, atopic dermatitis and asthma. Cystic fibrosis is a condition characterized primarily by the accumulation of thick mucus, which predisposes the patient to chronic lung infections and obstruction of the pancreas, resulting in poor absorption of nutrients and poor nutrition. The crystalline TNFR2 polypeptides can be used to treat cystic fibrosis. If desired, treatment with crystalline TNFR2 polypeptides can be administered concurrently with corticosteroids, mucus thinning agents such as inhaled recombinant deoxyribonuclease 1 (such as PULMOZIMA® or TOBI® or other treatments for cystic fibrosis.) The TNFR2 polypeptide crystalline alone or in combination with IFN? -1b can be administered together with other treatments currently used to treat fibrotic lung disease Such additional treatments include glucocorticoids, azathioprine, cyclophosphamide, penicillamine, colchisine, supplemental oxygen, etc. Patients with fibrotic lung disease, such as IPF, often present with nonproductive cough, progressive dyspnea, and show a restrictive ventilatory pattern in pulmonary function tests.Chest radiographs reveal fibrotic accumulations in the lungs of patients.When treating acronym fibrotic lung disease With the methods described, sufficiency of treatment can be detected by observing a reduction in the patient's cough (when cough is present), or by using standard lung function tests to detect improvements in total lung capacity, Vital capacity, residual lung volume, or when administering an arterial blood gas determination that measures desaturation under exercise conditions, and which shows that the lung function of the patient has improved according to one or more of these measurements. Additionally, the improvement of the patient can be determined through chest radiography results that show that the progression of fibrosis in the lungs of patients has come to be stopped or reduced. Additionally, the crystalline TNFR2 polypeptides are useful for treating organ fibrosis when administered in combination with relaxin, a hormone which downregulates collagen production thereby inhibiting fibrosis, or when given in combination with agents that block the fibrogenic activity of TGF- H.H. Combination therapies using the crystalline TNFR2 polypeptide and recombinant human relaxin are useful, for example, to treat systemic sclerosis or fibrotic lung disease, which includes cystic fibrosis, ibriopathic pulmonary fibrosis, radiation-induced pulmonary fibrosis, and induced pulmonary fibrosis. for bleomycin.
Skin and Rheumatic Disorders Other embodiments provide methods for using the described TNFR2 crystalline polypeptides, compositions and / or combination therapies to treat a variety of rheumatic disorders. The use of TNF-alpha inhibitors in the treatment of rheumatoid arthritis is reviewed in Moreland, LW, 1991, J Rheumatol 26 Supp 57: 7-15, and the use of TNF-alpha inhibitors in the treatment of spondyropathy and ankylosing spondylitis. they are described in Schnarr et al., Clin Exp Rheumatol 20 (Supp.28): S126-129 and in Gorman et al., 2002, N Engl J Med 346 (18): 1349-1356, respectively. Conditions that can be treated with the crystalline TNFR2 polypeptides, compositions and / or combination therapies include: adult and juvenile rheumatoid arthritis; systemic lupus erythematosus; drop; osteoarthritis; Polymyalgia rheumatica; seronegative spondyloarthropathies, including ankylosing spondylitis; and Reiter's disease (reactive arthritis). The subject TNFR2 polypeptides, compositions, and / or combination therapies are also used to treat psoriatic arthritis and chronic Lime arthritis; the use of TNF-alpha inhibitors in the treatment of psoriatic arthritis is described in Ruderman, EM, 2002, Am J Manag Care 8: S171-S180 and in Salvarani et al., 2002, Clin Exp Rheumatol 20 (Suppl.28): S71-S75. Also treatable with these compounds, compositions, and / or combination therapies are Still's disease and uveitis associated with rheumatoid arthritis. Additionally, the compounds, compositions and / or combination therapies of the invention are used in the treatment of disorders that result in the inflammation of the voluntary muscle, which includes dermatomyositis and polymyositis. Furthermore, the compounds, compositions and / or combinations described herein are used to treat myositis of the body of sorádica inclusion, since the TNF-alpha can play an important role in the progression of the disease of this muscle. Additionally, the compounds, compositions and / or combinations described herein are used to treat multicentric reticuloistiocytosis, a disease in which the destruction of the joint and the papular nodules of the face and hands are associated with the excess production of proinflammatory cytokines by cells Multinucleated giants. The crystalline TNFR2 polypeptides, compositions and / or combination therapies of the invention can be used to inhibit hypertrophic burns, a phenomenon that is believed to result in part from the excessive secretion of TNF-alpha. The crystalline TNFR2 polypeptides can be administered alone or concurrently with other agents that inhibit hypertrophic burn, such as TNF-alpha inhibitors.
Disorders involving the skin or mucosal membranes are also treatable by using the described TNFR2 crystalline polypeptides, compositions and / or combination therapies. Such disorders include acantholytic diseases, which includes Darier disease, follicular keratosis, and pemphigus vulgaris. Also treatable with described TNFR2 crystalline polypeptides, compositions and / or combination therapies are acne; acne rosacea; alopecia areata; aphthous stomatitis, pemphigoid bolus; Burns; dermatitis herpetiforme; eczema; erythema, which includes erythema multiforme and bullous erythema multiforme (Stevens-Johnson syndrome); inflammatory skin disease; lichen planus; IgA linear bullous disease (chronic childhood dermatosis huullosa); loss of skin elasticity; ulcer of the mucosal surface; neutrophilic dermatitis (Sweet syndrome); pitiriasis rubra pilaris; psoriasis; pyoderma gangrenosum; and toxic epidermal necrolysis. In another embodiment, the described TNFR2 crystalline polypeptides are used to treat and prevent the recurrence of lipodermatosclerosis and chronic venous ulcers, which very often are located in the legs. Studies have shown that TNF-alpha can contribute to the pathogenesis of lipodermatosclerosis and chronic venous ulcers by activating the matrix (MMP2) metalloproteinase 2, and by inducing the production of TGF and other cytokines. Oxpentifillin and pentoxifylline have been shown to be effective in this configuration.
The described TNFR2 crystalline polypeptides, which include TNFR2: crystalline Fc or crystalline etanercept, can be used to treat chronic venous ulcers alone or in combination with oxpentifiline, pentoxifylline, GM-CSF, leptin, PDGF, bFGF, EGF, TGF, and / or IGF. These treatments will speed healing and prevent recurrences. The administration can be systemic or local. For local administration the crystalline TNFR2 polypeptide is applied topically in an ointment, lotion, gel or cream, or is injected perilesionally on or within about 10 centimeters of the ulcer.
Additional Disorders Methods are also used to deliver crystalline TNFR2 polypeptides, compositions and / or combination therapies to treat various disorders of the endocrine system. For example, the crystalline TNFR2 polypeptides are used to treat juvenile diabetes attack (which includes type of insulin-dependent and autoimmune diabetes) and also to treat mature diabetes attack (which includes obesity-mediated and non-insulin-dependent diabetes). Additionally, the subject compounds, compositions, and / or combination therapies are used to treat secondary conditions associated with diabetes, such as diabetic retinopathy, rejection of kidney transplantation in diabetic patients, insulin resistance mediated by obesity and renal failure, that in itself can be associated with proteinuria and hypertension. Other endocrine disorders are also treatable with these compounds, compositions and / or combination therapies including polycystic ovarian disease, X-linked adrenoleukodystrophy, hypothyroidism, and thyroiditis, which includes Hashimoto thyroiditis (i.e., autoimmune thyroiditis). The described TNFR2 crystalline polypeptides, such as TNFR2: Fc, compositions and / or combination therapies are additionally used to treat liver combinations such as hepatitis, which include acute alcoholic hepatitis, viral hepatitis or acute drug induced, hepatitis A, B and C, sclerosing cholangitis, autoimmune hepatitis, idiopathic portal hypertension, and inflammation of the liver due to unknown causes. The above liver diseases can be treated with a crystalline TNFR2 polypeptide, such as TNFR2: Fc, currently with other medications used to treat the same conditions. As an example, the crystalline TNFR2 polypeptides can be used to treat hepatitis C, which includes chronic hepatitis C, in patients who are concurrently treated with interferon-alpha (IFNalfa). The high expression of TNF-alpha in the liver interferes with the action of IFNalfa, thus interfering with the patient's response to IFNalfa treatment (Hong et al., 2001, FASEB J 15: 1595-1597). Treatments that can be administered concurrently with the crystalline TNFR2 polypeptides to treat hepatitis C include pegylated IFNalpha, ribavirin, or a combination of ribavirin and interferon-alpha or pegylated interferon-alpha. Portions of interferon-alpha suitable for concurrent use with crystalline TNFR2 polypeptides include IFN-alpha-2a (such as ROFERON®, Hoffmann-LaRoche), pegylated IFN-alpha-2a (such as PEGASYS®, Hoffmann-LaRoche), and pegylated IFN-alpha-2a or -2b as described in US20020127203A1, or the conjugates
Pegylated IFNalpha described in WO 9964016. In another embodiment, hepatitis C can be treated by concurrent administration of interferon-alpha and a crystalline TNFR2 polypeptide different from TNFR2: crystalline Fc, such as crystalline forms of lenercept or onercept. Gastrointestinal system conditions are also treatable with described crystalline TNFR2 polypeptides, compositions and / or combination therapies, including celiac disease; the use of TNF-alpha inhibitors in the treatment of Crohn's disease is described in Ricart et al., 2002, Drugs of Today 38 (11): 725-744. Additionally, the compounds, compositions and / or combination therapies of the invention are used to treat Crohn's disease; nausea associated with gastrointestinal disorders or other systemic disorders; Ulcerative colitis; linguistic gastroparesis; cholelithiasis (gallstones); pancreatitis, which includes chronic pancreatitis and lung injury associated with acute pancreatitis; and ulcers, which include gastric and duodenal ulcers. Also included are methods for using the subject crystalline TNFR2 polypeptides, compositions and / or combination therapies to treat disorders of the genitourinary system, such as glomerulonephritis, including autoimmune glomerulonephritis, glomerulonephritis due to exposure due to toxins or glomerulonephritis secondary to infections with haemolytic streptococcus. or other infectious agents. Also treatable with the compounds, compositions and / or combination therapies of the invention are urinary syndrome and its clinical complications (e.g., renal failure, anemia and hypertrophic cardiomyopathy) including uraemic syndrome associated with exposure to environmental toxins, drugs or other Causes. Additional conditions treatable with the compounds, compositions and / or combination therapies of the invention are complications of hemodialysis, prostate conditions, including benign prostatic hypertrophy, non-bacterial prostatitis and chronic prostatitis; and complications of hemodialysis. Additionally, the described TNFR2 crystalline polypeptides, compositions and / or combination therapies are used to treat various disorders involving hearing loss, such as those that are associated with abnormal TNF-alpha expression. One of these is the inner ear or hearing loss associated with the cochlear nerve that is believed to result from an autoimmune process, that is, autoimmune hearing loss. This condition is currently treated with steroids, methotrexate and / or cyclophosphamide, which can be administered concurrently with TNFR2: crystalline Fc or another crystalline TNFR2 polypeptide.
Also treatable with the described TNFR2 crystalline polypeptides, compositions and / or combination therapies is cholesteatoma, a disorder of the middle ear, often associated with hearing loss. Additionally, the subject invention provides crystalline TNFR2 polypeptides, compositions and / or combination therapies for the treatment of non-arthritic medical conditions of bones and joints. This encompasses osteoclast disorders that lead to bone loss, such as but not limited to osteoporosis, which includes postmenopausal osteoporosis, periodontitis that results in loosening or loss of teeth and loosening of prosthesis after joint replacement (generally associated with an inflammatory response to use waste). This last condition is also called "orthopedic implant osteolysis". Other conditions treatable by administering crystalline TNFR2 polypeptides such as TNFR2: Crystalline Fc include temporal joint mandibular dysfunction (TMJ) and bone loss due to hypercalcemia of cancer that includes bone metastasis, such as, for example, may occur in melanoma or carcinoma of the lung, breast, lung, squamous cell carcinoma, neck and head cancer, kidney cancer, or prostate cancer. Disorders associated with transplantation are also treatable with the described TNFR2 crystalline polypeptides, compositions and / or combination therapies, such as host disease versus graft, and other complications resulting from solid organ transplantation including transplantation of heart, liver, lung, skin, kidney and other organs. Such crystalline TNFR2 polypeptides can be administered, for example, to prevent or inhibit the development of bronchiolitis obliterans, such as bronchiolitis obliterans after lung transplantation and bronchiolitis obliterans which causes pneumonia. Patients suffering from autologous hematopoietic stem cell transplantation in the form of peripheral blood stem cell transplantation may develop "graft syndrome" or "ES", which is a generally and adversely self-limiting response that occurs near the time of the hematopoietic graft that can result in lung deterioration. ES can be treated with inhibitors of I L-8 or TNF-alpha (such as TNFR2: Crystalline Fc or other crystalline TNFR2 polypeptides), or with a combination of inhibitors against both of these cytokines. The described TNFR2 crystalline polypeptides are also useful for treating or preventing graft failure, such as rejection of bone marrow graft or failure of the recipient body to accept other types of grafts, such as corneal transplantation, or such as liver or other transplants. of solid organs, in which rejection of the graft is often accompanied by high levels of TNF-alpha and I L-10. The graft rejection can be treated with a combination of crystalline TNFR2 polypeptide and an IL-10 inhibitor. Ocular disorders with the described TNFR2 polypeptides, compositions and / or combination therapies, including regmatogenous retina separation, and inflammatory eye disease, and inflammatory eye disease associated with cigarette smoking as well as with associated macular degeneration are also treatable. with cigarette consumption or associated with old age. The crystalline TNFR2 polypeptides such as TNFR2: Crystalline Fc, the compositions and / or combination therapies described herein are useful for treating disorders that affect the female reproductive system. Examples include, but are not limited to, multiple implant failure / fertility; fetal loss syndrome; loss of human IV embryo (spontaneous abortion); preeclamptic pregnancy or eclampsia; and endometriosis. Additionally, the disorders of crystalline TNFR2 polypeptides described, compositions and / or combination therapies are useful for treating obesity, which includes treatment to lead to a reduction in leptin formation, or weight gain associated with the use of antidepressant drugs. As well, the compounds, compositions, and / or combination therapies of the invention are used to treat neurogenic pain, sciatica, symptoms of aging, severe reactions to drugs, (for example, ll-2 toxicity or bleomycin-induced neuropathy and fibrosis), or suppress the above inflammatory response, during, after the transfusion of blood cells in cardiac surgery, or other surgery, or in the treatment of a traumatic injury to a limb or joint, such as traumatic knee injury. Several other treatable medical disorders with described TNFR2 crystalline polypeptides, compositions and / or combination therapies include; multiple sclerosis, Behcet syndrome; Sjogren syndrome; hemolytic autoimmune anemia; beta thalassemia; Lateral amyotrophic sclerosis (Lou Gehrig disease); Parkinson's disease; and tenosynovitis of unknown origin, as well as various autoimmune disorders or diseases associated with hereditary deficiencies. Additionally, the object crystalline TNFR2 polypeptides, compositions and / or combination therapies are used to treat hereditary conditions such as Gaucher's disease, Huntington's disease, linear IgA disease, and muscular dystrophy. In yet another embodiment of the invention, the crystalline TNFR2 polypeptides described herein are used to treat autism spectrum disorder and other pervasive developmental disorders. It has been shown that proinflammatory cytokines, including TNF-alpha and IL-1, are produced in a subset of autistic patients, indicating that these patients have excessive innate immune responses and / or aberrant reduction of regulatory cytokines for T cell responses. Thus, methods for treating autism spectrum disorder are administered here by administering a crystalline TNFR2 polypeptide such as TNFR2: Crystalline Fc.
Additional Combination Therapies Several other medications used to treat the diseases described herein can also be administered concurrently with compositions comprising crystalline TNFR2, or compositions prepared using crystalline TNFR2. Such medications include: antivirals; antibiotics; analgesics; non-steroidal anti-inflammatory drugs (NSAIDS); antirheumatic drugs that modify the disease (DMARD); corticosteroids; topical steroids, systemic steroids, (for example, predmisons); cytokines; inflammatory cytokine antagonists; T cell surface proteins against antibodies; oral retinoids; salicylic acid and hydroxyurea. Suitable analgesics for such combinations include: acetaminophen, codeine, napsylate propoxyphene, oxycodone hydrochloride, hydrocodone bitartrate, and tramadol.
NSAIDs suitable for the subject treatments include: salicylic acid (aspirin) and salicylate derivatives; ibuprofen; indomethacin; celecoxib (CELEBREX®); rofecoxib (VIOXX®); valdecoxib (BEXTRA®); quetorolac; Nambumetone; piroxicam; naproxen; oxaprozin; sulindac; quetoprofen; diclofenac; and other COX-1 and COX-2 inhibitors, propionic acid derivatives, acetic acid derivatives, fumaric acid derivatives, carboxylic acid derivatives, butyric acid derivatives, oxican, pyrazoles and pyrazolones, including newly developed anti-inflammatories. DMARDs suitable for such combinations include: azathioprine, cyclophosphamide, cyclosporine, hydroxychloroquine sulfate, methotrexate, leflunomide, minocycline, penicillamine, sulfasalasin,. and gold compounds such as oral gold, gold sodium thiomalate and aurothioglucose. Examples of cytokine inhibitors that can be used in combination with crystalline TNFR2 include, for example, antagonists of TGBβ, IL-6, or I L-8. Crystalline TNFR2 polypeptides can also be administered in combination with the cytokines GM-CSF, IL-2, and / or inhibitors of protein kinase A type 1 to improve the proliferation of T cells in HIV-infected patients receiving antiretroviral therapy. Additionally, the crystalline TNFR2 polypeptides can be combined with inhibitors of I L-13 to treat Hodgkin's disease. Nerve growth factors can also be combined with crystalline TNFR2 polypeptides to treat certain conditions. Such conditions include neurodegenerative diseases, spinal cord injury and multiple sclerosis. Other conditions treatable with this combination are glaucoma and diabetes. Additionally, the crystalline TNFR2 polypeptides can be administered in combination with antimalarials or colchicine. Other compounds suitable for treating the diseases described herein in combination with crystalline TNFR2 polypeptides include small molecules such as thalidomide or thalidomide analogs, pentoxifylline, or metalloproteinase (MMP) matrix inhibitors or other small molecules. Suitable MMP inhibitors for this purpose include, for example, those described in U.S. Pat. No. 5,883,131,5,863,949, and 5,861,510 as well as the mercapto alkyl peptidyl compounds described in U.S. Pat. 5,872,146. Other small molecules capable of reducing the production of TNF-alpha, include, for example, the molecules described in U.S. Pat. No. 5,508,300, 5,596,013, and 5,563,143, any of which can be administered in combination with the crystalline TNFR2 polypeptides. Additional useful molecules in combination with the crystalline TNFR2 polypeptides to treat the diseases described herein include the MMP inhibitors described in U.S. 5,747,514, U.S. 5,691,382, as well as the hydroxamic acid derivatives described in U.S. 5,821,262. The diseases described herein can also be treated with combination therapies including small molecules that inhibit phosphodiesterase IV and the production of TNF-alpha, such as substituted oxime derivatives (WO 96/00215), quinoline sulfonamides (US 5,834,485), derivatives of aryl furan (WO 99/18095) and heterorobicyclic derivatives (WO 96/01825; GB 2 291 422 A). Also useful in combination with the crystalline TNFR2 polypeptides are the thiazolo derivatives that suppress TNF-alpha and IFN? (WO 99/15524), as well as xanthine derivatives that suppress TNF-alpha and other proinflammatory cytokines (see, for example, U.S. 5,118,500, U.S. 5,096,906, and U.S. 5,196,430). Additionally small molecules useful for treating conditions described herein concurrently with crystalline TNFR2 polypeptides include those described in U.S. 5,547,979. Additionally, crystalline TNFR2 polypeptides can be combined with a second TNF-alpha antagonist, which includes an antibody to TNF-alpha or TNF-alpha receptors, a TNF-alpha-derived peptide that acts as a competitive inhibitor of TNF-alpha (such as described in US 5,795,859 or US 6,107,273), a soluble TNFR different from the fusion Ig protein, or other molecules that reduce endogenous TNF-alpha levels, such as antisense oligonucleotides or ribozymes that inhibit the production of TNF-alpha or inhibitors of TNF-alpha that convert enzymes (see for example, US 5,594,106), or any of the small molecules or inhibitors of TNF-alpha that were described above, which include pentoxifylline or thalidomide or derivatives thereof. Thalidomide or thalidomide derivatives can be administered concurrently with the crystalline TNFR2 polypeptides to treat, for example, oncological and hematological disorders. Examples of such disorders, any of which can be treated with the crystalline TNFR2 polypeptides alone, include host disease versus graft, myelodysplastic syndromes, aplastic anemia, vasocclusive sickle cell crisis, acute myelogenous leukemia (AML), chronic lymphocytic leukemia (CLL), leukemia by tricholeucites, paraneoplastic syndrome of cachexia and hypercalcemia, multiple myeloma and POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes), myelofibrosis / myeloid metaplasm, Kaposi carcinoma, cachexia associated with cancer, amyloidosis, anemia of disease chronic, squamous cell carcinoma, thrombotic thrombocytopenic purpura (TTP), autoimmune hemolytic anemia, and beta thalassemia. In one embodiment of the invention, the crystalline TNFR2 polypeptide used in combination with thalidomide is TNFR2: crystalline Fc or crystalline etanercept. Additionally, the subject invention provides methods for treating a human patient in need thereof, the method involves administering to the patient a therapeutically effective amount of a crystalline TNFR2 polypeptide and an IL-4 inhibitor, as described in U.S. 2001/0021380 A1, which is incorporated herein by reference in its entirety. Conditions effectively treated by a combination of a crystalline TNFR2 polypeptide and an inhibitor I L-4 includes asthma, chronic obstructive pulmonary disease, pulmonary alveolar proteinosis, pleomycin-induced neuropathy and fibrosis, radiation-induced pulmonary fibrosis, cystic fibrosis, collagen accumulation in the lungs, ARDS; various skin disorders, including but not limited to dermatitis herpetiformis (Duhring's disease), atopic dermatitis, contact dermatitis, urticaria (which includes chronic idiopathic urticaria), and autoimmune blister-forming diseases, including pemphigus vulgaris and pemphigoid bullous myasthenia gravis, sarcoidosis, which includes pulmonary sarcoidosis, scleroderma, reactive arthritis, hyper IgE syndrome, multiple sclerosis, and idiomatic hypereosinophilic syndrome; allergic reactions to medication, and as an adjuvant for allergic immunotherapy. In certain embodiments, combinations of crystalline TNFR2 polypeptides and IL-4 inhibitors are administered one or more times per week by subcutaneous injection or by aerosolized pulmonary administration, for example by nebulizer. Other treatments for the diseases described herein include administering crystalline TNFR2 polypeptides concurrently with compounds that block the binding of RANK and RANK ligand., such as antagonistic antibodies against RANK or RANK ligand, osteoprotegerin or soluble forms of RANK, including RANK: Fc, and soluble forms of RANK ligand that do not activate RANK. In one embodiment of the invention, antibodies that specifically bind to human RANKK are administered concurrently with crystalline TNFR2 polypeptide, such as TNFR2: Crystalline Fc. The soluble forms of RANK suitable for these combinations are described, for example, in U.S. 6,017,729. Concurrent administration of the crystalline TNFR2 polypeptides together with the RANK: Fc or osteoprotegerin is useful to prevent bone destruction in various configurations including but not limited to osteoporosis, multiple myeloma or other modalities that cause bone degeneration, or therapy antitumor that helps the prevention of metastasis to the bone, or destruction of bone associated with waste by uses of prosthesis or with ediodontitis. Tumors that are treatable with a combination of a crystalline TNFR2 polypeptide and a RANK inhibitor include breast cancer, lung cancer, melanoma, bone cancer, squamous cell carcinoma, neck and head cancer, kidney cancer, prostate cancer, and cancers associated with hypercalcemia.
Additional Uses Transfection of lymphocytes without viral vectors can lead to apoptosis of the target cell through a pathway mediated by CD95 and TNF-alpha (see, for example, Ebert et al., Citokines, Cell &Mol Ther 5: 165 -73 (1999) .The crystalline TNFR2 polypeptides, such as TNFR2: Fc, can be used alone or in combination with a CD95 inhibitor, such as a CD95 antibody, to inhibit this apoptosis.This treatment will increase gene transfer to lymphocytes when viral vectors are not used, particularly when using receptor-mediated or liposome-mediated gene transfer methods, such treatments will improve the incorporation of the exogenous gene into the target cells. Additionally, the present compositions can also be used to manufacture one or more medicaments for treatment or improvement of the conditions that the crystalline TNFR2 polypeptide is intended to treat.
The following examples are offered for further illustration of the invention, but do not constitute as imitating the scope of this. Example 1 Method for Crystallization of ENBREL® (etanercept)
The etanercept polypeptide consists of a domain portion of human tumor receptor necrosis factor 2 (TNFR p75) fused to a portion of human immunoglobulin G1 (IgG1), as described above. The etanercept polypeptide was prepared by expressing the DNA construct encoding etanercept in mammalian host cells and then simplified for substantial homogeneity. By the following crystallization experiments the etanercept polypeptide was suspended in a phosphate buffer. Crystallization of etanercept was achieved by using a crystallization selection (PEG / Lic Gray Screen, Hampton Research, Aliso Viejo, CA), which employs a method for crystallization of molecules known as "hanging drop" vapor diffusion. A drop composed of a mixture of the polypeptide sample and the crystallization reagent (the "crystallization buffer" or the "mother liquor") is deposited on the underside of a sialanized strip and then the drop on the strip is sealed with grease and placed on a 24-well VDX tray that creates equilibrium vapor with a liquid reagent reservoir. To achieve equilibrium, the water vapor exchanges between the drop and one milliliter of a reservoir solution in the well of the tray. Because the water leaves the drop, the polypeptide sample experiences an increase in the relative concentration which can eventually lead to supersaturation. This is the increased concentration of the polypeptide sample that is required for crystallization to take place. Typically the drop contains a lower concentration of reagent than the reservoir, and typically, the drop contains half the concentration of the reagent in the reservoir, since equal volumes of sample and reagents are mixed to form the drop. In those experiments, the initial polypeptide concentration in the drop was usually 25.48 mg / mL or 50.96 mg / mL, but crystallization was also observed at etanercept polypeptide concentrations of approximately 6 mg / mL, and can be obtained in higher concentrations such as 100 mg / mL, or at lower concentrations of polypeptide such as about 3 mg / mL, but at lower concentrations, incubation for long periods for crystal growth may be required, depending on the initial size of the drop. The crystallization selection was established in 24-well VDX polypropylene tissue culture trays. Each position in the VDX tray contains 1 mL of reactive reservoir, with the reservoir of reagent in each well that differs in composition from that in the other wells, to establish a test of different crystallization buffer conditions. One microliter of polypeptide solution in each concentration of polypeptide was added to 1 microliter of reservoir solution to form the drops. The trays were incubated at 5 ± 3 degrees C or at room temperature (20 ± 3 degrees C). The crystals appeared in approximately 48 hours in some of the wells incubated at room temperature, and growth continued during the following days. In the initial selections, crystals were obtained in the following conditions, using a concentration-etanercept of 25.48 mg / mL or a concentration of 50.96 mg / mL: 1. 1.0M lithium chloride, 0.1M HEPES ph 7.0; 30% polyethylene glycol 6000. 2. 1.0M lithium chloride, 0.1M Tris-HCL ph 8.0; 30% polyethylene glycol 6000. 3. 1.0M lithium chloride, 0.1M Bicine pH 9.0; 30% polyethylene glycol 6000. 4. 0.2M lithium sulfate, 0.1M Tris-HCl pH 8.5, 30% polyethylene glycol 4000. 5. 0.2M lithium sulfate, 0.1M Tris-HCl pH 8.5, 25% polyethylene glycol 3350 6. 0.5M lithium sulphate, 0.1M Tris-HCl pH 8.5.
The etanercept crystals formed under the first three conditions above formed bars or groups of bars approximately 0.1-0.2 mm in length, and were often accompanied by an amorphous precipitant. The etanercept crystals formed under the conditions of lithium sulphate formed bars of approximately 0.1-0.2 mm in length, and were produced without seeing the amorphous precipitate under the conditions of lithium chloride. Some of the etanercept crystals were tested by X-ray diffraction and did not show a salt-like diffraction pattern, a result consistent with such crystals containing the polypeptide material. Some of the etanercept crystals were solubilized and their polypeptide content was partially sub-sequenced by seven cycles of automated Edman degradation; a partial amino acid sequence of 3-4 pmol was obtained from these crystals and it was confirmed that they hunt the N-terminal portion of the etanercept sequence (LPAQVAF, see amino acids 1 to 7 of Sec.
No.:4) Figure 1 is a photograph of etanercept crystals formed from a polypeptide solution containing 50.96 mg of etanercept per milliliter, with a crystallization reservoir buffer of 0.1 M HEPES pH 7.0, 30% PEG 6000, 0.7 M chloride of lithium; after seven days at room temperature the crystals were manually harvested, washed extensively in the buffer of the previous reservoir, and a photograph was taken. The crystals of this group were presented for the N-terminal amino acid sequence analysis described above. Another crystallization condition-1M lithium sulfate, 0.1M Tris HCl pH 8.5, 0.01 M nickel chloride-produced crystals; however, the polypeptide content of these crystals was not confirmed and therefore according to this particular combination of conditions it is thought that the salt crystals have been formed. Based on these results, each of the three parameters of the first three conditions above (Lie concentration, pH, and (PEG) 6000 polyethylene glycol expressed as% (weight / volume)) was varied in additional experiments, resulting in crystal formation in each drop in the additional experimental trays. The lithium chloride conditions between 0.7M and 1.2M, PEG 6000 between 22% and 32%, and 0.1M HEPES values between pH 6.8 and 7.3 all resulted in successful crystallization in approximately 48 hours at room temperature, in concentrations of 25.48 and 50.96 mg / mL. Additional experiments expanded the range of successful crystallization conditions to include 0.2M to 1.2M Lie, and 16% to 32% PEG 6000, although crystallization of etanercept can not occur in each combination of conditions that includes 0.2M Lie, and / or etanercept crystals that may be larger to form when 0.2M Lie is used. Therefore, all combinations of the following conditions-lithium chloride concentrations between 0.3M and 1.2M, concentrations of PEG 6000 between 16% and 32%, and pH values HEPES 0.1M between pH 6.8 and 7.3 - are considered are suitable conditions for etanercept crystallization; Additionally, conditions containing between 0.2M and 0.5M lithium sulfate, 0.1M Tris-HCl at pH about 8.5, and optionally include up to 30% PEG in the varying size of PEG 3350-PEG 4000, are considered to be suitable conditions for etanercept crystallization. Example 2 Additional Methods for Crystallization of ENBREL® (etanercept)
The method of "hanging drops" of crystallization, as described in the previous example, is used to prepare additional crystals of etanercept. Etanercept was reconstituted from commercially available ENBREL® iiofilized powder as product instructions; a bottle of lyophilized powder of ENBREL® contains 25 mg of etanercept, 40 mg of mannitol, 10 mg of sucrose, and 1.2 mg of tromethamine, which is reconstituted with 1 ml of sterile bacterial water for injection, USP (which contains 0.9% benzyl alcohol). The reconstituted etanercept solution was dialyzed into water by using a 10,000 molecular weight cut dialysis cassette, and then concentrated to 100 mg / mL using a centrifugal 10,000 molecular weight cut-off filter. Each crystallization well contained 1.0 mL of a particular crystallization reagent, as listed below, in the reservoir. The drops were made by adding 1 microliter of 100 mg / mL of etanercept solution to 1 microliter of that crystallization reagent. The crystals grew at room temperature (approximately 22 degrees C); the needle-like crystals of etanercept of about 100 micrometers in length formed in all the crystallization reagents are listed below, in some cases as little as two days, and in other cases over a period of two or four weeks.
The additional crystallization experiments, needle-like crystals of etanercept about 100 micrometers in length formed over a period of two to four weeks according to the following crystallization conditions:
Example 3 Additional Expansion of Crystallization Conditions
Steam diffusion crystallization methods, such as the "droplet drop" method described for the crystallization of etanercept in Example 1 above, can be varied in order to achieve crystallization of polypeptides such as TNFR2 polypeptides. For example, other sample volumes of polypeptide-related reagents can be mixed to vary the difference in reagent concentration between the drop and the reservoir, and also the initial polypeptide concentration in the drop. Mixing one part of the reagent to nine parts of the polypeptide sample will produce a drop with an initial concentration of reagent that is 0.1 times that of the concentration of the reservoir reagent. In certain embodiments of the invention, the initial concentration of crystallization reagent in the drop is about 0.05, 0.1, 0.2, 0.3, 0.4, 0.45, 0.5, 0.55, 0.6, 0.7, 0.8, 0.85, 0.9, or 0.95 times at that of the concentration of the crystallization reagent in the reservoir. The initial polypeptide concentration in the drop can be at least as low as about 6 mg / mL and at least as high as 100 mg / mL and possibly as high as 120 mg / mL; lower concentrations of polypeptide such as 3 mg / mL may form crystals, but may require longer incubation times before the crystals can be detected.
Further expansion of the crystallization conditions may produce additional conditions that are appropriate for obtaining etanercept crystals or other TNFR2 polypeptides, as described below. For example, combinations of a salt condition, a buffer condition, an optional PEG condition, and an optional cofactor condition can be made, wherein each condition is selected from the corresponding group of the conditions described below.
Example 4 Test Properties of the Crystal Polypeptides
After the polypeptide crystals are formed, they can be subjected to various analyzes to confirm their polypeptide content to further examine their physical structure. For example, if the necessary individual crystals can be removed from the crystallization solution and washed with aqueous or organic solvents or additives, then dried (for example, by drying, by air when a stream of inert gas passes over the glass, by lyophilization , or vacuum). The crystals can be isolated, removed from the crystals that grow in droplet, and then assembled for X-ray diffraction. As another example, the polypeptide crystals can be removed from the crystallization solution and washed or rinsed, or most of the Crystallization solution can be removed from the crystals and replaced with a different solution. In this way, the particular salt that is used in the crystallization process can be replaced in the crystal lattice with a different salt. In one embodiment of the dimension, the crystallized TNFR2 polypeptides such as crystalline etanercept are separated from the crystallization buffer and placed in a solution containing a sodium, potassium, or magnesium salt (eg, sodium acetate, sodium chloride, sodium citrate, sodium phosphate, sodium sulfate, potassium chloride, potassium citrate, or magnesium sulfate). By X-ray diffraction, the replacement solution can contain heavy atoms useful in determining the atomic coordinates of the crystallized polypeptide. As a further embodiment, TNFR2 polypeptides can be co-crystallized with their ligand, for example etanercept can be co-crystallized with TNF-alpha, for the determination of the detailed structure of the TNFR-ligand interaction. In an additional example, the polypeptide crystals can be removed from the crystallization solution and solubilized in a suitable buffer for further testing, such as a buffer containing SDS for analysis of the polypeptide that has been crystallized by gel electrophoresis. Methods for protein analysis by gel electrophoresis are well known and include gel dyeing with silver or blue dye, and comparing the electrophoretic migration of the polypeptide that has been crystallized with the migration of polypeptide markers of known molecular weight. In another method, the polypeptide is visualized on the gel by the use of a labeled antibody that specifically binds to the polypeptide. Polypeptides that have been crystallized can also be solubilized in buffers appropriate for amino acid sequencing by Edman degradation, for mass spectrometry, for spectrographic scattering, refraction, diffraction, or absorption studies, or for labeling the polypeptide by adhesion of a molecule labeled to the polypeptide. Example 5 ENBREL® Crystal Protein Content Assay (etanercept) The crystallization "droplet drop" method, as described in Example 1 above, is used to prepare additional etanercept crystals. Each well contains 100 microliters of the crystallization reagent in the reservoir; the crystallization reagent in this experiment was 0.2M of ammonium acetate, 0.1M Tris pH 8.5, and 45% of 2-methyl-2,4-pentanediol (MPD). Etanercept was placed into a solution containing 25 mM sodium phosphate pH 6.3, 100 mM NaCl, then concentrated to 29-30 mg / mL, for example, at 29.6 mg / mL. The drops were made by adding 1 microliter of this 29 mg / mL solution of etanercept to 1 microliter of the crystallization reagent, for final etanercept concentration in the drop of approximately 14.5-15 mg / mL. The final concentration of etanercept in the drug was found to be an important factor in achieving crystallization according to these particular crystallization conditions, a final etanercept concentration of approximately 15 mg / mL is effective for crystallization in repeated experiments, whereas Final concentrations of less than 10 mg / mL or greater than 25 mg / mL were not effective. The drops were allowed to exchange steam with reagent in the reservoir for approximately one to three weeks at room temperature (20 ± 3 degrees C). The crystals, usually from two to four independent nucleations per drop, formed and look like multirams or dendritic structures with numerous projections or branches that leave the main structure. The overall dimensions of each intact branch was about 50 micrometers in length of the nucleation center, about 30 micrometers wide, and about 10 micrometers in thickness or depth. One such branch was removed from the glass with a nylon ring, washed with the above crystallization reagent and washed in three series, solubilized in Laemmli 4XSDS buffer, and then placed in the well of a SDS polyacrylamide gel and underwent electrophoresis. After electrophoresis the gel was stained with silver, and there is a silver-stained band clearly visible in the path that runs from the crystallized protein that migrates to the same extent as the protein in the etanercept preparation used to produce the crystal. This SD polyacrylamide gel electrophoresis assay was repeated using other crystal branches produced in the same experiments, and the dyeing of a band of solubilized crystalline material, with the same electrophoretic migration as etanercept, was also achieved using blue dyeing Coomassie Therefore, the crystals that formed from the solution contain material that appears to be etanercept, because it migrates on a SDS polyacrylamide gel and produces a protein band on the gel in the same way as a known sample does. of protein etanercept. Example 6: Biological Activity Assay of Crystallized Polypeptides As described in the previous example, the polypeptide crystals can be coated from the crystallization solution, optionally placed in a different solution, washed, and / or dried to remove the buffer. crystallization, and then solubilized in an appropriate solution for further testing. The biological activities of TNFR2 polypeptides can be tested by using any of a number of assays, for example, binding assays to determine the ability of previously-crystallized TNFR2 (ie reconstituted TNFR2 polypeptide) to bind to its ligand. The following examples illustrate assays for measuring the biological activity of those TNFR2 polypeptides that bind to TNF-alpha, such as etanercept (see for example, Mohier et al., 1993, J Immunol 151: 1548-1561), but those skilled in the art. the art will recognize that such assays can be modified for use in the measurement of the biological activities of other TNFR2 polypeptides.
Binding Competition Assay Human labeled TNF-alpha such as [125l] TNF-alpha at 0.5 nM is incubated in binding medium (RPMl 1640, 2.5% BSA, 50mM HEPES pH 7.4, 0.4% NaN3) for two hours at 4 C grades with serially diluted competitive binding agents (eg, etanercept reconstituted in crystalline form, or another TNFR2 binding polypeptide TNF-alpha that has been reconstituted from the crystalline form, or unlabeled human TNF-alpha, or noncrystallized etanercept as a control) and 2x106 U937 cells. Duplicate aliquots are subsequently removed, centrifuged through a mixture of eftalate oil to separate bound and free ligand, and radioactivity [125 l] TNF-alpha) is measured using a gamma counter. Non-specific binding values are determined by the inclusion of an unlabeled 200X molar excess TNF-alpha and subtracted from the total binding data to produce specific binding values (see for example Park et al., 1990, J Exp Med 171 : 1073-1089).
Rescue of LPS-Induced Mortality Injection of a lethal dose of LPS (lipopolysaccharide) raises serum TNF-alpha levels in mice, which leads to mortality if a sufficient amount of an agent neutralizes the effects of TNF-alpha either it is administered (see for example Mohier et al., 1993, J Immunol 151: 1548-1561). LPS, such as bacterial LPS derived from E. coli, is resuspended in 10 mg / mL in sterile saline and stored at -20 degrees C in small aliquots. The LPS is diluted to the appropriate concentration and sonicated for one minute before injection. Mice such as female BALB / c mice (18 to 20g) are injected intravenously with a LD60 to LD100 dose of LPS (300 to 400 micrograms) in 0.2 mL of saline. The LPS is injected either alone or in conjunction with reconstituted etanercept from the crystalline form, or another TNFR2-binding TNF-α polypeptide that has been reconstituted from the crystalline form, or control proteins such as non-crystallized etanercept or Human IgG Survival is monitored for at least 5 days. The presence of the active reconstituted TNF-α binding TNFR2 polypeptide is indicated by the increased survival of mice injected with LPS, when a sufficient amount of the reconstituted TNF-α binding TNFR2 polypeptide is administered. The present invention has been described in terms of particular embodiments found or proposed to comprise certain forms for the practice of the invention. It will be appreciated by those skilled in the art that, in light of the present disclosure, numerous modifications and changes may be made to the particular embodiments exemplified without departing from the proposed scope of the invention. SEQUENCES PRESENTED IN THE SEQUENCE LIST
Claims (27)
1. A crystal of etanercept.
2. A crystal of etanercept as described in claim 1, wherein the crystal is in the form of a rod.
3. A crystal of etanercept as described in claim 1, wherein the crystal has a maximum length of between 0.05 millimeters and 1.5 millimeters.
4. A crystal of etanercept as described in claim 1, wherein the crystal has a maximum length of between 0.05 millimeters and 0.3 millimeters.
5. A crystal of etanercept as described in claim 1, wherein the crystal comprises a salt selected from the group consisting of ammonium acetate, ammonium phosphate, ammonium sulfate, hydrogen diammonium phosphate, lithium chloride, lithium sulfate , magnesium sulfate, potassium chloride, potassium citrate, potassium phosphate, sodium acetate, sodium chloride, sodium citrate, sodium phosphate, and sodium sulfate.
6. A crystal of etanercept as described in claim 1, wherein the crystal comprises a salt selected from the group consisting of ammonium acetate, ammonium phosphate, diammonium hydrogen phosphate, and sodium chloride.
7. A method for making a crystal of etanercept, wherein the method comprises combining a polypeptide solution of etanercept with a crystallization buffer comprising a salt.
The method of claim 7, wherein the combination is placed in vapor equilibrium with a reservoir of crystallization buffer.
The method of claim 7, wherein the crystallization buffer has a pH between 4.0 and 10.5.
The method of claim 7, wherein the salt is selected from the group consisting of ammonium acetate, ammonium phosphate, ammonium sulfate, diammonium hydrogenphosphate, lithium chloride, lithium sulfate, magnesium sulfate, chloride of potassium, potassium citrate, potassium phosphate, sodium acetate, sodium chloride, sodium citrate, sodium phosphate, and sodium sulfate.
The method of claim 7, wherein the salt concentration in the crystallization buffer is between 0.04M and 1.2M.
The method of claim 7, wherein the crystallization buffer further includes 2-methyl-2,4-pentanediol (MPD) or polyethylene glycol (PEG).
The method of claim 7, further comprising removing a portion of the crystallization buffer after the crystals have been formed.
The method of claim 13, wherein the portion of the crystallization buffer is removed by centrifugation.
15. The method of claim 13, wherein the crystals are placed in a solution containing an organic additive.
16. The method of claim 13, further comprising adding an excipient.
The method of claim 16 wherein the excipient is selected from the group consisting of sucrose trehalose, or sorbitol.
18. The method of claim 15 wherein the organic additive is ethanol or isopropanol.
19. The method of claim 7, further comprising drying the crystals that have been formed.
The method of claim 19 wherein the crystals are dried by exposure to air, or by exposure to a vacuum, or by exposure to nitrogen gas.
21. A crystal of etanercept produced by the method of any of claims 7 to 20.
22. A composition comprising etanercept in crystalline form.
23. A composition produced by reconstituting crystalline etanercept.
24. The use of an etanercept crystal as in any one of claims 1 to 21 or a composition as in any of claims 22-23 in the preparation of a medicament.
25. The use of claim 24 wherein the medicament is for treating a condition characterized by excessive TNF-alpha levels.
26. The use of claim 25 wherein the medicament reduces the levels of TNF-alpha in the serum or tissues of the subject.
27. The use of claim 25 wherein the condition is rheumatoid arthritis, psoriatic arthritis, psoriasis, or ankylosing arthritis.
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