EP1278699A1 - Peptides and compounds that bind to the il-5 receptor - Google Patents
Peptides and compounds that bind to the il-5 receptorInfo
- Publication number
- EP1278699A1 EP1278699A1 EP99965307A EP99965307A EP1278699A1 EP 1278699 A1 EP1278699 A1 EP 1278699A1 EP 99965307 A EP99965307 A EP 99965307A EP 99965307 A EP99965307 A EP 99965307A EP 1278699 A1 EP1278699 A1 EP 1278699A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- compound
- patient
- seq
- effective amount
- therapeutically effective
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/52—Cytokines; Lymphokines; Interferons
- C07K14/54—Interleukins [IL]
- C07K14/5409—IL-5
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Definitions
- the present invention provides peptides and compounds that bind the interleukin 5 receptors (IL-5R), methods for assaying interleukin 5 (IL-5), and methods for inhibiting the binding of IL-5 to the IL-5R.
- IL-5R interleukin 5 receptors
- the invention has application in the fields of biochemistry and medicinal chemistry and particularly provides IL-5 antagonists for use in the treatment of human disease.
- Interleukin-5 is a lymphokine secreted by T cells and mast cells having biological activities on B cells and eosinophils.
- IL-5 is a selective signal for the proliferation and differentiation of the eosinophilic lineage.
- IL-5 function shows analogies with colony-stimulating factors for other myeloid lineages.
- human (h) IL-5 is very potent in the activation of human eosinophils. See Lopez et al., J. Exp. Med.
- IL-5 mediates its activity through a cell membrane receptor-complex. This complex has been characterized physicochemically in both the murine and human system.
- Mouse pre-B cell lines depending on IL-5 for their growth have been developed from bone marrow and are used for IL-5 receptor analysis. See Rolink et al., J Exp. Med. 169:1693-1701 (1989).
- the human IL-5 receptor can be studied on a subclone of the promyelocytic cell line HL60 induced towards eosinophil differentiation. See Plaetinck et al., J. Exp. Med.
- cross-linking studies reveal the presence of two polypeptide chains involved in IL-5 binding, i.e., IL-5R- ⁇ and IL-5R- ⁇ chains.
- IL-5R- ⁇ and IL-5R- ⁇ chains devos et al., Canadian Patent Publication 2,058,003 describes a recombinant ⁇ chain of human IL-5R or parts thereof, DNA-sequences coding for such a receptor or parts thereof, and host cells transformed with such vectors.
- Takatsu et al. European Patent Publication 475,746 provides an isolated cDNA sequence coding for murine and human IL-5 receptor.
- the extracellular domain (ECD) of the human IL-5R- ⁇ chain can be expressed in cells, such as CHO cells, in a manner that allows for the enzymatic harvest of the receptor from the cell surface and its subsequent immobilization using a capture antibody (E.A. Whitehorn, et al., Bio/Technology 13:1215 (1995).
- a soluble human IL-5R- ⁇ chain can be used as an IL-5 antagonist in chronic asthma or other disease states with demonstrated eosinophilia.
- Eosinophils are white blood cells of the granulocytic lineage. Their normal function appears to be combating parasitic infections, particularly helminthis infections. However, their accumulation in tissues, a condition referred to as eosinophilia, is also associated with several disease states, most notably asthma. It is believed that the damage to the epithelial lining of the bronchial passages in severe asthmatic attacks is largely caused by the compounds released by degranulating eosinophils. In U.S. Patent No.
- 5,096,704 there is specifically disclosed the use of compounds which block the stimulatory effects of IL-5 in order to inhibit production and accumulation of eosinophils.
- the stimulatory effects of IL-5 were blocked by administering an effective amount of an antagonist to human interleukin-5, preferably using monoclonal antibodies or binding compositions derived therefrom by standard techniques.
- Monoclonal antibodies were selected by their ability to inhibit IL-5 induced effects in standard IL-5 bioassays, such as the ability to stimulate the growth and development of eosinophils in in vitro colony forming assays, and the ability to augment in vitro proliferation of the in vivo passaged BCL1 lymphoma cells.
- glucocorticoid steroids are the most effective drugs for treating the acute effects of allergic diseases, such as asthma.
- the availability of alternative or complementary approaches to the treatment of disorders associated with eosinophilia would have important clinical utility. Asthma has become the most common chronic disease in industrialized countries.
- the peptides are fourteen to fifty or more amino acid residues in length, preferably fourteen to twenty amino acid residues in length, and comprise a core sequence of amino acids selected from the following:
- X is hydrogen or acyl
- X 2 is -NH 2 or -OH wherein -NH 2 indicates that the carboxy terminus of the compound has been amidated and -OH indicates that the carboxy terminus of the compounds has not been derivatized
- X 3 is Cys, Lys, or Dpr wherein Dpr is diaminopropionic acid
- X 4 is Nal (where Nal is 1-naphthylalanine), Tip, or Phe.
- Particularly preferred compounds include the following:
- Another embodiment is directed towards those compounds having an intramolecular disulfide linkage between two Cys residues.
- this invention provides dimers of the above sequences. These dimers can be formed via intermolecular disulfide, amide, carbamate, or urea linkages.
- the dimeric compounds may also contain intramolecular cysteine linkages, as well.
- the monomeric subunits will be dimerized to yield compounds having both intramolecular and intermolecular disulfide bonds as follows:
- the compound is covalently attached to one or more of a variety of hydrophilic polymers.
- the hydrophilic polymer(s) may be attached, for example, to one or both of the peptide chains in the dimeric compounds. If a hydrophilic polymer is attached to both peptide chains, the polymers may be the same or different, preferably they will be the same. Preferably, such attachment is at the amino terminus of the compound. It will be appreciated by those of skill in the art that when the compounds are attached to one or more of a variety of hydrophilic polymers at the amino terminus (i.e., at X,), then X ! is the hydrophilic polymer residue.
- the hydrophilic polymer has an average molecular weight of between about 500 to about 40,000 daltons, and more preferably, between about 5,000 and
- the hydrophilic polymer is selected from the group consisting of polyethylene glycol (PEG), polypropylene glycol, polylactic acid, polyglycolic acid and copolymers thereof. Most preferably, the polymer is polyethylene glycol.
- PEGylated A compound to which PEG is conjugated is herein termed "PEGylated.”
- a peptide is conjugated to a PEG polymer, preferably at the amino terminus.
- the peptide may be a dimer comprising PEGylated peptides.
- the invention also provides for pharmaceutical compositions comprising one or more of the compounds described herein and a physiologically acceptable carrier.
- These pharmaceutical compositions can be in a variety of forms including oral dosage forms, as well as inhalable powders and solutions and injectable and infusible solutions.
- Suitable pharmaceutically acceptable derivatives of the compounds include pharmaceutically acceptable salts and acid addition salts, pharmaceutically acceptable esters, pharmaceutically acceptable amides, labeled compounds and compounds that are covalently attached to one or more of a variety of hydrophilic polymers as defined hereinafter.
- the peptides and peptide mimetics of the invention are useful for therapeutic purposes in treating conditions mediated by IL-5 or involving improper production of or response to IL-5 and can be used to inhibit production and accumulation of eosinophils.
- the present invention also provides a method for treating a patient having a disorder that is susceptible to treatment with a IL-5 inhibitor, wherein the patient receives, or is administered, a therapeutical ly effective dose or amount of a compound of the present invention.
- a further aspect of the invention is drawn to a methods for treating conditions mediated by IL-5 or involving improper production of or response to IL-5 or for inhibiting production and accumulation of eosinophils comprising the steps of administering a compound that effects homodimerization of the alpha chain of the IL-5 receptor, thus preventing alpha chain participation in the IL-5/alpha chain/beta chain complex required for IL-5 signal transduction.
- these compounds are dimeric in structure wherein each monomeric subunit is capable of binding to the alpha chain of the IL-5 receptor.
- Peptides and peptide mimetics suitable for therapeutic and/or diagnostic purposes have an IC 50 of about 2 mM or less, as determined by the binding affinity assay set forth below wherein a lower IC 50 correlates to a stronger binding affinity to IL-5R.
- the peptides and peptidomimetics preferably have an IC 50 of no more than about 100 ⁇ M.
- the peptides and peptide mimetics When used for diagnostic purposes, the peptides and peptide mimetics preferably are labeled with a detectable label and, accordingly, the peptides and peptide mimetics without such a label serve as intermediates in the preparation of labeled peptides and peptide mimetics.
- Peptides meeting the defined criteria for molecular weight and binding affinity for IL-5R comprise 15 or more amino acids wherein the amino acids are naturally occurring or synthetic (non-naturally occurring) amino acids.
- Peptide mimetics include peptides having one or more of the following modifications: peptides wherein one or more of the peptidyl [-C(O)NR-] linkages (bonds) have been replaced by a non-peptidyl linkage such as a -CH 2 -carbamate linkage [-CH 2 -OC(O)NR-]; a phosphonate linkage; a -CH 2 -sulfonamide [-CH 2 -S(O) 2NR-] linkage; a urea [-NHC(O)NH-] linkage; a -CH 2 -secondary amine linkage; or an alkylated peptidyl linkage [-C(O)NR 6 - where R ⁇ is lower alkyl]; peptides wherein the N-
- preferred peptides and peptide mimetics comprise a compound having a binding affinity to IL-5R as expressed by an I Q of no more than about 100 ⁇ M, wherein from zero to all of the -C(O)NH- linkages of the peptide have been replaced by a linkage selected from the group consisting of a -CH 2 OC(O)NR- linkage; a phosphonate linkage; a -CH 2 S(O) 2 NR- linkage; a -CH 2 NR- linkage; and a -C ⁇ NR ⁇ linkage; and a -NHC(O)NH- linkage where R is hydrogen or lower alkyl and R ⁇ is lower alkyl, further wherein the N-terminus of said peptide or peptide mimetic is selected from the group consisting of a -NRR, group; a -NRC(O)R group; a -NRC(O)OR group; a -NRS(O) 2 R group
- the invention is directed to a labeled peptide or peptide mimetic comprising a peptide or peptide mimetic described as above having covalently attached thereto a label capable of detection.
- Figure 1 shows the results of a competitive binding experiment demonstrating blockade of IL-5 binding by AF 18748.
- Figure 2 shows the results of a functional binding experiment demonstrating 15 inhibition of IL-5-induced eosinophil adhesion by AF 18748.
- Figure 3 shows the specificity of action of AF 18748, which has no effect on eosinophil adhesion induced by GM-CSF, IL-3, TNF ⁇ or fMet-Leu-Phe.
- Figure 4 shows fluorescence as a function of the concentration of AF 18748 (closed circles), AF17121 (open circles) or human IL-5 (open squares) added to microtiter plates 0 containing IL-5R ⁇ ECD-coated beads.
- Figure 5 shows a gel filtration chromatograph where IL-5R ⁇ ECD (dashed line), IL- 5R ⁇ ECD plus AF17121 (dotted line) or IL-5R ⁇ ECD plus AF 18748 (solid line).
- Figure 6 shows the results of velocity sedimentation experiments with IL-5R ⁇ ECD (3.3S) and IL-5R ⁇ ECD in the presence of AF 18748: another peak appears at 5. IS indicating 5 dimerization.
- Figure 7 shows the response of cells expressing chimeric IL-5R ⁇ /EGFR treated with AF 18748 (open circles), AF17121 (closed circles) or IL-5 (open squares).
- Figure 8 shows the response of cells expressing chimeric IL-5R ⁇ /EGFR treated with 200 pM AF18748 in the presence of increasing amounts of IL-5.
- Figure 9 shows the stability of AF18748 (closed circles), AF25123 (closed upward- pointing triangles) and AF25122 (closed downward-pointing triangles) in vivo.
- “Pharmaceutically acceptable salts” refer to the non-toxic alkali metal, alkaline earth metal, and ammonium salts commonly used in the pharmaceutical industry including the sodium, potassium, lithium, calcium, magnesium, barium, ammonium, and protamine zinc salts, which are prepared by methods well known in the art.
- the term also includes non-toxic acid addition salts, which are generally prepared by reacting the compounds of this invention with a suitable organic or inorganic acid.
- Representative salts include the hydrochloride, hydrobromide, sulfate, bisulfate, acetate, oxalate, valerate, oleate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napsylate, and the like.
- “Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free bases and which are not biologically or otherwise undesirable, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, menthanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.
- inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like
- organic acids such as acetic acid, propionic acid, glycolic acid,
- “Pharmaceutically acceptable ester” refers to those esters which retain, upon hydrolysis of the ester bond, the biological effectiveness and properties of the carboxylic acid or alcohol and are not biologically or otherwise undesirable.
- esters are typically formed from the corresponding carboxylic acid and an alcohol.
- ester formation can be accomplished via conventional synthetic techniques. (See, e.g., March, Advanced Organic Chemistry. 3rd Ed., John Wiley & Sons, New York (1985) p. 1157 and references cited therein, and Mark et al., Encyclopedia of Chemical Technology.
- the alcohol component of the ester will generally comprise (i) a C 2 -C 12 aliphatic alcohol that can or can not contain one or more double bonds and can or can not contain branched carbon chains or (ii) a C 7 -C, 2 aromatic or heteroaromatic alcohols.
- This invention also contemplates the use of those compositions which are both esters as described herein and at the same time are the pharmaceutically acceptable acid addition salts thereof.
- “Pharmaceutically acceptable amide” refers to those amides which retain, upon hydrolysis of the amide bond, the biological effectiveness and properties of the carboxylic acid or amine and are not biologically or otherwise undesirable.
- pharmaceutically acceptable amides as prodrugs, see Bundgaard, H., ed., supra. These amides are typically formed from the corresponding carboxylic acid and an amine.
- amide formation can be accomplished via conventional synthetic techniques. (See, e.g., March, Advanced Organic Chemistry. 3rd Ed., John Wiley & Sons, New York (1985) p. 1152 and Mark et al., Encyclopedia of Chemical Technology. John Wiley & Sons, New York (1980).)
- This invention also contemplates the use of those compositions which are both amides as described herein and at the same time are the pharmaceutically acceptable acid addition salts thereof.
- compositions of the instant invention refers to the amount of composition sufficient to induce a desired biological result. That result can be alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. In the present invention, the result will typically involve a decrease in the immunological and/or inflammatory responses to infection or tissue injury.
- Amino acid residues in peptides are abbreviated as follows: Phenylalanine is Phe or F; Leucine is Leu or L; Isoleucine is He or I; Methionine is Met or M; Valine is Val or V; Serine is Ser or S; Proline is Pro or P; Threonine is Thr or T; Alanine is Ala or A; Tyrosine is Tyr or Y; Histidine is His or H; Glutamine is Gin or Q; Asparagine is Asn or N; Lysine is
- Lys or K Aspartic Acid is Asp or D; Glutamic Acid is Glu or E; Cysteine is Cys or C; Tryptophan is Trp or W; Arginine is Arg or R; and Glycine is Gly or G.
- abbreviation Nal is used to denote 1-naphthylalanine
- peptidomimetics or peptide analogs are also provided.
- Peptide analogs are commonly used in the pharmaceutical industry as non-peptide drugs with properties analogous to those of the template peptide. These types of non-peptide compound are termed "peptide mimetics” or “peptidomimetics” (Fauchere, J., Adv. Drug Res. 15:29 (1986); Veber and Freidinger, TINS p.392 (1985); and Evans et al., J. Med. Chem. 30:1229 (1987), which are incorporated herein by reference).
- Peptide mimetics that are structurally similar to therapeutically useful peptides may be used to produce an equivalent or enhanced therapeutic or prophylactic effect.
- a particularly preferred non-peptide linkage is -CH 2 NH-.
- Such peptide mimetics may have significant advantages over polypeptide embodiments, including, for example: more economical production, greater chemical stability, enhanced pharmacological properties (half-life, absorption, potency, efficacy, etc.), altered specificity (e.g., a broad-spectrum of biological activities), reduced antigenicity, and others.
- the immobilized ⁇ chain, ⁇ chain, and heterodimer, as well as the extracellular domains of the single chains of the IL-5 receptors were produced in recombinant host cells.
- the DNA encoding IL-5R was obtained by PCR of cDNA from TF-1 cells using primers obtained from the published receptor sequences. See Murata (1992) J. Exp. Med. 175:341-351 and Hayashida (1990) Proc. Natl. Acad. Sci. USA 87:9655-9659, each of which is incorporated herein by reference.
- IL-5R is constructed by expressing the protein as a soluble protein in baculovirus transformed host cells using standard methods; another useful form is constructed with a signal peptide for protein secretion and for glycophospholipid membrane anchor attachment. This form of anchor attachment is called "PIG-tailing.” See Caras and Wendell, Science 243:1196-1 198 (1989) and Lin et al., Science 249:677-679 (1990). Using the PIG-tailing system, one can cleave the receptor from the surface of the cells expressing the receptor (e.g., transformed CHO cells selected for high level expression of receptor with a cell sorter) with phospholipase C.
- PIG-tailing See Caras and Wendell, Science 243:1196-1 198 (1989) and Lin et al., Science 249:677-679 (1990).
- the cleaved receptor still comprises a carboxy terminal sequence of amino acids, called the "HPAP tail," from the signal protein for membrane attachment and can be immobilized without further purification.
- the recombinant receptor protein can be immobilized by coating the wells of microtiter plates with an anti-HPAP tail antibody (Ab 179), blocking non-specific binding with bovine serum albumin (BSA) in PBS, and then binding cleaved recombinant receptor to the antibody. Using this procedure, one should perform the immobilization reaction in varying concentrations of receptor to determine the optimum amount for a given preparation, because different preparations of recombinant protein often contain different amounts of the desired protein. See U.S. Patent Application Serial No. 07/947,339, filed September 18, 1992, incorporated herein by reference.
- X, -EGYVX 3 VEX 4 AACPTCR-X 2 (SEQ ID NO: 7) wherein X, is hydrogen or acyl; X 2 is -NH 2 or -OH wherein -NH 2 indicates that the carboxy terminus of the compound has been amidated and -OH indicates that the carboxy terminus of the compounds has not been derivitized; X 3 is Cys, Lys, or Dpr wherein Dpr is diaminopropionic acid, and X 4 is Nal, T ⁇ , or Phe. Another embodiment is directed towards those compounds an intramolecular disulfide linkage between two cysteine residues. Particularly preferred compounds include the following:
- (H)-GYVCVEWARCPTCR-(OH) (SEQ ID NO: 18); where -(NH 2 ) indicates that the carboxy terminus of the compound has been amidated; where -(OH) indicates that the carboxy terminus of the compound has not been derivatized; where (Ac)- indicates that the amino terminus of the compound has been acetylated; and where (Ahx)- indicates that the amino terminus of the compound has been acylated with aminohexanoic acid. More preferably, this invention provides dimers of the above sequences. For example, a sidechain primary amino group of one monomeric subunit can be coupled to a sidechain primary amino group of a second monomeric subunit via a urea linkage.
- side chain functionality of one monomeric subunit can be coupled to side chain functionality of a second subunit through a ' variety of strategies, including without limitation, intermolecular disulfide, ester, amide, carbamate, or urea linkages.
- binding assays were used to determine whether the peptides inhibit the binding of IL-5 to the extracellular domain of the IL-5 receptor ⁇ -chain.
- a microphysiometer assay was used to determine whether the peptide blocked the response of TF-l cells to IL-5 (5 ng/ml).
- IL-5R agonist and antagonist activity were tested for IL-5R agonist and antagonist activity in a microphysiometer assay using the IL-5 responsive human leukemia cell line, TF-1. Following overnight IL-5 starvation, these cells exhibit a rapid and robust increase in metabolic activity upon addition of IL-5 to the cell culture medium.
- a preferred compound was tested in the TF-1 cell microphysiometer assay and found to almost completely block the response of the cells to 400 pM IL-5 when tested at 10 ⁇ M concentration.
- the peptide was of sufficiently high affinity to allow us to determine an accurate microphysiometer assay IC 50 value.
- the IC 50 values were determined using the free peptide, although in some instances, it may be preferable to amidate the C-terminus or to prepare an ester or other carboxy amide.
- the N-terminal and C-terminal amino acids of the synthetic peptides are often preceded by one or two glycine residues. These glycines are not believed to be necessary for binding or activity.
- Peptides and peptidomimetics having an IC 50 of greater than about 100 mM lack sufficient binding to permit use in either the diagnostic or therapeutic aspects of this invention.
- the peptides and peptidomimetics have an IC 50 of about 2.5 mM or less and, for pharmaceutical pu ⁇ oses, the peptides and peptidomimetics have an IC 50 of about 2 mM or less.
- the peptides of the invention can be prepared by classical methods known in the art, for example, by using standard solid phase techniques.
- the standard methods include exclusive solid phase synthesis, partial solid phase synthesis methods, fragment condensation, classical solution synthesis, and even by recombinant DNA technology. See, e.g., Merrifield (1963) J. Am. Chem. Soc. 85:2149.
- the synthesis is typically commenced from the C-terminal end of the peptide using an alpha-amino protected resin.
- a suitable starting material can be prepared, for instance, by attaching the required alpha-amino acid to a chloromethylated resin, a hydroxymethyl resin, or a benzhydrylamine resin.
- the compounds of the invention can be prepared by coupling an alpha-amino protected amino acid to the chloromethylated resin with the aid of, for example, cesium bicarbonate catalyst, according to the method described by Gisin (1973) Helv. Chim. Acta
- the alpha-amino protecting group is removed by a choice of reagents including trifluoroacetic acid (TFA) or hydrochloric acid (HC1) solutions in organic solvents at room temperature.
- TFA trifluoroacetic acid
- HC1 hydrochloric acid
- the alpha-amino protecting groups are those known to be useful in the art of stepwise synthesis of peptides. Included are acyl type protecting groups (e.g. formyl, trifluoroacetyl, acetyl), aromatic urethane type protecting groups (e.g. benzyloxycarboyl (Cbz) and substituted Cbz), aliphatic urethane protecting groups (e.g. t-butyloxycarbonyl (Boc), isopropyloxycarbonyl, cyclohexyloxycarbonyl) and alkyl type protecting groups (e.g. benzyl, triphenylmethyl, and fluorenylmethyl oxycarbonyl (Fmoc)).
- acyl type protecting groups e.g. formyl, trifluoroacetyl, acetyl
- aromatic urethane type protecting groups e.g. benzyloxycarboyl (Cbz) and substituted Cbz
- Boc and Fmoc are preferred protecting groups.
- the side chain protecting group remains intact during coupling and is not split off during the deprotection of the amino-terminus protecting group or during coupling.
- the side chain protecting group must be removable upon the completion of the synthesis of the final peptide and under reaction conditions that will not alter the target peptide.
- the side chain protecting groups for Tyr include tetrahydropyranyl, tert-butyl, trityl, benzyl, Cbz, Z-Br-Cbz, and 2,5-dichlorobenzyl.
- the side chain protecting groups for Asp include benzyl, 2,6-dichlorobenzyl, methyl, ethyl, and cyclohexyl.
- the side chain protecting groups for Thr and Ser include acetyl, benzoyl, trityl, tetrahydropyranyl, benzyl, 2,6-dichlorobenzyl, and Cbz.
- the side chain protecting group for Thr and Ser is benzyl.
- the side chain protecting groups for Arg include nitro, Tosyl (Tos), Cbz, adamantyloxycarbonyl mesitoylsulfonyl (Mts), or Boc.
- the side chain protecting groups for Lys include Cbz, 2-chlorobenzyloxycarbonyl (2-Cl-Cbz), 2-bromobenzyloxycarbonyl (2-BrCbz), Tos, or Boc.
- each protected amino acid is coupled stepwise in the desired order.
- An excess of each protected amino acid is generally used with an appropriate carboxyl group activator such as dicyclohexylcarbodiimide (DCC) in solution, for example, in methylene chloride (CH Z C1 2 ), dimethyl formamide (DMF) mixtures.
- DCC dicyclohexylcarbodiimide
- CH Z C1 2 methylene chloride
- DMF dimethyl formamide
- the desired peptide is decoupled from the resin support by treatment with a reagent such as trifluoroacetic acid or hydrogen fluoride (HF), which not only cleaves the peptide from the resin, but also cleaves all remaining side chain protecting groups.
- a reagent such as trifluoroacetic acid or hydrogen fluoride (HF)
- HF hydrogen fluoride
- the side chain protected peptide can be decoupled by treatment of the peptide resin with ammonia to give the desired side chain protected amide or with an alkylamine to give a side chain protected alkylamide or dialkylamide. Side chain protection is then removed in the usual fashion by treatment with hydrogen fluoride to give the free amides, alkylamides, or dialkylamides.
- Other synthetic amino acids that can be substituted into the peptides of the present invention include L-hydroxypropyl, L-3, 4-dihydroxyphenylalanine, ⁇ amino acids such as L- ⁇ -hydroxylysine and D- ⁇ -methylalanine, L- ⁇ methylalanine, ⁇ amino acids, and isoquinoline. D amino acids and non-naturally occurring synthetic amino acids can also be inco ⁇ orated into the peptides of the present invention.
- proline analogs in which the ring size of the proline residue is changed from 5 members to 4, 6, or 7 members can be employed.
- Cyclic groups can be saturated or unsaturated, and if unsaturated, can be aromatic or non-aromatic.
- the peptides typically are synthesized as the free acid but, as noted above, could be readily prepared as the amide (i.e., designated with a -(NH 2 ) at the carboxy terminus of the compound) or ester.
- Amino terminus modifications include methylating (i.e., -NHCH 3 or -NH(CH 3 ) 2 ), acetylating, adding a carbobenzoyl group, or blocking the amino terminus with any blocking group containing a carboxylate functionality defined by RCOO-, where R is selected from the group consisting of naphthyl, acridinyl, steroidyl, and similar groups.
- Carboxy terminus modifications include replacing the free acid with a carboxamide group or forming a cyclic lactam at the carboxy terminus to introduce structural constraints.
- N-terminal amino group can then be reacted as follows: (a) to form an amide group of the formula RC(O)NH- where R is as defined above by reaction with an acid halide [e.g., RC(O)Cl] or acid anhydride.
- an acid halide e.g., RC(O)Cl
- the reaction can be conducted by contacting about equimolar or excess amounts (e.g., about 5 equivalents) of an acid halide to the peptide in an inert diluent (e.g., dichloromethane) preferably containing an excess (e.g., about 10 equivalents) of a tertiary amine, such as diisopropylethylamine, to scavenge the acid generated during reaction.
- Reaction conditions are otherwise conventional (e.g., room temperature for 30 minutes).
- the succinic group can be substituted with, for example, C 2 -C 6 alkyl or -SR substituents which are prepared in a conventional manner to provide for substituted succinimide at the N-terminus of the peptide.
- alkyl substituents are prepared by reaction of a lower olefin ( - ) with maleic anhydride in the manner described by Wollenberg et al.
- -SR substituents are prepared by reaction of RSH with maleic anhydride where R is as defined above;
- the inert diluent contains excess tertiary amine (e.g., ten equivalents) such as diisopropylethylamine, to scavenge the acid generated during reaction.
- Reaction conditions are otherwise conventional (e.g., room temperature for 30 minutes); (e) to form a carbamate group by reaction with an equivalent amount or an excess (e.g., 5 equivalents) of R-OC(O)Cl or R-OC(O)OC 6 H 4 -p-NO 2 in a suitable inert diluent (e.g., dichloromethane) to convert the terminal amine into a carbamate where R is as defined above.
- a suitable inert diluent e.g., dichloromethane
- the inert diluent contains an excess (e.g., about 10 equivalents) of a tertiary amine, such as diisopropylethylamine, to scavenge any acid generated during reaction.
- Reaction conditions are otherwise conventional (e.g., room temperature for 30 minutes); and
- a suitable inert diluent e.g., dichloromethane
- the inert diluent contains an excess (e.g., about 10 equivalents) of a tertiary amine, such as diisopropylethylamine.
- Reaction conditions are otherwise conventional (e.g., room temperature for about 30 minutes).
- a benzhydrylamine resin is used as the solid support for peptide synthesis.
- hydrogen fluoride treatment to release the peptide from the support results directly in the free peptide amide (i.e., the C-terminus is
- the C-terminal carboxyl group or a C-terminal ester can be induced to cyclize by internal displacement of the -OH or the ester (-OR) of the carboxyl group or ester respectively with the N-terminal amino group to form a cyclic peptide.
- the free acid is converted to an activated ester by an appropriate carboxyl group activator such as dicyclohexylcarbodiimide (DCC) in solution, for example, in methylene chloride (CH 2 C1 2 ), dimethyl formamide (DMF) mixtures.
- DCC dicyclohexylcarbodiimide
- the cyclic peptide is then formed by internal displacement of the activated ester with the N-terminal amine. Internal cyclization as opposed to polymerization can be enhanced by use of very dilute solutions. Such methods are well known in the art.
- C-terminal functional groups of the compounds of the present invention include amide, amide lower alkyl, amide di(lower alkyl), lower alkoxy, hydroxy, and carboxy, and the lower ester derivatives thereof, and the pharmaceutically acceptable salts thereof.
- the peptide compounds of the invention also serve as structural models for non-peptidic compounds with similar biological activity.
- Those of skill in the art recognize that a variety of techniques are available for constructing compounds with the same or similar desired biological activity as the lead peptide compound but with more favorable activity than the lead with respect to solubility, stability, and susceptibility to hydrolysis and proteolysis. See Morgan and Gainor (1989) Ann. Rep. Med. Chem. 24:243-252, inco ⁇ orated herein by reference. These techniques include replacing the peptide backbone with a backbone composed of phosphonates, amidates, carbamates, sulfonamides, secondary amines, and N-methylamino acids.
- Peptide mimetics wherein one or more of the peptidyl linkages [-C(O)NH-] have been replaced by such linkages as a -CH 2 -carbamate linkage, a phosphonate linkage, a
- Suitable reagents include, for example, amino acid analogues wherein the carboxyl group of the amino acid has been replaced with a moiety suitable for forming one of the above linkages.
- replacement of an amido linkage in the peptide with a phosphonate linkage can be achieved in the manner set forth in U.S. Patent Nos. 5,359,1 15 and 5,420,328 to Campbell et al. and in U.S. Patent Application Serial No.08/081,577, the disclosures of which are inco ⁇ orated herein by reference in their entirety.
- Replacement of an amido linkage in the peptide with a -CH 2 -sulfonamide linkage can be achieved by reducing the carboxyl (-COOH) group of a suitably protected amino acid to the -CH 2 OH group and the hydroxyl group is then converted to a suitable leaving group such as a tosyl group by conventional methods.
- Secondary amine linkages wherein a -CH 2 NH- linkage replaces the amido linkage in the peptide can be prepared by employing, for example, a suitably protected dipeptide analogue wherein the carbonyl bond of the amido linkage has been reduced to a CH 2 group by conventional methods. For example, in the case of diglycine, reduction of the amide to the amine will yield after deprotection H 2 NCH 2 CH 2 NHCH 2 COOH which is then used in N-protected form in the next coupling reaction.
- the preparation of such analogues by reduction of the carbonyl group of the amido linkage in the dipeptide is well known in the art.
- the suitably protected amino acid analogue is employed in the conventional peptide synthesis in the same manner as would the corresponding amino acid.
- typically about 3 equivalents of the protected amino acid analogue are employed in this reaction.
- An inert organic diluent such as methylene chloride or DMF is employed and, when an acid is generated as a reaction by-product, the reaction solvent will typically contain an excess amount of a tertiary amine to scavenge the acid generated during the reaction.
- One particularly preferred tertiary amine is diisopropylethylamine which is typically employed in about 10 fold excess.
- the reaction results in inco ⁇ oration into the peptide mimetic of an amino acid analogue having a non-peptidyl linkage. Such substitution can be repeated as desired such that from zero to all of the amido bonds in the peptide have been replaced by non-amido bonds.
- C-terminal functional groups of the compounds of the present invention include amide, amide lower alkyl, amide di(lower alkyl), lower alkoxy, hydroxy, and carboxy, and the lower ester derivatives thereof, and the pharmaceutically acceptable salts thereof.
- the compounds of the present invention may exist in a cyclized form with an intramolecular disulfide bond between the thiol groups of the cysteines.
- an intermolecular disulfide bond between the thiol groups of the cysteines can be produced to yield a dimeric (or higher oligomeric) compound.
- One or more of the cysteine residues may also be substituted with a homocysteine.
- n and n are independently 1 or 2.
- the amino-terminus of the peptide can be capped with an alpha-substituted acetic acid, wherein the alpha substituent is a leaving group, such as an ⁇ -haloacetic acid, for example, ⁇ -chloroacetic acid, ⁇ -bromoacetic acid, or ⁇ -iodoacetic acid.
- the compounds of the present invention can be cyclized or dimerized via displacement of the leaving group by the sulfur of the cysteine or homocysteine residue. See, e.g., Barker et al., J Med. Chem. 35:2040-2048 (1992) and Or et al., J. Org. Chem.
- Nonproteinaceous polymers suitable for use in accordance with the present invention include, but are not limited to, polyalkylethers as exemplified by polyethylene glycol and polypropylene glycol; polylactic acid; polyglycolic acid; polyoxyalkenes; polyvinylalcohol; polyvinylpyrrolidone; cellulose and cellulose derivatives; dextran and dextran derivatives; etc.
- hydrophilic polymers have an average molecular weight ranging from about 500 to about 100,000 daltons, more preferably from about 2000 to about 40,000 daltons, and even more preferably, from about 5,000 to about 20,000 daltons. In preferred embodiments, such hydrophilic polymers have an average molecular weight of about 5,000 daltons, 10,000 daltons, or 20,000 daltons.
- the compounds of the invention can be derivatized with or coupled to such polymers using any of the methods set forth in Zallipsky Bioconjugate Chem. 6:150-165 (1995); Monfardini et al., Bioconjugate Chem. 6:62-69 (1995); U.S. Patent No. 4,640,835; U.S. Patent No.
- the compounds of the present invention are derivatized with polyethylene glycol (PEG).
- PEG is a linear, water-soluble polymer of ethylene oxide repeating units with two terminal hydroxyl groups.
- PEGs are classified by their molecular weights which typically range from about 500 daltons to about 40,000 daltons. In a presently preferred embodiment, the PEGs employed have molecular weights ranging from 5,000 daltons to about 20,000 daltons.
- PEGs coupled to the compounds of the present invention can be either branched or unbranched. See, e.g., Monfardini et al., Bioconjugate Chem. 6:62-69 (1995). PEGs are commercially available from Shearwater Polymers Inc. (Huntsville, Alabama), Sigma Chemical Co., and other companies.
- PEGs include, but are not limited to, monomethyoxypolyethylene glycol (MePEG-OH); monomethoxypolyethylene glycol-succinate (MePEG-S); monomethoxypolyethylene glycol-succinimidyl succinate (MePEG-S-NHS); monomethoxypolyethylene glycol amine (MePEG-NH2); monomethoxypolyethylene glycol-tresylate (MePEG-TRES); and monomethoxypolyethylene glycol-imidazolyl-carbonyl (MePEG-IM).
- MePEG-OH monomethyoxypolyethylene glycol
- MePEG-S monomethoxypolyethylene glycol-succinate
- MePEG-NHS monomethoxypolyethylene glycol-succinimidyl succinate
- MePEG-NH2 monomethoxypolyethylene glycol amine
- MePEG-TRES monomethoxypolyethylene glycol-tre
- the hydrophilic polymer which is employed is preferably capped at one end by an unreactive protecting group, such as a methoxy or ethoxy. Thereafter, the polymer is activated at the other end by reaction with a suitable activating agent, such as cyanuric halide (e.g., cyanuric chloride, bromide, or fluoride), diimadozole, an anhydride reagent (e.g., a dihalosuccinic anhydride, such as dibromosuccinic anhydride), acyl azide, p-diazoiumbenzyl ether), 3-(p-diazoniumphenoxy)-2-hydroxypropylether and the like.
- cyanuric halide e.g., cyanuric chloride, bromide, or fluoride
- diimadozole e.g., an anhydride reagent (e.g., a dihalosuccinic anhydride, such as dibromosuccinic an
- the activated polymer is then reacted with a compound of the present invention to produce a compound derivatized with a polymer.
- the amount of derivatization will be dependent, in part, upon the availability of free amine groups in the compound of the present invention. For example, if all but one of the primary amine groups of the compound is protected, e.g., by an acyl group, a monoPEGylated compound will be formed.
- the amino terminus of a peptide or peptide mimetic compound is derivatized with PEG.
- a functional group in the compounds of the invention can be activated for reaction with the polymer, or the two groups can be joined in a concerted coupling reaction using known coupling methods. It will be readily appreciated that the compounds of the invention can be derivatized with PEG using a myriad of other reaction schemes known to and used by those of skill in the art.
- One embodiment of this invention is drawn to dimers wherein side chain amino groups of each monomeric subunit are coupled via a urea linkage. Other embodiments are drawn to dimers wherein side chain amino groups of each monomeric subunit are coupled via disulfide, amide, or carbamate linkages.
- the dimeric compounds may also contain intramolecular cysteine linkages. Most preferably, the monomeric subunits will be dimerized to yield compounds having both intramolecular and intermolecular disulfide bonds. These dimers can be prepared as described below using techniques known to those of skill in the art and appropriate protecting group strategies.
- a dimeric compound is derivatized with a hydrophilic polymer, such as PEG.
- One or both of the monomers may be derivatized with a hydrophilic polymer.
- the compound comprises a dimer with PEG covalently bound to the amino termini of both of the monomers.
- the activity of the compounds of the present invention can be evaluated in vivo in one of the numerous animal models of asthma. See Larson, "Experimental Models of Reversible Airway Obstruction," in The Lung: Scientific Foundations. Crystal, West et al., eds., Raven Press, New York, 1991 ; Warner et al., Am. Rev. Respir. Dis. 141 :253-257 (1990).
- An ideal animal model would duplicate the chief clinical and physiological features of human asthma, including: airway hyperresponsiveness to chemical mediators and physical stimuli; reversal of airway obstruction by drugs useful in human asthma
- ⁇ -adrenergics ⁇ -adrenergics, methylxanthines, corticosteroids, and the like
- airway inflammation with infiltration of activated leukocytes ⁇ -adrenergics, methylxanthines, corticosteroids, and the like
- chronic inflammatory degenerative changes such as basement membrane thickening, smooth muscle hypertrophy, and epithelial damage.
- Species used historically as animal models include mice, rats, guinea pigs, rabbits, dogs, and sheep. All have some limitations, and the proper choice of animal model depends upon the question which is to be addressed.
- the compounds of this invention are also useful for the treatment of other immunomediated inflammatory disorders in which tryptase activity contributes to the pathological condition.
- diseases include inflammatory diseases associated with mast cells, such as rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions, inflammatory bowel disease, peptic ulcer and various skin conditions.
- RPAR Passive Arthus Reaction
- Assays for determining the therapeutic value of compounds in the treatment of various skin conditions, such as hype ⁇ roliferative skin disease, are well known in the art, for example, the Arachidonic Acid Mouse Ear Test (Id.).
- the compounds of the instant invention can be evaluated for their antiulcer activity according to the procedures described in Chiu et al., Archives Internationales de Pharmacodynamie et de Therapie 270:128-140 (1984).
- the compounds of the invention are useful in vitro as unique tools for understanding the biological role of IL-5, including the evaluation of the many factors thought to influence, and be influenced by, the production of IL-5 and the receptor binding process.
- the present compounds are also useful in the development of other compounds that bind to the IL-5R, because the present compounds provide important information on the relationship between structure and activity that should facilitate such development.
- the compounds are also useful as competitive inhibitors or tracers in assays to screen for new IL-5 receptor blockers.
- the compounds of the invention can be used without modification or can be modified in a variety of ways; for example, by labeling, such as covalently or non-covalently joining a moiety which directly or indirectly provides a detectable signal.
- the materials thereto can be labeled either directly or indirectly.
- Possibilities for direct labeling include label groups such as: radiolabels such as [ 125 I], enzymes (US Patent 3,645,090) such as peroxidase and alkaline phosphatase, and fluorescent labels (US Patent 3,940,475) capable of monitoring the change in fluorescence intensity, wavelength shift, or fluorescence polarization.
- Possibilities for indirect labeling include biotinylation of one constituent followed by binding to avidin coupled to one of the above label groups.
- the compounds may also include spacers or linkers in cases where the compounds are to be attached to a solid support.
- compositions and methods of the present invention also can be used in vitro for testing a patient's susceptibility to varying treatment regimens for disorders associated with the ove ⁇ roduction of IL-5 or an improper response to IL-5 using an in vitro diagnostic method whereby a specimen is taken from the patient and is treated with a IL-5R binding, IL-5 blocking compound of the present invention to determine the effectiveness and amount of the compound necessary to produce the desired effect.
- the blocking compound and dosage can be varied. After the blocking compounds are screened, then the appropriate treatment and dosage can be selected by the physician and administered to the patient based upon the results. Therefore, this invention also contemplates use of a blocking compound of this invention in a variety of diagnostic kits and assay methods.
- a further aspect of the invention is the use of compounds of the present inventions for the manufacture of a medicament for the treatment and/or prevention of a variety of IL-5 disorders.
- the compounds of the invention can also be administered to warm blooded animals, including humans, to block the binding of IL-5 to the IL-5R in vivo.
- the present invention encompasses methods for therapeutic treatment of IL-5 related disorders that comprise administering a compound of the invention in amounts sufficient to block or inhibit the binding of IL-5 to the IL-5R in vivo.
- the peptides and compounds of the invention can be administered to treat symptoms related to the ove ⁇ roduction of IL-5 or an improper response to IL-5.
- the compositions and methods described herein will find use for the treatment and/or prevention of a variety of IL-5 related disorders.
- the compositions of the present invention are useful for preventing or ameliorating asthma.
- the compounds typically will be administered prophylactically prior to exposure to allergen or other precipitating factor, or after such exposure.
- the compounds of the instant invention are particularly useful in ameliorating the late-phase tissue destruction seen in both seasonal and perennial rhinitis.
- Another aspect of the present invention is directed to the prevention and treatment of other immunomediated inflammatory disorders associated with mast cells such as urticaria and angioedema, and eczematous dermatitis (atopic dermatitis), and anaphylaxis, as well as hype ⁇ roliferative skin disease, peptic ulcers, and the like.
- the present invention also provides pharmaceutical compositions comprising, as an active ingredient, at least one of the peptides or peptide mimetics of the invention in association with a pharmaceutical carrier or diluent.
- the compounds of this invention can be administered by oral, pulmonary, parenteral (intramuscular, intraperitoneal, intravenous (IV) or subcutaneous injection), inhalation (via a fine powder formulation), transdermal, nasal, vaginal, rectal, or sublingual routes of administration and can be formulated in dosage forms appropriate for each route of administration.
- aerosol when the compounds of the instant invention are to be used in the treatment of asthma, they will be formulated as aerosols.
- aerosol includes any gas-borne suspended phase of the compounds of the instant invention which is capable of being inhaled into the bronchioles or nasal passages.
- aerosol includes a gas-borne suspension of droplets of the compounds of the instant invention, as may be produced in a metered dose inhaler or nebulizer, or in a mist sprayer. Aerosol also includes a dry powder composition of a compound of the instant invention suspended in air or other carrier gas, which may be delivered by insufflation from an inhaler device, for example.
- the preferred range of concentration of the compounds of the instant invention is 0.1-100 milligrams (mg)/ milliliter (mL), more preferably 0.1-30 mg/mL, and most preferably, 1-10 mg/mL.
- a physiologically compatible buffer such as phosphate or bicarbonate.
- the usual pH range is 5 to 9, preferably 6.5 to 7.8, and more preferably 7.0 to
- sodium chloride is added to adjust the osmolarity to the physiological range, preferably within 10% of isotonic.
- Suspensions of the compounds of the present invention in hydro fluoronalkane propellants especially 1,1,1,2-tetrafluoroethane of 1,1, 1,2,3,3, 3-heptafluoropropane, optionally in the presence of a surfactant and/or cosolvent (e.g., ethanol) in a pressurized canister may also be provided together with a suitable delivery device for the treatment of the above mentioned respiratory disorders, especially asthma and allergic rhinitis.
- a surfactant and/or cosolvent e.g., ethanol
- suitable delivery device for the treatment of the above mentioned respiratory disorders, especially asthma and allergic rhinitis.
- Solutions of the compounds of the instant invention may be converted into aerosols by any of the known means routinely used for making aerosol inhalant pharmaceuticals.
- such methods comprise pressurizing or providing a means of pressurizing a container of the solution, usually with an inert carrier gas, and passing the pressurized gas through a small orifice, thereby pulling droplets of the solution into the mouth and trachea of the animal to which the drug is to be administered.
- a mouthpiece is fitted to the outlet of the orifice to facilitate delivery into the mouth and trachea.
- devices of the present invention comprise solutions of the compounds of the instant invention connected to or contained within any of the conventional means for creating aerosols in asthma medication, such as metered dose inhalers, jet nebulizers, or ultrasonic nebulizers.
- such device may include a mouthpiece fitted around the orifice.
- a device may comprise a solution of a compound of the instant invention in a nasal sprayer.
- a dry powder comprising a compound of the instant invention, optionally with an excipient, is another embodiment of the present invention. This may be administered by a drug powder inhaler containing the above described powder.
- the compounds of the inventions can also be used in the treatment of immunomediated inflammatory skin conditions, such as urticaria and angioedema, eczematous dermatitis, and hype ⁇ roliferative skin disease, e.g., psoriasis, in mammals.
- immunomediated inflammatory skin conditions such as urticaria and angioedema, eczematous dermatitis, and hype ⁇ roliferative skin disease, e.g., psoriasis
- a remission of the symptoms can be expected.
- one affected by an immunomediated inflammatory skin condition can expect a decrease in scaling, erythema, size of the plaques, pruritus, and other symptoms associated with the skin condition.
- the dosage of medicament and the length of time required for successfully treating each individual patient may vary, but those skilled in the art will be able to recognize these variations and adjust the course of therapy accordingly.
- Lotions may be formulated with an aqueous or oily base and will, in general, also include one or more of the following: stabilizing agents, emulsifying agents, dispersing agents, suspending agents, thickening agents, coloring agents, perfumes, and the like.
- Powders may be formed with the aid of any suitable powder base, e.g., talc, lactose, starch, and the like.
- Drops may be formulated with an aqueous base or non-aqueous base also comprising one or more dispersing agents, suspending agents, solubilizing agents, and the like.
- the topical pharmaceutical compositions according to this invention may also include one or more preservatives or bacteriostatic agents, e.g., methyl hydroxybenzoate, propyl hydroxybenzoate, chlorocresol, benzalkonium chlorides, and the like.
- the topical pharmaceutical compositions also can contain other active ingredients such as antimicrobial agents, particularly antibiotics, anesthetics, analgesics, and antipruritic agents.
- Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
- the active compound is admixed with at least one inert pharmaceutically acceptable carrier such as sucrose, lactose, or starch.
- Such dosage forms can also comprise, as is normal practice, additional substances other than inert diluents, e.g., lubricating agents such as magnesium stearate.
- the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings.
- Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, with the elixirs containing inert diluents commonly used in the art, such as water. Besides such inert diluents, compositions can also include adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents.
- Preparations according to this invention for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, or emulsions.
- non-aqueous solvents or vehicles are propylene glycol, polyethylene glycol, vegetable oils, such as olive oil and corn oil, gelatin, and injectable organic esters such as ethyl oleate.
- Such dosage forms may also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents. They may be sterilized by, for example, filtration through a bacteria retaining filter, by inco ⁇ orating sterilizing agents into the compositions, by irradiating the compositions, or by heating the compositions. They can also be manufactured using sterile water, or some other sterile injectable medium, immediately before use.
- compositions for rectal or vaginal administration are preferably suppositories which may contain, in addition to the active substance, excipients such as cocoa butter or a suppository wax.
- Compositions for nasal or sublingual administration are also prepared with standard excipients well known in the art.
- compositions and methods of this invention can be used in combination with other agents exhibiting the ability to modulate IL-5 synthesis, release, and/or binding and with other agents for the treatment of immunomediated inflammatory disorders, and particularly asthma.
- ⁇ -Adrenergic agonists are especially useful in these combinations, because they provide symptomatic relief of the initial asthmatic response, whereas the compounds of the present invention provide relief for the late asthmatic response.
- Preferred ⁇ -adrenergic agonists in these solutions include any of the usual ⁇ -agonists employed for the relief of asthma, such as albuterol, terbutaline, formoterol, fanoterol, or prenaline.
- compositions containing the compounds can be administered for prophylactic and/or therapeutic treatments.
- compositions are administered to a patient already suffering from a disease, as described above, in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications.
- An amount adequate to accomplish this is defined as "therapeutically effective dose.” Amounts effective for this use will depend on the severity of the disease and the weight and general state of the patient.
- compositions containing the compounds of the invention are administered to a patient susceptible to or otherwise at risk of a particular disease. Such an amount is defined to be a "prophylactically effective dose.”
- a prophylactically effective dose In this use, the precise amounts again depend on the patient's state of health and weight.
- the quantities of the IL-5 blocking compound necessary for effective therapy will depend upon many different factors, including means of administration, target site, physiological state of the patient, and other medicants administered. Thus, treatment dosages should be titrated to optimize safety and efficacy.
- dosages used in vitro may provide useful guidance in the amounts useful for in situ administration of these reagents. Animal testing of effective doses for treatment of particular disorders will provide further predictive indication of human dosage.
- the peptides and peptide mimetics of this invention are effective in treating IL-5 mediated conditions when administered at a dosage range of from about 0.001 mg to about 10 mg/kg of body weight per day.
- the specific dose employed is regulated by the particular condition being treated, the route of administration as well as by the judgement of the attending clinician depending upon factors such as the severity of the condition, the age and general condition of the patient, and the like.
- ligand-binding receptors are comprised of multiple subunits. Where the ligand binding and the signal transduction activities of the receptor are found on different subunits, receptor activation may be reduced or abolished by compounds that interfere with the association of the ligand-binding subunits with the signal-transducing subunits. It is herein disclosed that compounds that bind with high affinity to two or more ligand-binding subunits of heteromeric receptors are effective receptor antagonists. It has been discovered that providing a multivalent compound effective to bind with high affinity to two or more ligand-binding subunits of a receptor macromolecule is effective to antagonize the action of a ligand at a receptor.
- the IL-5 receptor comprises an ⁇ subunit and a ⁇ subunit, where the ⁇ subunit is the signal-transducing subunit.
- IL-5 ⁇ subunits are herein disclosed to be potent, highly specific IL-5 receptor antagonists.
- Compounds that bind with high affinity to two ⁇ subunits of the interleukin 3 (IL-3) receptor and compounds that bind with high affinity to two ⁇ subunits of the granulocyte/macrophage colony-stimulating factor (GM-CSF) receptor are likewise expected to be potent, highly specific receptor antagonists.
- the protein gpl30 is the common signaling subunit for the heteromeric receptors of a number of different ligands, such as interleukin 6 (IL-6), leukemia inhibitory factor (LIF), oncostatin M, interleukin 12
- the interleukin 2 (IL-2) receptor is also a heteromeric receptor with distinct ligand-binding and signaling subunits suitable for antagonism by compounds that bind with high affinity to two ligand- binding IL-2 subunits.
- a method for identifying compounds that dimerize to ligand-binding receptor subunits involves the following steps listed below. Firstly, peptide libraries are screened against the ligand-binding receptor subunit, using suitable screening methods known in the art and as disclosed above. Clones that compete with ligands for binding at the target receptor are identified in this screening step. Next, those clones with an odd number of cysteine residues are identified. Peptides from the clones with an odd number of cysteine residues are then synthesized, with the cysteine(s) in reduced form. These peptides are then allowed to oxidize in aqueous solution to form peptide dimers. Finally, these dimeric peptides are tested for dimeric binding of the receptor subunit. Alternatively, combinatorial libraries of dimeric molecules can be screened against the ligand-binding subunit. Compounds that compete with ligand for binding should be tested to determine if the compounds dimerize to receptor subunits.
- a third method comprises developing reporter cell lines that express chimeric receptors consisting of the extracellular ligand-binding domain of a homomeric receptor such as GM-CSF.
- a homomeric receptor such as GM-CSF.
- An example of such a chimera is provided above (IL-5 ⁇ ECD).
- Such reporter cells would contain a reporter gene such as luciferase whose transcription is up- regulated when the chimeric receptor is activated by a dimerized ligand. These cells would then be used to screen libraries of dimeric molecules as in the preceding step.
- BSA bovine serum albumin
- DMEM Dulbecco's Minimal Essential Medium
- DMEM/F12 Dulbecco's Minimal Essential Medium /Hamm's F12 Medium
- ECD Extracellular domain
- HMP p-hydroxymethylphenoxymethyl polystyrene resin
- HPLC High Pressure Liquid Chromatography
- HBTU O-(benzotriazol-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate
- HOBt 1 -hydroxybenzotriazole
- IL-5 Interleukin 5
- IL-5R ⁇ the alpha chain subunit of the human IL-5 Receptor
- IL-5R ⁇ ECD ECD of the human IL-5 receptor ⁇ chain
- PAL 5-(4-aminomethyl-3,5-dimethoxyphenoxy)valeric acid
- PBS phosphate buffered saline
- Tris Tris(hydroxymethyl)aminomethane
- TNF Tumor Necrosis Factor EXAMPLE 1
- the peptides were assembled using standard protocols of the Applied Biosystems Inc. (ABI) System Software version 1.01. Each coupling was performed for one-two hours with HBTU and HOBt. Double-couplings were performed at each step.
- the resin used was HMP resin or PAL resin (Milligen/Biosearch), which is a cross-linked polystyrene resin with
- Trityl (Trt), and/or t-butyl (tBu) were utilized as protecting groups for the Cys residues.
- the Fmoc group was used for amino protection during the coupling procedure.
- Primary amine protection on amino acids was achieved with Fmoc and side chain protection groups were t-butyl for serine, tyrosine, aspartic acid, glutamic acid, and threonine; Pmc
- the first disulfide bond is formed by selectively removing the first set of protecting groups.
- the second disulfide bond is formed by removing the second set of protecting groups from the peptide as shown schematically below.
- the reaction mixture is stirred for three hours at room temperature and filtered into cold ether. The precipitate is further washed three times with cold ether. Then the dried crude peptide is suspended in DMSO-1 M HC1 (80:20 v/v). The concentration is 2.5 mg /1ml solution. After stirring overnight, the peptide is further purified by RP-HPLC.
- the fractions are collected and further analyzed by analytical HPLC.
- the pure fractions are pooled together, lyophilized and characterized by MS.
- the overall yield is 12% by weight.
- the linear peptide with 3 -SH is oxidized in Tris buffer, pH 7.8 for two days. The course of the reaction is monitored by HPLC. The product can be purified by RP-HPLC.
- DIMER SYNTHESIS ORTHOGONAL PROTECTING GROUPS
- the dimeric form of AF 17362 was digested with trypsin and analyzed by LC-electrospray-MS and MALDI-MS.
- MS analysis of the tryptic digest revealed fragments consistent with the presence of a single symmetrical dimer structure containing an interchain disulfide bond between the cysteines in position 9 and intrachain disulfide bonds between the cysteines in positions 15 and 18 on each chain:
- a dimer peptide was prepared synthetically using orthogonal protecting groups. 0 Synthesis was performed on HMP resin using an ABI peptide synthesizer 431 A or 433 A and Fmoc- chemistry. Each step was double coupled using HBTU/HOBt reagent.
- the acetamidomethyl (Acm-) protecting group was used for the Cys in position 9 and trityl (Trt- ) for the Cys in positions 15 and 18.
- Other protecting groups were tBu- for Thr and Tyr, -OtBu for Asp and Glu, Boc- for Trp and Pmc- for Arg.
- the N- 5 terminal Fmoc- group was removed.
- the peptide was cleaved and deprotected from the resin with TFA-DCM-anisole-2 mercaptoethanol (89.7%-10%-0.1%-0.2%).
- the crude peptide was further purified by C lg RP-HPLC.
- the peptide was oxidized overnight in 30% DMSO-water at 1 mg/ml to form the intrachain disulfide bond [J. P. Tarn, C.-R. Wu, W. Liu, J.-W. Zhang, J. Am. Chem. Soc. 113: 6657 (1991)].
- the interchain disulfide bond was 0 formed by using AgOTf-TFA followed by DMSO-aq.HCl (Tamamura et al., Chem.
- AF18748 The ability of AF18748 to bind to the native IL-5R ⁇ / ⁇ complex on TF-1 cells was assessed in a competition binding assay (as described in McKinnon et al., J. Exp. Med. 186: 121 (1997)).
- AF 18748 The functional activity of AF 18748 was assessed in a human eosinophil adhesion assay (following the method of D. Fattah, et al, Cytokine 8:248 (1996)).
- the peptide alone was devoid of agonist activity, but completely inhibited IL-5 induced eosinophil adhesion to immobilized IgG with an IC 50 of 348 ⁇ 67 pM ( Figure 2).
- AF 18748 up to 1 ⁇ M had no effect on eosinophil adhesion induced by the related cytokines GM-CSF and IL-3, the unrelated cytokine TNF ⁇ or the chemotactic peptide fMet-Leu-Phe ( Figure 3).
- AF 18748 is therefore a potent and selective antagonist of IL-5 in a human eosinophil functional assay.
- Bioactivity of synthetic peptides and MBP-peptide fusions is measured using a Cytosensor microphysiometer (Molecular Devices) to record the metabolic response of TF-1 cells (a human leukemia cell line) to IL-5 in the presence or absence of peptide. After overnight incubation without IL-5, these cells exhibited a robust increase in metabolic activity when IL-5 is added to the medium. This increase was measured by the microphysiometer as an increase in the rate of acidification of weakly buffered tissue culture medium.
- TF-1 cells were seeded into microphysiometer chambers at a density of 1.5 x 10 5 cells/chamber and grown overnight in DMEM tissue culture medium containing 10% fetal bovine serum, but lacking the 1 ng/ml IL-5 (R&D Systems) that is required for long-term maintenance of these cells in culture.
- the chambers were then placed in the microphysiometer and incubated with weakly buffered DMEM F12 medium containing 1% human serum albumin until a baseline rate of medium acidification was established. Varying dilutions of test peptide were then introduced for 15 min. None of the peptides tested had any effect on the baseline acidification rate.
- IL-5 at 10 ng/ml was then introduced for 25 minutes in the continued presence of test peptide.
- test peptides were able to reduce or completely block the response of the TF-1 cells to IL-5.
- Other, randomly chosen control peptides at the same or higher concentrations, had no effect.
- the test peptides also had no effect on the robust microphysiometer response of TF-1 cells to TNF ⁇ , indicating that the test peptides were exhibiting their effect by specifically antagonizing IL-5 action.
- the IC 50 for test peptides was defined as that peptide concentration which gave a 50% reduction in the maximal IL-5 response when compared to the response to IL-5 alone.
- Binding affinities of synthetic peptides for IL-5R ⁇ were measured in a competition binding assay using radio-iodinated IL-5.
- Immulon 4 (Dynatech) microtiter wells were coated with streptavidin (Sigma) by incubating 100 ⁇ l of a 50 ⁇ g/ml solution in PBS for 30 min. at 37°. The wells were blocked with 200 ⁇ l of 1 % BSA in PBS for 15 min. at 37°, followed by 100 ⁇ l of biotinylated monoclonal antibody, designated mAb 179, at 5 ⁇ g/ml in PBS.
- Soluble IL-5R ⁇ was then immobilized in the wells by incubating 100 ⁇ l of a solution of soluble receptor harvest diluted 1 :5000 in PBS/0.1% BSA for 1 hr. at 4°. After washing away unbound receptor, 50 ⁇ l of various concentrations of test peptide diluted in PBS/0.1 % BSA were added to the wells, followed by 50 ⁇ l of a fixed concentration of [ 1 5 I]
- Binding affinities of synthetic peptides for IL-5R ⁇ were measured in a scintillation proximity assay (SPA) using radio-iodinated IL-5.
- Streptavidin coated SPA beads (Amersham) were suspended in IL-5 binding buffer (phosphate buffered saline, 0.1% bovine serum albumin, 0.2%> NaN 3 ) at 2 mg beads/ml of buffer.
- Biotinylated mAb 179 was adsorbed onto the beads at a ratio of 2 ⁇ g Ab/mg beads by incubating the beads and antibody with agitation for at least 2 h. at 4°. The beads were pelleted at 2500 rpm and resuspended at 2 mg/ml in binding buffer.
- Soluble IL-5R ⁇ was then adsorbed onto the beads by diluting a solution of soluble receptor harvest 1 :500 into the bead suspension and incubating with agitation for 2 hr at 4°. The beads were again pelleted at 2500 rpm and resuspended at 2 mg/ml in binding buffer. Competition binding assays were carried out in lOO ⁇ l reactions in white polystyrene microtiter plates. These reactions contained 0.05 mg of receptor coated SPA beads, various concentrations of test peptide diluted in binding buffer, and 20 pM [ 125 I] IL-5 (Amersham).
- IL-5R ⁇ ECD the extracellular domain (ECD) of the human IL-5 receptor ⁇ chain
- ECD extracellular domain
- IL-5R ⁇ ECD fluorescently labeled IL-5R ⁇ ECD was incubated with IL-5R ⁇ ECD- coated polystyrene beads and serial dilutions of AF 18748 (open circles), AF17121 (closed circles), or human IL-5 (open squares).
- the binding reactions were incubated in microtiter plates overnight at room temperature, then microvolume fluorimetry measurements of bead- associated fluorescence were made using an FMAT instrument (Perkin-Elmer). The data points represent averages of triplicate determinations from a single representative experiment, providing biochemical evidence of AF18748-induced IL-5- ⁇ dimerization.
- IL-5R ⁇ ECD was loaded onto the column alone (dashed line) or in the presence of equimolar amounts of AF17121(dotted line) or AF 18748 (solid line). Elution volumes and calculated molecular weights are given in Table 3. Results shown are from a single experiment, representative of three separate runs for each condition.
- a system comprising a chimeric IL-5R- ⁇ /EGFR reported cell assay was designed to analyze receptor binding stoichiometry in a cellular context.
- a chimeric receptor consisting of the IL-5R ⁇ ECD fused to the transmembrane spanning and intracellular domains of the epidermal growth factor receptor (EGFR) was constructed, and stably expressed in Ba/F3 cells that also contained a luciferase reporter gene under the transcriptional control of the c-fos enhancer and minimal thymidine kinase promoter.
- Ba/F3 cells expressing a chimeric IL-5R ⁇ /EGFR receptor and containing a luciferase reporter gene were starved overnight of the WEHI conditioned medium in which they were maintained, then seeded into microtiter wells at a density of 10 5 cells/well. Following stimulation, the cells were incubated for 4 hr at 37° in a 5% CO 2 incubator. LucLite reagent (Packard) was then added to the wells according to the manufacturer's instructions and the plates were assayed for luciferase activity by counting in a Topcount instrument (Packard). Data points represent mean ⁇ SEM for 3 separate experiments performed in triplicate. The data has been normalized to the stimulation induced by l ⁇ M AF 18748 in each experiment. The experiments shown in Figure 7, with cells treated with serial dilutions of AF18748 (closed circles), AF17121 (open circles) or IL-
- homodimerization of the IL-5R ⁇ /EGFR chimera should likewise induce expression of the luciferase transgene. Stimulation of Ba/F3 cells expressing the chimera with AF 18748 resulted in a dose dependent increase in luciferase activity while the monovalent ligands IL- 5 or AF 17121 had no effect (Figure 7).
- the length of time that peptide dimers remain in circulation was measured by injection of peptides into mice and subsequently measuring the amount of peptide remaining in circulation at various times after injection.
- three peptide dimers with the same peptide sequence but differing in the amount of PEGylation were investigated.
- the compounds used were dimers comprising the peptide sequence SEQ ID NO: 8; the peptide dimer AF 18748 (lacking PEG), the mono-PEGylated peptide dimer AF25123, and the diPEGylated peptide dimer AF25122, where PEGylation was with 20 kDa PEG linked to the N-terminus of one or both peptides of a dimer.
- Peptides were dissolved at 0.125mM (AF 18748) or 0.5mM (AF25122, AF25123) in 0.9%o (w/v) saline and dosed into individual female CD-I mice (about 25 g) via a lateral tail vein (100 microliter injection).
- terminal blood samples (2 animals per timepoint) were collected, by cardiac puncture, into heparinized tubes and centrifuged to yield plasma which was stored frozen.
- Peptides were extracted from the plasma by the addition of an equal volume of ice-cold acetonitrile and, following centrifugation, the supernatants containing the peptides were dried down and stored at 4°C.
- the amount of peptide present in the serum extracts was evaluated by surface plasmon resonance techniques using a competition binding assay format on a BIAcore 1000 machine (Biacore AB, Uppsala, Sweden).
- a disulfide-linked dimer peptide of the sequence EGYVCVEWARCPTCK (SEQ ID NO: 1 1) was chemically coupled onto a CM-5 Biosensor chip using the manufacturer's standard protocol.
- Purified recombinant IL-5 receptor alpha chain extracellular domain was passed over the peptide coated chip and the binding of the IL-5 receptor to the EGYVCVEWARCPTCK (SEQ ID NO: 11) peptide dimer was monitored.
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US5677280A (en) * | 1995-06-07 | 1997-10-14 | Glaxo Group Limited | Peptides and compounds that bind to the IL-5 receptor |
US5683983A (en) * | 1995-06-07 | 1997-11-04 | Glaxo Group Limited | Peptides and compounds that bind to the IL-5 receptor |
WO1998057979A1 (en) * | 1997-06-14 | 1998-12-23 | Glaxo Group Limited | Peptides and compounds that bind to the il-5 receptor |
WO1998057991A1 (en) * | 1997-06-16 | 1998-12-23 | Glaxo Group Limited | Peptides and compounds that bind to the il-5 receptor |
-
1999
- 1999-12-16 CA CA002394323A patent/CA2394323A1/en not_active Abandoned
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US5677280A (en) * | 1995-06-07 | 1997-10-14 | Glaxo Group Limited | Peptides and compounds that bind to the IL-5 receptor |
US5683983A (en) * | 1995-06-07 | 1997-11-04 | Glaxo Group Limited | Peptides and compounds that bind to the IL-5 receptor |
WO1998057979A1 (en) * | 1997-06-14 | 1998-12-23 | Glaxo Group Limited | Peptides and compounds that bind to the il-5 receptor |
WO1998057991A1 (en) * | 1997-06-16 | 1998-12-23 | Glaxo Group Limited | Peptides and compounds that bind to the il-5 receptor |
Non-Patent Citations (4)
Title |
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DEVOS R ET AL: "INTERLEUKIN-5 AND ITS RECEPTOR: A DRUG TARGET FOR EOSINOPHILIA ASSOCIATED WITH CHRONIC ALLERGIC DISEASE" JOURNAL OF LEUKOCYTE BIOLOGY, FEDERATION OF AMERICAN SOCIETIES FOR EXPERIMENTAL, US, vol. 57, 1 June 1995 (1995-06-01), pages 813-819, XP002056891 ISSN: 0741-5400 * |
ENGLAND BRUCE P ET AL: "A potent dimeric peptide antagonist of interleukin-5 that binds two interleukin-5 receptor alpha chains" PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES, vol. 97, no. 12, 6 June 2000 (2000-06-06), pages 6862-6867, XP002277632 June 6, 2000 ISSN: 0027-8424 * |
UINGS IAIN ET AL: "Development of IL-5 receptor antagonists" CURRENT PHARMACEUTICAL DESIGN, vol. 8, no. 20, 2002, pages 1837-1844, XP009029675 ISSN: 1381-6128 * |
UINGS IAIN J ET AL: "Modified peptide antagonists of interleukin 5 exhibit extended in vivo persistence but restricted species specificity" CYTOKINE, vol. 15, no. 1, 7 July 2001 (2001-07-07), pages 10-19, XP002277633 ISSN: 1043-4666 * |
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