Composition and method of treating t-cell lymphoma

Abstract

Disclosed herein is a compound that has properties to treat a subject with T cell lymphoma as compared to conventional interferon. In addition, methods to use such compound to treat T-cell lymphoma are also disclosed.

Description

COMPOSITION AND METHOD OF TREATING T-CELL LYMPHOMATECHNICAL FIELD

[0001] The present disclosure relates in general to the field of cancer therapy. More specifically, treatments of subjects with T-cell lymphoma.BACKGROUND

[0002] T-cell lymphomas (TCL) are a form of non-Hodgkin lymphoma (NHL) that can develop in lymphoid tissues such as the lymph nodes and spleen, or outside of lymphoid tissues (i.e., gastrointestinal tract, liver, nasal cavity, skin, and others). T-cell lymphomas include cutaneous T- cell lymphomas (CTCL); peripheral T cell lymphoma non-specific type (PTCL-NOS); anaplastic large cell lymphoma (ALCL); angioimmunoblastic T-cell lymphoma (AITL); extranodal natural killer / T-cell lymphoma; enteropathy-associated intestinal T-cell lymphoma (EATL); monomorphic epitheliotropic intestinal T cell lymphoma (MEITL); and mycosis fungoides (MF).

[0003] One of the common types of TCL is Cutaneous T-cell lymphomas (CTCLs), which are a heterogeneous and relatively rare family of extranodal non-Hodgkin’ s lymphomas (NHL) that are primarily localized to the skin. Most patients present with cutaneous patches, plaques, tumors, more rarely with erythroderma. The type of skin lesions and the surface extent of skin involvement, as well as the presence of extracutaneous disease, are the most important prognostic factors in patients with CTCL. Patients with early-stage disease can be effectively treated with skin-directed therapies only. As the disease progresses, systemic therapy often becomes necessary.

[0004] The most common types of CTCL are mycosis fungoides (MF) and Sezary syndrome (SS). MF is an indolent lymphoma of mature T cells that primarily affects the skin and makes up 60% of cases of CTCL. The clinical course often begins with patches that progress to plaques and eventually tumors over the course of years in a subset of patients. SS, in comparison, is a leukemic form of CTCL that arises from thymic memory T cells and manifests with significant blood involvement, pruritic erythroderma, and generalized lymphadenopathy. SS accounts for 2% of all CTCL cases.

[0005] Although interferon (IFN) gained traction as a treatment modality for TCL and / or CTCL, there is no standard systemic therapy for patients with advanced stage MF and SS. Both the Food and Drug Administration (FDA) approved, and unapproved agents are used in these patients including immune modulators, antibodies, single agent or combination chemotherapy, or other investigational agents. Current guidelines by the National Comprehensive Cancer Network (NCCN) recommend a variety of medications or a clinical trial as a first-line therapy. There are sixFDA approved agents in the US for the treatment of CTCL: bexarotene, vorinostat, denileukin diftitox (DD), romidepsin, brentuximab and most recently mogamulizumab. DD has not been available in the US since 2014. IFN alfa-2a (Roferon, trademarked) and IFN alfa-2b (Intron- A, trademarked), which are produced via genetically engineered Escherichia coli-containing DNA that codes for human protein and historically could be used to attempt to treat CTCL; however, Roferon is no longer manufactured in the United States or Europe, and Intron-A was discontinued in countries such as Canada, citing "business reasons”, see FIGURE 3. Although PEGylated interferon A (Pegysys, trademarked) is proposed as an alternative, it is still not widely available such as in Canada and is in a global supply shortage at the time of this disclosure. All of these agents are indicated only after patients have failed at least one other systemic therapy.

[0006] Therefore, there is an unmet medical need for TCL and / or CTCL (for any type) patients, and one of many aims of this disclosure is to serve the public for such unmet needs. Accordingly, the present disclosure presents anew way to alleviate / treat / assist / prevent one or more of the above issues with subjects or a subject in need having TCL or CTCL.SUMMARY

[0007] The present disclosure relates in general to a composition, composition mixture, and / or method of treating, preventing, slowing the progression, inhibiting and / or ameliorating subjects with T-cell lymphoma (including CTCL, for example MF or SS) comprising administering to said subject or subject in need thereof an effective amount of ropeginterferon alfa-2b, and / or said pharmaceutical composition thereof, wherein IFN is interferon alfa-2b.

[0008] In an aspect, the present disclosure relates to a method of treating a subject or a subject in need having T-cell lymphoma (TCL) comprising administering to said subject or subject in need in need thereof an effective amount of ropeginterferon alfa-2b including the structure:

[0009] In another aspect, a pharmaceutical composition comprising the ropeginterferon alfa-2b of the above structure, and a pharmaceutically acceptable carrier, salt, a solvate or prodrug thereof, an adjuvant, and / or a diluent is disclosed herein.

[0010] In an aspect, the present disclosure also relates to a method of treating a subject or a subject in need having T-cell lymphoma (TCL) comprising administering to said subject or subject in need thereof an effective amount of said pharmaceutical composition.

[0011] In some aspect, the method can treat T-cell lymphoma comprising cutaneous T-cell lymphomas (CTCL); peripheral T cell lymphoma non-specific type (PTCL-NOS); anaplastic large cell lymphoma (ALCL); angioimmunoblastic T-cell lymphoma (AITL); extranodal natural killer / T-cell lymphoma; enteropathy-associated intestinal T-cell lymphoma (EATL); monomorphic epitheliotropic intestinal T cell lymphoma (MEITL); and / or mycosis fungoides (MF). The CTCL can comprise subtypes of mycosis fungoides (MF) and / or Sezary syndrome (SS).

[0012] In an aspect, the ropeginterferon alfa-2b. and / or said pharmaceutical composition is administered subcutaneously to the subject or subject in need.

[0013] In another aspect, the ropeginterferon alfa-2b, and / or said pharmaceutical composition thereof includes each rnPEG having between about 19 to about 23 KDa.

[0014] Yet in an aspect, the effective amount of ropeginterferon alfa-2b, and / or said pharmaceutical composition thereof for treating, preventing, slowing the progression, inhibiting and / or ameliorating subjects or subject in need with T-cell lymphoma (including CTCL, for example MF or SS) has an effective amount comprising a first dosage, a second dosage, a third dosage, and / or subsequent doses administered about every 1, 2, 3, 4, 5, 6, 7, or 8 weeks. Additionally, and / or alternatively, said first dosage comprises about 250 pg, the second dosage comprises about 350 pg, and the third dosage and / or subsequent dosages comprise about 500 pg of ropeginterferon alfa-2b , and / or pharmaceutical composition thereof.

[0015] In an aspect, the effective amount comprises between about 50 pg to about 540 pg of ropeginterferon alfa-2b, and / or pharmaceutical composition thereof is also disclosed. Additionally, and / or alternatively, for treating, preventing, slowing the progression, inhibiting and / or ameliorating subjects with T-cell lymphoma (including CTCL, for example MF or SS), said second, third dosage, or subsequent dosages is maintained at a constant level, or is adjusted upward or downward during a treatment period.

[0016] Yet in an aspect, for the effective amount, treating, preventing, slowing the progression, inhibiting and / or ameliorating subjects with T-cell lymphoma (including CTCL. for example MF or SS), it can contain a first dosage about 450 pg of ropeginterferon alfa-2b , and / or pharmaceutical composition thereof. Additionally, and / or alternatively, the subsequent dosages after said three doses are maintained at a constant level.

[0017] In another aspect, the ropeginterferon alfa-2b , and / or pharmaceutical composition thereof treating, preventing, slowing the progression, inhibiting and / or ameliorating subjects with T-cell lymphoma (including CTCL, for example MF or SS) is administered for a period of between about 2 to 13 weeks, about 2 to 26 weeks, about 2 to 52 weeks, or longer than about 52 weeks.

[0018] Yet in another aspect, the method of treatment decreases said subject or subject in need’s AE rate. Additionally, and / or alternatively, the method increases said subject or subject in need’s complete remission, partial response, stable disease, progressive disease; and / or overall survival rate.

[0019] In an aspect, the present disclosure relates to use of the substantially homogenous composition or pharmaceutical formulation comprising ropeginterferon alfa-2b including the structure:for the preparation of a medicament for the treatment of a subject or a subject in need having T- cell lymphoma. The T-cell ly mphoma includes, but are not limited to cutaneous T-cell lymphomas (CTCL); peripheral T cell lymphoma non-specific type (PTCL-NOS); anaplastic large cell lymphoma (ALCL); angioimmunoblastic T-cell lymphoma (AITL); extranodal natural killer / T- cell lymphoma; enteropathy-associated intestinal T-cell lymphoma (EATL); monomorphic epitheliotropic intestinal T cell lymphoma (MEITL); or mycosis fungoides (MF). For CTCL, it also includes subtypes of mycosis fungoides (MF) and / or Sezary syndrome (SS).

[0020] In an aspect, the use also includes the usage of ropeginterferon alfa-2b where each can further comprise a pharmaceutically acceptable carrier, salt, a solvate or prodrug thereof, an adjuvant, and / or a diluent. The administration method can include subcutaneous delivery to a subject or subject in need.

[0021] In any of the uses, and / or methods above, where said ropeginterferon alfa-2b and / or isomer, and / or pharmaceutical composition thereof can include two mPEG, where each having between about 19 to about 23 KDa.

[0022] In another aspect, the uses stated above, where said ropeginterferon alfa-2b and / or isomer, and / or pharmaceutical composition thereof treating, preventing, slowing the progression,inhibiting and / or ameliorating subjects with T-cell lymphoma (including CTCL, for example MF or SS) can have an effective amount comprising a first dosage, a second dosage, a third dosage, and / or subsequent doses of ropeginterferon alfa-2b administered about even' 1, 2, 3, 4, 5, 6, 7, or 8 weeks.

[0023] Yet in an aspect, the use can have an effective amount comprising between about 50 pg to about 540 pg of ropeginterferon alfa-2b and / or isomer, and / or pharmaceutical composition thereof.

[0024] Alternatively, or additionally, the use treating, preventing, slowing the progression, inhibiting and / or ameliorating subjects with T-cell lymphoma (including CTCL, for example MF or SS) can have an effective amount wherein said second, third dosage or subsequent dosages is maintained at a constant level and / or is adjusted upward or downward during a treatment period.

[0025] In an aspect, the uses can increase a subject or subject in need’s complete remission, partial response, stable disease, progressive disease; and / or overall survival rate who has TCL. Furthermore, it can reduce the AE rate and / or severity of AE in a subject or subject in need.

[0026] Yet in an aspect, a substantially homogenous composition or pharmaceutical formulation comprising ropeginterferon alfa-2b including the structure:characterized that for use in treating a subject or a subject in need having T-cell lymphoma is disclosed herein.

[0027] In another aspect, the T-cell lymphoma include, but not limited to cutaneous T-cell lymphomas (CTCL); peripheral T cell lymphoma non-specific type (PTCL-NOS); anaplastic large cell lymphoma (ALCL); angioimmunoblastic T-cell lymphoma (AITL); extranodal natural killer / T-cell lymphoma; enteropathy-associated intestinal T-cell lymphoma (EATL); monomorphic epitheliotropic intestinal T cell lymphoma (MEITL); and / or mycosis fungoides (MF), and wherein said CTCL can comprise subtypes of mycosis fungoides (MF) and / or Sezary syndrome (SS).

[0028] In an aspect, the present disclosure excludes virus induced Adult T-cell leukemia (ATL or ATLL). ATL includes acute, lymphoma, chronic, and smoldering type, which is cause by infectionof Human T-lymphotropic virus type 1 (HTLV-1), a retrovirus which causes a chronic lifelong infection in humans.

[0029] Yet in an aspect, the pharmaceutical formulation stated above, wherein the ropeginterferon alfa-2b can comprise a pharmaceutically acceptable carrier, salt, a solvate or prodrug thereof, an adjuvant, and / or a diluent. Such pharmaceutical formulation can be administered subcutaneously, for example, to the subject or subject in need.

[0030] In an aspect, the substantially homogenous composition or pharmaceutical formulation stated above each can contain mPEG including between about 19 to about 23 KDa.

[0031] In another aspect, the substantially homogenous composition or pharmaceutical formulation’s effective amount treating, preventing, slowing the progression, inhibiting and / or ameliorating subjects with T-cell lymphoma (including CTCL, for example MF or SS) comprises a first dosage, a second dosage, a third dosage, and / or subsequent doses of ropeginterferon alfa-2b administered about every 1, 2, 3, 4, 5, 6, 7, or 8 weeks. Alternatively, or additionally, said effective amount can comprise between about 50 pg to about 540 pg of ropeginterferon alfa-2b .

[0032] In some aspects, the substantially homogenous composition or pharmaceutical formulation treating, preventing, slowing the progression, inhibiting and / or ameliorating subjects with T-cell lymphoma (including CTCL, for example MF or SS) can include a second, third dosage or subsequent dosages maintained at a constant level or is adjusted upward or downward during a treatment period.

[0033] In an aspect, the substantially homogenous composition or pharmaceutical formulation can treat subject or subject in need where it increases said subject’s complete remission, partial response, stable disease, progressive disease; and / or overall survival rate. Alternatively, or additionally, it can reduce the rate of AE or the severity of AE.

[0034] In an aspect, the present disclosure also relates to a composition comprising ropeginterferon alfa-2b including the structure:for use in treatment of T-cell lymphoma in a subject or subject in need. Alternatively, or additionally, the composition further comprises a pharmaceutical carrier thereby forming a pharmaceutical composition.

[0035] In another aspect, the composition can treat T-cell lymphoma comprising cutaneous T-cell lymphomas (CTCL); peripheral T cell lymphoma non-specific type (PTCL-NOS); anaplastic large cell lymphoma (ALCL); angioimmunoblastic T-cell lymphoma (AITL); extranodal natural killer / T-cell lymphoma; enteropathy-associated intestinal T-cell lymphoma (EATL); monomorphic epitheliotropic intestinal T cell lymphoma (MEITL); or mycosis fungoides (MF), wherein said CTCL comprises subtypes of mycosis fungoides (MF) and / or Sezary syndrome (SS).

[0036] Yet in an aspect, the composition treating, preventing, slowing the progression, inhibiting and / or ameliorating subjects with T-cell lymphoma (including CTCL, for example MF or SS) comprises providing to the subject or subject in need an effective amount including a first dosage including about 250 pg, a second dosage including between about 250 pg to 400 pg. and more than one additional dosage at a constant amount between about 350 pg to 540 pg of ropeginterferon alfa-2b , and / or pharmaceutical composition thereof. Alternatively, or additionally, the constant amount comprises about 500 pg of ropeginterferon alfa-2b, and / or pharmaceutical composition thereof.

[0037] In an aspect, the composition can increase said subject or subject in need’s complete remission, partial response, stable disease, progressive disease; and / or overall survival rate who has TCL. Alternatively, or additionally, the composition can reduce the rate and / or severity of AE.BRIEF DESCRIPTION OF THE DRAWINGS

[0038] For a more complete understanding of the features and advantages of the present disclosure, reference is now made to the detailed description of the disclosure along with the accompanying figures and in which:FIGURE 1 denotes the chemical structure of Pl 101. Each mPEG has a molecular weight range from about 10 KD to 30 KD, and / or at about 19 to 23 kD. IFN is interferon alpha 2b.FIGURE 2 denotes an example of clinical design to use Pl 101 to treat subjects having TCL or CTCL.FIGURE 3 denotes the historical treatments used for CTCL known in the art.FIGURE 4(a) to FIGURE 4(d) denote dose-dependent inhibition of cell viability in the CTCL cells by Pl 101.FIGURE 5(a) to FIGURE 5(d) denote Pl 101 induces interferon-stimulated genes inhuman cutaneous T cell lymphoma cell lines.FIGURE 6 denotes Pl 101 induces type I interferon receptor signaling in human cutaneous T cell lymphoma cell lines.DETAILED DESCRIPTION

[0039] While the making and using of various embodiments of the present disclosure are discussed in detail below, it should be appreciated that the present disclosure provides many applicable inventive concepts that can be embodied in a wide variety of specific contexts. The specific embodiments discussed herein are merely illustrative of specific ways to make and use the disclosure and do not delimit the scope of the disclosure.

[0040] To facilitate the understanding of this disclosure, a number of terms are defined below. Terms defined herein have meanings as commonly understood by a person of ordinary skill in the areas relevant to the present disclosure. Terms such as “a”, "an" and "the” are not intended to refer to only a singular entity but include the general class of which a specific example may be used for illustration. The terminology herein is used to describe specific embodiments of the disclosure, but their usage does not delimit the disclosure, except as outlined in the claims.

[0041] The following terms, unless otherwise indicated, shall be understood to have the following meanings.

[0042] As used herein, "administering” or “administer” mean oral administration, administration as a suppository, topical contact, intravenous, intraperitoneal, intramuscular, intralesional, intranasal or subcutaneous administration, or the implantation of a slow-release device e.g., a mini- osmotic pump, to the subject. Administration is by any route including parenteral, and transmucosal (e.g., oral, nasal, vaginal, rectal, or transdermal). Parenteral administration includes, e.g., intravenous, intramuscular, intra-arteriole, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Moreover, where injection is to treat a tumor, e.g., induce apoptosis, administration may be directly to the tumor and / or into tissues surrounding the tumor. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, etc.

[0043] As used herein, the term “isolated molecule” as referring to a molecule (where the molecule is, for example, a polypeptide, a polynucleotide, or an antibody) that by virtue of its origin or source of derivation (1) is not associated with naturally associated components that accompany it in its native state, (2) is substantially free of other molecules from the same source, e g., species, cell from which it is expressed, library', etc., (3) is expressed by a cell from a different species, or (4)does not occur in nature. Thus, a molecule that is chemically synthesized, or expressed in a cellular system different from the system from which it naturally originates, will be “isolated” from its naturally associated components. A molecule also can be rendered substantially free of naturally associated components by isolation, using purification techniques well known in the art. Molecule purity or homogeneity may be assayed by a number of methods known in the art. For example, the purity’ of a polypeptide sample may be assayed using polyacrylamide gel electrophoresis and staining of the gel to visualize the polypeptide using techniques known in the art. For certain purposes, higher resolution may be provided by using HPLC or other means known in the art for purification.

[0044] As used herein, the terms “treating” or “treatment” or “to treat” or “alleviating” or “to alleviate” all refer to (1) therapeutic measures that cure, slow' down, lessen symptoms of, and / or halt progression of a diagnosed pathologic condition or disorder and / or (2) prophylactic or preventative measures that prevent and / or slow the development of a targeted pathologic condition or disorder. Thus, those in need of treatment include those already with the disorder; those prone to have the disorder; and those in whom the disorder is to be prevented. In certain aspects, a subject is successfully “treated” according to the methods and molecules of the present disclosure if the patient shows, e.g.. total, partial, or transient remission of a certain type of disorder, while keeping subject within a regulatory approved range of safety parameters.

[0045] The term “subject”, or “patient” are used interchangeably and refer to a living organism suffering from or prone to a condition that can be prevented or treated by administration of a molecule such as Pl 101 as provided herein and includes both humans and animals.

[0046] As used herein, “branched” in reference to the geometry' or overall structure of a polymer, for example, it can refer to a polymer having 2 or more arms.

[0047] A “host cell” includes an individual cell or cell culture that can be or has been a recipient for vector(s) for incorporation of polynucleotide inserts. Host cells include progeny of a single host cell, and the progeny may not necessarily be completely identical (in morphology or in genomic DNA complement) to the original parent cell due to natural, accidental, or deliberate mutation. A host cell includes cells transfected in vivo with a polynucleotide(s) of this disclosure. One example is E. Colt.

[0048] As used herein, any concentration range, percentage range, ratio range or integer range is to be understood to include the value of any integer as indicated per se, as well as within the recited range and, when appropriate, fractions thereof (such as one tenth and one hundredth of an integer), unless otherwise indicated.

[0049] As used herein, the term “TCL” refers T-cell leukemia / lymphoma, which includes but not limited to peripheral T cell lymphoma non-specific type (PTCL-NOS); anaplastic large cell lymphoma (ALCL); angioimmunoblastic T-cell lymphoma (AITL); extranodal natural killer / T- cell lymphoma; enteropathy-associated intestinal T-cell lymphoma (EATL); monomorphic epitheliotropic intestinal T cell lymphoma (MEITL); mycosis fungoides (MF); and / or cutaneous T-cell lymphomas (CTCL), but exclude virus induced adult T-cell leukemia / lymphoma (ATLL or ATL).

[0050] As used herein, an “effective dosage” or “effective amount” of drug, compound, or pharmaceutical composition is an amount sufficient to affect any one or more beneficial, safe (e.g., within a given regulator}’ agency’s tolerance level), and / or desired results. In more specific aspects, an effective amount prevents, alleviates, ameliorates symptoms of disease, and / or prolongs the survival of the subject being treated. For prophylactic use, beneficial or desired results include, but not limited to eliminating or reducing the risk, lessening the severity, or delaying the outset of the disease, including biochemical, histological and / or behavioral symptoms of the disease, its complications and intermediate pathological phenotypes presenting during development of the disease. For therapeutic use. beneficial or desired results include, but not limited to safe clinical results such as reducing one or more symptoms of a disease such as cancer including, for example without limitation, different types of TCL or CTCL (MF and / or SS), decreasing the dose of other medications required to treat TCL or CTCL, enhancing the effect of another medication, and / or delaying the progression of TCL or CTCL in patients. An effective dosage can be administered in one or more administrations. For purposes of this disclosure, an effective dosage of drug, compound, or pharmaceutical composition is an amount sufficient to accomplish prophylactic or therapeutic treatment either directly or indirectly in a safe manner within a given regulatory agency’s parameter. As is understood in the clinical context, an effective dosage of a drug, compound, or pharmaceutical composition may or may not be achieved in conjunction with another drug, compound, or pharmaceutical composition. Thus, an “effective dosage” or “effective amount” may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable result along w ith safety may be or is achieved.

[0051] As used herein, the term “per dose”, “dosage”, or “dose” means administering a given numeric amount of drug to a subject. Per dose can be administered in separate injections or tablet at the same time, at about the same time and / or different time, so long as a subject receives the denoted drug amount.

[0052] As used herein, the term “stabilizer” can include a pharmaceutical acceptable excipient, which assist, and / or inhibits the active pharmaceutical ingredient and / or the formulation from chemical and / or physical degradation during manufacturing, storage and application. Chemical and physical degradation pathways of protein pharmaceuticals are known in the art. Stabilizers can include, but are not limited to sugars, amino acids, polyols, cyclodextrines, e.g. hydroxypropyl- beta-cyclodextrine, sulfobutylethyl-beta-cyclodextrin, beta-cyclodextrin, polyethylenglycols, e.g. PEG 3000. PEG 3350, PEG 4000, PEG 6000, albumine, human serum albumin (EISA), bovine serum albumin (BSA), salts, e.g. sodium chloride, magnesium chloride, calcium chloride, chelators, e.g. EDTA.

[0053] As used herein, the term “per injection” means administering the entire denoted amount of drug to a subject for a given dose in a single injection or tablet.

[0054] The term “PEG” generally refers to a polyalkylene glycol compound or derivative thereof, with or without linkers or activating moieties. The term PEG as used herein includes, but is not limited to, polyethylene glycol homopolymers, copolymers of ethylene glycol with propylene glycol and derivatives and equivalents thereof, wherein said homopolymers and copolymers are unsubstituted or substituted, for example, at one end with an alkyl group. The PEG polymers for use with the present disclosure can be linear, branched, comb, and / or star-shaped with a wide range of molecular weights. The term “mPEG” refers to the methoxy version of any of the above wherein PEG is capped with a methoxy group at the end. The average molecular weight of the mPEG for use with embodiments of the present disclosure can range from about 5 to about 100 kDa, about 10 to about 50 KD, about 10 to about 30 KT), and / or about 19 to 23 KD. The term “mPEG” refers to the methoxy version of any of the above wherein PEG is capped with a methoxy group at the end.

[0055] The term “preventing” or “prevent” refers to (a) keeping a disorder from occurring or (b) delaying the onset of a disorder or onset of symptoms of a disorder of skin lesion progression and / or tumor progression for subjects diagnosed with TCL or CTCL or subtype of CTCL such as MF and / or SS.

[0056] As used herein, “pharmaceutically acceptable carrier” or “pharmaceutical acceptable excipient” includes any material which, when combined with an active ingredient, allows the ingredient to retain biological activity or stability and does not cause adverse effect to a subject. Examples include, but are not limited to. any of the pharmaceutical carriers such as a phosphate buffered saline solution, water, emulsions such as oil / water emulsion, and various types of wetting agents. Example diluents such as for aerosol or parenteral administration can be phosphate buffered saline (PBS) or normal (0.9%) saline.

[0057] The term “intradermal administration”, “i.d.”, or “administered intradermally,” in the context of administering a substance to a mammal including a human, refers to the delivery of the substance into the dermis layer of the skin of the mammal. The skin of a mammal is composed of an epidermis layer, a dermis layer, and a subcutaneous layer. The epidermis is the outer layer of the skin. The dermis, which is the middle layer of the skin, contains nen e endings, sweat glands and oil (sebaceous) glands, hair follicles, and blood vessels. The subcutaneous layer is made up of fat and connective tissue that houses larger blood vessels and nerves. In contrast in intradermal administration, “s.c.”, or “subcutaneous administration”, refers to the administration of a substance into the subcutaneous layer and “topical administration” refers to the administration of a substance onto the surface of the skin.

[0058] As used herein, “about” mean within an acceptable error range for the particular value as determined by one of ordinary skill in the art. which will depend in part on how the value is measured or determined, i.e.. the limitations of the measurement system. For example, “about” can mean within 1 or more than 1 standard deviation per the practice in the art. Alternatively, “about” can mean a range of up to 5%, 7.5%, 10%, 12.5%, 15%, 17.55, 20%, 22.5% 25%, 27.5%, 30%, 32.5%, 35%, 37.5%, or 40% of difference in either direction (positive or negative) compared to a reference value. Furthermore, particularly with respect to biological systems or processes, the terms can mean up to an order of magnitude or up to 1 , 2, 3, 4, or 5-folds of a value. When particular values are provided in the application and claims, unless otherwise stated, the meaning of “about” should be assumed to be within an acceptable error range for that particular value. Reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. For example, description referring to “about X” includes description of “X”. Numeric ranges are inclusive of the numbers defining the range.

[0059] As used herein, the terms “Pl 101”, “Ropeg”, “ropeginterferon alfa-2b-njft”, or “ropeginterferon alfa-2b” are used interchangeably. Pl 101 is known in the art, for example, see U.S. Patent Numbers: US 8,143,214. US 8,273,343, US 8,617,532, and / or US 8,106,160, the content of all of which are incorporate herein in their entirety. Also see U.S. Patent Application Numbers: US 20170326206, US 20220152156, US 20220362343, and / or US 20230057788, the content of all of which are incorporate herein in their entirety. Briefly, for example, the chemical formula, method of manufacturing, and its uses are disclosed therein. For convenience, its structure is briefly denoted in FIGURE 1. More specifically, the interferon (IFN) is the version that is functional in human subjects for Pl 101. The term “mPHOl” denotes the mouse version of IFN that has the same PEGylation.

[0060] In an embodiment, Pl 101, Pl 101 stereoisomer, and / or Pl 101 pharmaceutical composition can treat one or more of the following types of TCL. For example, one type of TCL is Lymphoblastic lymphoma / leukemia (also known as T cell acute lymphoblastic leukemia / lymphoma) accounts for about 1% of all lymphomas. It’s most common in teens or young adults, with males being affected more often than females. It can be thought of as either a lymphoblastic lymphoma (LBL) or a type of acute lymphoblastic leukemia (ALL), depending on how much of the bone marrow is involved (leukemias have more cancer cells in the bone marrow). This lymphoma often starts in the thymus (a small organ behind the breastbone and in front of the heart, which is where many T cells are made) and can grow into a large tumor in the mediastinum (the area between the lungs). This can cause trouble breathing and swelling in the arms and face. This lymphoma is fast-growing.

[0061] Another type of TCL is Peripheral T-cell lymphomas. The first type is Cutaneous T-cell lymphomas, abbreviated as CTCL which includes, but not limited to mycosis fungoides. Sezary syndrome, and other types. These lymphomas start in the skin. For Mycosis Fungoides CTCL: this is the most common type of CTCL, often characterized by patches of skin lesions that can evolve into plaques or tumors. The skin lesions may appear as itchy, scaly patches, or rashes, and can sometimes mimic other skin conditions. For Sezary Syndrome: this is a leukemic variant of mycosis fungoides where lymphoma cells are present in the blood, skin, and lymph nodes. It is characterized by a widespread rash, often involving the entire body, and can be more aggressive than mycosis fungoides. For Lymphomatoid Papulosis: this is a non-aggressive type of CTCL characterized by persistent, inflammatory papules or nodules on the skin. It is often regarded as a low-grade variant of CTCL with a generally good prognosis. For Primary Cutaneous Anaplastic Large Cell Lymphoma (pcALCL): this is a type of CTCL characterized by large, atypical cells with a kidney-shaped nucleus, known as "hallmark cells," and it can be aggressive. For Granulomatous Slack Skin Disease: this is a rare variant of CTCL characterized by lax skin and granulomatous inflammation. Besides the ones mentioned above, there are various other less common types of CTCL, including pagetoid reticulosis, and subcutaneous panniculitis-like T-cell lymphoma.

[0062] Another type is Angioimmunoblastic T-cell lymphoma (AITL): It is more common in older adults. It tends to involve the lymph nodes and bone marrow , as well as the spleen or liver, which can become enlarged. People with this lymphoma usually have fever, weight loss, skin rashes, and often develop infections. This lymphoma often progresses quickly. Treatment often works at first, but the lymphoma tends to come back (recur).

[0063] Yet another type is Extranodal natural killer / T-cell lymphoma, nasal type: This rare type often involves the upper airway passages, such as the nose and upper throat, but it can also invade the skin, digestive tract, and other organs. It is much more common in parts of Asia and South America. Cells of this lymphoma are similar in some ways to natural killer (NK) cells, another ty pe of lymphocyte.

[0064] TCL also includes Enteropathy-associated intestinal T-cell lymphoma (EATL): EATL is a lymphoma that occurs in the lining of the intestine. It is most common in the small intestine, but it can also occur in the colon. Symptoms can include severe abdominal (belly) pain, nausea, vomiting, and bleeding from the intestine. This lymphoma occurs in some people with celiac disease (also called gluten-sensitive enteropathy). Celiac disease is an autoimmune disease in which eating gluten, a protein found mainly in wheat and barley, causes the immune system to attack the lining of the intestine and other parts of the body. This lymphoma is more common in people diagnosed as older adults. It is more common in men than women.

[0065] Yet another TCL is Monomorphic epitheliotropic intestinal T cell lymphoma (MEITL): This type of lymphoma also affects the lining of the intestines, but it is not linked to celiac disease.

[0066] Another type of TCL is Anaplastic large cell lymphoma (ALCL): It is more common in young people (including children), but it can also affect older adults. This type of lymphoma tends to be fast growing, but many people with this lymphoma can be cured. There are different forms of ALCL: Primary cutaneous ALCL only affects the skin. This is discussed in more detail in Lymphoma of the Skin. Systemic ALCL can affect the lymph nodes and other organs, including the skin. Systemic ALCL is divided into 2 types based on whether the lymphoma cells have a change in the ALK gene. ALK-positive ALCL is more common in younger people and tends to have a better prognosis (outlook) than the ALK-negative type. Breast implant-associated ALCL is a rare type of ALCL that can develop in the breasts of women who have had implants. It seems to be more likely to happen if the implant surfaces are textured (as opposed to smooth).

[0067] Other examples of TCL include Peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS): This name is given to T-cell lymphomas that don’t fit well into any of the groups above. Most people diagnosed with these lymphomas are in their 60s. These lymphomas often involve the lymph nodes, but they can also affect the skin, bone marrow, spleen, liver, and digestive tract. As a group, these lymphomas tend to spread and grow quickly. Some of these lymphomas respond well to chemotherapy, but over time they tend to become harder to treat.

[0068] The present disclosure specifically excludes vims induced Adult T-cell leukemia (ATL). ATL (also known as ATLL) can include acute, lymphoma, chronic, and smoldering type which iscaused by infection of Human T-lymphotropic virus type 1 (HTLV-1), a retrovirus which causes a chronic lifelong infection in humans.

[0069] P1101

[0070] With respect to P1101 characterization, pharmacokinetics, pharmacodynamics etc., they are also known in the art. For example, see European Medicinal Agency’s published Besremi (trademarked) assessment report, with all of the contents incorporated herein by reference in their entirety7. Pl 101 has PEGylation site that is at the N-terminus of the drug intermediate, i.e., ropeginterferon alfa-2b consists of a single mono-PEGylated form. By contrast, Pegintron (trademarked), another PEGylated interferon product, consists of 14 positional isomers. Pegintron uses a less stable carbamate linkage which results in a fairly short half-life in serum and thus requires a weekly dosing interval for Pegintron. The molecular weight of the PEG molecule in 40kDa branched PEG in Pl 101 is significantly higher than Pegintron’s 12kDa thus impacting on the half-life both in-vitro and in-vivo. Moreover, clinical data published have shown that Pl 101’s prolonged half-life in human serum, allowing the dosing interval to be significantly extended versus Pegintron, i.e. dosing once every two to four weeks instead of the traditional once every week; thus leading to improved patient tolerability and compliance. Accordingly, due to the prolonged half-life in human serum allowing a prolonged dosing interval patient tolerability and compliance is considered to be improved.

[0071] In general, ropeginterferon alfa-2b can be produced by covalent attachment of an about 40 kDa branched mPEG molecule to the N-terminal proline residue of a Proline-Interferon alfa-2b (Pro-IFN alfa-2b). Proline-interferon alfa-2b can be generated by recombinant DNA technology introducing an extra proline residue to a human interferon alpha-2b at N-terminus, giving a polypeptide of total 166 amino acids in length. . It is then PEGy lated with an about 40 kDa mPEG moiety forming an about 60 kDa PEGylated proline-interferon alfa-2b or ropeginterferon alfa-2b.

[0072] The ropeginterferon alfa-2b conjugate denoted in FIGURES 1 also described in detail in W02009 / 023826A1. In particular. W02009 / 023826A1 disclosed a method of making Pl 101, and the content of which are incorporated herein by reference in their entirety. More specifically, for example, its purity, purification and method of making, physical characteristics as well as utility are all incorporated herein.

[0073] In an embodiment, adverse events (“AE”) with respect to CTCL can include, but not limited to: anemia, thrombocytopaenia, hyper-and hypothyroidism, anorexia, depression, headache, poor concentration, cough, gastrointestinal complaints, hair loss, dermatitis, arthralgias and myalgias, viral and bacterial infections, fever and / or fatigue. Other AE can include leukopenia, gamma-glutamine amino transferase elevated (gamma-GT), flu-like illness, itching, elevated alanine aminotransferase (ALT), lower extremity pain, alopecia, neutropenia, elevated aspartate aminotransferase (AST), headache, diarrhea, chills, dizziness, and / or injection site reaction.

[0074]

[0075] The term "‘interval” as used herein refers to the time between administration of two consecutive doses. In any of the methods described herein, the Pl 101 can be administered at an interval of between about every 1 to about every 8 weeks, e.g., about every 1, 2, 3, 4, 5, 6, 7, 8 weeks, or longer than 8 weeks. An interval that is defined in days or months is also disclosed. A regular interval of about every 10 to 60 days (e.g., about every 7, 14, 21, 25, 26, 27. 28, 29, 30, 31, 35. 42, 49, and / or 56 days), one month, or two months can also be used in the method.

[0076] In an aspect, a treatment period for the treatment of TCL, such as CTCL can be at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 24, 36, 42, 48, 54, 60, 66, 72, 78, 84 or more than 84 months. In some embodiments, the treatment period is about 0.1, 0.25, 0.5, 0.75, 1, 2, 3, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10 or more than 10 years. In some embodiments, the treatment period is at least about 0.1, 0.25, 0.5, 0.75, 1, 2. 3, 4, 5. 6, 7, 8, 12, 14, 15, 16, 17, 18, 19, 20, 24, 28. 32, 36, 40, 44, 48, 52, 56, 60 weeks or longer than 60 weeks for the treatment of TCL, such as CTCL.

[0077] In another embodiment, Pl 101 can be administered using between about 50 to 540 pg per dose or per injection subcutaneously, via i.d., or other routes. Alternatively, or additionally, a dose or injection of Pl 101 can be administered during the treatment period ranges from about 250 to about 650 pg. The dose / inj ection can also be up to about 250 pg, up to about 255 pg, up to about 260 pg. up to about 265 pg, up to about 270 pg, up to about 275 pg, up to about 280 pg, up to about285 pg, up to about 290 pg, up to about 295 pg, up to about 300 pg, up to about 305 pg, up to about310 pg, up to about 315 pg, up to about 320 pg, up to about 325 pg, up to about 330 pg, up to about335 pg. up to about 340 pg, up to about 345 pg, up to about 350 pg, up to about 400 pg, up to about450 pg, up to about 500 pg, up to about 540 pg. or up to about 650 pg. Alternatively, or additionally, a dose or injection of 135 pg or 180 pg of Pl 101 can be administered for the treatment of TCL, such as CTCL.

[0078] In another embodiment, Pl 101 can be administered using between about 50 to 540 pg per dose or per injection subcutaneously, via i.d., or other routes every week. Alternatively, or additionally, a dose or injection of Pl 101 can be administered during the treatment period ranges from about 250 to about 650 pg. The dose / inj ection can also be up to about 250 pg, up to about 255 pg, up to about 260 pg, up to about 265 pg, up to about 270 pg, up to about 275 pg, up to about280 ig. up to about 285 pg, up to about 290 pg, up to about 295 pg, up to about 300 pg, up to about305 pg. up to about 310 pg, up to about 315 pg, up to about 320 pg, up to about 325 pg, up to about330 pg, up to about 335 pg, up to about 340 pg, up to about 345 pg, up to about 350 pg, up to about400 pg, up to about 450 pg, up to about 500 pg, up to about 540 pg, or up to about 650 pg every week. Alternatively, or additionally, a dose or injection of 135 pg or 180 pg of Pl 101 can be administered every week for the treatment of TCL, such as CTCL.

[0079] In another embodiment, Pl 101 can be administered using between about 50 to 540 pg per dose or per injection subcutaneously, via i.d., or other routes every 2 weeks. Alternatively, or additionally, a dose or inj ection of P 1101 can be administered during the treatment period ranges from about 250 to about 650 pg. The dose / inj ection can also be up to about 250 pg, up to about 255 pg, up to about 260 pg, up to about 265 pg, up to about 270 pg, up to about 275 pg, up to about280 pg. up to about 285 pg, up to about 290 pg, up to about 295 pg, up to about 300 pg, up to about305 pg. up to about 310 pg, up to about 315 pg, up to about 320 pg, up to about 325 pg, up to about330 pg, up to about 335 pg, up to about 340 pg, up to about 345 pg, up to about 350 pg, up to about400 pg, up to about 450 pg, up to about 500 pg, up to about 540 pg, or up to about 650 pg every 2 weeks. Alternatively, or additionally, a dose or injection of 135 pg or 180 pg of Pl 101 can be administered every 2 weeks for the treatment of TCL. such as CTCL.

[0080] In another embodiment, Pl 101 can be administered using between about 50 to 540 pg per dose or per injection subcutaneously, via i.d., or other routes every 3 weeks. Alternatively, or additionally, a dose or injection of Pl 101 can be administered during the treatment period ranges from about 250 to about 650 pg. The dose / inj ection can also be up to about 250 pg, up to about 255 pg. up to about 260 pg, up to about 265 pg, up to about 270 pg, up to about 275 pg, up to about280 pg. up to about 285 pg, up to about 290 pg, up to about 295 pg, up to about 300 pg, up to about305 pg, up to about 310 pg, up to about 315 pg, up to about 320 pg, up to about 325 pg, up to about330 pg, up to about 335 pg, up to about 340 pg, up to about 345 pg, up to about 350 pg, up to about400 pg, up to about 450 pg, up to about 500 pg, up to about 540 pg, or up to about 650 pg every 3 weeks. Alternatively, or additionally, a dose or injection of 135 pg or 180 pg of Pl 101 can be administered every 3 weeks for the treatment of TCL, such as CTCL.

[0081] In another embodiment, Pl 101 can be administered using between about 50 to 540 pg per dose or per injection subcutaneously, via i.d., or other routes every 4 weeks. Alternatively, or additionally, a dose or injection of Pl 101 can be administered during the treatment period ranges from about 250 to about 650 pg. The dose / inj ection can also be up to about 250 pg, up to about 255 pg. up to about 260 pg, up to about 265 pg, up to about 270 pg, up to about 275 pg, up to about 280 pg, up to about 285 pg, up to about 290 pg, up to about 295 pg, up to about 300 pg, up to about305 ig. up to about 310 pg, up to about 315 pg, up to about 320 pg, up to about 325 pg, up to about 330 pg. up to about 335 pg, up to about 340 pg, up to about 345 pg, up to about 350 pg, up to about 400 pg, up to about 450 pg, up to about 500 pg, up to about 540 pg, or up to about 650 pg every 4 weeks. Alternatively, or additionally, a dose or injection of 135 pg or 180 pg of Pl 101 can be administered every 4 weeks for the treatment of TCL, such as CTCL.

[0082] In one embodiment, Pl 101 can be administered or dosed according to the formula 0.75-1.5 pg / kg / wk where the pg is amount of Pl 101, kg is a subject's weight and wk is week.

[0083] In some embodiments, an initial (starting) dose can be about 250 to about 500 pg (e.g., about 250 pg, about 300 pg. about 350, about 400 pg, about 450 pg, or about 500 pg) of Pl 101 administered to the subject. The initial dose / inj ection can be maintained or varied during the treatment period depending on patient’s need and / or physician’s recommendation for the treatment of TCL, such as CTCL.

[0084] In any of the methods or treatment periods described herein, Pl 101 can be titrated incrementally upwards or downwards for the treatment of TCL, such as CTCL. As non-limiting example, a subject can be treated with a lower starting dose / inj ection (e.g., about 50 pg, about 100 pg. about 150 pg, about 200 pg, or about 250 to about 500 pg) of the Pl 101. If the subject responds well (e.g., lack of significant drug-related adverse events, significant self-reported discomfort, abnormal hematological responses, or other symptoms) after a time (e.g., between about 1 to 26 weeks, 1 to 52 weeks, or more than 52 weeks), the dose / inj ection given to the subject can be increased incrementally (e.g., by between about 50 to 250 pg. such as at about 50 pg. about 75 pg, about 100 pg, about 125 pg, about 150 pg, about 200 pg, about 250 pg or a combination thereof) every 2 to 16 weeks (e.g., every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 weeks, or a combination thereof) until the dose reaches a target dose (e.g., at least about 400 pg, at least about 425 pg, at least about 450 pg, at least about 475 pg, at least about 500 pg, at least about 525 pg, at least about 550 pg. or at least about 650 pg). After that, a target dose can be maintained constant during the treatment period, increased, and / or decreased depending on subject’s condition. The dose / inj ection frequency can also be increased successively until the desired target dose is reached. For example, if the Pl 101 can be administered once every 1, 2, 3. 4, 5, 6, 7, or 8 weeks, the dose / inj ection can be increased every 1. 2, 3, 4. 5, 6, 7 or 8 weeks, respectively for the treatment of TCL, such as CTCL. In some embodiments, a subject can be given a starting dose / inj ection of 250 pg (i.e., at week 0). If the subject responds well to the initial dose / inj ection, the dose / inj ection can be increased by about 100 to about 150 pg every72 to 8 weeks until it reaches a target dose of about 500 pg, about 550 pg, and / or 600 pg for the treatment of TCL, such as CTCL. For example, a 250-350-500 pg dosing schedule can be implemented (i.e., about 250 pg at week 0, about 350 pgbetween about week 2 to 8, and about 500 ig at the third administration 2 to 8 weeks after the initial second dose, w ithout other intervening doses). Alternative, and / or additionally, a subject can be given a starting dose / inj ection of about 350 pig and a second dose of about 500 pig between about 2 to 16 weeks thereafter without an intervening dose (i.e., 350-500) for the treatment of TCL, such as CTCL. Exemplary dosing schedules can be abbreviated, nonetheless, each number is approximated. For example, 250-350-500 includes 1stdose / inj ection administered at about 250 pg, 2nddose / inj ection administered at about 350 pg, and 3rddose / inj ection administered at about 500 pg for the treatment of TCL, such as CTCL. Other embodiments include, but are not limited to: 50-100-150-200-250-300-350-400-450-500, 250-400-500, 250-400, 250-500, 250-400-500, 250- 450, 250-350-400-500, 250-300-400-500, 250-350-450-500, 250-350-450, 250-250-350-500, 250-250-250-350-500. 250-350-350-500. 250-500-500-500 (and remain at 500 afterwards for example), 350-500, 350-400-500, 350-400-450-500, 350-450-500, 350-400, 350-450, 350-350- 500, 350-350-350-500, 400-450-500, 400-500, 400-400-500, 450-500 pg for the treatment of TCL, such as CTCL. In some embodiments, the target dose and / or desirable effect is reached between about 1 to 13 weeks, about 1 to 26 weeks, 1 to 52 weeks, or more than 52 weeks from the initial administration. During the titration process, any dose, prior to reaching the target dose, may be maintained for a time period (e.g., between about 4 to 16 weeks) or a number of successive doses dose / inj ection (e.g., between 2 to 8 successive doses dose / inj ection, e.g., 250-350-350-500 pg) or reduced depending on the subject's response for the treatment of TCL, such as CTCL. In some embodiments, the target dose is reached within about 2 to 8 successive doses. In further embodiments, once the subject is clinically stable, the dose / inj ection can be maintained at a constant level for a given treatment period, which can be at least about 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 14, 15, 16, 17, 18, 19, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40. 42. 44, 46, 48, 50, 52, 54, 56, 58, 60 weeks, or longer for the treatment of TCL, such as CTCL.

[0085] In an aspect, an initial dose / inj ection or starting dose / inj ection of Pl 101 refers to the first dose administered to a subject during a treatment period (i.e., week 0). wherein, prior to the treatment period, the subject is interferon-treatment naive or has not been administered the same active ingredient as Pl 101. A subject who is interferon-treatment naive is a subject who has not been treated with any form of interferon, whether pegylated or non-pegylated (e.g., recombinant interferon, or peginterferon alfa-2b that is not Pl 101. or peginterferon alfa-2a approved to be administered weekly).

[0086] In another embodiment, all of the above recited dosages treating, preventing, slowing the progression, inhibiting and / or ameliorating subjects with T-cell lymphoma (including CTCL, for example MF or SS) can be administered per dose, and / or per injection. Non-limiting exampleinclude administering about 250-350-500 ig of drug using about 5()pg per about 5 injections at about the same time and / or different times, so long as the subject receives a total of about 250 pg dose, or about 100 pg per injection about 5 times at about the same time and / or different times for a total of about 500 pg dose. The combination can be pick and choose depending on patient or subject convenience and / or medical need. In another non-limiting example, the entire about 250pg can be all administered in a single injection (per injection) at a single time point for the desired 250 pg dose.

[0087] FIGURE 2 shows an example of Pl 101 administration regimen to a subject or a subject in need with TCL and / or CTCL, where the initial dose is 250 ug, follow by 350 ug at week 2, follow by 500 ug at week 4, and follow by constant 500 ug administration from week 6 and beyond. Alternatively, or additionally, week 6 and beyond dosages can be adjusted and / or titrated upward and / or downwards depending on the subject tolerance to Pl 101.

[0088] In an embodiment, any of the above-mentioned dosage, or dosage scheme treating, preventing, slowing the progression, inhibiting and / or ameliorating subjects with T-cell lymphoma (including CTCL, for example MF or SS) can be use, and / or in a mix-and-match fashion, depending on the subject’s tolerance and a physician’s assessment (e.g., based on number and / or types of AE).

[0089] In an embodiment, Pl 101 can be administered by any means known in the art, e.g., via subcutaneous or intravenous route. Pl 101 can be formulated as an injectable formulation. For example, it can be in the form of a ready-to-use prefilled syringe and / or injectable pen, containing, e.g., between about 0.2 to about 2 mL of solution, that can be for self-inj ection. Each prefilled syringe can contain a labeled amount of the drug product including, for example, sodium chloride, sodium acetate anhydrous, acetic acid, benzyl alcohol, TWEEN (trademarked) and / or polysorbate 80. The vehicle for the drug product can be sterile water for injection and the drug product solution can have a pH of about 6, 6.5, 7. 7.5 or 8.

[0090] In an embodiment, Pl 101 can be used for subcutaneous injection to a subject. Alternative, or additionally, Pl 101 can be administered via topical contact, intravenous, intraperitoneal, intramuscular, intralesional, intranasal or the implantation of a slow-release device e.g., a mini- osmotic pump, to a subject. Other administration is by any route including parenteral, and transmucosal (e.g.. oral, nasal, vaginal, rectal, or transdermal). Parenteral administration includes, e.g., intravenous, intramuscular, intra-arteriole. intradermal, intraperitoneal, intraventricular, and / or intracranial. Moreover, where injection is to treat a tumor, e.g., induce apoptosis, administration may be directly to the tumor and / or into tissues surrounding the tumor. Other modesof delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches.

[0091] In certain embodiments, Pl 101 is administered once daily, about once weekly, about once every two weeks, about once every three weeks, about once every four weeks, about once every five weeks, about once every six weeks, or about once every three months. P l 101 can be administered within about twenty-four hours of a dose of chemotherapy and / or radiation therapy. In certain embodiments, Pl 101 is administered at least once about 3, once about 7, once about 10, once about 14. once about 17 or once about 21 days before or after a dose of other combination therapy for the treatment of TCL, such as CTCL. In an embodiment, Pl 101 can be administered to a patient immediately after, at about the same time, and / or any time during any other available known therapy.

[0092] In one embodiment, Pl 101 of present disclosure can be used to treat, slow the progression, increase OR (overall survival), change or improve the categorization of TCL or CTCL disease as listed in Table 1 and Table 2 (CR / Cru / PR / PFS / DFS). and / or prevent TCL or CTCL in a subject. In addition, Pl 101 can decrease AE on subjects who has TCL or CTCL which can include but not limited to different classifications or subty pes of TCL or CTCL such as MF and / or SS.

[0093] In another embodiment, Pl 101 can be used to treat, slow the progression, increase OR, change or improve the categorization of TCL or CTCL disease (CR / Cru / PR / PFS / DFS), prevent TCL or CTCL, and / or decrease AE on a subject having MF and / or SS CTCL.

[0094] In an embodiment, the present disclosure’s composition can be formulated by methods known in order to treat TCL or CTCL. For example, a sterile injectable composition can be a solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are mannitol, water, Ringer's solution, and isotonic sodium chloride solution. In addition, fixed oils are conventionally employed as a Solvent or Suspending medium (e.g., synthetic mono- or di glycerides). Fath’ acid, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions can also contain along chain alcohol diluent or dispersant, or carboxymethyl cellulose or similar dispersing agents. Other commonly used surfactants such as Tweens or Spans or other similar emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms can also be used for the purpose of formulation.

[0095] In another aspect, the present disclosure’s composition can be formulated for oral administration can be any orally acceptable dosage form including capsules, tablets, emulsions, and aqueous suspensions, dispersions, and solutions. In the case of tablets, carriers include lactose and com starch, lubricating agents such as magnesium stearate, can also be added. For oral administration in capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions or emulsions are administered orally, the active ingredient can be suspended or dissolved in an oily phase combined with emulsifying or suspending agents. If desired, certain sweetening, flavoring, or coloring agents can be added.

[0096] Alternative, or additionally, a nasal aerosol or inhalation composition can be prepared according to techniques well know n in the art of pharmaceutical formulation. For example, such a composition can be prepared as a solution in saline, employing benzyl alcohol or other preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other solubilizing or dispersing agents known in the art. A composition having one or more of the abovedescribed compounds can also be administered in the form of suppositories for rectal administration.

[0097] Other pharmaceutically acceptable carriers can be used with one or more active above- mentioned compounds. The carrier in the pharmaceutical compositions is “acceptable1in the sense that it is compatible with the active ingredient of the composition (and for example, capable of stabilizing the active ingredient) and not deleterious to the patient to be treated. One or more solubilizing agents can be utilized as pharmaceutical excipients for delivery of an above-mentioned compound. Examples of other carriers include, but not limited to colloidal silicon oxide, magnesium Stearate, cellulose, sodium laurylsulfate, and D&C Yellow #10.

[0098] In an embodiment, the present disclosure relates to using the composition disclosed (e.g., Formula I) and combine with another known therapy to treat TCL or CTCL. Example of such combination includes total skin electron beam therapy (TSEBT) and / or psoralen plus Ultraviolet A therapy (PUVA), Bexarotene, interferons, MTX (Folic acid metabolism inhibitors), Pralatrexate, Histone deacetylase (HD AC) inhibitors, Vorinostat, Romidepsin, Brentuximab vedotin, Mogamulizumab, DD (DAB389IL-2), Gemcitabine, Pegylated liposomal doxorubicin, or Pentostatin. The combination can be performed in conjunction, during, before, and / or after the Pl 101 therapy.

[0099] Surprising Efficacy, Advantages and Improvement

[0100] In an embodiment, the present disclosure describes Pl 101 having surprising and unexpected improved in vitro, in vivo, ex vivo and / or clinical performance for the treatment ofTCL, such as CTCL over one or more of the known treatments mentioned in this disclosure or known in the art. For the below surprising embodiment, CR refers to complete remission; PR refers to partial response; SD refers to stable disease: PD refers to progressive disease; and OR refers to overall survival.

[0101] In another embodiment, the present disclosure describes using Pl 101 to treat TCL or CTCL subjects having surprising and unexpected improved clinical outcome as compared to known treatment by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 30%. at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about one fold, at least about1.5 fold, at least about 2 fold, at least about 2.5 fold, at least about 3 fold, at least about 4 fold, and / or at least about 5 fold of ORR (overall survival rate) and / or median ORR.

[0102] In another embodiment, the present disclosure describes using Pl 101 to treat TCL or CTCL subjects having surprising and unexpected improved clinical outcome as compared to known treatment by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about one fold, at least about1.5 fold, at least about 2 fold, at least about 2.5 fold, at least about 3 fold, at least about 4 fold, and / or at least about 5 fold of subjects having CR (complete response), median CR, or improve disease category as listed in Table 1 and / or Table 2.

[0103] In another embodiment, the present disclosure describes using Pl 101 to treat TCL or CTCL subjects having surprising and unexpected improved clinical outcome as compared to known treatment by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%. at least about one fold, at least about1.5 fold, at least about 2 fold, at least about 2.5 fold, at least about 3 fold, at least about 4 fold, and / or at least about 5 fold of subjects having Cru (complete response unconfirmed), median Cru, and / or improve disease category' as listed in Table 1 and / or Table 2.

[0104] In another embodiment, the present disclosure describes using Pl 101 to treat TCL or CTCL subjects having surprising and unexpected improved clinical outcome as compared to known treatment at least about 5%, at least about 10%, by at least about 15%, at least about 20%, at least about 30%. at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about one fold, at least about1.5 fold, at least about 2 fold, at least about 2.5 fold, at least about 3 fold, at least about 4 fold,and / or at least about 5 fold of subjects having increase number of PFS (progression-free survival), median PFS, and / or improve disease category as listed in Table 1 and / or Table 2.

[0105] In another embodiment, the present disclosure describes using Pl 101 to treat TCL or CTCL subjects having surprising and unexpected improved clinical outcome as compared to known treatment at least about 5%, at least about 10%, by at least about 15%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about one fold, at least about1.5 fold, at least about 2 fold, at least about 2.5 fold, at least about 3 fold, at least about 4 fold, and / or at least about 5 fold of subjects having increase number of PR (partial response), median PR, and / or improve disease category as listed in Table 1 and / or Table 2.

[0106] In another embodiment, the present disclosure describes using Pl 101 to treat TCL or CTCL subjects having surprising and unexpected improved clinical outcome as compared to known treatment by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 30%. at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about one fold, at least about1.5 fold, at least about 2 fold, at least about 2.5 fold, at least about 3 fold, at least about 4 fold, at least about 5 fold of subjects having TCL or CTCL remission, and / or improve disease category as listed in Table 1 and / or Table 2.

[0107] In another embodiment, the present disclosure describes using Pl 101 to treat TCL or CTCL subjects having surprising and unexpected improved clinical outcome as compared to known treatment at least about 5%, at least about 10%, by at least about 15%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about one fold, at least about1.5 fold, at least about 2 fold, at least about 2.5 fold, at least about 3 fold, at least about 4 fold, at least about 5 fold of subjects having increase number of time to treatment failure (TTF). and / or improve disease category as listed in Table 1 and / or Table 2.

[0108] In another embodiment, the present disclosure describes using Pl 101 to treat TCL or CTCL subjects having surprising and unexpected improved clinical outcome as compared to known treatment at least about 5%, at least about 10%, by at least about 15%, at least about 20%, at least about 30%. at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%. at least about one fold, at least about1.5 fold, at least about 2 fold, at least about 2.5 fold, at least about 3 fold, at least about 4 fold, at least about 5 fold of subjects having increase number of disease control rate (DCR), and / or improve disease category as listed in Table 1 and / or Table 2.

[0109] In another embodiment, the present disclosure describes using Pl 101 to treat TCL or CTCL subjects having surprising and unexpected improved clinical outcome as compared to known treatment at least about 5%, at least about 10%, by at least about 15%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about one fold, at least about 1.5 fold, at least about 2 fold, at least about 2.5 fold, at least about 3 fold, at least about 4 fold, and / or at least about 5 fold of subjects having fewer number of adverse event(s) and / or decrease one or more AE such as those listed in the present disclosure.

[0110] In another embodiment, the present disclosure describes using Pl 101 to treat TCL or CTCL subjects having surprising and unexpected improved clinical outcome as compared to known treatment by reducing cancer severity by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%. at least about 70%, at least about 80%, at least about 90%, at least about 95%. at least about one fold, at least about 1.5 fold, at least about 2 fold, at least about 2.5 fold, at least about 3 fold, at least about 4 fold, at least about 5 fold for subjects, and / or improve disease category as listed in Table 1 and / or Table 2.

[0111] In an embodiment, any of the above improvements can be reached at week 4, 6, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48. 52 weeks, or longer for the treatment of TCL, such as CTCL.

[0112] In another embodiment, ways to measure determine the progression of TCL or CTCL are known and reproduced in Table 1 and Table 2 below:Table 1Clinical staging system for cutaneous T-cell lymphoma. Also known as TNMB classification.Table 2This stage classification uses the TMN staging system to subclassify theclinical disease progression.

[0113] In an embodiment, any of the above improvements of classifications listed in Table 1 can be reached at week 4, 6, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 weeks, or longer for the treatment of TCL, such as CTCL.

[0114] In an embodiment, any of the above improvements of stages listed in Table 2 can be reached at week 4, 6, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 weeks, or longer for the treatment of TCL, such as CTCL.

[0115] In an embodiment, for CTCL, lesion size can be defined as the area of the lesion and is typically computed as maximum length (cm) x maximum width (cm). The skin response can be defined as the response of the intralesionally injected lesions during the therapy, and the response can be rated as follows: complete response (CR), 100% clearance of injected lesions; partial response (PR), 50-99% clearance of skin disease from baseline without new tumors (T3) in patients with Tl, T2, or T4 only skin disease; stable disease (SD), <25% increase to <50% clearance in skin disease from baseline without new tumors (T3) in patients with Tl, T2, or T4 only skin disease; progressive disease (PD), >25% increase in skin disease from baseline, or new tumors (T3) in patients with Tl, T2 or T4 only skin disease, or loss of response (increase in skinscore greater than the sum of nadir plus 50% baseline score in those with complete or partial response); or relapse, any disease recurrence in those with CR.

[0116] In an embodiment, any of the above improvements of CR, PR, SD (stable disease), improved PD (progressive disease) and / or improved OR (overall survival) refers to overall survival can be reached at week 4, 6, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 weeks, or longer for the treatment of TCL, such as CTCL.

[0117] Examples

[0118] Example 1

[0119] P1101

[0120] Ropeginterferon alfa-2b (Pl 101) structure and method of making is known in the art. Briefly, Ropeginterferon alfa-2b has a molecular mass of approximately 60 kilodaltons (kDa). Ropeginterferon alfa-2b is a covalent conjugate of a recombinant proline-interferon alfa-2b and a two-arm methoxypolyethylene glycol (mPEG) moiety. Pro-IFN alfa-2b, produced in Escherichia coli, is apolypeptide of 166 amino acids: with an approximately 40 kDa two-arm PEG moiety attaches to its N-termmal proline.

[0121] The making of Pl 101 process starts with fermentation in E. coll. The initial cell expressing protein is expressed as an intracellular protein in the form of inclusion bodies. The product is extracted by lysing the cells followed by washing with buffers, and then solubilizing the inclusion bodies that contain the product. Downstream processing steps include protein refolding and chromatography and ultrafiltration / diafdtration purification steps.

[0122] Proline-interferon alfa-2b is then PEGylated by attaching an about 40 kDa two-arm branched mPEG intermediate to the N-terminal proline. It is then further purified via chromatography and UF / DF steps to produce the formulated active substance.

[0123] Briefly, the generation of the cell substrate includes using a cell substrate for expression of the recombinant protein is based on E. coli strain BLR (DE3). Construction of the expression plasmid is documented and the gene encoding Pro-IFN alfa-2b was cloned by polymerase chain reaction (PCR).

[0124] A master cell bank (MCB) and working cell bank (WCB) has been established; characterization of the cell banks including testing for identity, purity, viability and genetic characterization. Testing demonstrating genetic stability has been performed at the end of production cells (EPC) derived from the MCB and WCB.

[0125] The route of synthesis as well as the process parameters and in-process controls of the about 40 kDa PEG intermediate are known in the art as described in various patents and patent applications as well as described in the present disclosure.

[0126] Example 2.

[0127] Pl 101 Characterization. Ropeginterferon alfa-2b is a PEGylated recombinant human IFN alpha-2b with addition of an extra amino acid (proline) at the N-terminus. It is a long- acting interferon with one major PEGylated form , in contrast to the 8-14 isomers of other PEGylated interferon products.

[0128] Characterization studies for the intermediate as well as for the active substance (AS) were performed with batches manufactured.

[0129] Interferon alfa-2 is a polypeptide chain of 165 amino acid residues. Different ty pes of alfa-2 interferon exist, varying in the amino acid residue. Proline-interferon alfa-2b contains an identical amino acid sequence to interferon alpha-2b plus an extra proline at the N-terminus (166 amino acid residues). Ropeginterferon alfa-2b is a PEGylated proline-interferon alfa-2b synthesized by conjugating a single (about) 40 kDa mPEG branched molecule to the N-terminal proline residue.

[0130] The structures of the intermediate and the active substance were elucidated using a variety of physico-chemical (e g. peptide mapping, N- and C-terminal sequencing, electrophoretic and liquid chromatography-mass spectrometry analysis (LC-MS), SE-HPLC, RP-HPLC, IEX- HPLC, etc.), biophysical, and biological (cytopathic effect (CPE)-based potency assay and surface plasmon resonance (SPR) binding assay) techniques to provide a comprehensive understanding of their structure and functional properties and impurity profile.

[0131] The primary7sequence was confirmed using peptide mapping and / or other known techniques with 100% sequence coverage. Molecular mass of the intact protein, extinction coefficient, and presence of disulfide bridges as well as secondary and tertiary structure profiles of sample and respective reference batches were confirmed to be superimposable. Only one main PEGylation site was determined.

[0132] The primary sequence of the AS was confirmed using peptide map / RP-HPLC / LC- MS / MS with 100% sequence coverage. Molecular mass of the intact protein, extinction coefficient, and presence of disulfide bridges as well as secondary and tertiary structure profiles of AS sample and respective reference batches were confirmed to be superimposable. Only one main PEGylation site was determined; positional isomers, i.e. mono-PEGylated products with different PEGylation sites, were detected at relatively low7level using HPLC.

[0133] Active substance’s biological characterization includes cytopathic effect-based potency assay (antiviral assay) and ligand / receptor binding assay. The antiviral bioassay is proposed for routine use while the ligand / receptor binding assay, intended for characterization use, monitors the binding affinity of AS intermediate active substance toward both chains (IFNAR1 and IFNAR2) of the Type I IFN receptor.

[0134] Example 3.

[0135] In vitro assay of Ropeginterferon alfa-2b (P1101) efficacy towards T cell lymphoma cells.

[0136] In this example, the efficacy of Pl 101 on the viability of a subtype of TCL named cutaneous T cell lymphoma cells (CTCL) was evaluated in vitro. A representative human CTCL cell line (HuT78) derived from a patient with Sezary Syndrome was used to determine the effects of Pl 101. An erythroleukemia cell line (HEL 92. 1.7) with a known activating mutation in Janus kinase 2 and therefore potential sensitivity' to Pl 101 based on its known mechanism of action was included for comparison. FIGURES 4a-4d show a dose-dependent inhibition of cell viability' in the CTCL cell line HuT78 on day 6 post treatment with Pl 101 compared with the erythroleukemia cell line HEL 92. 1.7. The Cell titer Gio kit from Promega was used to measure cell viability after 6 days of treatment with different concentrations of Pl 101. After 6 days of treatment in vitro, Pl 101 dose-dependently inhibited the viability7of the human CTCL cell line HuT78 with an ICso of 29.46 ng / ml; 165.7 ng / mL; 26.55 ng / mL; and 145.4 ng / mL respectively. FIGURES 4(a) to 4(d) delineate the detailed dose dependency graphs.

[0137] Example 4

[0138] Expression of interferon stimulated genes (ISG) from human T cell lymphoma cell lines induced by Pl 101

[0139] This example demonstrates the expression of interferon stimulated genes (ISG) from a subtype of human T cell lymphoma cell lines named human cutaneous T cell lymphoma (CTCL) cell lines (HuT78, and HH) that were stimulated with Pl 101 . The MJ human adult T cell leukemia / lymphoma(ATLL) cell line was included for comparison as control. The CTCL cell tines derived from patients represent 2 different disease subtypes: HuT78 cells for Sezary syndrome and HH cells for mycosis fungoides. ISGs to evaluate are C-X-C motif chemokine ligand 10 (CXCL10), 2’-5’-oligoadenylate synthase 1 (OAS 1), interferon alpha inducible protein 27 (IFI27), and 44 like (IFI44L). CXCL10 is a pro-inflammatory cytokine that mediates chemotaxis, differentiation, apoptosis, and activation of peripheral immune cells. OAS1 plays a key role in innate cellular antiviral response, including apoptosis. IFI27 and IFI44L are adaptor proteins forsignaling pathways to mediate cellular responses, including apoptosis, to viral and bacterial infections. Expression of ISGs, assessed by real time quantitative polymerase chain reaction (RT- qPCR), were measured at 3 and 24 hours (h) post treatment of Pl 101 or untreated (UT). Relative expression was determined by delta-delta Ct calculations and normalized to respective 3h UT groups. Experimental replicates are represented by dots on FIGURES 5(a) to FIGURE 5(d). About 2.2 mg / ml of Pl 101 were used.

[0140] As observed, in FIGURE 5(a), P1101 induced expression of CXCL10 in HuT78 and HH cells at both time points relative to respective 3h untreated cells. No significant change in CXCL10 expression was observed in MJ cells.

[0141] As observed, in FIGURE 5(b). Pl 101 induced expression of OAS1 in HuT78, MJ, and HH cells. Increased expression was also observed at 24 hours compared to 3 hours.

[0142] As observed, in FIGURE 5(c), Pl 101 induced expression of IFI27 in HuT78, MJ, and HH cells. Increased expression was also observed at 24 hours compared to 3 hours.

[0143] As observed, in FIGURE 5(d), Pl 101 induced expression of IFI44L in HuT78, MJ, and HH cells. Increased expression was also observed at 24 hours compared to 3 hours.

[0144] In brief, human CTCL cell lines demonstrate Pl 101-induced expression of ISGs. The ATL cell line MJ had the lowest induction of ISGs from Pl lOlcompared to HuT78 and HH cells. Overall, CTCL cell lines responded to Pl lOlby increasing expression of known type 1 interferon target genes.

[0145] Example 5

[0146] Pl 101 induces type I interferon receptor signaling in T cell lymphoma cell lines.

[0147] This example demonstrated the activation of Signal Transducer and Activator of Transcription 1 (STAT1) transcription factor by Pl 101 on a subtype of TCL named human cutaneous T cell lymphoma (CTCL) cell lines (HuT78 and HH). The adult T cell leukemia / lymphoma cell line MJ was included for comparison. The CTCL cell lines derived from patients represent 2 different disease subtypes: HuT78 cells for Sezar ' syndrome and HH cells for mycosis fungoides. Activated STAT1 mediates expression of a variety of genes involved with cell viability in response to different cell stimuli and pathogens. Activation of the transcription factor was measured by ELISA detecting the phosphory lation of STAT1 at the Tyr701 site. CTCL and ATL cells were treated w ith different doses of Pl 101 to determine the ECso (potency) required to activate STAT1. About 2.2 mg / ml of Pl 101 was used.

[0148] As observed, FIGURE 6 demonstrated Pl 101 induced activation of STAT1 in CTCL and ATL cell lines. HH. HuT78, and MJ have an average ECso of 15.8 ng / mL, 30.61 ng / mL, and 73.36 ng / mL, respectively.

[0149] In brief, human CTCL cell lines demonstrate Pl lOl-induced activation of the STAT1 transcription factor. The two CTCL cell lines were more sensitive / responsive to Pl 101 in terms of both potency (ECso) and maximal effect (Emax) compared to the ATL cell line. Overall, CTCL cell lines are capable of responding to P1101 by activating the transcription factor STATE

[0150] Example 6

[0151] Efficacy of Ropeginterferon alfa-2b (P1101) in Subjects or a subject in need with TCL.

[0152] This example denotes a clinical design using Pl 101 as a therapy for a subty pe of CTL named CTCL or any of its CTCL subtype such as MF and / or SS.

[0153] Pl 101 is administered subcutaneously for treatment of CTCL and by physicians or other medical personnel, family members of patients who have been trained in subcutaneous injection of syringe injections, or patients themselves. The injection site is under the skin of the abdomen (5 cm around the navel) or thighs and should not be inj ected into the skin that may be painful, red, bruised, infected or bruised. Pl 101 is contained in a syringe for injection, and the syringe is marked with a scale of 50 micrograms to 500 micrograms, and the dosage is adjustable using a graduation of 50 micrograms at intervals of 50 micrograms.

[0154] Subcutaneous injections are given every 2 weeks to a subject. The starting dose is 250 micrograms, and if there are no obvious drug-related side effects after injection, and the subject does not complain of discomfort, or abnormal biochemical / hematological values, the dose can be gradually increased by 100 micrograms per cycle, that is, to 350 micrograms after 2 weeks, and to 500 micrograms after 4 weeks. The maximum dose is 500 ug.

[0155] Maintenance dose. Subcutaneous injections are given every 2 weeks and should be continued every 2 weeks, after which the interval between injections is extended according to the patient's individual circumstances. If adverse reactions occur during treatment, the dose are reduced or temporarily discontinued until the adverse effects subside. Subsequently, it can be reinitiated and administered at a lower dose rather than at the dose where the adverse effect occurred. After administration, subjects exhibit alleviation and / or improvement according to Table 1 and / or 2.

[0156] Adjustment dose. Dose and frequency of administration with subject who shows intolerance to Pl 101, an / or exhibit significant AE are adjusted downward according to physician’s discretion. After such subject is recovered from intolerance symptoms, dose and frequency of administration can be readjusted upwards to the maximum of about 500ug per dose every 2 weeks.

[0157] Statistical methods are applied to the primary and secondary endpoints. The analysis of categorical values is summarized in frequency, percentage, and 95% confidence intervals. Continuous variables display the total number (n), mean, standard deviation, median, minimum and maximum values.

[0158] Statistical analysis is performed using SAS software or other valid statistical software, as appropriate. The details of the statistical analysis are described in a separate statistical analysis plan (SAP) and signed before the first database lock.

[0159] After the start of the treatment, one or more patients exhibit increased complete remission, partial response, stable disease, progressive disease; and / or overall survival rate. In addition, one or more patients exhibit decrease in AE rate and / or AE severity.

[0160] It is contemplated that any embodiment discussed in this specification can be implemented with respect to any method, kit, reagent, or composition of the disclosure, and vice versa. Furthermore, compositions of the disclosure can be used to achieve methods of the disclosure.

[0161] It will be understood that particular embodiments described herein are shown by way of illustration and not as limitations of the disclosure. The principal features of this disclosure can be employed in various embodiments without departing from the scope of the disclosure. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific procedures described herein.

[0162] All publications and patent applications mentioned in the specification are indicative of the level of skill of those skilled in the art to which this disclosure pertains. All publications and patent applications are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.

[0163] The use of the word “a” or “an” when used in conjunction with the term “comprising” in the claims and / or the specification may mean “one,” but it is also consistent with the meaning of “one or more,” “at least one,” and “one or more than one.” The use of the term “or” in the claims is used to mean “and / or” unless explicitly indicated to refer to alternatives onlyor the alternatives are mutually exclusive, although the disclosure supports a definition that refers to only alternatives and "and / or."

[0164] As used in this specification and claim(s), the words “comprising’" (and any form of comprising, such as “comprise” and “comprises”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of including, such as “includes” and “include”) or “containing” (and any form of containing, such as “contains” and “contain”) are inclusive or open- ended and do not exclude additional, unrecited elements or method steps.

[0165] The term “or combinations thereof’ as used herein refers to all permutations and combinations of the listed items preceding the term. For example, “A, B, C, or combinations thereof’ is intended to include at least one of: A, B, C. AB, AC. BC, or ABC, and if order is important in a particular context, also BA, CA, CB, CBA, BCA, ACB, BAC, or CAB. Continuing with this example, expressly included are combinations that contain repeats of one or more item or term, such as BB, AAA, AB, BBC, AAABCCCC, CBBAAA, CABABB, and so forth. The skilled artisan will understand that typically there is no limit on the number of items or terms in any combination, unless otherwise apparent from the context.

[0166] All of the compositions and / or methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. While the compositions and methods of this disclosure have been described in terms of embodiments, it will be apparent to those of skill in the art that variations may be applied to the compositions and / or methods and in the steps or in the sequence of steps of the method described herein without departing from the concept, spirit and scope of the disclosure.

Claims

What is claimed is:

1. A method of treating a subject or a subject in need having T-cell lymphoma (TCL) comprising administering to said subject or subject in need in need thereof an effective amount of ropeginterferon alfa-2b including the structure of fonnula I(Formula I).

2. A pharmaceutical composition comprising the ropeginterferon alfa-2b of claim 1 and a pharmaceutically acceptable carrier, salt, a solvate or prodrug thereof, an adjuvant, and / or a diluent.

3. A method of treating a subject or a subject in need having T-cell lymphoma (TCL) comprising administering to said subject or subject in need in need thereof an effective amount of said pharmaceutical composition of claim 2.

4. The method according to claim 1 or 3, wherein said T-cell lymphoma comprises cutaneous T-cell lymphomas (CTCL); peripheral T cell lymphoma non-specific type (PTCL- NOS); anaplastic large cell lymphoma (ALCL); angioimmunoblastic T-cell lymphoma (AITL); extranodal natural killer / T-cell lymphoma; enteropathy-associated intestinal T-cell lymphoma (EATL); monomorphic epitheliotropic intestinal T cell lymphoma (MEITL); and / or mycosis fungoides (MF).

5. The method according to claim 1 or 3, wherein said T-cell lymphoma does not comprise virus induced Adult T-cell leukemia / lymphoma.

6. The method according to claim 1 or 3, wherein said T-cell lymphoma comprises cutaneous T-cell lymphomas (CTCL).

7. The method according to claim 6, wherein said CTCL comprises mycosis fungoides cutaneous T-cell lymphomas, Sezary syndrome cutaneous T-cell lymphomas, lymphomatoid papulosis cutaneous T-cell lymphomas, primary cutaneous anaplastic large cell lymphoma, adultT-cell leukemia / lymphoma, granulomatous slack skin disease, pagetoid reticulosis cutaneous T- cell lymphomas, and / or subcutaneous panniculitis-like T-cell lymphoma subtypes.

8. The method according to claim 1 or 3, wherein said ropeginterferon alfa-2b, and / or said pharmaceutical composition is administered subcutaneously to the subject or subject in need.

9. The method according to claim 1 or 3, wherein each said mPEG comprises between about 19 to about 23 KDa.

10. The method according to claim 1 or 3. wherein said effective amount comprises a first dosage, a second dosage, a third dosage, and / or subsequent doses of ropeginterferon alfa-2b pharmaceutical composition thereof administered about every’ 1, 2, 3, 4, 5, 6, 7 or 8 weeks.1 1. The method according to claim 10, wherein said first dosage comprises about 250 pg, the second dosage comprises about 350 pg, and the third dosage and / or subsequent dosages comprise about 500 pg of ropeginterferon alfa-2b , and / or pharmaceutical composition thereof.

12. The method according to claim 1 or 3, wherein said effective amount comprises between about 50 pg to about 540 pg of ropeginterferon alfa-2b , and / or pharmaceutical composition thereof.

13. The method according to claim 11, wherein said second, third dosage, or subsequent dosages is maintained at a constant level, or is adjusted upward or downward during a treatment period.

14. The method according to claim 11, wherein said first dosage is about 450 pg.

15. The method according to claim 11 , wherein the subsequent dosages after said three doses are maintained at a constant level.

16. The method according to claim 10, wherein said ropeginterferon alfa-2b, and / or pharmaceutical composition thereof is administered for a period of between about 2 to 13 weeks, about 2 to 26 weeks, about 2 to 52 weeks, or longer than about 52 weeks.

17. The method according to claim 1 or 3, wherein said method decreases said subject or subject in need’s AE rate.

18. The method according to claim 1 or 3, wherein said method increases said subject or subject in need’s complete remission, partial response, stable disease, progressive disease; and / or overall survival rate.

19. Use of a substantially homogenous composition or pharmaceutical formulation comprising ropeginterferon alfa-2b including the structure of formula I(Formula I) for the preparation of a medicament for the treatment of a subject or a subject in need having T- cell lymphoma.

20. The method according to claim 19, wherein said T-cell lymphoma does not comprise virus induced Adult T-cell leukemia / lymphoma.

21. The use according to claim 19, wherein said T-cell lymphoma comprises cutaneous T-cell lymphomas (CTCL); peripheral T cell lymphoma non-specific type (PTCL-NOS); anaplastic large cell lymphoma (ALCL); angioimmunoblastic T-cell lymphoma (AITL); extranodal natural killer / T-cell lymphoma; enteropathy-associated intestinal T-cell lymphoma (EATL); monomorphic epitheliotropic intestinal T cell lymphoma (MEITL); or mycosis fungoides (MF).

22. The use according to claim 19. wherein said T-cell lymphoma comprises cutaneous T-cell lymphomas (CTCL).

23. The use according to claim 22. wherein said CTCL comprises mycosis fungoides cutaneous T-cell lymphomas, Sezary syndrome cutaneous T-cell lymphomas, lymphomatoid papulosis cutaneous T-cell lymphomas, primary cutaneous anaplastic large cell lymphoma, adult T-cell leukemia / lymphoma, granulomatous slack skin disease, pagetoid reticulosis cutaneous T- cell lymphomas, and / or subcutaneous panniculitis-like T-cell lymphoma subtypes.

24. The use according to claim 19, wherein said ropeginterferon alfa-2b further comprises a pharmaceutically acceptable carrier, salt, a solvate or prodrug thereof, an adjuvant, and / or a diluent.

25. The use according to claim 19, wherein said ropeginterferon alfa-2b is administered subcutaneously to the subject or subject in need.

26. The use according to claim 19, wherein each said ropeginterferon alfa-2b includes two mPEG, each having between about 19 to about 23 KDa.

27. The use according to claim 19, wherein said use comprises a first dosage, a second dosage, a third dosage, and / or subsequent doses of ropeginterferon alfa-2b administered about every 1, 2, 3, 4, 5, 6, 7 or 8 weeks.

28. The use according to claim 19. wherein said use comprises using between about 50 pg to about 540 pg of ropeginterferon alfa-2b.

29. The use according to claim 27, wherein said second, third dosage or subsequent dosages is maintained at a constant level or is adjusted upward or downw ard during a treatment period.

30. The use according to any of claims 19 to 29, wherein said use increases said subject or subject in need’s complete remission, partial response, stable disease, progressive disease, and / or overall survival rate.

31. A substantially homogenous composition or pharmaceutical formulation comprising ropeginterferon alfa-2b including the structure of formula I(Formula I) characterized that for used in treating a subject or a subject in need having T-cell lymphoma.

32. The substantially homogenous composition or pharmaceutical formulation according to claim 31. wherein said T-cell lymphoma comprises cutaneous T-cell lymphomas (CTCL); peripheral T cell lymphoma non-specific type (PTCL-NOS); anaplastic large cell lymphoma (ALCL); angioimmunoblastic T-cell lymphoma (AITL); extranodal natural killer / T-cell lymphoma; enteropathy-associated intestinal T-cell lymphoma (EATL); monomorphic epitheliotropic intestinal T cell lymphoma (MEITL); or mycosis fungoides (MF).

33. The substantially homogenous composition or pharmaceutical formulation according to claim 32. wherein said T-cell lymphoma does not comprise virus induced Adult T-cell leukemia / lymphoma.

34. The substantially homogenous composition or pharmaceutical formulation according to claim 31, wherein said T-cell lymphoma comprises cutaneous T-cell lymphomas (CTCL).

35. The substantially homogenous composition or pharmaceutical formulation according to claim 34. wherein said CTCL comprises mycosis fungoides cutaneous T-cell lymphomas, Sezary syndrome cutaneous T-cell lymphomas, lymphomatoid papulosis cutaneous T-cell lymphomas, primary cutaneous anaplastic large cell lymphoma, granulomatous slack skin disease, pagetoid reticulosis cutaneous T-cell lymphomas, and / or subcutaneous panniculitis-like T-cell lymphoma subtypes.

36. The substantially homogenous composition or pharmaceutical formulation according to claim 31 to 35. wherein said ropeginterferon alfa-2b further comprises a pharmaceutically acceptable carrier, salt, a solvate or prodrug thereof, an adjuvant, and / or a diluent.

37. The substantially homogenous composition or pharmaceutical formulation according to claim 31, wherein said ropeginterferon alfa-2b, and / or pharmaceutical formulation thereof is administered subcutaneously to the subject or subject in need.

38. The substantially homogenous composition or pharmaceutical formulation according to any of claim 31 to 37, wherein each said mPEG includes between about 19 to about 23 KDa.

39. The substantially homogenous composition or pharmaceutical formulation according to any of claim 31 to 37, wherein said effective amount comprises a first dosage, a second dosage, a third dosage, and / or subsequent doses of ropeginterferon alfa-2b administered about every 1, 2, 3, 4, 5, 6, 7 or 8 weeks.

40. The substantially homogenous composition or pharmaceutical formulation according to any of claim 31 to 37, wherein said effective amount comprises between about 50 pg to about 540 pg of ropeginterferon alfa-2b.

41. The substantially homogenous composition or pharmaceutical formulation according to claim 40, wherein said second, third dosage or subsequent dosages is maintained at a constant level or is adjusted upward or downward during a treatment period.

42. The substantially homogenous composition or pharmaceutical formulation according to any of claim 31 to 37, wherein said use increase said subject or subject in need’s complete remission, partial response, stable disease, progressive disease; and / or overall survival rate.

43. A composition comprising ropeginterferon alfa-2b including the structure of formula I(Formula I) for use in treatment of T-cell lymphoma in a subject or subject in need.

44. The composition according to claim 43, wherein said ropeginterferon alfa-2b further comprises a pharmaceutical carrier.

45. The composition according to claim 43, wherein said T-cell lymphoma comprises cutaneous T-cell lymphomas (CTCL); peripheral T cell lymphoma non-specific type (PTCL- NOS); anaplastic large cell lymphoma (ALCL); angioimmunoblastic T-cell lymphoma (A1TL); extranodal natural killer / T-cell lymphoma; enteropathy-associated intestinal T-cell lymphoma (EATL); monomorphic epitheliotropic intestinal T cell lymphoma (MEITL); or mycosis fungoides (MF).

46. The composition according to claim 43, wherein said T-cell lymphoma does not comprise virus induced Adult T-cell leukemia / lymphoma.

47. The composition according to claim 46, wherein said T-cell lymphoma comprises cutaneous T-cell lymphomas (CTCL).

48. The composition according to claim 47, wherein said CTCL comprises mycosis fungoides cutaneous T-cell lymphomas, Sezary' syndrome cutaneous T-cell lymphomas, lymphomatoid papulosis cutaneous T-cell lymphomas, primary cutaneous anaplastic large cell lymphoma, granulomatous slack skin disease, pagetoid reticulosis cutaneous T-cell lymphomas, and / or subcutaneous panniculitis-like T-cell lymphoma subty pes.

49. The composition according to claim 43, wherein said use comprises providing to the subject or subject in need a first dosage including about 250 pg, a second dosage including between about 250 pg to 400 pg, and more than one additional dosage at a constant amount between about 350 pg to 540 pg of ropeginterferon alfa-2b.

50. The composition according to claim 49, wherein said constant amount comprises about51. The composition according to any of claim 43 to 50, wherein said use increase said subject or subject in need’s complete remission, partial response, stable disease, progressive disease; and / or overall survival rate.

52. The composition according to any of claim 43 to 51, wherein said use decrease said subject or subject in need’s AE rate or AE severity.

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