Patient selection for ocular treatment

Abstract

Methods of reducing intraocular pressure, producing a sustained reduction in ocular inflammation and / or reducing or treating ocular inflammation while preventing an increase in risk of developing glaucoma or progression of glaucoma by administering a pharmaceutical composition comprising a phosphorylcholine-tuftsin conjugate comprising at least one phosphorylcholine moiety or a derivative thereof and tuftsin or a derivative thereof are provided. Methods of selecting subjects for treatment are also provided as are pharmaceutical compositions and kits.

Description

PATIENT SELECTION FOR OCULAR TREATMENTCROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority of U.S. Provisional Patent Application No. 63 / 530,327, filed August 2, 2023, the contents of which are all incorporated herein by reference in their entirety.REFERENCE TO AN ELECTRONIC SEQUENCE LISTING

[0002] The contents of the electronic sequence listing (TARS-P-007-PCT SQL.xml; Size: 2,554 bytes; and Date of Creation: July 25, 2024) is herein incorporated by reference in its entirety.FIELD OF THE INVENTION

[0003] The present invention is directed to the field of ocular inflammation treatment.BACKGROUND OF THE INVENTION

[0004] Ocular inflammation, an inflammation of any part of the eye is one of the most common ocular diseases. Ocular inflammation actually refers to a wide range of inflammatory diseases of the eye, one of them is uveitis. These diseases are prevalent in all age groups, and some are associated with systemic diseases such as Crohn’s disease, Behcet disease, Juvenile idiopathic arthritis and others. The inflammation can also be associated with other common eye symptoms such as dry eye and dry macular degeneration. Several drugs also have the known side effect of causing uveitis and / or dry eye. The most common treatment for ocular inflammation, is steroids and specifically corticosteroids. However, these treatments have several known and sometimes severe side effects.

[0005] Ocular hypertension or increased intraocular pressure (IOP) is often associated with ocular inflammation though it can also be found on its own. Steroids, the most common treatment for ocular inflammation, are known to cause both ocular hypertension and glaucoma.

[0006] Dazdotuftide is a novel bi-specific small molecule with immunomodulatory activities. Tuftsin (Thr-Lys-Pro-Arg) is a self-natural immunomodulating peptide produced by enzymatic cleavage of the Fc-domain of the heavy chain of IgG in the spleen. Phosphorylcholine (PC) is a small zwitterionic molecule secreted by helminths which permits helminths to survive in the host by inducing a situation of immune tolerance as well as on the surface of some bacteria and apoptotic cells. Dazdotuftide is one example of a Phosphorylcholine-tuftsin conjugate (PTC).

[0007] Methods of treating ocular inflammation which do not rely on steroids are greatly needed. Additionally, methods of improving efficacy, patient response and decreasing IOP are all also needed.SUMMARY OF THE INVENTION

[0008] Methods of reducing intraocular pressure, producing a sustained reduction in ocular inflammation and / or reducing or treating ocular inflammation while preventing an increase in risk of developing glaucoma or progression of glaucoma by administering a pharmaceutical composition comprising a phosphorylcholine-tuftsin conjugate comprising at least one phosphorylcholine moiety or a derivative thereof and tuftsin or a derivative thereof are provided. Methods of treating an eye disease and methods of selecting subjects for treatment are also provided as are pharmaceutical compositions and kits.

[0009] According to a first aspect, there is provided a method of reducing or treating ocular inflammation while preventing an increase in risk of developing glaucoma or while preventing progression of glaucoma in a subject in need thereof, the method comprising administering to an eye of the subject a pharmaceutical composition comprising a phosphorylcholine-tuftsin conjugate comprising at least one phosphorylcholine moiety or a derivative thereof and tuftsin or a derivative thereof, thereby treating ocular inflammation while preventing an increase in risk of developing glaucoma.

[0010] According to another aspect, there is provided a method for reducing intraocular pressure (IOP) in a subject in need thereof, the method comprising administering to an eye of the subject a pharmaceutical composition comprising a phosphorylcholine-tuftsin conjugate comprising at least one phosphorylcholine moiety or a derivative thereof and tuftsin or a derivative thereof, thereby reducing IOP.[Oi l] According to another aspect, there is provided a method of producing a sustained reduction in ocular inflammation, intraocular pressure or both in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising a phosphorylcholine-tuftsin conjugate comprising at least one phosphorylcholine moiety or a derivative thereof and tuftsin or a derivative thereof, wherein the sustained reduction is a reduction that persists for at least 2 weeks after cessation of the administering, thereby producing a sustained reduction in ocular inflammation, intraocular pressure or both.

[0012] According to some embodiments, the method is also a method for decreasing ocular inflammation.

[0013] According to some embodiments, the method comprises selecting a subject with an eye comprising an IOP of 16 mmHg or more and administering the pharmaceutical composition to the eye comprising an IOP of 16 mmHg or more.

[0014] According to some embodiments, the treating comprises maintaining an IOP of less than 16 mmHg in the eye of the subject.

[0015] According to some embodiments, the method is a method of preventing glaucoma in a subject at risk of developing glaucoma.

[0016] According to some embodiments, the phosphorylcholine moiety or a derivative thereof and the tuftsin or a derivative thereof are linked.

[0017] According to some embodiments, the phosphorylcholine moiety or a derivative thereof and the tuftsin or a derivative thereof are separated by a spacer.

[0018] According to some embodiments, the spacer is at least two amino acids.

[0019] According to some embodiments, the spacer is Glycine-Tyrosine.

[0020] According to some embodiments, the conjugate is represented by Formula 1 :

[0021] According to some embodiments, the reducing intraocular pressure comprises a reduction of at least 20%.

[0022] According to some embodiments, the pharmaceutical composition is an eye drop.

[0023] According to some embodiments, the reducing inflammation comprises reducing secretion of at least one pro-inflammatory cytokine in the eye of the subject, increasing secretion of at least one anti-inflammatory cytokine in the eye of the subject or both.

[0024] According to some embodiments, the subject suffers from ocular inflammation, ocular hypertension or both.

[0025] According to some embodiments, the subject suffers from uveitis.

[0026] According to some embodiments, the subject suffers from uveitic glaucoma.

[0027] According to some embodiments, the subject suffers from glaucoma.

[0028] According to some embodiments, the method prevents progression of the glaucoma.

[0029] According to some embodiments, the method further comprises administering at least one intraocular pressure lowering agent selected from a carbonic anhydrase inhibitor, a prostaglandin analog, an alpha-2 adrenergic agonist, a cholinergic and a beta-blocker.

[0030] According to some embodiments, the intraocular pressure lowering agent is selected from Acetazolamide, Bimatoprost, Brimonidine, Pilocarpine and Timolol.

[0031] According to some embodiments, the pharmaceutical composition is formulated for ocular administration.

[0032] According to some embodiments, the formulated for ocular administration comprises any one of an eye drop formulation, an ointment formulation, and an injection formulation.

[0033] According to some embodiments, the pharmaceutical composition comprises any one of a viscosity enhancer, a permeation enhancer or both.

[0034] According to some embodiments, the pharmaceutical composition comprises the conjugate at a concentration of about 1%.

[0035] According to some embodiments, the subject is refractory to, is allergic to, or has had at least one adverse event in response to at least one intraocular pressure lowering agent.

[0036] According to some embodiments, the method further comprises administering a prostaglandin or analog thereof.

[0037] According to some embodiments, the prostaglandin or analog thereof is selected from latanoprost, bimatoprost, travoprost, tafluprost, unoprostone and latanoprostene bunod.

[0038] According to another aspect, there is provided a method of determining suitability of a subject suffering from ocular inflammation and being treated with or having been treated with a steroid to be treated with a pharmaceutical composition comprising a phosphorylcholine-tuftsin conjugate comprising at least one phosphorylcholine moiety or a derivative thereof and tuftsin or a derivative thereof, the method comprising: a. receiving a measurement of IOP in an eye of the subject before treatment with the steroid; b. receiving a measurement of IOP in an eye of the subject after treatment with the steroid; and c. determining an increase in IOP from before treatment with the steroid to after treatment with the steroid, wherein a subject with a determined increase in IOP is suitable to be treated with the pharmaceutical composition, thereby determining suitability.

[0039] According to some embodiments, the method further comprises discontinuing administering the steroid to the subject, administering a reduced dose of the steroid to the subject, administering the pharmaceutical composition to the subject or a combination thereof.

[0040] According to another aspect, there is provided a kit comprising: a. a phosphorylcholine-tuftsin conjugate comprising at least one phosphorylcholine moiety or a derivative thereof and tuftsin or a derivative thereof; andb. a prostaglandin or an analog thereof.

[0041] According to some embodiments, the prostaglandin or analog thereof is selected from latanoprost, bimatoprost, travoprost, tafluprost, unoprostone and latanoprostene bunod.

[0042] Further embodiments and the full scope of applicability of the present invention will become apparent from the detailed description given hereinafter. However, it should be understood that the detailed description and specific examples, while indicating preferred embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.BRIEF DESCRIPTION OF THE DRAWINGS

[0043] Some embodiments of the invention are herein described, by way of example only, with reference to the accompanying drawings. With specific reference now to the drawings in detail, it is stressed that the particulars shown are by way of example and for purposes of illustrative discussion of embodiments of the invention. In this regard, the description together with the drawings makes apparent to those skilled in the art how embodiments of the invention may be practiced.

[0044] Figure 1 : Bar graph of IOP reduction in subjects receiving a solution of 0.1 % or 1 % PTC over the course of 4 weeks.

[0045] Figure 2: Table of characteristics of patients receiving PTC (TRS01) or steroids.

[0046] Figure 3: Bar graph of the percentage of patients with prolonged total resolution of inflammation receiving steroids or PTC (no inflammation two weeks off therapy).

[0047] Figure 4: Bar graph of the percent of patients with total resolution of inflammation with an IOP increase of at least 5, 7 or 10 mmHg. * = p-val < 0.05

[0048] Figure 5: Bar graph of the percent of patients with total resolution of inflammation with an IOP increase from less than 16 mmHg before treatment to greater than 16 mmHg during treatment. * = p-val < 0.05

[0049] Figure 6: Line graph of the average IOP per visit of patients with total resolution of inflammation that received either TRS01 or steroids. * = p-val < 0.05DETAILED DESCRIPTION OF THE INVENTION

[0050] The present invention, in some embodiments, provides methods of reducing intraocular pressure, producing a sustained reduction in ocular inflammation and / or reducing or treating ocular inflammation while preventing an increase in risk of developing glaucoma or progression of glaucoma by administering a pharmaceutical composition comprising a phosphorylcholine- tuftsin conjugate comprising at least one phosphorylcholine moiety or a derivative thereof and tuftsin or a derivative thereof are provided. Methods of treating an eye disease and methods of selecting subjects for treatment are also provided as are pharmaceutical compositions and kits.

[0051] By a first aspect, there is provided a method for treating or preventing an eye disease or condition in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising a phosphorylcholine-tuftsin conjugate comprising at least one phosphorylcholine moiety or a derivative thereof and tuftsin or a derivative thereof, thereby treating or preventing an eye disease or condition.

[0052] By another aspect, there is provided a method of reducing or treating ocular inflammation while preventing ocular hypertension in a subject, the method comprising administering to the subject a pharmaceutical composition comprising a phosphorylcholine-tuftsin conjugate comprising at least one phosphorylcholine moiety or a derivative thereof and tuftsin or a derivative thereof, thereby reducing or treating ocular inflammation while preventing ocular hypertension.

[0053] By another aspect, there is provided a method of reducing or treating ocular inflammation while preventing an increase in risk of developing glaucoma in a subject, the method comprising administering to the subject a pharmaceutical composition comprising a phosphorylcholine- tuftsin conjugate comprising at least one phosphorylcholine moiety or a derivative thereof and tuftsin or a derivative thereof, thereby reducing or treating ocular inflammation while preventing an increase in risk of developing glaucoma.

[0054] By another aspect, there is provided a method of reducing or treating ocular inflammation while preventing glaucoma in a subject, the method comprising administering to the subject apharmaceutical composition comprising a phosphorylcholine-tuftsin conjugate comprising at least one phosphorylcholine moiety or a derivative thereof and tuftsin or a derivative thereof, thereby reducing or treating ocular inflammation while preventing glaucoma.

[0055] By another aspect, there is provided a method of reducing or treating ocular inflammation while preventing progression of glaucoma in a subject, the method comprising administering to the subject a pharmaceutical composition comprising a phosphorylcholine-tuftsin conjugate comprising at least one phosphorylcholine moiety or a derivative thereof and tuftsin or a derivative thereof, thereby reducing or treating ocular inflammation while preventing progression of glaucoma.

[0056] By another aspect, there is provided a method of producing a sustained reduction in ocular inflammation, intraocular pressure or both in a subject, the method comprising administering to the subject a pharmaceutical composition comprising a phosphorylcholine-tuftsin conjugate comprising at least one phosphorylcholine moiety or a derivative thereof and tuftsin or a derivative thereof, thereby producing a sustained reduction in ocular inflammation, intraocular pressure or both.

[0057] By another aspect, there is provided a method of treating glaucoma or uveitic glaucoma in a subject, the method comprising administering to the subject a pharmaceutical composition comprising a phosphorylcholine-tuftsin conjugate comprising at least one phosphorylcholine moiety or a derivative thereof and tuftsin or a derivative thereof, thereby treating glaucoma or uveitic glaucoma.

[0058] The term “phosphorylcholine (PC) conjugate” as used herein, refers to a phosphorylcholine moiety or a derivative thereof linked to tuftsin (T), optionally via a spacer. The terms “PC conjugate”, “TPC”, “phophorylcholine tuftsin conjugate” and “PTC” are used herein interchangeably.

[0059] The term “phosphorylcholine tuftsin conjugate” (PTC) as used herein, refers to a phosphorylcholine moiety covalently linked to tuftsin or to a tuftsin derivative, optionally via a spacer. The term “phosphorylcholine tuftsin conjugate” as used herein further encompasses any salt (e.g., a pharmaceutically acceptable salt and any isotope thereof).

[0060] As used herein, the term “tuftsin” refers to a tetra-peptide (threonine-lysine -prolinearginine, TKPR; SEQ ID NO: 1). In some embodiments, the PTC is or comprises tuftsin (i.e. a peptide having an amino acid sequence as defined in SEQ ID NO: 1) covalently bound to a phosphorylcholine moiety via a side chain (e.g. phosphate group is bound directly to a side-chain of threonine, or to a side chain of lysine). In some embodiments, the PTC is or comprises tuftsin (i.e., a peptide having an amino acid sequence as defined in SEQ ID NO: 1) covalently bound to a phosphorylcholine moiety via the amino terminus (e.g. phosphate group is bound directly to the amino group, generating phosphoramidate). In some embodiments, the PTC is or comprises tuftsin (i.e., a peptide having an amino acid sequence as defined in SEQ ID NO: 1) covalently bound to a phosphorylcholine moiety via the amino terminus (e.g. phosphate group is bound directly to the amino group, generating phosphoramidate). In some embodiments, the PTC is or comprises tuftsin (i.e. a peptide having an amino acid sequence as defined in SEQ ID NO: 1) covalently bound to a phosphorylcholine moiety via the carboxy terminus (e.g. carboxy group is bound directly to the phosphate, generating a phosphorylated carboxylate).

[0061] The term “phosphorylcholine moiety” encompasses phosphoryl choline, i.e., and a derivative of phosphorylcholine. The term “derivative of phosphorylcholine” as used herein, refers to any compound that is based on phosphorylcholine. In some embodiments, the derivative retains the immunomodulatory effects of phosphorylcholine. In some embodiments, the phosphorylcholine derivative is a derivative comprising phosphorylcholine.

[0062] In some embodiments, the derivative of phosphorylcholine is selected from: phenylphosphorylcholine, a substituted phenyl-phosphorylcholine (e.g. aminophenylphosphorylcholine, nitrophenyl-phosphorylcholine, halophenyl- phosphorylcholine, hydroxyphenyl- phosphorylcholine, alkylphenyl- phosphorylcholine) and 12-(3- iodophenyl)dodecyl-phosphocholine among others. Each possibility is a separate embodiment of the invention.

[0063] In some embodiments, the derivative of phosphorylcholine is represented by Formula 2:wherein each R independently is an optionally substituted alkyl(e.g. methyl, or any Cl-10, or C2-C10 alkyl); and wherein X is a spacer. In some embodiments, X comprises a small molecule such as a natural and / or unnatural amino acid(s), a C5- ClOcycloalkylene, optionally substituted Cl-C6alkylene, -C(=O)-Cl-C6alkylene, optionally substituted C6-C10arylene, aryl(or heteroaryl)-azo, heteroaromatic ring (s), a carbocyclyl; a bond (such as an amide bond, an ester bond, azo bond, a thioester bond, a disulfide bond, -N-C(=O)-, - C(=O)N-, CONR ’-, -CNNR’-, -CSNR’-, -NC(=O)O-, -NC(=S)O-, -NC(=S)N-, -SO2-, -SO-, -SR’, -C(=O)-, -OC(=O)-, -OC(=O)O-, -OC(=S)O-, and -OC(=S)N-; -S-C(=O)), a glycol of formula - (RO)x-, wherein R represents C1-C10 alkyl; and x is an integer ranging between 1 and 10, or any combination thereof.

[0064] In some embodiments, X is or comprises a linear or a branched chain. In some embodiments, X comprises a backbone comprising a linear or a branched chain. In some embodiments, X comprises a cyclic (aromatic or aliphatic) backbone.

[0065] In some embodiments, the derivative of phosphorylcholine is represented by Formula 2, wherein R is methyl.

[0066] In some embodiments,

[0067] In some embodiments, the spacer has a MW less than 500 Da, less than 400 Da, less than 300 Da, less than 200 Da, less than 100 Da, or between 14 and 100 Da, between 14 and 200 Da, between 14 and 300 Da, including any range between.

[0068] In some embodiments, the spacer is between 1 and 50, between 1 and 100, between 2 and 100, between 2 and 80, between 2 and 60, between 5 and 50, between 10 and 50, between 10 and 40, between 2 and 30, between 2 and 20, between 2 and 10, between 1 and 5, between 5 and 10, between 5 and 15, between 5 and 25, between 5 and 50 single C-C bonds long, including any range in between.

[0069] The term “tuftsin derivative” refers to tuftsin (TKPR, SEQ ID NO: 1) attached to at least one additional amino acid which are independently selected. Non-natural amino acids, and optionally non-charged and non-polar non-natural amino acids such as P-alanine-6- aminohexanoic acid and 5-aminopentanoic acid, may also be comprised in the tuftsin derivative. In some embodiments, the tuftsin derivative is TKPR(X1)(X2), wherein XI is any amino acid and X2 is any amino acid. In some embodiments, the tuftsin derivative is TKPR(X1)(X2), wherein XI is an amino acid selected from Tyr, Gly, Ala, Vai, Thr, Leu, He, and Met; and wherein X2 is an amino acid selected from Tyr, Trp, Phe, Cys, Ser, Thr, Gly, Ala, Vai, Thr, Leu, He, and Met.

[0070] In some embodiments, the tuftsin derivative is a peptide comprising TKPR and retaining the immunomodulatory effects of tuftsin. A derivative is not merely a fragment of the polypeptide, nor does it have amino acids replaced or removed (an analog), rather it may have additional amino acid residues and / or modification made to the polypeptide, such as a post- translational modification.

[0071] In some embodiments, the tuftsin derivative is Threonine-Lysine-Proline-Arginine- Glycine-Tyrosine (TKPRGY, SEQ ID NO: 2).

[0072] In some embodiments, the term “moiety” as used herein refers to a part of a molecule, which lacks one or more atom(s) compared to the corresponding molecule. The term “moiety”, as used herein, may further relate to a part of a molecule that may include either whole functional groups or parts of functional groups as substructures (e.g. an amino group lacking a hydrogen, a phosphate group lacking hydrogen or hydroxy, amino acid residue, etc). The term “moiety” further means part of a molecule that exhibits a particular set of chemical and / or pharmacologic characteristics which are similar to the corresponding molecule.

[0073] The terms “linked” or “attached” as used herein refer to a bond between at least two molecules or moieties such that they are a single molecule. In some embodiments, the bond is a chemical bond. In some embodiments, the bond is a covalent bond. According to the principles of the present invention, the natural and non-natural amino-acids comprised in the tuftsin derivative are adjacent and attached to one another, while the at least one phosphorylcholine derivative is attached to the at least one tuftsin derivative either directly or indirectly via a spacer. In some embodiments, the at least one phosphorylcholine or derivative thereof is linked to theN-terminus of at least one tuftsin or derivative thereof. In some embodiments, the at least one phosphorylcholine or derivative thereof is linked to the C-terminus of at least one tuftsin or derivative thereof.

[0074] In some embodiments, the phosphorylcholine-tuftsin conjugate comprises one or more phosphorylcholine moiety(s) attached to a tuftsin derivative. In certain embodiments, the phosphorylcholine moiety (i.e., a derivative of phosphorylcholine represented by Formula 2) is covalently bound to a tuftsin derivative. In some embodiments, covalently bound is via a side chain of the tuftsin derivative. In some embodiments, covalently bound is via a side chain of Tyr (e.g. via an azo bond bound to the side chain of Tyr). In some embodiments, the phosphorylcholine-tuftsin conjugate is represented by Formula 1, below.

[0075] In certain embodiments, the phosphorylcholine-tuftsin conjugate described above comprises one phosphorylcholine derivative attached to one tuftsin derivative. In certain embodiments, the phosphorylcholine-tuftsin conjugate described above comprises a plurality of phosphorylcholine derivatives attached to a plurality of tuftsin derivatives. In certain embodiments, the phosphorylcholine-tuftsin conjugate described above comprises a plurality of tuftsin derivatives attached to one phosphorylcholine derivative. In certain embodiments, the phosphorylcholine-tuftsin conjugate described above comprises a plurality of phosphorylcholine derivatives attached to one tuftsin derivative.

[0076] In certain embodiments, the phosphorylcholine-tuftsin conjugate described above comprises at least one phosphorylcholine or derivative thereof and the at least one tuftsin or derivative thereof separated by a spacer.

[0077] In some embodiments, the peptide is between 3 and 50, between 3 and 10, between 3 and 20, between 3 and 5, between 5 and 10 amino acid residues long, including any range between.

[0078] As used herein, the terms “peptide”, “polyaminoacid”, “polypeptide” and “protein” are used interchangeably and refer to a polymer of amino acid residues. In some embodiments, the peptide of the invention is or comprises a therapeutic peptide sequence. The term “therapeutic peptide sequence” refers to any peptide sequence configured for inducing a therapeutic effect within a subject (e.g., treating, preventing, reducing symptoms of a disease, etc.). Further, the term “therapeutic peptide sequence” encompasses any polyamino acid sequence capable of modifying the activity, functionality, survival, fitness, appearance, structure, development,behavior, or any combination thereof, of a cell. In some embodiments, the therapeutic sequence is capable of binding an intracellular target (e.g. enzyme), so as to control (upregulate, or downregulate) the activity of the intracellular target.

[0079] The terms “peptide”, “polyaminoacid”, “polypeptide” and “protein” as used herein encompass native peptides, peptide derivatives such as beta peptides, peptidomimetics (typically including non-peptide bonds or other synthetic modifications,) and the peptide analogs peptoids and semi-peptoids or any combination thereof. In another embodiment, the terms “peptide”, “ polyaminoacid” and “protein” apply to amino acid polymers in which at least one amino acid residue is an artificial chemical analog of a corresponding naturally occurring amino acid.

[0080] The term “derivative” or “chemical derivative” includes any chemical derivative of the polypeptide having one or more residues chemically derivatized (or chemically modified) by reaction on the side chain or on any functional group within the peptide. Such derivatized molecules include, for example, peptides bearing one or more protecting groups (e.g., side chain protecting group(s) and / or N-terminus protecting groups), and / or peptides in which free amino groups have been derivatized to form amine hydrochlorides, p-toluene sulfonyl groups, carbobenzoxy groups, t-butyloxycarbonyl groups, acetyl groups or formyl groups. Free carboxyl groups may be derivatized to form amides thereof, salts, methyl and ethyl esters or other types of esters or hydrazides. Free hydroxyl groups may be derivatized to form O-acyl or O-alkyl derivatives. The imidazole nitrogen of histidine may be derivatized to form N-im- benzylhistidine. Also included as chemical derivatives are those peptides, which contain one or more naturally occurring amino acid derivatives of the twenty standard amino acid residues. For example: 4-hydroxyproline may be substituted for proline; 5-hydroxylysine may be substituted for lysine; 3 -methylhistidine may be substituted for histidine; homoserine may be substituted or serine; and Dab, Daa, and / or ornithine (O) may be substituted for lysine.

[0081] In addition, a peptide derivative can differ from the natural sequence of the peptide of the invention by chemical modifications including, but are not limited to, terminal-NH2 acylation, acetylation, or thioglycolic acid amidation, and by amidation of the terminal and / or side-chain carboxy group, e.g., with ammonia, methylamine, and the like. Peptides can be either linear, cyclic, or branched and the like, having any conformation, which can be achieved using methods known in the art.

[0082] The term “amino acid” as used herein means an organic compound containing both a basic amino group and an acidic carboxyl group. Included within this term are naturally occurring amino acids, protected amino acids (e.g., comprising one or more protecting groups at the carboxyl, at the amine, and / or at the side chain of the amino acid), unusual, non-naturally occurring amino acids (such as D-amino acids), as well as amino acids which are known to occur biologically in free or combined form but usually do not occur in proteins. Included within this term are modified and unusual amino acids, such as those disclosed in, for example, Roberts and Vellaccio (1983) The Peptides. 5: 342-429. Modified, unusual or non-naturally occurring amino acids include, but are not limited to, D-amino acids, hydroxylysine, 4-hydroxyproline, N-Cbz- protected aminovaleric acid (Nva), ornithine (O), aminooctanoic acid (Aoc), 2,4-diaminobutyric acid (Abu), homoarginine, norleucine (Nle), N-methylaminobutyric acid (MeB), 2- naphthylalanine (2Np), aminoheptanoic acid (Ahp), phenylglycine, P-phenylproline, tert-leucine, 4-aminocyclohexylalanine (Cha), N-methyl-norleucine, 3,4-dehydroproline, N,N- dimethylaminoglycine, N-methylaminoglycine, 4-aminopipetdine-4-carboxylic acid, 6- aminocaproic acid, trans-4- (aminomethyl) - cyclohexanecarboxylic acid, 2-, 3-, and 4- (aminomethyl) - benzoic acid, 1 -aminocyclopentanecarboxylic acid, 1- aminocyclopropanecarboxylic acid, cyano-propionic acid, 2-benzyl-5- aminopentanoic acid, Norvaline (Nva), 4-O-methyl-threonine (Tme), 5-O-methyl-homoserine (hSM), tert-butyl- alanine (tBu), cyclopentyl-alanine (Cpa), 2-amino-isobutyric acid (Aib), N-methyl-glycine (MeG), N-methyl-alanine (MeA), N-methyl -phenylalanine (MeF), 2-thienyl-alanine (2Th), 3- thienyl-alanine (3Th), O-methyl-tyrosine (Yme), 3-Benzothienyl-alanine (Bzt) and D-alanine (Dal).

[0083] The term “polyaminoacid” further encompasses random polymers (i.e., devoid of a specific amino acid sequence within the entire composition and include a random population of polymers of different lengths and of different sequences) and polypeptides having a specific amino acid sequence). The terms “peptide sequence” and “amino acid sequence” are used herein interchangeably. In some embodiments, the peptide sequence is or comprises D-amino acid sequence. In some embodiments, at least 5%, at least 70%, at least 80%, at least 90%, at least 95% of the amino acids within the peptide sequence are in D-configuration. In some embodiments, the amino acids within the peptide sequence are in D-configuration.

[0084] In some embodiments, the PTC is represented by Formula 1:

[0085] In some embodiments, the administering is to an eye of the subject. Ocular administration of a drug or composition is well known in the art. In some embodiments, ocular administration comprises dropping the composition on to the eye. In some embodiments, ocular administration comprises application to the eye, to the out surface of the eye, to the interior of the eye, to the blood vessels in contact with the eye, to the orbit, to the socket of the eye, to the epidermal surface and tissues that surround the eye, to the eyelid, to the eyelashes, and to the fatty deposits surrounding the eye. In some embodiments, a blood vessel in contact with the eye is selected from the ophthalmic artery, the central retinal artery, a posterior ciliary artery, and an anterior ciliary artery. In some embodiments, ocular administration comprises application to the eye, to the fluid around the eye, to the corner of the eye, to the tear ducts, to the anterior chamber of the eye, to the posterior chamber of the eye, to the choroid, to the retina, to the lens, to the uvea, or under the eye lids. Each possibility represents a separate embodiment of the invention.

[0086] As used herein, the term “pharmaceutical composition” refers to any composition comprising the phosphorylcholine conjugate and at least one other ingredient, as well as any product which results, directly or indirectly, from combination, complexation, or aggregation of any two or more of the ingredients, from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the term “pharmaceutical composition” as used herein may encompass, inter alia, any composition made by admixing a pharmaceutically active amount of the conjugate and one or more pharmaceutically acceptable carriers. In some embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable carrier, diluent or excipient.

[0087] As used herein, the term “carrier,” “adjuvant” or “excipient” refers to any component of a pharmaceutical composition that is not the active agent. As used herein, the term “pharmaceutically acceptable carrier” refers to non-toxic, inert solid, semi-solid liquid filler, diluent, encapsulating material, formulation auxiliary of any type, or simply a sterile aqueous medium, such as saline or water for injection. Some examples of the materials that can serve aspharmaceutically acceptable carriers are sugars, such as lactose, glucose and sucrose, starches such as corn starch and potato starch, cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt, gelatin, talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol, polyols such as glycerin, sorbitol, mannitol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate, agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline, Ringer’s solution; ethyl alcohol and phosphate buffer solutions, as well as other non-toxic compatible substances used in pharmaceutical formulations. Some non-limiting examples of substances which can serve as a carrier herein include sugar, starch, cellulose and its derivatives, powered tragacanth, malt, gelatin, talc, stearic acid, magnesium stearate, calcium sulfate, vegetable oils, polyols, alginic acid, pyrogen-free water, isotonic saline, phosphate buffer solutions, cocoa butter (suppository base), emulsifier as well as other non-toxic pharmaceutically compatible substances used in other pharmaceutical formulations. Wetting agents and lubricants such as sodium lauryl sulfate, as well as coloring agents, flavoring agents, excipients, stabilizers, antioxidants, and preservatives may also be present. Any non-toxic, inert, and effective carrier may be used to formulate the compositions contemplated herein. Suitable pharmaceutically acceptable carriers, excipients, and diluents in this regard are well known to those of skill in the art, such as those described in The Merck Index, Thirteenth Edition, Budavari et al., Eds., Merck & Co., Inc., Rahway, N.J. (2001); the CTFA (Cosmetic, Toiletry, and Fragrance Association) International Cosmetic Ingredient Dictionary and Handbook, Tenth Edition (2004); and the “Inactive Ingredient Guide,” U.S. Food and Drug Administration (FDA) Center for Drug Evaluation and Research (CD ER) Office of Management, the contents of all of which are hereby incorporated by reference in their entirety. Examples of pharmaceutically acceptable excipients, carriers and diluents useful in the present compositions include distilled water, physiological saline, Ringer’s solution, dextrose solution, Hank’s solution, and DMSO. These additional inactive components, as well as effective formulations and administration procedures, are well known in the art and are described in standard textbooks, such as Goodman and Gillman’s: The Pharmacological Bases of Therapeutics, 8th Ed., Gilman et al. Eds. Pergamon Press (1990); Remington’s Pharmaceutical Sciences, 18th Ed., Mack Publishing Co., Easton, Pa. (1990); and Remington: The Science and Practice of Pharmacy, 21stEd., Lippincott Williams & Wilkins, Philadelphia, Pa., (2005), each of which is incorporated by reference herein in its entirety. The presently described composition may also be contained in artificially created structures such as liposomes, ISCOMS, slow-releasing particles, and other vehicles which increase the half-life of the peptides or polypeptides. Liposomes include emulsions, foams, micelies, insoluble monolayers, liquid crystals, phospholipid dispersions, lamellar layers and the like. Liposomes for use with the presently described peptides are formed from standard vesicle-forming lipids which generally include neutral and negatively charged phospholipids and a sterol, such as cholesterol. The selection of lipids is generally determined by considerations such as liposome size and stability in the blood. A variety of methods are available for preparing liposomes as reviewed, for example, by Coligan, J. E. Et al, Current Protocols in Protein Science, 1999, John Wiley & Sons, Inc., New York, and see also U.S. Pat. Nos. 4,235,871, 4,501,728, 4,837,028, and 5,019,369.

[0088] The carrier may comprise, in total, from about 0.1% to about 99.99999% by weight of the pharmaceutical compositions presented herein.

[0089] In some embodiments, the salt of the PTC is a pharmaceutically acceptable salt. Pharmaceutically acceptable salts are well-known in the art, including inter alia within alkali metal salts, alkaline earth metal salts and / or ammonium salts, as well as halide (e.g., chloride), citrate, acetate, trifluoroacetate, phosphate, borate, lactate and the like salts and mixtures thereof. In some embodiments, the peptide (e.g., PTC) disclosed herein is a pharmaceutical grade active agent (e.g., characterized by chemical purity above 97%). In some embodiments, the entire constitutes of the composition of the invention are substantially chemically pure compounds.

[0090] In some embodiments, the composition of the invention is a pharmaceutical composition comprising a pharmaceutically effective amount of the PTC and further comprising a pharmaceutically acceptable carrier. In some embodiments, the composition of the invention is a pharmaceutical composition comprising a pharmaceutically effective amount of a peptide and further comprising a pharmaceutically acceptable carrier.

[0091] In some embodiments, the composition of the invention is formulated for ocular administration. In some embodiments, the pharmaceutical composition is an ophthalmic composition. In some embodiments, the terms “ophthalmic composition” and “pharmaceutical composition” are used herein interchangeably. In some embodiments, the pharmaceuticalY1composition is formulated for ocular administration. In some embodiments, the ophthalmic composition is formulated as drops. In some embodiments, the ophthalmic composition is formulated as an ointment. In some embodiments, the ophthalmic composition is formulated for topical administration to the eye. In some embodiments, the ophthalmic composition is formulated for injection. In some embodiments, injection is injection into the eye. In some embodiments, into the eye is in to the vitreous fluid. In some embodiments, the composition of the invention comprises the phosphorylcholine-tuftsin conjugate as the only pharmaceutically active ingredient. In some embodiments, the composition of the invention is substantially devoid of any additional pharmaceutically active ingredient. In some embodiments, the composition of the invention is substantially devoid of any additional peptide. In some embodiments, the composition of the invention is substantially devoid of any additional anti-inflammatory agent.

[0092] In some embodiments, the pharmaceutical composition is formulated for ocular administration. Medicinal compositions for ocular administration are well known in the art and may comprise adjuvants, excipients or carriers specific for this purpose. Examples of such include but are not limited to, fluids at biological pH (6.5-7.5), preservatives, viscosity enhancers and permeation enhancers. In some embodiments, the pharmaceutical composition comprises a permeation enhancer, a viscosity enhancer or both. In some embodiments, the pharmaceutical composition comprises a viscosity enhancer. In some embodiments, the pharmaceutical composition comprises a preservative. In some embodiments, a formulation for ocular administration comprises any one of an eye drop formulation, an ointment formulation, and an injection formulation. In some embodiments, a formulation for ocular administration comprises an eye drop formulation. In some embodiments, eye drops are administered.

[0093] In some embodiments, the ophthalmic composition comprises an effective amount of a preservative. In some embodiments, the effective amount is a preservative effective amount. In some embodiments, the effective amount is an antimicrobial effective amount. In some embodiments, the effective amount of the preservative within the ophthalmic composition of the invention is reduced relative to the label claim of the preservative (i.e., the effective concentration of the specific preservative as prescribed by the relevant regulatory authority).

[0094] In some embodiments, the effective amount of the preservative within the ophthalmic composition of the invention is reduced by at least 10%, at least 50%, at least 70%, at least 2times, at least 5 times, at least 10 times, at least 50 times, at least 100 times, at least 500 times, or between about 2 and about 20 times, between about 2 and about 15 times, between about 2 and about 10 times, between about 5 and about 20 times, between about 5 and about 15 times, including any range or value therebetween, wherein reduced is relative to the label claim of the preservative. In some embodiments, the ophthalmic composition comprises a reduced amount of the preservative, wherein reduced is relative to effective amount of the preservative within a similar composition devoid of PC (or comprising an active agent which is not PC).

[0095] In some embodiments, the effective amount of the preservative is determined based on a PET test, according to USP <51>, or any alternative PET test.

[0096] In some embodiments, the ophthalmic composition comprises between 0.001 and 1% w / w of a preservative, including any range between. In some embodiments, the ophthalmic composition comprises at least 0.001%w / w and below the label claim of the preservative, wherein below the label claim encompasses a concentration of the preservative being reduced by at least 10%, at least 50%, at least 70%, at least 2 times, at least 5 times, at least 10 times, at least 50 times, at least 100 times, at least 500 times, or between about 2 and about 20 times, between about 2 and about 15 times, between about 2 and about 10 times, between about 5 and about 20 times, between about 5 and about 15 times, including any range or value therebetween, relative to the label claim of the preservative.

[0097] In some embodiments, a w / w concentration of the preservative within the ophthalmic composition is between 0.001 and 1%, between 0.001 and 0.1%, between 0.001 and 0.01%, between 0.001 and 0.02%, between 0.001 and 0.018%, between 0.001 and 0.015%, between 0.002 and 0.018%, between 0.002 and 0.015%, between 0.003 and 0.018%, between 0.003 and 0.015%, between 0.05 and 0.1%, between 0.1 and 0.2%, between 0.2 and 0.3%, between 0.3 and 0.4%, between 0.4 and 0.5%, between 0.5 and 0.7%, between 0.7 and 1%, including any range or value therebetween. In some embodiments, the preservative is suitable for use in an ophthalmic composition. In some embodiments, the preservative is or comprises a quaternary ammonium cation, such as benzalkonium (BAK) including any salt thereof, for example benzalkonium chloride. In some embodiments, the quaternary ammonium cation is a pharmaceutically acceptable compound. In some embodiments, the quaternary ammonium cation comprises a pharmaceutically acceptable counter anion.

[0098] Additional preservatives are well-known in the art. Non-limiting examples of preservatives include but are not limited to, chlorobutanol, sodium perborate, and stabilized oxychloro complex (SOC) or any combination thereof.

[0099] In some embodiments, the preservative as disclosed herein is the only preservative in the ophthalmic composition of the invention. In some embodiments, the preservative within the ophthalmic composition is a benzalkonium, including any salt and any derivative thereof.

[0100] As used herein, a “viscosity enhancer” refers to any substance that increases the viscosity of the solution to be administered to the eye. In some embodiments, the viscosity enhancer increases viscosity of an aqueous solution. A person skilled in the art will appreciate that increased viscosity improves residence time on the eye and increases bioavailability upon topical administration. Examples of viscosity enhancers include, but are not limited to hydroxy methyl cellulose, hydroxy ethyl cellulose, sodium carboxy methyl cellulose, hydroxypropyl methyl cellulose, sodium alginate and polyalcohol.

[0101] As used herein, a “permeation enhancer” refers to any substance that improves corneal uptake by modifying corneal integrity and thus increase bioavailability in the eye. Examples of permeation enhancers include, but are not limited to, benzalkonium chloride, polyoxyethylene glycol esters, polycarbophil-cysteine and cyclodextrins.

[0102] The term “therapeutically effective amount” refers to the amount of the conjugate effective to treat a disease or disorder in a mammal. The term “a therapeutically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic or prophylactic result. The exact dosage form and regimen would be determined by the physician according to the patient’s condition.

[0103] In some embodiments, the pharmaceutical composition comprises at most 10 mg / ml, 9 mg / ml, 8 mg / ml, 7 mg / ml, 6 mg / ml, 5 mg / ml, 4 mg / ml, 3 mg / ml, 2 mg / ml, 1 mg / ml, 500 pg / ml, 100 pg / ml, 50 pg / ml, 10 pg / ml, 5 pg / ml, 0.5 pg / ml, 0.1 pg / ml, 0.05 pg / ml, 0.01 pg / ml, 0.005 pg / ml, 0.0005 pg / ml, 0.00005 pg / ml, 0.000005 pg / ml, 0.0000005 pg / ml, 0.00000005 pg / ml TPC. Each possibility represents a separate embodiment of the invention. In some embodiments, the pharmaceutical composition comprises at most 10 mg / ml. In some embodiments, a dose is at or below 0.5, 0.05, 0.005, 0.0005, 0.00005, 0.000005, 0.0000005, or 0.00000005 pg / ml. Each possibility represents a separate embodiment of the invention. In some embodiments, thepharmaceutical composition comprises about 1% PTC. In some embodiments, the pharmaceutical composition comprises at least 1% PTC. In some embodiments, the pharmaceutical composition comprises at least 0.001, 0.005, 0.01, 0.05, 0.1, 0.5, 1, 2, 3, 4, 5, 6 ,7 ,89 or 10% PTC. Each possibility represents a separate embodiment of the invention. In some embodiments, the pharmaceutical composition comprises about 0.1, 0.5, 1, 2, 3, 4, 5, 6 ,7 ,8 9 or 10% PTC. Each possibility represents a separate embodiment of the invention. In some embodiments, the pharmaceutical composition comprises between 1-5% PTC.

[0104] In some embodiments, uveitis, ocular hypertension or glaucoma is treated with an eyedrop composition comprising 1% PTC. It will be understood by a skilled artisan that this particular dose produced the surprising effects described herein below and that this dose is particularly and unexpectedly suited to treat these diseases. In some embodiments, uveitis is treated. In some embodiments, ocular hypertension is treated. In some embodiments, glaucoma is treated. In some embodiments, a combination of uveitis and ocular hypertension is treated. In some embodiments, a combination of ocular hypertension and glaucoma is treated. In some embodiments, a combination of uveitis, ocular hypertension and glaucoma is treated.

[0105] In some embodiments, the dose is a daily dose. In some embodiments, the daily dose is a twice daily dose. In some embodiments, the daily dose is a four times daily dose. In some embodiments, the same dose is administered at each dosing. In some embodiments, at a dosing 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 drops are administered. Each possibility represents a separate embodiment of the invention. In some embodiments, at a dosing one drop is administered. In some embodiments, at a dosing two drops are administered. In some embodiments, at a dosing three drops are administered. In some embodiments, at a dosing four drops are administered.

[0106] In some embodiments, the subject suffers from ocular inflammation. In some embodiments, the condition is ocular inflammation. In some embodiments, the disease is characterized by ocular inflammation. As used herein, the term “ocular inflammation” refers to any inflammation of any part of the eye. In some embodiments, the inflammation is of the middle layer of the eye. In some embodiments, the inflammation is uveitis. In some embodiments, the inflammation is uveitic glaucoma. In some embodiments, the inflammation is glaucoma. In some embodiments, the ocular inflammation comprises dry eye or dry macular degeneration. In some embodiments, the ocular inflammation is associated with another disease. Non-limiting examplesof systemic diseases which can result in ocular inflammation are Crohn’s disease, Bechet disease, Juvenile idiopathic arthritis. In some embodiments, the ocular inflammation is associated with an adverse reaction to a drug or environmental trigger. Non-limiting examples of such include Rifabutin, quinolones, vaccines and allergens. In some embodiments, the ocular inflammation is associated with post operation inflammation. Non-limiting examples of such include postcataract surgery, laser eye surgery and corneal transplantation.

[0107] As used herein, the terms “treatment” or “treating” of ocular inflammation encompasses alleviation of at least one symptom thereof, a reduction in the severity thereof, or inhibition of the progression thereof. Treatment need not mean that the disease, disorder, or condition is totally cured. To be an effective treatment, a useful composition herein needs only to reduce the severity of a disease, disorder, or condition, reduce the severity of symptoms associated therewith, or provide improvement to a patient or subject’s quality of life. In some embodiments, treating ocular inflammation comprises at least one of preventing the onset of ocular inflammation, attenuating the progress of ocular inflammation and inhibiting the progression of ocular inflammation.

[0108] In some embodiments, treating comprises reducing inflammation. In some embodiments, treating comprises reducing abnormal inflammation. In some embodiments, treating comprises reducing inflammation in an eye of the subject. In some embodiments, the method is a method for decreasing ocular inflammation. In some embodiments, the method is a method for decreasing intraocular pressure. In some embodiments, treating comprises reducing intraocular pressure. In some embodiments, the method is a method of reducing intraocular pressure. In some embodiments, the pressure is in the eye. In some embodiments, treating comprises reducing intraocular pressure associated with ocular inflammation. In some embodiments, treating comprises reducing intraocular pressure and ocular inflammation. In some embodiments, treating comprises maintaining an IOP of less than 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 mmHg in the eye of the subject. Each possibility represents a separate embodiment of the invention. In some embodiments, treating comprises maintaining an IOP of less than 16 mmHg in the eye of the subject. In some embodiments, the eye is the eye being treated. In some embodiments, the eye is the eye comprising inflammation. In some embodiments, treating comprises reducing the IOP of the subject to below a predetermined threshold. In some embodiments, the threshold is an IOP of 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 mmHg. Eachpossibility represents a separate embodiment of the invention. In some embodiments, the threshold is an IOP of 16.

[0109] In some embodiments, treating comprises a sustained treatment. In some embodiments, sustained comprises at least one effect that lasts after treatment is discontinued. In some embodiments, after treatment is at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50 or 52 weeks after treatment. Each possibility represents a separate embodiment of the invention. In some embodiments, the after treatment is at least 2 weeks after treatment. In some embodiments, the after treatment is at least 4 weeks after treatment. In some embodiments, the at least one effect is a reduction in inflammation. In some embodiments, the at least one effect is a reduction in IOP. In some embodiments, the at least one effect is a reduction in inflammation and IOP. In some embodiments, a lasting effect comprises an absence of relapse. In some embodiments, relapse is a flare up of inflammation.

[0110] In some embodiments, reducing is reducing by at least 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 93, 95, 97, 99 or 100%. Each possibility represents a separate embodiment of the invention. In some embodiments, reducing is reducing by at least 20%. In some embodiments, reducing is reducing to healthy levels. In some embodiments, reducing is as compared to a subject treated with steroids.

[0111] In some embodiments, the subject suffers from intraocular pressure. In some embodiments, intraocular pressure is pathological pressure. In some embodiments, the subject suffers from ocular hypertension. In some embodiments, the subject suffers from glaucoma. In some embodiments, the subject suffers from uveitic glaucoma. In some embodiments, the subject suffers from steroid- induced ocular hypertension. In some embodiments, the subject suffers from steroid-induced glaucoma. In some embodiments, uveitic glaucoma is glaucoma associated with uveitis. In some embodiments, uveitic glaucoma is glaucoma associated with ocular inflammation. In some embodiments, the method comprises selecting a subject suffering from intraocular pressure. In some embodiments, the method comprises selecting a subject suffering from glaucoma. In some embodiments, the method comprises selecting a subject suffering from ocular hypertension. In some embodiments, the method comprises selecting a subject suffering from uveitic glaucoma. In some embodiments, the method comprises selecting a subject at risk of developing ocular hypertension. In some embodiments, the method comprises selecting asubject at risk of developing glaucoma. In some embodiments, the method comprises selecting a subject suffering from glaucoma. In some embodiments, the method prevents progression of glaucoma. In some embodiments, progression is worsening.

[0112] In some embodiments, the method of treating or preventing further comprises administering a steroid. In some embodiments, the steroid is a corticosteroid. In some embodiments, PTC and a steroid are administered together. In some embodiments, PTC and a steroid are administered concomitantly. In some embodiments, the PTC is administered first. In some embodiments, the steroid is administered first. In some embodiments, a very low dose of PTC is administered with the steroid. In some embodiments, the PTC counteracts the pressure increasing effect of the steroid. In some embodiments, pressure is IOP.

[0113] In some embodiments, treating comprises reducing secretion of at least one pro- inflammatory cytokine. In some embodiments, reducing inflammation comprises reducing secretion of at least one pro-inflammatory cytokine. In some embodiments, the secretion is in an eye of the subject. In some embodiments, treating comprises reducing secretion of a plurality of pro-inflammatory cytokines. In some embodiments, reducing inflammation comprises reducing secretion of a plurality of pro-inflammatory cytokines. In some embodiments, at least 1, 2, 3, 4, or 5 pro-inflammatory cytokines are reduced. Each possibility represents a separate embodiment of the invention. In some embodiments, treating comprises reducing the levels of at least one pro- inflammatory cytokine in the subject. In some embodiments, reducing inflammation comprises reducing the levels of at least one pro-inflammatory cytokine in the subject. In some embodiments, the levels are reduced in an eye. In some embodiments, the pro-inflammatory cytokine is TNFa. Other examples of pro-inflammation cytokines include, but are not limited to, IL-1, IL-1B, interferon gamma (IFNy), IL-12, IL-18 and colony- stimulating factor 2 (CSE2).

[0114] In some embodiments, reducing inflammation comprises at least one of increasing secretion of at least one anti-inflammatory cytokine in the eye of the subject, decreasing secretion of at least one pro-inflammatory cytokine in the eye of the subject, increasing the number of Tregs in the eye of the subject and increasing the number of M2 macrophages in the eye of the subject. T regulatory cells (Tregs) are well known in the art and are known to have immunosuppressant effects and the ability to locally lower inflammation. M2 macrophages also are immunotolerant and secret anti-inflammatory cytokines.

[0115] In some embodiments, treating comprises increasing secretion of at least one antiinflammatory cytokine. In some embodiments, reducing inflammation comprises increasing secretion of at least one anti-inflammatory cytokine. In some embodiments, the secretion is in an eye of the subject. In some embodiments, treating comprises increasing secretion of a plurality of anti-inflammatory cytokines. In some embodiments, reducing inflammation comprises increasing secretion of a plurality of anti-inflammatory cytokines. In some embodiments, at least 1, 2, 3, 4, or 5 anti-inflammatory cytokines are increased. Each possibility represents a separate embodiment of the invention. In some embodiments, the levels are increased in an eye of the subject. In some embodiments, the anti-inflammatory cytokine is IL-10. Other examples of antiinflammation cytokines include, but are not limited to, IL-4, IL- 13, IFNa and transforming growth factor beta (TGF[3).

[0116] In some embodiments, reducing comprises at least a 1%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99% or 100% reduction. Each possibility represents a separate embodiment of the invention. It will be understood by one skilled in the art that each cytokine need not be reduced by the same amount. Some cytokines may be reduced by more than others.

[0117] In some embodiments, increasing comprises at least a 1%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, 100%, 150%, 200%, 300%, 400%, 500%, 1000%, or 10000% increase. Each possibility represents a separate embodiment of the invention. It will be understood by one skilled in the art that each cytokine need not be increased by the same amount. Some cytokines may be increased by more than others.

[0118] As used herein, the terms “administering”, “administration”, and like terms refer to any method which, in sound medical practice, delivers a composition containing an active agent to a subject in such a manner as to provide a therapeutic effect. In some embodiments, the administering is ocular or intraocular.

[0119] According to other embodiments, the pharmaceutical composition is in the form of solution, suspension, eye drops, ointment, an intraocular injection among other types of pharmaceutical compositions. Each possibility is a separate embodiment of the invention. According to other embodiments, the pharmaceutical composition is in the form of eye drops.

[0120] In some embodiments, the composition is a long-lasting comprising. In some embodiments, the composition does not require tapering. In some embodiments, the treating doesnot comprise tapering. In some embodiments, the administering is performed for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 26, 48, or 60 months. Each possibility represents a separate embodiment of the invention. In some embodiments, the administering is performed indefinitely. In some embodiments, the administering is performed without tapering. In some embodiments, the administering is continued even in the absence of inflammation. In some embodiments, the administering is preventative of future inflammation.

[0121] In some embodiments, the method further comprises selecting a subject that will respond to treatment. In some embodiments, the subject that will respond comprises an eye comprising an elevated IOP. In some embodiments, elevated IOP is IOP above a predetermined threshold. In some embodiments, elevated is an IOP is an IOP of 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 mmHg or more. Each possibility represents a separate embodiment of the invention. In some embodiments, an elevated IOP is an IOP of 16 mmHg or more.

[0122] In some embodiments, the method further comprises administering at least one potentiating agent. In some embodiments, the potentiating agent increases the efficacy of the PTC. In some embodiments, the potentiating agent increases the levels of melanin in an eye of the subject. In some embodiments, an eye is the eyes. In some embodiments, an eye is an eye to be treated. In some embodiments, an eye is an eye in need of treatment. It will be understood by a skilled artisan that since the drug is more efficacious in eyes with more melanin the administration of a drug that increases melanin will also increase the efficacy of the drug. In some embodiments, a potentiating agent is a prostaglandin. In some embodiments, a potentiating agent is an analog of a prostaglandin. Examples of therapeutic prostaglandins include, but are not limited to latanoprost, bimatoprost, travoprost, tafluprost, unoprostone and latanoprostene bunod. Bimatoprost is sold under the brand name Lumigan. Travoprost is sold under the brand name Travatan or Travatan Z. Latanoprost is sold under the brand name Xalatan. Tafluprost is sold under the brand name Zioptan. Unoprostone is sold under the brand name Rescula. Latanoprostene is sold under the brand name Vyzulta. In some embodiments, the method further comprises administering a prostaglandin or analog thereof. In some embodiments, the prostaglandin or analog thereof is selected from latanoprost, bimatoprost, travoprost, tafluprost, unoprostone and latanoprostene bunod.

[0123] In some embodiments, the method further comprises administering at least one intraocular pressure lowering agent. In some embodiments, the method further comprises administering at least one agent that lowers IOP. In some embodiments, the agent is selected from a carbonic anhydrase inhibitor, a prostaglandin analog, an alpha-2 adrenergic agonist, a cholinergic and a beta-blocker. In some embodiments, the agent is a carbonic anhydrase inhibitor. In some embodiments, the agent is a prostaglandin analog. In some embodiments, the agent is an alpha-2 adrenergic agonist. In some embodiments, the agent is a cholinergic. In some embodiments, the agent is a beta-blocker. In some embodiments, the agent is selected from Acetazolamide, Bimatoprost, Brimonidine, Pilocarpine and Timolol. In some embodiments, the carbonic anhydrase inhibitor is Acetazolamide. In some embodiments, the prostaglandin analog is Bimatoprost. In some embodiments, the alpha-2 adrenergic agonist is Brimonidine. In some embodiments, the cholinergic is Pilocarpine. In some embodiments, the beta-blocker is Timolol. In some embodiments, the method further comprises administering the PTC.

[0124] In some embodiments, the subject is refractory to the IOP lowering agent. In some embodiments, the subject doesn’t respond to the IOP lowering agent. In some embodiments, the subject is allergic to the IOP lowering agent. In some embodiments, the subject is at risk for or has experienced at least one adverse event in response to the IOP lowering agent. In some embodiments, the subject is unsuitable to receive steroids due to increased IOP. In some embodiments, increased is above healthy levels. In some embodiments, healthy levels comprise at most 20 mmHg. In some embodiments, healthy levels comprise at most 16 mmHg. In some embodiments, healthy levels comprise at most 10 mmHg. In some embodiments, healthy levels comprise less than 20 mmHg. In some embodiments, healthy levels comprise less than 16 mmHg. In some embodiments, healthy levels comprise 10-20 mmHg. In some embodiments, a subject with ocular hypertension comprises IOP levels above healthy levels. In some embodiments, a subject with ocular hypertension comprises IOP levels above 20. In some embodiments, a subject with ocular hypertension comprises IOP levels of at least 21 mmHg. In some embodiments, a subject with ocular hypertension comprises IOP levels above 16 mmHg.

[0125] In some embodiments, the subject is a responder to anti-inflammatory treatment. In some embodiments, a responder is a subject with total resolution of inflammation. In some embodiments, a responder is a responder to PTC. In some embodiments, a responder is a responder to the composition of the invention. In some embodiments, a responder shows asustained response. In some embodiments, the method is a method of producing a sustained response in a responder. In some embodiments, the method is a method of lowering IOP in a responder. In some embodiments, the method is a method of reducing the risk of developing glaucoma in a responder. In some embodiments, the method is a method of preventing progression of glaucoma in a responder.

[0126] In some embodiments, the subject is a mammal. In some embodiments, the subject is a human. In some embodiments, the subject is in need of a method of the invention. In some embodiments, the subject is at risk of developing glaucoma. In some embodiments, the subject has a family history of glaucoma. In some embodiments, the subject is at risk of developing IOP levels above healthy levels.

[0127] By another aspect, there is provided a composition comprising a phosphorylcholine - tuftsin conjugate comprising at least one phosphorylcholine moiety or a derivative thereof and tuftsin or a derivative thereof for use in a method of the invention.

[0128] By another aspect, there is provided a composition comprising a phosphorylcholine - tuftsin conjugate comprising at least one phosphorylcholine moiety or a derivative thereof and tuftsin or a derivative thereof for use in the production of a medicament for performance of a method of the invention.

[0129] By another aspect, there is provided a composition comprising a phosphorylcholine - tuftsin conjugate at a concentration of about 1%.

[0130] By another aspect, there is provided a composition comprising a phosphorylcholine - tuftsin conjugate and a potentiating agent.

[0131] By another aspect, there is provided a kit comprising a phosphorylcholine-tuftsin conjugate and a potentiating agent.

[0132] In some embodiments, the composition is a pharmaceutical composition. In some embodiments, the composition is formulated for ocular administration. In some embodiments, the composition is eye drops. In some embodiments, the kit comprises two compositions. In some embodiments, the compositions are labeled for use with each other. In some embodiments, the kit comprises instructions for use. In some embodiments, the use is combined use. In some embodiments, the instructions are for the performance of a method of the invention. In someembodiments, the composition is for use in a method of the invention. In some embodiments, the kit is for use in a method of the invention. In some embodiments, the kit comprises a prostaglandin or an analog thereof. In some embodiments, the composition comprises a prostaglandin or an analog thereof. In some embodiments, the prostaglandin or analog thereof is selected from latanoprost, bimatoprost, travoprost, tafluprost, unoprostone and latanoprostene bunod.

[0133] By another aspect, there is provided a method of determining suitability of a subject suffering from ocular inflammation and being treated with steroids or having been treated with steroids to be treated with a composition of the invention, the method comprising: a. receiving a measurement of IOP in an eye of the subject before treatment with the steroid; b. receiving a measurement of IOP in an eye of the subject after treatment with the steroid; wherein an increase in IOP from before treatment to after treatment indicates the subject is suitable for treatment with a composition of the invention; thereby determining suitability.

[0134] In some embodiments, the subject is being treated with steroids. In some embodiments, the subject has been treated with steroids. In some embodiments, the subject was treated with steroids within the past 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 15, 16, 20, or 24 weeks. Each possibility represents a separate embodiment of the invention. In some embodiments, the subject was treated with steroids with the past year.

[0135] In some embodiments, the method further comprises calculating the change in IOP from before the treatment to after the treatment. In some embodiments, if the change in IOP is an increase it is indicative of a suitable subject. In some embodiments, the method comprises determining an increase in IOP from before treatment to after treatment in an eye of the subject. In some embodiments, a subject with a determined increase in IOP is suitable to be treated. In some embodiments, the method further comprises administering the composition to a suitable subject. In some embodiments, the method further comprises discontinuing administering the steroid to a subject determined to be suitable. In some embodiments, the method furthercomprises administering a reduced dose of the steroid to a subject determined to be suitable. In some embodiments, reduced is as compared to the dose the subject was receiving before being found suitable. In some embodiments, the method further comprises administering the pharmaceutical composition and a reduced dose of the steroid to a subject determined to be suitable.

[0136] As used herein, the term “about” when combined with a value refers to plus and minus 10% of the reference value. For example, a length of about 1000 nanometers (nm) refers to a length of 1000 nm+- 100 nm.

[0137] It is noted that as used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a polynucleotide” includes a plurality of such polynucleotides and reference to “the polypeptide” includes reference to one or more polypeptides and equivalents thereof known to those skilled in the art, and so forth. It is further noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology as “solely,” “only” and the like in connection with the recitation of claim elements, or use of a “negative” limitation.

[0138] In those instances where a convention analogous to “at least one of A, B, and C, etc.” Is used, in general such a construction is intended in the sense one having skill in the art would understand the convention (e.g., “a system having at least one of A, B, and C” would include but not be limited to systems that have A alone, B alone, C alone, A and B together, A and C together, B and C together, and / or A, B, and C together, etc.). It will be further understood by those within the art that virtually any disjunctive word and / or phrase presenting two or more alternative terms, whether in the description, claims, or drawings, should be understood to contemplate the possibilities of including one of the terms, either of the terms, or both terms. For example, the phrase “A or B” will be understood to include the possibilities of “A” or “B” or “A and B.”

[0139] It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination. All combinations of the embodiments pertaining to the invention are specificallyembraced by the present invention and are disclosed herein just as if each and every combination was individually and explicitly disclosed. In addition, all sub-combinations of the various embodiments and elements thereof are also specifically embraced by the present invention and are disclosed herein just as if each and every such sub-combination was individually and explicitly disclosed herein.

[0140] Additional objects, advantages, and novel features of the present invention will become apparent to one ordinarily skilled in the art upon examination of the following examples, which are not intended to be limiting. Additionally, each of the various embodiments and aspects of the present invention as delineated hereinabove and as claimed in the claims section below finds experimental support in the following examples.

[0141] Various embodiments and aspects of the present invention as delineated hereinabove and as claimed in the claims section below find experimental support in the following examples.EXAMPLES

[0142] Generally, the nomenclature used herein and the laboratory procedures utilized in the present invention include molecular, chemical, biochemical, microbiological and recombinant DNA techniques. Such techniques are thoroughly explained in the literature. See, for example, “Molecular Cloning: A laboratory Manual” Sambrook et al., (1989); “Current Protocols in Molecular Biology” Volumes I-III Ausubel, R. M., ed. (1994); Ausubel et al., “Current Protocols in Molecular Biology”, John Wiley and Sons, Baltimore, Maryland (1989); Perbal, “A Practical Guide to Molecular Cloning”, John Wiley & Sons, New York (1988); Watson et al., “Recombinant DNA”, Scientific American Books, New York; Birren et al. (eds) “Genome Analysis: A Laboratory Manual Series”, Vols. 1-4, Cold Spring Harbor Laboratory Press, New York (1998); methodologies as set forth in U.S. Pat. Nos. 4,666,828; 4,683,202; 4,801,531; 5,192,659 and 5,272,057; “Cell Biology: A Laboratory Handbook”, Volumes I-III Cellis, J. E., ed. (1994); “Culture of Animal Cells - A Manual of Basic Technique” by Freshney, Wiley-Liss, N. Y. (1994), Third Edition; “Current Protocols in Immunology” Volumes I-III Coligan J. E., ed.(1994); Stites et al. (eds), “Basic and Clinical Immunology” (8th Edition), Appleton & Lange, Norwalk, CT (1994); Mishell and Shiigi (eds), “Strategies for Protein Purification and Characterization - A Laboratory Course Manual” CSHL Press (1996); all of which are incorporated by reference. Other general references are provided throughout this document.Example 1: Reducing intraocular pressure in subjects suffering from uveitic glaucoma

[0143] Subjects suffering from both ocular inflammation and high intraocular pressure (IOP) are difficult to treat. Many anti-inflammatory agents, especially steroids, are known to increase IOP and thus are not suitable for subjects suffering from ocular hypertension and glaucoma. Indeed, steroid-induced ocular hypertension and steroid-induced glaucoma are well-known phenomena.

[0144] Seven subjects diagnosed with non-infectious anterior uveitis with anterior chamber cell Grades of 2 (6-15 cells) or 3 (16-30 cells) were treated with an eye drop solution containing 1% Dazdotuftide (Phosphorylcholine-tuftsin conjugate; PTC; TRS01) 4 times daily. The IOP of the subjects was measured at their first visit (visit 1) before the commencement of treatment and at their fifth visit (visit 5) after the completion of treatment. The results are summarized in Table 1. All subjects showed a reduction in IOP from the first visit to the fifth of between 20 and 30%. Two of the subjects had pressure readings of greater than 20 millimeters of mercury (mmHg) before the commencement of treatment indicating ocular hypertension, and treatment with TPC eyedrops successfully reduced the pressure for both patients into the healthy range (10-20 mmHg). It is thus evident that PTC effectively reduces intra ocular pressure in addition to reducing ocular inflammation and is an effective treatment for subjects suffering from ocular hypertension. It is particularly effective as a replacement for steroids in the eye, as it can reduce both inflammation and IOP whereas steroids have the inverse effect on IOP.

[0145] Table 1: IOP reduction in subjects treated with 1% solution of PTC.

[0146] A lower dose (0.1%) of PTC / TRS01 was also tested. Subjects applied eye drops with either 0.1% or 1% PTC (TRS01) four times daily and IOP was measured each week over a 4- week dosing period. As can be seen in Figure 1 , while the lower dose produced an effect, the higher dose produced a greatly superior one.Example 2: PTC is as effective as steroids but with a longer lasting effect and no increase in IOP

[0147] Subjects suffering from uveitis were treated with an eye drop solution containing 1% PTC or steroids 4 times daily (see Figure 2 for patient characteristics). Treatment was halted after 4 weeks, but the subjects who showed total resolution of inflammation (ACC=0; complete responders) were monitored for inflammation recurrence two weeks later. In the steroid group, of the patients with total resolution of inflammation after 4 weeks (complete responders; ACC=0) a significant number of subjects suffered an inflammation recurrence within this 2-week followup period - 27% had a recurrence of inflammation, leaving only 73% of the complete responders having a prolonged anti-inflammatory effect. In the PTC complete responders group only 11 % showed recurrence thus a larger percentage showed a prolonged anti-inflammatory effect (Fig. 3). The development of a rebound effect following steroid treatment is a well-known phenomenon. This demonstrates the long-lasting effect of PTC and its superiority to steroids.

[0148] It has been found that during and in the follow-up to uveitis treatment, elevation in interocular pressure (IOP) is a strong predictor for glaucoma. IOP of 16-20 mmHg was associated with a 5.3-fold higher incidence of glaucoma as compared to IOP of < 16 mmHg. This means that IOP change from baseline is a clinically relevant endpoint for assessing risk of developingglaucoma. Additionally, it has been found that even doses of 1 to 2 steroid drops daily in pediatric patients can lead to higher risk for IOP elevation.

[0149] Further, 8.1% of complete responders in the TRS01 group and 25.0% of subjects receiving steroids had an IOP increase from baseline of at least 5 mmHg in the study eye (p=0.0319, Fig. 4). For an increase of at least 7 mmHg, the percentage of complete responders was 2.7% and 21.9% respectively (p=0.0188, Fig. 4). For an increase of at least 10 mmHg, the percentage of complete responders was 0.0% and 15.6% respectively (p=0.0184, Fig. 4). That is, none of the total responders had an increase of 10 mmHg or more.

[0150] Finally, as 16 mmHg has been reported in the literature to be a predictive cutoff for the development of glaucoma, subjects with a starting IOP of <16 mmHg were examined for developing an IOP over 16 mmHg at the end of treatment. In the complete responders 7.4% of those treated with TRS01 had an increase that raised their IOP to over 16 mmHg, whereas 31.8% of those treated with steroids had such an increase (p=0.0318, Fig. 5). This result was highly significant and demonstrates that steroid treatment of uveitis risks causing glaucoma even in patients whose inflammation is successfully treated. In contrast, TRS01 successfully treats the inflammation without raising the risk of developing glaucoma.

[0151] Notably, a linear increase in IOP across visits was observed in the complete responders (patients with total resolution of inflammation) that received steroids (Fig. 6). This increase was not observed in the responders receiving TRS01. Thus, it is feasible to monitor IOP during steroid treatment for uveitis and if an increase in IOP is observed switch the subject to TRS01.

[0152] Although the invention has been described in conjunction with specific embodiments thereof, it is evident that many alternatives, modifications and variations will be apparent to those skilled in the art. Accordingly, it is intended to embrace all such alternatives, modifications and variations that fall within the spirit and broad scope of the appended claims.

Claims

CLAIMS1. A method of reducing or treating ocular inflammation while preventing an increase in risk of developing glaucoma or while preventing progression of glaucoma in a subject in need thereof, the method comprising administering to an eye of said subject a pharmaceutical composition comprising a phosphorylcholine-tuftsin conjugate comprising at least one phosphorylcholine moiety or a derivative thereof and tuftsin or a derivative thereof, thereby treating ocular inflammation while preventing an increase in risk of developing glaucoma.

2. A method for reducing intraocular pressure (IOP) in a subject in need thereof, the method comprising administering to an eye of said subject a pharmaceutical composition comprising a phosphorylcholine-tuftsin conjugate comprising at least one phosphorylcholine moiety or a derivative thereof and tuftsin or a derivative thereof, thereby reducing IOP.

3. A method of producing a sustained reduction in ocular inflammation, intraocular pressure or both in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising a phosphorylcholine-tuftsin conjugate comprising at least one phosphorylcholine moiety or a derivative thereof and tuftsin or a derivative thereof, wherein said sustained reduction is a reduction that persists for at least 2 weeks after cessation of said administering, thereby producing a sustained reduction in ocular inflammation, intraocular pressure or both.

4. The method of claim 2, wherein said method is also a method for decreasing ocular inflammation.

5. The method of claim 2 or 4, comprising selecting a subject with an eye comprising an IOP of 16 mmHg or more and administering said pharmaceutical composition to said eye comprising an IOP of 16 mmHg or more.

6. The method of claim 1 , wherein said treating comprises maintaining an IOP of less than 16 mmHg in said eye of said subject.

7. The method of any one of claims 1 to 6, wherein said method is a method of preventing glaucoma in a subject at risk of developing glaucoma.

8. The method of any one of claims 1 to 7, wherein said phosphorylcholine moiety or a derivative thereof and said tuftsin or a derivative thereof are linked.

9. The method of any one of claims 1 to 8, wherein said phosphorylcholine moiety or a derivative thereof and said tuftsin or a derivative thereof are separated by a spacer.

10. The method of claim 9, wherein said spacer is at least two amino acids.

11. The method of claim 10, wherein said spacer is Glycine-Tyrosine.

12. The method of any one of claims 1 to 11, wherein said conjugate is represented by Formula 1:

13. The method of any one of claims 1, 3 and 6 to 12, wherein said reducing intraocular pressure comprises a reduction of at least 20%.

14. The method of any one of claims 1 to 13, wherein said pharmaceutical composition is an eye drop.

15. The method of any one of claims 1 and 3 to 14, wherein said reducing inflammation comprises reducing secretion of at least one pro-inflammatory cytokine in said eye of said subject, increasing secretion of at least one anti-inflammatory cytokine in said eye of said subject or both.

16. The method of any one of claims 1 to 15, wherein said subject suffers from ocular inflammation, ocular hypertension or both.

17. The method of any one of claims 1 to 16, wherein said subject suffers from uveitis.

18. The method of any one of claims 1 to 16, wherein said subject suffers from uveitic glaucoma.

19. The method of any one of claims 1 to 16, wherein said subject suffers from glaucoma.

20. The method of claim 18 or 19, wherein said method prevents progression of said glaucoma.

21. The method of any one of claims 1 to 20, further comprising administering at least one intraocular pressure lowering agent selected from a carbonic anhydrase inhibitor, a prostaglandin analog, an alpha-2 adrenergic agonist, a cholinergic and a beta-blocker.

22. The method of claim 21, wherein said intraocular pressure lowering agent is selected from Acetazolamide, Bimatoprost, Brimonidine, Pilocarpine and Timolol.

23. The method of any one of claims 1 to 22, wherein said pharmaceutical composition is formulated for ocular administration.

24. The method of claim 23, wherein said formulated for ocular administration comprises any one of an eye drop formulation, an ointment formulation, and an injection formulation.

25. The method of any one of claims 1 to 24, wherein said pharmaceutical composition comprises any one of a viscosity enhancer, a permeation enhancer or both.

26. The method of any one of claims 1 to 25, wherein said pharmaceutical composition comprises said conjugate at a concentration of about 1%.

27. The method of any one of claims 1 to 26, wherein said subject is refractory to, is allergic to, or has had at least one adverse event in response to at least one intraocular pressure lowering agent.

28. The method of any one of claims 1 to 27, further comprising administering a prostaglandin or analog thereof.

29. The method of claim 28, wherein said prostaglandin or analog thereof is selected from latanoprost, bimatoprost, travoprost, tafluprost, unoprostone and latanoprostene bunod.

30. A method of determining suitability of a subject suffering from ocular inflammation and being treated with or having been treated with a steroid to be treated with a pharmaceutical composition comprising a phosphorylcholine-tuftsin conjugate comprising at least one phosphorylcholine moiety or a derivative thereof and tuftsin or a derivative thereof, the method comprising:a. receiving a measurement of IOP in an eye of said subject before treatment with said steroid; b. receiving a measurement of IOP in an eye of said subject after treatment with said steroid; and c. determining an increase in IOP from before treatment with said steroid to after treatment with said steroid, wherein a subject with a determined increase in IOP is suitable to be treated with said pharmaceutical composition, thereby determining suitability.

31. The method of claim 30, further comprising discontinuing administering said steroid to said subject, administering a reduced dose of said steroid to said subject, administering said pharmaceutical composition to said subject or a combination thereof.

32. A kit comprising: a. a phosphorylcholine-tuftsin conjugate comprising at least one phosphorylcholine moiety or a derivative thereof and tuftsin or a derivative thereof; and b. a prostaglandin or an analog thereof.

33. The kit of claim 32, wherein said prostaglandin or analog thereof is selected from latanoprost, bimatoprost, travoprost, tafluprost, unoprostone and latanoprostene bunod.

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