Treatment methods for alopecia areata and atopic dermatitis

Abstract

This specification provides a method for treating alopecia areata and / or atopic dermatitis, the method comprising administering an anti-OX40 antibody provided herein to an individual in need thereof. Provided herein is the use of the anti-OX40 antibody described herein for the treatment of alopecia areata and / or atopic dermatitis.

Description

[Technical Field]

[0001] Reference to electronically submitted sequence listings This application incorporates by reference an array listing of an XML file titled "9 007-003-01PCT.XML" which was created on 24 July 2023 and has a size of 32,687 bytes.

[0002] This invention relates to molecular biology, cell biology, and immunology. This specification provides a method useful for treating alopecia areata and atopic dermatitis using an anti-OX40 antibody. [Background technology]

[0003] Alopecia areata (AA) is a chronic, relapsing-remitting autoimmune disease characterized by non-scarring hair loss on the scalp, face, and / or body. AA significantly impacts patients' daily lives and often causes severe psychological distress, social isolation, anxiety, and depression. Current treatment options for AA are limited. These include topical, oral, and systemic medications. Topical treatments have limited efficacy and are not suitable for widespread or long-term use. Oral corticosteroids are also not suitable for widespread or chronic use. Oral Janus kinase (JAK) inhibitors baricitinib and ritrecitinib have recently been approved by the U.S. Food and Drug Administration (FDA) for severe and very severe AA, but their use in the chronic management of AA will likely be limited due to potential serious safety risks.

[0004] Atopic dermatitis (AD) is a common inflammatory skin disease characterized by sensitive, dry skin and localized or systemic eczematous lesions, usually accompanied by severe itching. Many patients experience co-occurring AA and AD. Currently, topical medications are the first-line pharmacological treatment for AD. Systemic therapy is necessary for patients with moderate to severe AD who do not respond adequately to topical medications or who experience side effects. Despite the availability of new targeted systemic therapies such as mAbs for IL-4 and IL-13, many patients still do not achieve optimal efficacy. Drug-specific safety concerns are another limiting factor.

[0005] Therefore, a significant unmet need remains for safe, effective, and novel targeted systemic therapies for the long-term treatment of AA and AD. The methods and compositions provided herein meet these needs and offer other related advantages. [Overview of the project]

[0006] This specification provides a method for treating alopecia areata (AA) in subjects requiring treatment for alopecia areata (AA). This specification also provides a method for treating atopic dermatitis (AD) in subjects requiring treatment for atopic dermatitis (AD). The method provided herein involves administering a therapeutically effective amount of an anti-OX40 antibody or an antigen-binding fragment to a subject, comprising (1) a light chain variable region (VL) comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively, and (2) a heavy chain variable region (VH) comprising VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 4, 5, and 6, respectively. In some embodiments, the anti-OX40 antibody or antigen-binding fragment is a chimeric antibody or antigen-binding fragment, a humanized antibody or antigen-binding fragment, or a human antibody or antigen-binding fragment. In some embodiments, the anti-OX40 antibody or antigen-binding fragment is a humanized antibody or antigen-binding fragment.

[0007] In some embodiments of the methods described herein, the anti-OX40 antibody or its antigen-binding fragment comprises VL and VH, where (1) VL has at least 85%, at least 90%, at least 95%, at least 98%, or 100% sequence identity with the amino acid sequence of SEQ ID NO: 7, and / or (2) VH has at least 85%, at least 90%, at least 95%, at least 98%, or 100% sequence identity with the amino acid sequence of SEQ ID NO: 8. In some embodiments, VL has the amino acid sequence of SEQ ID NO: 7, 9, or 10, and VH has the amino acid sequence of SEQ ID NO: 8, 11, or 12. In some embodiments, VL and VH have the amino acid sequences of SEQ ID NO: 7 and 8, respectively.

[0008] In some embodiments of the methods described herein, the anti-OX40 antibody or its antigen-binding fragment is selected from the group consisting of Fab, Fab', F(ab')2, Fv, scFv, and (scFv)2. In some embodiments of the methods described herein, the anti-OX40 antibody is an IgG1 antibody, an IgG2 antibody, an IgG3 antibody, or an IgG4 antibody.

[0009] In some embodiments of the methods described herein, the anti-OX40 antibody is a humanized IgG1 antibody. In some embodiments, the anti-OX40 antibody comprises a light chain constant region (CL) having at least 85% sequence identity with kappa CL (Cκ; SEQ ID NO: 13) or lambda CL (Cλ; SEQ ID NO: 14). In some embodiments, CL is Cκ (SEQ ID NO: 13). In some embodiments, the anti-OX40 antibody comprises the wild-type heavy chain constant region (CH) (SEQ ID NO: 16) of human IgG1, or a variant thereof with reduced binding to FcγR. In some embodiments, the anti-OX40 antibody comprises the CH region of human IgG1 having the N297A substitution. In some embodiments, the anti-OX40 antibody comprises a light chain having the amino acid sequence of SEQ ID NO: 19 and a heavy chain having the amino acid sequence of SEQ ID NO: 20.

[0010] This specification provides methods for treating alopecia areata in subjects requiring treatment for AA. In some embodiments, subjects have moderate or severe AA. In some embodiments, subjects have 50% or more of the scalp affected by hair loss, or a Saliva Severity Tool (SALT) score of at least 50. In some embodiments, subjects have diffuse alopecia areata, alopecia areata monolocularis, alopecia areata multilocularis, serpentine alopecia, alopecia areata barbae, alopecia areata totalis, or alopecia areata universalis. In some embodiments, subjects have been diagnosed with AA and have been experiencing hair loss for more than 6 months. In some embodiments, the methods provided herein are therapeutically effective in achieving at least a 30% reduction from the individual's baseline SALT score. In some embodiments, the methods provided herein are therapeutically effective in achieving a reduction in baseline SALT score in about 8, 12, 16, 20, 24, or 32 weeks. In some embodiments, the methods provided herein are therapeutically effective in achieving a reduction in baseline SALT score in about 16 weeks. In some embodiments, the methods described herein are therapeutically effective in inducing hair regrowth in at least 90% of the scalp of subjects suffering from AA (i.e., a SALT score of 10 or less) or inducing hair regrowth in at least 80% of the scalp of subjects suffering from AA (i.e., a SALT score of 20 or less).

[0011] This specification provides methods for treating Alzheimer's disease (AD) in subjects requiring treatment for AD. In some embodiments, subjects have moderate to severe AD. In some embodiments, subjects have a) an Eczema Area and Severity Index (EASI) score of at least 12, b) an Investigator General Assessment (IGA)-AD score of at least 3, and c) a Body Surface Area (BSA) of 10% or more. In some embodiments, subjects have an EASI score of at least 16. In some embodiments, subjects have been diagnosed with AD for at least 6 months. In some embodiments, the methods provided herein are therapeutically effective in achieving at least a 75% reduction from the individual's baseline EASI score, at least a 90% reduction from the individual's baseline EASI score, or at least a 4-point reduction in the DLQI score. In some embodiments, the methods provided herein are therapeutically effective in achieving a reduction in the baseline EASI score at approximately 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 ​​weeks, or 52 weeks from the start of treatment. In some embodiments, the methods provided herein are therapeutically effective in achieving a reduction in the baseline EASI score at approximately 12 weeks. In some embodiments, the methods provided herein are therapeutically effective in achieving an IGA-AD score of 0 or 1, or a reduction of at least 2 points from the baseline IGA-AD score.

[0012] In some embodiments, the anti-OX40 antibody is administered by intravenous infusion.

[0013] In some embodiments, the methods provided herein include administering approximately 1 mg to approximately 1200 mg of anti-OX40 antibody to a target. In some embodiments, the methods provided herein include administering approximately 300 mg of anti-OX40 antibody to a target. In some embodiments, the methods provided herein include administering approximately 600 mg of anti-OX40 antibody to a target.

[0014] In some embodiments, the methods provided herein include administering one or more doses of anti-OX40 antibody. In some embodiments, the anti-OX40 antibody is administered once every two weeks. In some embodiments, the methods provided herein include administering three doses of anti-OX40 antibody, each administered two weeks apart.

[0015] In some embodiments, the methods provided herein include achieving results that do not result in any serious adverse events related to treatment.

[0016] In some embodiments provided herein, the anti-OX40 antibody is administered in combination with a second therapeutic agent or therapy. [Modes for carrying out the invention]

[0017] This disclosure provides a method for treating alopecia areata and atopic dermatitis (AD) in subjects requiring treatment of alopecia areata and atopic dermatitis (AD), the method comprising administering a therapeutically effective dose of the anti-OX40 antibody disclosed herein to the subject.

[0018] Alopecia areata (AA) is a chronic, relapsing-remitting autoimmune disease characterized by non-scarring hair loss on the scalp, face, and / or body. It can affect children and adults of any age, race, and sex, but is more common in women and non-Caucasians, particularly Asians. Approximately 2% of the general population may experience AA at some point in their lives. AA typically presents as well-defined patches of hair loss, most commonly on the scalp, but can also occur on the beard, eyebrows, eyelashes, and nails. In severe cases, AA can affect the entire scalp (alopecia totalis, AT) or the entire body (alopecia universalis, AU). AA, including AT and AU, in which more than 50% of the hair on the scalp is lost, is considered an advanced form. AA is associated with other inflammatory and autoimmune diseases. AA significantly impacts patients' daily lives and often leads to severe psychological distress, social isolation, anxiety, and depression.

[0019] The pathogenesis of AA involves a complex interplay of genetics, environmental factors, and adaptive immune responses to unknown antigens. It has been proposed that the disruption of hair follicle immune privilege can activate and infiltrate immune cells, primarily CD4+ and CD8+ T cells, as well as natural killer cells, mast cells, and dendritic cells, to attack the hair follicles. Hair follicle cells then release more cytokines and chemokines, which further attract T cells and other immune cells, forming a positive feedback loop that shortens and distorts the hair cycle. Activation of T cell subsets, including T helper (Th) type 1 (Th1) and Th2 cells, in AA patients is associated with disease severity or chronicity.

[0020] Atopic dermatitis (AD) is a common inflammatory skin disease characterized by sensitive, dry skin and localized or systemic eczematous lesions, usually accompanied by severe itching. AD is one of the most common diseases worldwide, affecting 4-7% of adults and 15-25% of children, and significantly impacting patients' quality of life. AD and AA coexist in many patients. The causes of AD include defects in the epidermal barrier and dysregulation of the innate and adaptive immune systems, resulting in a complex inflammatory response involving cytokines and chemokines. T cells (including subsets of T helper [Th] cells such as Th2, Th1, and Th17) are established as the etiology of atopic dermatitis.

[0021] OX40 (CD134) is a member of the tumor necrosis factor receptor (TNFR) family and is expressed on both activated CD4+ and CD8+ T cells, neutrophils, and natural killer cells. Unlike other constitutive T cell co-stimulatory receptors, OX40 is a secondary co-stimulatory immune checkpoint molecule that is not expressed on naive T cells and can be expressed after T cells are activated. OX40L (i.e., OX40 ligand) is also a member of the TNFR superfamily and is expressed on activated antigen-presenting cells such as dendritic cells, activated B cells, and macrophages. When OX40 ligand binds to the OX40 receptor on T cells, T cell death is prevented and, as a result, cytokine production increases. Therefore, OX40-OX40L signaling is thought to promote T cell proliferation and survival, enhance the clonal expansion and function of effector T cells and memory T cells, and mediate the development of various inflammatory and autoimmune diseases.

[0022] The monoclonal anti-OX40 antibodies or antigen-binding fragments disclosed herein can block the binding of OX40 ligand to OX40, prevent the trimerization of OX40, and thereby inhibit the activation of T cells induced by OX40 activation and the associated inflammatory response.

[0023] In describing the present disclosure in detail, it should be understood that the present disclosure is not limited to the specific embodiments described herein, and it should also be understood that the terms used herein are for the purpose of describing specific embodiments and are not intended to be limiting.

[0024] 1.1 Definitions Unless otherwise defined herein, scientific and technical terms used in this disclosure shall have the meanings commonly understood by those skilled in the art. Further, unless the context requires otherwise, singular terms shall include plural objects and plural terms shall include singular objects. In general, the nomenclature and techniques used in connection with cell and tissue culture, molecular biology, immunology, microbiology, genetics, and protein and nucleic acid chemistry and hybridization described herein are well known and commonly used in the art.

[0025] The term "a" or "an" entity refers to one or more of that entity. For example, "an antibody" is understood to represent one or more antibodies.

[0026] As used herein, the term "and / or" is to be construed as specifically disclosed for each of the two features or components described, whether or not the other is present. Thus, the term "and / or" as used in phrases such as "A and / or B" herein is intended to include "A and B", "A or B", "A" (alone), and "B" (alone). Similarly, the term "and / or" as used in phrases such as "A, B, and / or C" is intended to encompass each of the following aspects: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0027] As used herein, the term “approximately” is used to indicate that a value includes inherent variations in error in the apparatus or method used to determine this value, or variations that exist between the objects being tested. The term “approximately” encompasses the exact numbers listed. In some embodiments, “approximately” means within plus or minus 10% of a given value or range. In some embodiments, “approximately” means that the variation is ±5%, ±4%, ±3%, ±2%, ±1%, ±0.5%, ±0.2%, or ±0.1% of the value indicated by “approximately”. In some embodiments, “approximately” means that the variation is ±1%, ±0.5%, ±0.2%, or ±0.1% of the value indicated by “approximately”.

[0028] The terms “polypeptide,” “peptide,” “protein,” and their grammatical synonyms, as used interchangeably herein, refer to polymers of amino acids of any length, which may be linear or branched. They may contain unnatural or modified amino acids, or may be interrupted by non-amino acids. Polypeptides, peptides, or proteins may also be modified, for example, by the formation of disulfide bonds, glycosylation, lipidization, acetylation, phosphorylation, or any other operation or modification.

[0029] In this specification, the term “variant” as used in reference to a protein or polypeptide having a particular sequence characteristic (“reference protein” or “reference polypeptide”) means a different protein or polypeptide having one or more amino acid substitutions, deletions, and / or additions (e.g., about 1 to about 30, about 1 to about 25, about 1 to about 20, about 1 to about 15, about 1 to about 10, or about 1 to about 5) compared to the reference protein or reference polypeptide. Amino acid sequence changes may be amino acid substitutions. Amino acid sequence changes may be conservative amino acid substitutions. Amino acid sequence changes may be amino acid deletions. A variant may be a fragment of the reference protein or polypeptide. Functional variants of a protein or polypeptide maintain the basic structural and functional properties of the reference protein or polypeptide.

[0030] The terms “polynucleotide,” “nucleic acid,” and their grammatical synonyms, as used interchangeably herein, refer to polymers or oligomers of nucleotides of any length. Nucleotides can be deoxyribonucleotides, ribonucleotides, modified nucleotides or bases (such as methylated, hydroxymethylated, or glycosylated), non-natural nucleotides, non-nucleotide components exhibiting similar structure and / or function to natural nucleotides (i.e., “nucleotide analogs”), and / or any substrate that can be incorporated into a polymer by DNA or RNA polymerase. Nucleic acids or polynucleotides may be heterogeneous or homogeneous in composition and can be isolated from naturally occurring sources or produced artificially or synthetically. Furthermore, nucleic acids can be DNA or RNA, or mixtures thereof, and can exist permanently or transiently in single-stranded or double-stranded (including homo-double-stranded, hetero-double-stranded, and hybrid states). Nucleic acid structures include, for example, DNA / RNA helices, peptide nucleic acids (PNAs), morpholino nucleic acids (see, e.g., Braasch and Corey, Biochemistry, 4(14):4503-4510 (2002) and U.S. Patent Nos. 5,034,506), locked nucleic acids (LNAs; see Wahlestedt et al., Proc. Natl. Acad. Sci. USA, 97:5633-5638 (2000)), cyclohexenyl nucleic acids (see Wang, Am. Chem. Soc., 122:8595-8602 (2000)), and / or ribozymes.

[0031] As used herein in the context of two or more polynucleotides or polypeptides, the terms “identical” or “identity” percentage, and their grammatical synonyms, refer to two or more sequences or subsequences that are identical when compared and aligned (with gaps introduced where necessary) to obtain the greatest possible correspondence, without considering any conserved amino acid substitutions in part of the sequence identity, or two or more sequences or subsequences that have identical nucleotides or amino acid residues in a particular percentage. The identity percentage can be measured using sequence comparison software or algorithms, or by visual inspection. Various algorithms and software that can be used to obtain alignment of amino acid sequences or nucleotide sequences are well known in the art. These include, but are not limited to, BLAST, ALIGN, Megalign, BestFit, GCG Wisconsin Package, and their variations. In some embodiments, when the maximum correspondence is compared and aligned using a sequence comparison algorithm or by visual inspection, two polynucleotides or polypeptides provided herein are considered substantially identical to mean that they have at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, and in some embodiments, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% nucleotide or amino acid residue identity. In some embodiments, the identity exists over a region of amino acid sequence that is at least about 10 residues, at least about 20 residues, at least about 40–60 residues, at least about 60–80 residues, or any integer value in between. In some embodiments, the identity exists over a region longer than 60–80 residues, for example, at least about 80–100 residues, and in some embodiments, the sequences are substantially identical over the entire length of the sequences being compared, e.g., the coding region of a target protein or antibody.In some embodiments, identity exists over a region of the nucleotide sequence that is at least about 10 bases, at least about 20 bases, at least about 40–60 bases, at least about 60–80 bases, or any integer value in between. In some embodiments, identity exists over a region longer than 60–80 bases, for example, at least about 80–1000 bases or more, and in some embodiments, the sequence is substantially identical over the entire length of the sequence being compared, for example, the nucleotide sequence encoding the protein of interest.

[0032] "Isolated" polypeptides, peptides, proteins, antibodies, polynucleotides, vectors, cells, or compositions are polypeptides, peptides, proteins, antibodies, polynucleotides, vectors, cells, or compositions in a form not found in nature. Isolated polypeptides, peptides, proteins, antibodies, polynucleotides, vectors, cells, or compositions include those purified to such an extent that they are no longer found in nature. In some embodiments, isolated polypeptides, peptides, proteins, antibodies, polynucleotides, vectors, cells, or compositions are substantially pure.

[0033] The terms "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" refer to a material suitable for administering a drug to a subject together with an active agent without causing undesirable biological effects or interacting in a harmful manner with any other component of the pharmaceutical composition.

[0034] As used herein, the term “subject” refers to any animal (e.g., mammal) that is a recipient of a particular treatment, including but not limited to humans, non-human primates, dogs, cats, rodents, etc. A subject may be human. A subject may have a particular disease or condition.

[0035] Scope: Throughout this disclosure, various aspects of the invention may be presented in the form of a range. The range form is for convenience and brevity only and should not be interpreted as a definitive limitation on the scope of the invention. Accordingly, a range description is considered to specifically disclose not only the individual numbers within that range, but also all possible subranges. For example, a range description such as 1 to 6 is considered to specifically disclose subranges such as 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 6, 3 to 6, and the individual numbers within that range such as 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the breadth of the range.

[0036] Exemplary genes and polypeptides are described herein with reference to GenBank numbers, GI numbers, and / or sequence numbers. Those skilled in the art will understand that homologous sequences can be readily identified by referring to sequence sources, including but not limited to GenBank (ncbi.nlm.nih.gov / genbank / ) and EMBL (embl.org / ).

[0037] 1.2 Anti-OX40 antibody and antigen-binding fragment This specification provides a method for treating alopecia areata (AA) in subjects requiring treatment of the condition, comprising administering a therapeutically effective amount of an anti-OX40 antibody or antigen-binding fragment disclosed herein to the subject. This specification also provides a method for treating atopic dermatitis (AD) in subjects requiring treatment of the condition, comprising administering a therapeutically effective amount of an anti-OX40 antibody or antigen-binding fragment disclosed herein to the subject. The anti-OX40 antibody used in the methods described herein may be any anti-OX40 antibody disclosed in whole in WO2021209019A1, which is incorporated herein by reference.

[0038] As used herein, the term “antibody” and its grammatical synonyms refer to an immunoglobulin molecule that recognizes a target, e.g., a protein, polypeptide, peptide, carbohydrate, polynucleotide, lipid, or any combination thereof, and specifically binds to it via at least one antigen-binding site, which is usually located within the variable region of the immunoglobulin molecule. As used herein, “specifically binds” means that a polypeptide or molecule interacts with an epitope, protein, or target molecule more frequently, faster, for a longer period, with higher affinity, or in any combination thereof, compared to alternatives, including relevant and unrelated proteins. The binding site (e.g., antibody) that specifically binds to a target molecule (e.g., antigen) can be identified, for example, by immunoassays, ELISA, biolayer interference ("BLI"), SPR (e.g., Biacore), or other techniques known to those skilled in the art. Typically, a specific reaction is at least twice the background signal or noise, and may be more than ten times. For further consideration of antibody specificity, see, for example, Paul, ed., 1989. Fundamental Immunology Second Edition See pages 332-336 of Raven Press, New York. In some embodiments, "specifically binding" means, for example, that the binding site has a K content of approximately 0.1 mM or less on the molecular target. D This means that the polypeptide or molecule binds with K at a concentration of about 10 μM or less or about 1 μM or less. In some embodiments, "specifically binds" means that the polypeptide or molecule binds with K at a concentration of about 10 μM or less. D This means binding to the target. In some embodiments, "specifically binding" means that the polypeptide or molecule has a K content of about 0.1 μM or less, about 0.01 μM or less, or about 1 nM or less. D This means that it binds to the target.

[0039] As used herein, the term "antibody" includes intact polyclonal antibodies, intact monoclonal antibodies, single domain antibodies (sdAbs, e.g., camelid antibodies, alpaca antibodies), single-chain Fv (scFv) antibodies, heavy chain antibodies (HCAb), light chain antibodies (LCAb), multispecific antibodies, bispecific antibodies, monospecific antibodies, monovalent antibodies, and any other modified immunoglobulin molecule that contains an antigen-binding site as long as the antibody exhibits the desired biological activity (e.g., dual variable domain immunoglobulin molecules). Antibodies include, but are not limited to, mouse antibodies, camelid antibodies, chimeric antibodies, humanized antibodies, and human antibodies. Antibodies can be any of the five major immunoglobulin classes: IgA, IgD, IgE, IgG, and IgM, or their subclasses (isotypes) (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2), based on the identity of the heavy chain constant domains, designated alpha, delta, epsilon, gamma, and mu, respectively. As understood in the art, the term "monoclonal antibody" refers to a population of antibodies that contains a homogeneous or substantially homogeneous single antibody.

[0040] Unless explicitly indicated otherwise, the term "antibody" as used herein includes "antigen-binding fragments" of intact antibodies. The term "antigen-binding fragment" as used herein refers to a portion or fragment of an intact antibody that retains the ability to specifically bind to an antigen or is the variable antigen-determining region of an intact antibody. Examples of antigen-binding fragments include, but are not limited to, (i) a Fab fragment that refers to a monovalent fragment composed of V L , V H , C L , and C H1 domains, (ii) a Fab′ fragment that refers to a Fab fragment that includes a portion of the hinge region, (iii) an F(ab′)2 fragment that refers to a bivalent fragment that includes two Fab fragments linked by a disulfide bond in the hinge region, (iv) an Fd fragment that consists of V H and C H1 domains, (v) a single arm of an antibody consisting of V L and V H(vi) Fv fragment consisting of domains, (vi) dAb fragment containing a single variable domain (Ward et al., Nature 341:544-546 (1989); PCT publication WO90 / 05144), (vii) isolated CDR, (viii) V linked directly or via peptide chain L Domain and V H This includes single-chain Fv fragments, which refer to monovalent fragments formed from domains (Huston JS et al., Proc Natl Acad Sci USA, 85:5879 (1988)). Examples of antigen-binding fragments include, but are not limited to, heavy-chain antibodies (HCAb), light-chain antibodies (LCAb), disulfide-linked scFv (dsscFv), diabodies, tribodies, tetrabodies, minibodies, dual-variable-domain antibodies (DVD), single-variable-domain antibodies (sdAb, e.g., camel antibody, alpaca antibody), and single-variable-domain (VHH) antibodies of heavy-chain antibodies, as well as bispecific or multispecific antibodies formed from antibody fragments.

[0041] As used herein, the term "chimeric antibody" refers to a form of antibody in which a portion of the heavy chain and / or light chain is identical or identical to the corresponding sequence of an antibody derived from a particular species or belonging to a particular antibody class or subclass, and the remaining chain is identical or identical to the corresponding sequence of an antibody and its fragment derived from another species or belonging to another antibody class or subclass. For example, a human-mouse chimeric antibody may have mouse heavy chain and light chain variable regions and human heavy chain and light chain constant regions.

[0042] As used herein, the term “humanized antibody” refers to a form of non-human (e.g., mouse) antibody that is a specific immunoglobulin chain, chimeric immunoglobulin, or fragment thereof, containing minimal non-human sequences. Typically, a humanized antibody is a human immunoglobulin. In some cases, Fv framework region residues of a human immunoglobulin are replaced by corresponding residues in an antibody derived from a non-human species. In some cases, CDR residues are replaced by CDR residues of a non-human species (e.g., mouse, rat, hamster, camel) that have the desired specificity, affinity, and / or binding ability. Humanized antibodies can be further modified by substitution of further residues within the Fv framework region and / or replaced non-human residues to improve and optimize the antibody's specificity, affinity, and / or binding ability. As used herein, the term “human antibody” refers to an antibody produced by a human, or an antibody having an amino acid sequence corresponding to a human-produced antibody made using any technique known in the art.

[0043] When used in relation to antibodies, the term "heavy chain" refers to a polypeptide chain of approximately 50–70 kDa, with an amino-terminal portion containing a variable region of approximately 120–130 or more amino acids, and a carboxy-terminal portion containing a constant region. The constant region can be one of five distinct types, designated alpha (α), delta (δ), epsilon (ε), gamma (γ), and mu (μ), based on the amino acid sequence of the heavy chain constant region. Individual heavy chains differ in size, with α, δ, and γ containing approximately 450 amino acids, and μ and ε containing approximately 550 amino acids. When combined with a light chain, these different types of heavy chains produce five well-known classes of antibodies, IgA, IgD, IgE, IgG, and IgM, including the four subclasses of IgG, namely IgG1, IgG2, IgG3, and IgG4. The heavy chain can be a human heavy chain.

[0044] When used in relation to antibodies, the term "light chain" refers to a polypeptide chain of approximately 25 kDa, with an amino-terminal region containing a variable region of approximately 100 to 110 or more amino acids, and a carboxy-terminal region containing a constant region. The approximate length of a light chain is 211 to 217 amino acids. Based on the amino acid sequence of the constant domain, there are two distinct types, referred to as lambda (λ) and kappa (κ). Light chain amino acid sequences are well known in the art. The light chain may be a human light chain.

[0045] The term "variable domain" or "variable region" generally refers to a portion of the light or heavy chain of an antibody, located at the amino terminus of the light or heavy chain, with a length of approximately 120 to 130 amino acids in the heavy chain and approximately 100 to 110 amino acids in the light chain, and used for the binding and specificity of each particular antibody to its specific antigen. Variable domains differ significantly in sequence between different antibodies. While sequence variability is concentrated in the CDR, less variable portions of the variable domain are called framework regions (FRs). The CDRs of the light and heavy chains are primarily responsible for antibody-antigen interaction. The amino acid position numbers used herein follow the EU index described in Kabat et al. (1991) Sequences of proteins of immunological interest. (USD Department of Health and Human Services, Washington, DC)5 th The variable region may be the human variable region.

[0046] A CDR refers to one of three hypervariable regions (H1, H2, or H3) within the non-framework region of an immunoglobulin (Ig or antibody) VH β-sheet framework, or one of three hypervariable regions (L1, L2, or L3) within the non-framework region of an antibody VL β-sheet framework. Therefore, a CDR is a variable region sequence scattered within the framework region sequence. CDR regions are well known to those skilled in the art and are defined by various methods / systems. These systems and / or definitions have been developed and refined over many years and include Kabat, Chothia, IMGT, AbM, and Contact. For example, Kabat defines the most hypervariable region within the antibody variable (V) domain (Kabat et al, J. Biol. Chem. 252:6609-6616 (1977); Kabat, Adv. Prot. Chem. 32:1-75 (1978)). Chothia's definition is based on the location of structural loop regions, defining CDR region sequences as residues that are not part of a conserved β-sheet framework and are therefore capable of adapting to different conformations (Chothia and Lesk, J.Mol.Biol.196:901-917(1987)). Both terms are widely recognized in the art. Furthermore, the IMGT system is based on sequence variability and the structural location of the variable region. The AbM definition is a compromise between Kabat and Chothia. Contact's definition is based on an analysis of the crystal structure of available antibodies. Software programs (e.g., abYsis) are available and are known to those skilled in the art for antibody sequence analysis and CDR determination. The location of the CDR within a standard antibody variable domain has been determined by comparing numerous structures (Al-Lazikani et al, J.Mol.Biol.273:927-948 (1997), Morea et al, Methods 20:267-279 (2000)).Since the number of residues in the hypervariable region varies with different antibodies, additional residues at standard positions are conventionally numbered a, b, c, etc., next to the residue numbers in the standard variable domain numbering scheme (Al-Lazikani et al., (1997) cited above). Such nomenclature is also well known to those skilled in the art.

[0047] For example, the following table shows CDRs defined according to either the Kabat (highly variable) or Chothia (structured) designation. [Table 1]

[0048] One or more CDRs can also be incorporated into a molecule via covalent or non-covalent bonds to form an immunoadhesin. The immunoadhesin can incorporate the CDR(s) as part of a larger polypeptide chain, covalently to another polypeptide chain, or non-covalently. The CDRs allow the immunoadhesin to bind to a specific antigen of interest. The CDR region can be analyzed, for example, on the Abysis website (http: / / abysis.org / ).

[0049] In some embodiments, the anti-OX40 antibody or antigen-binding fragment used in the methods disclosed herein is an antagonist antibody having activity that inhibits OX40-mediated signaling. In some embodiments, the anti-OX40 antibody or antigen-binding fragment used in the methods disclosed herein is a monoclonal antibody or antigen-binding fragment. Monoclonal antibodies can be prepared by any method well known to those skilled in the art. In some embodiments, monoclonal antibodies are modified using recombinant DNA technology to produce another antibody. In some embodiments, the constant domains of the light and heavy chains of a mouse monoclonal antibody are replaced with the constant region of a human antibody to produce a chimeric antibody. In some embodiments, the constant region is cleaved or removed to produce a desired antibody fragment of the monoclonal antibody. In some embodiments, site-directed or high-density mutagenesis of the variable region(s) is used to optimize the specificity and / or affinity of the monoclonal antibody.

[0050] In some embodiments, the anti-OX40 antibody or antigen-binding fragment provided herein is isolated. In some embodiments, the anti-OX40 antibody or antigen-binding fragment provided herein is substantially pure.

[0051] In some embodiments, anti-OX40 antibodies are provided herein. In some embodiments, the antibody is an IgA, IgD, IgE, IgG, or IgM antibody. In some embodiments, the antibody is an IgA antibody. In some embodiments, the antibody is an IgD antibody. In some embodiments, the antibody is an IgE antibody. In some embodiments, the antibody is an IgG antibody. In some embodiments, the antibody is an IgM antibody. In some embodiments, the antibody provided herein may be an IgG1 antibody, an IgG2 antibody, an IgG3 antibody, or an IgG4 antibody. In some embodiments, the antibody is an IgG1 antibody. In some embodiments, the antibody is an IgG2 antibody. In some embodiments, the antibody is an IgG3 antibody. In some embodiments, the antibody is an IgG4 antibody.

[0052] In some embodiments, antigen-binding fragments of anti-OX40 antibodies are provided herein. In some embodiments, the antigen-binding fragments provided herein may be single-domain antibodies (sdAb), heavy-chain antibodies (HCAb), Fab, Fab', F(ab')2, Fv, single-chain variable fragments (scFv), or (scFv)2. In some embodiments, the antigen-binding fragment of the anti-OX40 antibody is a single-domain antibody (sdAb). In some embodiments, the antigen-binding fragment of the anti-OX40 antibody is a heavy-chain antibody (HCAb). In some embodiments, the antigen-binding fragment of the anti-OX40 antibody is Fab. In some embodiments, the antigen-binding fragment of the anti-OX40 antibody is Fab'. In some embodiments, the antigen-binding fragment of the anti-OX40 antibody is F(ab')2. In some embodiments, the antigen-binding fragment of the anti-OX40 antibody is Fv. In some embodiments, the antigen-binding fragment of the anti-OX40 antibody is scFv. In some embodiments, the antigen-binding fragment of the anti-OX40 antibody is a disulfide-linked scFv[(scFv)2]. In some embodiments, the antigen-binding fragment of the anti-OX40 antibody is a diabody (dAb).

[0053] In some embodiments, the anti-OX40 antibody or antigen-binding fragment provided herein includes a recombinant antibody or antigen-binding fragment. In some embodiments, the anti-OX40 antibody or antigen-binding fragment provided herein includes a monoclonal antibody or antigen-binding fragment. In some embodiments, the anti-OX40 antibody or antigen-binding fragment provided herein includes a polyclonal antibody or antigen-binding fragment. In some embodiments, the anti-OX40 antibody or antigen-binding fragment provided herein includes a camelid (e.g., camel, dromedary, and llama) antibody or antigen-binding fragment. In some embodiments, the anti-OX40 antibody or antigen-binding fragment provided herein includes a chimeric antibody or antigen-binding fragment. In some embodiments, the anti-OX40 antibody or antigen-binding fragment provided herein includes a humanized antibody or antigen-binding fragment. In some embodiments, the anti-OX40 antibody or antigen-binding fragment provided herein includes a human antibody or antigen-binding fragment. In some embodiments, a humanized anti-OX40 IgG1 antibody is provided herein.

[0054] In some embodiments, this specification provides anti-OX40 antibodies having the sequence features described below. The specific CDR sequences defined herein are generally based on Kabat's definitions. However, any general reference to heavy chain CDRs or multiple CDRs and / or light chain CDRs or multiple CDRs in a particular antibody is understood to encompass all CDR definitions known to those skilled in the art.

[0055] In some embodiments, the anti-OX40 antibody or antigen-binding fragment provided herein comprises one, two, three, four, five, and / or six CDRs of any one of the antibodies described herein. In some embodiments, the anti-OX40 antibody or antigen-binding fragment provided herein comprises a light chain variable region (VL) containing one, two, and / or three light chain CDRs (VL CDRs) from Table 1. In some embodiments, the anti-OX40 antibody or antigen-binding fragment provided herein comprises a heavy chain variable region (VH) containing one, two, and / or three heavy chain CDRs (VH CDRs) from Table 1. In some embodiments, the anti-OX40 antibody or antigen-binding fragment provided herein comprises one, two, and / or three VL CDRs and one, two, and / or three VH CDRs. [Table 2]

[0056] In some embodiments, this specification provides antibodies or antigen-binding fragments that specifically bind to OX40, comprising (a) VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively, or variants thereof having up to about 3, about 5, about 8, about 10, about 12, or about 15 amino acid substitutions, additions, and / or deletions in the VL CDR, or / or (b) VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 4, 5, and 6, respectively, or variants thereof having up to about 3, about 5, about 8, about 10, about 12, or about 15 amino acid substitutions, additions, and / or deletions in the VH CDR. [Table 3]

[0057] In some embodiments, this specification provides an antibody or antigen-binding fragment that specifically binds to OX40, comprising VL having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 7. In some embodiments, this specification provides an antibody or antigen-binding fragment that specifically binds to OX40, comprising VH having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 8.

[0058] In some embodiments, the anti-OX40 antibody described herein includes a VL having an amino acid sequence selected from the group consisting of SEQ ID NO: 7, SEQ ID NO: 9, and SEQ ID NO: 10. In some embodiments, the anti-OX40 antibody described herein includes a VH having an amino acid sequence selected from the group consisting of SEQ ID NO: 8, SEQ ID NO: 11, and SEQ ID NO: 12. In some embodiments, the anti-OX40 antibody described herein includes a VL having the amino acid sequence of SEQ ID NO: 7. In some embodiments, the anti-OX40 antibody described herein includes a VL having the amino acid sequence of SEQ ID NO: 9. In some embodiments, the anti-OX40 antibody described herein includes a VL having the amino acid sequence of SEQ ID NO: 10. In some embodiments, the anti-OX40 antibody described herein includes a VH having the amino acid sequence of SEQ ID NO: 8. In some embodiments, the anti-OX40 antibody described herein includes a VH having the amino acid sequence of SEQ ID NO: 11. In some embodiments, the anti-OX40 antibody described herein includes a VH having the amino acid sequence of SEQ ID NO: 12. In some embodiments, the anti-OX40 antibody described herein includes a VL and a VH having the amino acid sequences of SEQ ID NO: 7 and 8, respectively. In some embodiments, the anti-OX40 antibody described herein comprises VL and VH having the amino acid sequences of SEQ ID NOs. 7 and 11, respectively. In some embodiments, the anti-OX40 antibody described herein comprises VL and VH having the amino acid sequences of SEQ ID NOs. 7 and 12, respectively. In some embodiments, the anti-OX40 antibody described herein comprises VL and VH having the amino acid sequences of SEQ ID NOs. 9 and 8, respectively. In some embodiments, the anti-OX40 antibody described herein comprises VL and VH having the amino acid sequences of SEQ ID NOs. 9 and 11, respectively. In some embodiments, the anti-OX40 antibody described herein comprises VL and VH having the amino acid sequences of SEQ ID NOs. 9 and 12, respectively. In some embodiments, the anti-OX40 antibody described herein comprises VL and VH having the amino acid sequences of SEQ ID NOs. 10 and 8, respectively. In some embodiments, the anti-OX40 antibody described herein comprises VL and VH having the amino acid sequences of SEQ ID NOs. 10 and 11, respectively.In some embodiments, the anti-OX40 antibodies described herein include VL and VH having the amino acid sequences of SEQ ID NOs: 10 and 12, respectively.

[0059] In some embodiments, the anti-OX40 antibody provided herein is an IgA, IgD, IgE, IgG, or IgM antibody. In some embodiments, the antibody is an IgA antibody. In some embodiments, the antibody is an IgD antibody. In some embodiments, the antibody is an IgE antibody. In some embodiments, the antibody is an IgG antibody. In some embodiments, the antibody is an IgM antibody. In some embodiments, the antibody provided herein may be an IgG1 antibody, an IgG2 antibody, an IgG3 antibody, or an IgG4 antibody. In some embodiments, the antibody is an IgG1 antibody. In some embodiments, the antibody is an IgG2 antibody. In some embodiments, the antibody is an IgG3 antibody. In some embodiments, the antibody is an IgG4 antibody.

[0060] In some embodiments, the anti-OX40 antibody provided herein comprises a light chain and a heavy chain. The light chain may comprise a light chain constant domain (CL) and a light chain variable domain (VL). The heavy chain may comprise a heavy chain variable domain (VH) and a heavy chain constant domain (CH). VL / VH can be any of the VL / VH disclosed herein. In some embodiments, the light chain constant region (CL) has at least 85%, at least 90%, at least 95%, or at least 99% sequence identity with kappa CL (Cκ, SEQ ID NO: 13). In some embodiments, the light chain constant region (CL) is kappa CL (Cκ, SEQ ID NO: 13). In some embodiments, the light chain constant region (CL) has at least 85%, at least 90%, at least 95%, or at least 99% sequence identity with lambda CL (Cλ, SEQ ID NO: 14). In some embodiments, the light chain constant region (CL) is lambda CL (Cλ, SEQ ID NO: 14).

[0061] In some embodiments, the heavy chain may include a heavy chain constant domain (CH) derived from human IgA, IgD, IgE, IgM, or IgG. In some embodiments, the heavy chain may include a heavy chain constant domain (CH) having at least 85%, at least 90%, at least 95%, or at least 99% sequence identity with the CH of human IgG1 (e.g., SEQ ID NO: 15). In some embodiments, the heavy chain may include a heavy chain CH having at least 85%, at least 90%, at least 95%, or at least 99% sequence identity with the CH of human IgG2 (e.g., SEQ ID NO: 16). In some embodiments, the heavy chain may include a heavy chain CH having at least 85%, at least 90%, at least 95%, or at least 99% sequence identity with the CH of human IgG3 (e.g., SEQ ID NO: 17). In some embodiments, the heavy chain may include a heavy chain CH having at least 85%, at least 90%, at least 95%, or at least 99% sequence identity with the CH of human IgG4 (e.g., SEQ ID NO: 18). In some embodiments, the heavy chain may include a heavy chain constant domain (CH) derived from human IgG1 (e.g., SEQ ID NO: 15). In some embodiments, the heavy chain may include a heavy chain constant domain (CH) derived from human IgG2 (e.g., SEQ ID NO: 16). In some embodiments, the heavy chain may include a heavy chain constant domain (CH) derived from human IgG3 (e.g., SEQ ID NO: 17). In some embodiments, the heavy chain may include a heavy chain constant domain (CH) derived from human IgG4 (e.g., SEQ ID NO: 18). Explicitly considered herein are any combination of the VL / VH pairs disclosed herein and CL / CH pairs disclosed herein or known in the Art that specifically bind to OX40 (e.g., human OX40). [Table 4] [Table 5]

[0062] This disclosure further envisions additional variants and equivalents that are substantially homologous to the antibodies described herein. In some embodiments, it is desirable to improve the binding affinity of the antibody. In some embodiments, it is desirable to modulate the biological properties of the antibody, including but not limited to specificity, thermal stability, expression level, effector function(s), glycosylation, immunogenicity, and / or solubility. Those skilled in the art will understand that changes in amino acids may alter the post-translational processes of the antibody, such as changing the number or position of glycosylation sites or altering membrane anchoring properties.

[0063] Mutations can be substitutions, deletions, or insertions of one or more nucleotides encoding an antibody or polypeptide that result in a change in the amino acid sequence compared to the native antibody or polypeptide sequence. In some embodiments, amino acid substitutions are the result of a single amino acid substitution with another amino acid having similar structural and / or chemical properties, e.g., a substitution of leucine with serine (e.g., a conservative amino acid substitution). Insertions or deletions may range from about 1 to 5 amino acids. In some embodiments, substitutions, deletions, or insertions may include fewer than 25, 20, 15, 10, 5, 4, 3, or 2 amino acid substitutions relative to the parent molecule. In some embodiments, biologically useful and / or relevant amino acid sequence mutations may be identified by systematically inserting, deleting, or substituting the sequence and examining the activity of the resulting variant protein in comparison to the parent protein. In some embodiments, the variant includes substitutions, additions, and / or deletions of 1 to 5 amino acids in the parent antibody or antigen-binding fragment. In some embodiments, the variant includes substitutions, additions, and / or deletions of 1 to 3 amino acids in the parent antibody or antigen-binding fragment. In some embodiments, the amino acid substitution(s) are located within the CDR of the antibody or antigen-binding fragment. In some embodiments, the amino acid substitution(s) are not located within the CDR of the antibody or antigen-binding fragment. In some embodiments, the amino acid substitution(s) are located within the framework region of the antibody or antigen-binding fragment. In some embodiments, the amino acid substitutions, additions, and / or deletions are conservative amino acid substitutions.

[0064] It is known in the art that the constant region(s) of an antibody mediates several effector functions, and these effector functions can vary depending on the antibody isotype. For example, the binding of the complement C1 component to the Fc region of an IgG or IgM antibody (binding to an antigen) activates the complement system. Complement activation is important for opsonization and lysis of cellular pathogens. Complement activation can also stimulate inflammatory responses and may be involved in autoimmune hypersensitivity. Furthermore, the Fc region of an antibody can bind to cells expressing Fc receptors (FcRs). Binding of antibodies to Fc receptors on the cell surface triggers several important and diverse biological responses, including engulfment and destruction of antibody-coated particles, clearance of immune complexes, lysis of antibody-coated target cells by killer cells (known as antibody-dependent cell-mediated cytotoxicity or ADCC), release of inflammatory mediators, placental cross-section, and regulation of immunoglobulin production. In some embodiments, at least one constant region of an anti-OX40 antibody is modified or deleted. In some embodiments, the antibody includes modifications to one or more of the three heavy chain constant regions (CH1, CH2, or CH3) and / or to the light chain constant region (CL). In some embodiments, the modification of the constant region reduces or removes the ADCC and / or CDC of the antibody. In some embodiments, the antibody does not have one or more effector functions (e.g., an "effectorless" antibody). In some embodiments, the antibody does not bind to the Fc receptor and / or complement factor. In some embodiments, the antibody does not have one or more effector functions. In some embodiments, the constant region is modified to eliminate a disulfide bond or oligosaccharide moiety. In some embodiments, the constant region is modified to provide one or more cytotoxin, oligosaccharide, or carbohydrate binding sites by adding / substituting one or more amino acids. In some embodiments, the anti-OX40 antibody provided herein includes a variant Fc region manipulated using substitutions at specific amino acid positions compared to the native Fc region.

[0065] In some embodiments, the anti-OX40 antibodies disclosed herein include modifications to reduce or eliminate binding to FcR. In some embodiments, the anti-OX40 antibodies disclosed herein include modifications to reduce or eliminate ADCC activity.

[0066] In some embodiments, the anti-OX40 antibody described herein further comprises a variant of the Fc region. In some embodiments, the anti-OX40 antibody described herein comprises an IgG1 heavy chain constant region having an amino acid substitution at N297, numbered according to the EU index. In some embodiments, the substitution is N297A. The term “IgG1 N297A” refers to an Fc region variant of IgG1 in which asparagine is substituted with alanine at position 297 compared to the parent polypeptide (i.e., the wild-type Fc region of IgG1), and the numbering follows the EU index. It is expressly intended that the antibodies disclosed herein include a heavy chain constant region (CH) of any immunoglobulin disclosed herein or known in the art (e.g., human IgG1) having any combination of mutations known in the art that reduce or remove the ADCC and / or CDC of the antibody.

[0067] The anti-OX40 antibodies or antigen-binding fragments of this disclosure can be analyzed for their physical, chemical, and / or biological properties using a variety of methods known in the art. In some embodiments, the anti-OX40 antibody is tested for its ability to bind to OX40 (e.g., human OX40). In some embodiments, the anti-OX40 antibody is tested for its ability to bind to FcγR. Binding assays include, but are not limited to, BLI, SPR (e.g., Biacore), ELISA, and FACS. Furthermore, the antibodies can be evaluated for solubility, stability, thermal stability, viscosity, expression level, expression quality, and / or purification efficiency.

[0068] In some embodiments, the anti-OX40 antibody described herein comprises a light chain having an amino acid sequence that has at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity to SEQ ID NO: 19. In some embodiments, the light chain may have the amino acid sequence of SEQ ID NO: 19. In some embodiments, the anti-OX40 antibody described herein comprises a heavy chain having an amino acid sequence that has at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 20. In some embodiments, the heavy chain may have the amino acid sequence of SEQ ID NO: 20. The nucleic acid sequences encoding the light chain and heavy chain of the anti-OX40 antibody described herein include SEQ ID NO: 21 and SEQ ID NO: 22, respectively.

[0069] In some embodiments, the anti-OX40 antibodies described herein may include additional post-translational modifications. In some embodiments, the anti-OX40 antibodies described herein may be modified naturally or chemically by manipulation. In some embodiments, the anti-OX40 antibodies disclosed herein may be modified by glycosylation, oxidation, acetylation, pegylation, phosphorylation, amidation, deamidation, derivatization with known protective / blocking groups, proteolytic cleavage, and / or binding to cellular ligands or other proteins. Any of the numerous chemical modifications can be carried out by known techniques. The anti-OX40 antibodies may include one or more analogues of amino acids (e.g., including non-natural amino acids) in addition to other modifications known in the art. For example, the anti-OX40 antibodies described herein may include glycosylation sites, oxidation sites, and / or deamidation sites in the VL and / or VH regions. Specifically, as shown in Table 2, for anti-OX40 antibodies having VL and VH with the amino acid sequences of SEQ ID NOs. 7 and 8, potential oxidation sites are shown in bold, potential deamidation sites in italics and bold, and potential isomerization sites in underline and bold. Compared to the other two OX40 antagonists in which antibody-dependent cell-mediated cytotoxicity (ADCC) function is conserved (terazolimab) or enhanced (locatinlimab), the anti-OX40 antibodies described herein, which have modifications to the Fc region to remove glycosylation, eliminate ADCC and minimize potential toxicity associated with T cell depletion.

[0070] The OX40 antibodies described herein can be prepared using any method known in the art. Methods for antibody preparation are well known in the art. For example, see Harlow et al., Antibodies: A Laboratory Manual (Cold Spring Harbor Laboratory Press, 2nd ed. 1988), and Hammerling et al., in: Monoclonal Antibodies and T-Cell Hybridomas 563 681 (Elsevier, NY, 1981), both of which are incorporated herein by reference in their entirety. In some embodiments, monoclonal antibodies are prepared using hybridoma methods known to those skilled in the art. In some embodiments, monoclonal antibodies are produced using recombinant DNA techniques known to those skilled in the art. For example, the polynucleotide encoding the antibody is isolated from mature B cells or hybridoma cells using oligonucleotide primers that specifically amplify the genes encoding the heavy and light chains of the antibody, for example by RT-PCR, and their sequences are determined using standard techniques. The isolated polynucleotides encoding the heavy and light chains are then cloned into appropriate expression vectors, which, when transfected into host cells such as E. coli (which otherwise do not produce immunoglobulin proteins), monkey COS cells, Chinese hamster ovary (CHO) cells, or myeloma cells, produce monoclonal antibodies.

[0071] Peptides can also be synthesized whole or partially using chemical methods (see, e.g., Caruthers (1980) Nucleic Acids Res. Symp. Ser. 215, Horn (1980), and Banga, AK, Therapeutic Peptides and Proteins, Formula, Processing and Delivery Systems (1995) Technomic Publishing Co., Lancaster, PA). Peptide synthesis can be carried out using various solid-phase techniques (see, e.g., Roberge, Science 269:202 (1995); Merrifield, Methods. Enzymol. 289:3 (1997)), and automated synthesis can also be achieved using, for example, the ABI 431A peptide synthesizer (Perkin Elmer) according to the manufacturer's instructions. Peptides can also be synthesized using combinatorial methods. Synthetic residues and polypeptides can be synthesized using various procedures and methodologies known in the art (see, e.g., Organic Syntheses Collective Volumes, Gilman, et al. (Eds) John Wiley & Sons, Inc., NY). Modified peptides can be produced by chemical modification (see, e.g., Belousov, Nucleic Acids Res. 25:3440 (1997), Frenkel, Free Radic. Biol. Med. 19:373 (1995), and Blommers, Biochemistry 33:7886 (1994)). Variants, derivatives, substitutions, and modifications of peptide sequences can be produced using methods such as oligonucleotide-mediated (site-directed) mutagenesis, alanine scanning, and PCR-based mutagenesis.Site-directed mutagenesis (Carter et al., Nucl. Acids Res., 13:4331 (1986), Zoller et al., Nucl. Acids Res. 10:6487 (1987)), cassette mutagenesis (Wells et al., Gene 34:315 (1985)), restriction selection mutagenesis (Wells et al., Philos. Trans. R. Soc. London SerA 317:415 (1986)), and other techniques can be applied to cloned DNA to generate the peptide sequences, variants, fusions, and chimeras of the present invention, as well as their variants, derivatives, substitutions, and modifications.

[0072] In some embodiments, the anti-OX40 antibody is formulated as a pharmaceutical composition used in the manner disclosed herein. Exemplary pharmaceutical compositions or formulations are described, for example, in WO2023061424A1, which is incorporated herein by reference in whole. The anti-OX40 antibody can be present in a variety of concentrations. In some embodiments, the pharmaceutical compositions provided herein contain a soluble anti-OX40 antibody in a concentration of 1 to 500 mg / mL (e.g., about 1 to 180 mg / mL, about 10 to 160 mg / mL, about 15 to 140 mg / mL, about 20 to 120 mg / mL, about 25 to 100 mg / mL, about 30 to 80 mg / mL, about 40 to 60 mg / mL, or about 50 mg / mL).

[0073] In certain embodiments, the disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of anti-OX40 antibody and a pharmaceutical carrier. In some embodiments, the pharmaceutical composition is suitable for systemic administration. In certain embodiments, the disclosure provides an anti-OX40 antibody formulated in a pharmaceutical composition for use in intravenous administration.

[0074] In some embodiments, the anti-OX40 antibody disclosed herein is stored at 50 mg / mL in a suitable container (e.g., a 2R type I glass vial with a 13 mm rubber stopper integrated into a plastic cap) and can be diluted with isotonic saline (commercially available 0.9% sodium chloride) for administration (e.g., IV infusion).

[0075] 1.3 Treatment method This specification provides a method for treating alopecia areata (AA) in subjects requiring treatment of alopecia areata (AA), comprising administering a therapeutically effective amount of the anti-OX40 antibody disclosed herein to the subject. This specification also provides a method for treating atopic dermatitis (AD) in subjects requiring treatment of atopic dermatitis (AD), comprising administering a therapeutically effective amount of the anti-OX40 antibody disclosed herein to the subject.

[0076] In this specification, the term “treat” and its grammatical synonyms, as used in relation to a disease or condition, or an object having a disease or condition, refer to the act of suppressing, eliminating, reducing, and / or improving the symptoms, severity, and / or frequency of symptoms associated with the disease or disorder being treated.

[0077] As used herein, the term “administer” and its grammatical synonyms refer to the act of delivering or causing delivery of a therapeutic composition or pharmaceutical composition to a body of interest by means of a method described herein or otherwise known in the art. Administering a therapeutic composition or pharmaceutical composition includes prescribing a therapeutic composition or pharmaceutical composition to be delivered into a patient’s body. Exemplary forms of administration include oral forms, e.g., tablets, capsules, syrups, and suspensions; injectable forms, e.g., intravenous (IV), intramuscular (IM), or intraperitoneal (IP); transdermal forms, including creams, jellies, powders, or patches; buccal forms; inhalation powders, sprays, suspensions, and rectal suppositories.

[0078] As used herein, the terms “effective dose,” “therapeutic effective dose,” and their grammatical synonyms refer to the amount of a drug administered to a subject, either alone or as part of a pharmaceutical composition, as a single dose or as part of a series, that, when administered to the subject, produces a detectable positive effect against any symptom, aspect, or characteristic of a disease, disorder, or condition. The therapeutic effective dose can be determined by measuring the relevant physiological effect. The exact amount required will vary from subject to subject, depending on the subject’s age, weight, overall condition, severity of the condition being treated, and the clinician’s judgment. The appropriate “effective dose” in each individual case can be determined by those skilled in the art using routine experiments.

[0079] In some embodiments, the anti-OX40 antibody provided herein can be administered systemically. In one embodiment, the anti-OX40 antibody provided herein can be delivered by intravenous infusion.

[0080] 1.3.1 Treatment of Alopecia Areata This specification provides a method for treating alopecia areata (AA) in a subject requiring treatment of the condition, comprising administering a therapeutically effective amount of the anti-OX40 antibody described herein to the subject requiring treatment. This specification provides the use of the anti-OX40 antibody disclosed herein for the treatment of AA. In some embodiments, this specification provides the use of the anti-OX40 antibody provided herein for the preparation of a pharmaceutical product for the treatment of AA.

[0081] The severity of alopecia areata can be measured using standards and methods known in the art, including, for example, the SALT Alopecia Areata Severity Tool (SALT), the Preferred Outcome for Patients with Alopecia Areata (AAPPO), and the Hospital Anxiety and Depression Scale (HADS).

[0082] SALTThe Alopecia Areata Severity Tool (SALT) is a quantitative assessment of AA severity based on hair loss of terminal hairs in the scalp, and is established in Olsen EA et al. (2004), Alopecia areata investigational assessment guidelines--Part II. National Alopecia Areata Foundation. J Am Acad Dermatol. 51(3):440-447.

[0083] AAPPO The Alopecia Areata Patient Priority Outcomes (AAPPO) scale is an 11-item self-administered questionnaire that measures hair loss in the past week (4 items on a 5-point scale), emotional symptoms (4 items on a 5-point scale), and activity limitations (3 items on a 5-point scale). It was established in Wyrwich KW et al. (2022), Validation of the alopecia areata patient priority outcomes (AAPPO) questionnaire in adults and adolescents with alopecia areata, Dermatol Ther (Heidelb) 12(1):149-166.

[0084] HADS The Hospital Anxiety and Depression Scale (HADS) is a 14-item self-assessment scale that assesses the level of anxiety (7 items) and depression (7 items) experienced by patients in the past week. The HADS uses a 4-point Likert response scale (e.g., 0-3) for each item. Scores for each domain (anxiety and depression) range from 0 to 21, with higher scores indicating greater anxiety or depression, as established in Zigmond AS and Snaith RP, The hospital anxiety and depression scale (1983), Acta Psychiatr Scand. 67(6):361-370.

[0085] To support the assessment of AA severity, an additional set of assessments has also been developed, including investigator-investigator assessments of targeted scalp lesions (IATs), patient general impression of severity (PGIS) for alopecia areata (PGIS-AA) and scalp (PGIS-S).

[0086] IATs In the Investigator-Assisted Targeted Scalp Surgery (IATS) assessment, the selected targeted scalp lesion that best represents the overall severity of alopecia areata is evaluated based on SALT. The same targeted scalp lesion can be evaluated at each follow-up appointment during treatment. The investigator assesses the severity of the targeted scalp lesion on the day of the visit on a 5-point scale from 0 = "none" to 4 = "very severe". [Table 6]

[0087] PGIS-AA and PGIS-S The overall AA (PGIS-AA) and scalp AA (PGIS-S) of the Patient's General Impression of Severity (PGIS-AA) can be used to assess the patient's general impression of severity using a 5-point scale: 0 = "None", 1 = "Mild", 2 = "Moderate", 3 = "Severe", 4 = "Very Severe".

[0088] PGIC-AA and PGIC-S Patient's overall impression of change (PGIC) AA (PGIC-AA) and scalp AA (PGIC-S) can be measured using a 5-point scale: 1 = "Greatly improved", 2 = "Slightly improved", 3 = "No change", 4 = "Slightly worsened", 5 = "Very worsened".

[0089] This specification provides a method for treating alopecia areata in a subject requiring treatment, comprising administering a therapeutically effective amount of the anti-OX40 antibody described herein to the subject requiring treatment. The subject may be human. The subject may have alopecia areata of varying severity. In some embodiments, the subject has severe alopecia areata. In some embodiments, the subject has moderate alopecia areata. In some embodiments, the subject has mild alopecia areata. In some embodiments, the subject has diffuse alopecia areata. In some embodiments, the subject has monolocular alopecia areata. In some embodiments, the subject has multilocular alopecia areata. In some embodiments, the subject has serpentine alopecia. In some embodiments, the subject has barbae alopecia areata. In some embodiments, the subject has total alopecia areata. In some embodiments, the subject has universal alopecia areata.

[0090] In some embodiments, the subject is evaluated using SALT. In some embodiments, the subject is evaluated using AAPPO. In some embodiments, the subject is evaluated using HADS. In some embodiments, the subject is evaluated using SALT, AAPPO, and HADS. In some embodiments, the subject is evaluated using SALT, AAPPO, HADS, IATs, PGIS-AA, PGIS-S, PGIC-AA, PGIC-S, or any combination thereof.

[0091] In some embodiments, the SALT score of a subject requiring treatment is at least 30, at least 35, at least 40, at least 45, at least 50, at least 55, at least 60, at least 65, at least 70, at least 75, at least 80, at least 85, at least 90, at least 95, or 100. In some embodiments, the SALT score of a subject requiring treatment is about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 65, about 70, about 75, about 80, about 85, about 90, about 95, or about 100. A subject may have a SALT score of at least 30. A subject may have a SALT score of at least 35. A subject may have a SALT score of at least 40. A subject may have a SALT score of at least 45. A subject may have a SALT score of at least 50. A subject may have a SALT score of at least 55. A subject may have a SALT score of at least 60. The subject may have a SALT score of at least 65. The subject may have a SALT score of at least 70. The subject may have a SALT score of at least 75. The subject may have a SALT score of at least 80. The subject may have a SALT score of at least 85. The subject may have a SALT score of at least 90. The subject may have a SALT score of at least 95. The subject may have a SALT score of approximately 30. The subject may have a SALT score of approximately 35. The subject may have a SALT score of approximately 40. The subject may have a SALT score of approximately 45. The subject may have a SALT score of approximately 50. The subject may have a SALT score of approximately 55. The subject may have a SALT score of approximately 60. The subject may have a SALT score of approximately 65. The subject may have a SALT score of approximately 70. The subject may have a SALT score of approximately 75. The subject may have a SALT score of approximately 80. The subject may have a SALT score of approximately 85. The subject may have a SALT score of approximately 90. The subject may have a SALT score of approximately 95. The subject may have a SALT score of 100.

[0092] In some embodiments, the subject has scalp hair loss of 30% or more, 35% or more, 40% or more, 45% or more, 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, and 95% or more. The subject may have scalp hair loss of 30% or more. The subject may have scalp hair loss of 35% or more. The subject may have scalp hair loss of 40% or more. The subject may have scalp hair loss of 45% or more. The subject may have scalp hair loss of 50% or more. The subject may have scalp hair loss of 55% or more. The subject may have scalp hair loss of 60% or more. The subject may have scalp hair loss of 65% or more. The subject may have scalp hair loss of 70% or more. The subject may have scalp hair loss of 75% or more. The subject may have scalp hair loss of 80% or more. The subjects may have more than 85% scalp hair loss. The subjects may have more than 90% scalp hair loss. The subjects may have more than 30% scalp hair loss.

[0093] In some embodiments, subjects requiring treatment have a SALT score of approximately 50. In some embodiments, subjects requiring treatment have more than 50% scalp hair loss.

[0094] In some embodiments, the subject does not have male pattern baldness, scarring alopecia, secondary syphilis, tinea capitis, trichotillomania, or triangular alopecia. In some embodiments, the subject does not have scarring alopecia. In some embodiments, the subject does not have central centrifugal scarring alopecia. In some embodiments, the subject does not have traction alopecia. In some embodiments, the subject does not have male pattern baldness.

[0095] In some embodiments, subjects treated by the methods disclosed herein have a clinical diagnosis of AA and have a current alopecia duration of more than 6 months. In some embodiments, subjects may have a clinical diagnosis of AA and have a current alopecia duration of more than 1 year. Subjects may have a clinical diagnosis of AA and have a current alopecia duration of more than 2 years. Subjects may have a clinical diagnosis of AA and have a current alopecia duration of more than 3 years.

[0096] In some embodiments, subjects treated by the methods disclosed herein have a clinical diagnosis of AA and have a current hair loss duration of more than 6 months but less than 5 years. In some embodiments, subjects treated by the methods disclosed herein have a clinical diagnosis of AA and have a current hair loss duration of more than 6 months but less than 6 years. In some embodiments, subjects treated by the methods disclosed herein have a clinical diagnosis of AA and have a current hair loss duration of more than 6 months but less than 7 years. In some embodiments, subjects treated by the methods disclosed herein have a clinical diagnosis of AA and have a current hair loss duration of more than 6 months but less than 8 years. In some embodiments, subjects treated by the methods disclosed herein have a clinical diagnosis of AA and have a current hair loss duration of more than 6 months but less than 9 years. In some embodiments, subjects treated by the methods disclosed herein have a clinical diagnosis of AA and have a current hair loss duration of more than 6 months but less than 10 years.

[0097] In some embodiments, the subjects administered the anti-OX40 antibody described herein have previously received at least one therapeutic agent or therapy for the treatment of AA. In some embodiments, the at least one previously administered therapeutic agent or therapy for the treatment of AA is selected from topical agents and may be, for example, topical corticosteroids.

[0098] In some embodiments, subjects treated by the methods disclosed herein show no signs of regrowth of terminal hairs for at least one month. Subjects may show no signs of regrowth of terminal hairs within three months. In some embodiments, subjects treated by the methods disclosed herein show no signs of regrowth of terminal hairs within six months. Subjects may show no signs of regrowth of terminal hairs within one year. Subjects may show no signs of regrowth of terminal hairs within two years. Subjects may show no signs of regrowth of terminal hairs within three years.

[0099] The amount of anti-OX40 antibody administered to a subject according to the methods disclosed herein is generally a therapeutically effective dose. In some embodiments, the therapeutic dose may range from about 1 mg to about 1200 mg. In some embodiments, 300 mg of anti-OX40 antibody is administered. In some embodiments, 600 mg of anti-OX40 antibody is administered.

[0100] The amount of anti-OX40 antibody contained in each dose can also be expressed in milligrams of antibody per kilogram of body weight of the subject (i.e., mg / kg). In certain embodiments, the anti-OX40 antibody used in the method herein can be administered to the subject in doses of about 0.01 to about 100 mg per kg of body weight of the subject. In some embodiments, the method includes the administration of anti-OX40 antibody at a dose of about 4 mg per kg of body weight of the patient. In some embodiments, the method includes the administration of anti-OX40 antibody at a dose of about 8 mg per kg of body weight of the patient.

[0101] A treatment cycle may comprise one or more doses of the anti-OX40 antibody described herein. In some embodiments, a treatment cycle may comprise two doses of the anti-OX40 antibody described herein. A treatment cycle may comprise three doses of the anti-OX40 antibody described herein.

[0102] If multiple doses are administered during a treatment cycle, they may be administered at different frequencies. In some embodiments, the Specified Method is provided, which involves administering a single dose of the anti-OX40 antibody described herein to the target. In some embodiments, multiple doses of the anti-OX40 antibody are administered. In some embodiments, the Method provided herein involves administering the anti-OX40 antibody to the target at a frequency of approximately once every two weeks. For illustrative purposes, in some embodiments, the Method provided herein involves administering 600 mg of the anti-OX40 antibody described herein every two weeks, with three doses administered within four weeks to complete a treatment cycle. In some embodiments, the Method provided herein involves administering 300 mg of the anti-OX40 antibody described herein every two weeks, with three doses administered within four weeks to complete a treatment cycle.

[0103] All combinations and sequences of dosages and treatment plans described above are expressly intended herein. Dosage and frequency will vary depending on the half-life of the anti-OX40 antibody in the patient. In therapeutic use, relatively high doses at relatively short intervals may sometimes be required until disease progression is reduced or halted, and until the patient exhibits partial or complete remission of disease symptoms. Actual dose levels of the anti-OX40 antibody described herein may be varied to obtain an amount that is effective in achieving the desired therapeutic response for a particular patient, composition, and mode of administration without being toxic to the patient. The selected dosage level will depend on a variety of pharmacokinetic factors, including the specific composition described herein, route of administration, time of administration, excretion rate, duration of treatment, other drugs, compounds, and / or substances used in combination with the specific composition used, the age, sex, race, body mass index (BMI), condition, overall health status, liver function, kidney function, and prior medical history of the patient being treated, as well as similar factors well known in the medical field.

[0104] In some embodiments, the treatment methods described herein induce clinical remission of AA. In some embodiments, the treatment methods described herein maintain clinical remission of AA. In some embodiments, the treatment methods described herein induce and maintain clinical remission of AA. As used herein, clinical remission of AA means achieving 80% or more of the hair on the scalp (i.e., a SALT score of 20 or less) based on the SALT score at the end of treatment.

[0105] In some embodiments, the treatment methods described herein reduce the signs and / or symptoms of AA, for example, reducing hair loss. In some embodiments, the treatment methods described herein reduce the signs of AA. In some embodiments, the treatment methods described herein reduce the symptoms of AA.

[0106] In some embodiments, the treatment methods described herein induce and / or maintain a clinical response, such as inducing and / or maintaining hair growth. In some embodiments, the treatment methods described herein induce a clinical response. In some embodiments, the treatment methods described herein maintain a clinical response. As used herein, a clinical response in AA refers to achieving 50% or more of hair regrowth from baseline, based on the SALT score at the end of treatment.

[0107] In some embodiments, the treatment methods described herein are therapeutically effective in reducing hair loss in subjects diagnosed with AA. In some embodiments, the methods described herein are therapeutically effective in preventing hair loss in subjects diagnosed with AA. In some embodiments, the methods described herein are therapeutically effective in inducing hair growth in subjects diagnosed with AA. In some embodiments, the methods described herein are therapeutically effective in inducing hair regrowth in at least 90% of the scalp of subjects suffering from AA (i.e., a SALT score of 10 or less). In some embodiments, the methods described herein are therapeutically effective in inducing hair regrowth in at least 80% of the scalp of subjects suffering from AA (i.e., a SALT score of 20 or less). In some embodiments, the methods described herein are therapeutically effective in inducing hair regrowth in at least 70% of the scalp of subjects suffering from AA (i.e., a SALT score of 30 or less).

[0108] In some embodiments, the therapeutic effect is observed within 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 10 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 ​​weeks, or 52 weeks from the start of treatment. In some embodiments, the therapeutic effect is observed approximately 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 10 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 ​​weeks, or 52 weeks after the start of treatment. In some embodiments, the start of treatment refers to the first administration of the anti-OX40 antibody disclosed herein.

[0109] In some embodiments, the method provided herein is therapeutically effective in achieving at least a 30% reduction from the baseline Alopecia Severity Tool (SALT) score of the subject. In some embodiments, the method provided herein is therapeutically effective in achieving at least a 50% reduction from the baseline SALT score of the subject. In some embodiments, the method provided herein is therapeutically effective in achieving at least a 75% reduction from the baseline SALT score of the subject. In some embodiments, the method provided herein is therapeutically effective in achieving at least an 80% reduction from the baseline SALT score of the subject. In some embodiments, the method is therapeutically effective in achieving at least a 90% reduction from the SALT score of the subject. In some embodiments, the method is therapeutically effective in achieving at least a 30% reduction from the baseline SALT score of the subject about 16 weeks after the start of treatment. In some embodiments, the method is therapeutically effective in achieving at least a 30% reduction from the baseline SALT score of the subject about 24 weeks after the start of treatment. In some embodiments, the method is therapeutically effective in achieving at least a 30% reduction from the baseline SALT score of the subject about 32 weeks after the start of treatment. In some embodiments, the method is therapeutically effective in achieving at least a 30% reduction from the baseline SALT score of the subject approximately 40 weeks after the start of treatment. In some embodiments, the method is therapeutically effective in achieving at least a 30% reduction from the baseline SALT score of the subject approximately 48 weeks after the start of treatment. In some embodiments, the method is therapeutically effective in achieving at least a 30% reduction from the baseline SALT score of the subject within 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 ​​weeks, or 52 weeks after the start of treatment. In some embodiments, the method is therapeutically effective in achieving at least a 50% reduction from the SALT score of the subject.In some embodiments, the method is therapeutically effective in achieving at least a 50% reduction from the baseline SALT score of the subject approximately 16 weeks after the initiation of treatment. In some embodiments, the method is therapeutically effective in achieving at least a 50% reduction from the baseline SALT score of the subject approximately 24 weeks after the initiation of treatment. In some embodiments, the method is therapeutically effective in achieving at least a 50% reduction from the baseline SALT score of the subject approximately 32 weeks after the initiation of treatment. In some embodiments, the method is therapeutically effective in achieving at least a 50% reduction from the baseline SALT score of the subject approximately 40 weeks after the initiation of treatment. In some embodiments, the method is therapeutically effective in achieving at least a 50% reduction from the baseline SALT score of the subject approximately 48 weeks after the initiation of treatment. In some embodiments, the method is therapeutically effective in achieving at least a 50% reduction from the baseline SALT score within 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 ​​weeks, or 52 weeks from the start of treatment. In some embodiments, the method is therapeutically effective in achieving at least a 75% reduction from the baseline SALT score. In some embodiments, the method is therapeutically effective in achieving at least a 75% reduction from the baseline SALT score approximately 16 weeks after the start of treatment. In some embodiments, the method is therapeutically effective in achieving at least a 75% reduction from the baseline SALT score approximately 24 weeks after the start of treatment. In some embodiments, the method is therapeutically effective in achieving at least a 75% reduction from the baseline SALT score approximately 32 weeks after the start of treatment. In some embodiments, the method is therapeutically effective in achieving at least a 75% reduction from the baseline SALT score approximately 40 weeks after the start of treatment. In some embodiments, the method is therapeutically effective in achieving at least a 75% reduction from the baseline SALT score of the subject approximately 48 weeks after the start of treatment.In some embodiments, the method is therapeutically effective in achieving at least a 75% reduction from the baseline SALT score of the subject within 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 ​​weeks, or 52 weeks from the start of treatment.

[0110] In some embodiments, the method provided herein is therapeutically effective in reducing the baseline SALT score of a subject from 50 or higher to 10 or lower. In some embodiments, the method provided herein is therapeutically effective in reducing the baseline SALT score of a subject from 50 or higher to 20 or lower. In some embodiments, the method provided herein is therapeutically effective in reducing the baseline SALT score of a subject from 50 or higher to 25 or lower. In some embodiments, the method provided herein is therapeutically effective in reducing the baseline SALT score of a subject from 50 or higher to 30 or lower. In some embodiments, the reduction in the SALT score is achieved approximately 16 weeks after the start of treatment. In some embodiments, the reduction in the SALT score is achieved approximately 24 weeks after the start of treatment. In some embodiments, the reduction in the SALT score is achieved approximately 32 weeks after the start of treatment. In some embodiments, the reduction in the SALT score is achieved approximately 40 weeks after the start of treatment. In some embodiments, the reduction in the SALT score is achieved approximately 48 weeks after the start of treatment. In some embodiments, a reduction in the SALT score is achieved within 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 ​​weeks, or 52 weeks from the start of treatment.

[0111] In some embodiments, the methods provided herein are therapeutically effective in achieving a reduction of at least 1 point from the baseline IAT score of the subject. In some embodiments, the methods provided herein are therapeutically effective in achieving a reduction of at least 2 points from the baseline IAT score of the subject. In some embodiments, the reduction in the IAT score is achieved approximately 16 weeks after the start of treatment. In some embodiments, the reduction in the IAT score is achieved approximately 24 weeks after the start of treatment. In some embodiments, the reduction in the IAT score is achieved approximately 32 weeks after the start of treatment. In some embodiments, the reduction in the IAT score is achieved approximately 40 weeks after the start of treatment. In some embodiments, the reduction in the IAT score is achieved approximately 48 weeks after the start of treatment. In some embodiments, the reduction in the IAT score is achieved within 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 ​​weeks, or 52 weeks after the start of treatment.

[0112] In some embodiments, the methods provided herein are therapeutically effective in achieving an IAT score of 0. In some embodiments, the methods provided herein are therapeutically effective in achieving an IAT score of 1. In some embodiments, an IAT score of 0 or 1 is achieved approximately 16 weeks after the start of treatment. In some embodiments, an IAT score of 0 or 1 is achieved approximately 24 weeks after the start of treatment. In some embodiments, an IAT score of 0 or 1 is achieved approximately 32 weeks after the start of treatment. In some embodiments, an IAT score of 0 or 1 is achieved approximately 40 weeks after the start of treatment. In some embodiments, an IAT score of 0 or 1 is achieved approximately 48 weeks after the start of treatment. In some embodiments, an IAT score of 0 or 1 is achieved within 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 ​​weeks, or 52 weeks after the start of treatment.

[0113] In some embodiments, the methods provided herein are therapeutically effective in achieving a PGIS-AA score of 0. In some embodiments, the methods provided herein are therapeutically effective in achieving a PGIS-AA score of 1. In some embodiments, a PGIS-AA score of 0 or 1 is achieved approximately 16 weeks after the start of treatment. In some embodiments, a PGIS-AA score of 0 or 1 is achieved approximately 24 weeks after the start of treatment. In some embodiments, a PGIS-AA score of 0 or 1 is achieved approximately 32 weeks after the start of treatment. In some embodiments, a PGIS-AA score of 0 or 1 is achieved approximately 40 weeks after the start of treatment. In some embodiments, a PGIS-AA score of 0 or 1 is achieved approximately 48 weeks after the start of treatment. In some embodiments, a PGIS-AA score of 0 or 1 is achieved within 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 ​​weeks, or 52 weeks after the start of treatment.

[0114] In some embodiments, the methods provided herein are therapeutically effective in achieving a PGIS-S score of 0. In some embodiments, the methods provided herein are therapeutically effective in achieving a PGIS-S score of 1. In some embodiments, a PGIS-S score of 0 or 1 is achieved approximately 16 weeks after the start of treatment. In some embodiments, a PGIS-S score of 0 or 1 is achieved approximately 24 weeks after the start of treatment. In some embodiments, a PGIS-S score of 0 or 1 is achieved approximately 32 weeks after the start of treatment. In some embodiments, a PGIS-S score of 0 or 1 is achieved approximately 40 weeks after the start of treatment. In some embodiments, a PGIS-S score of 0 or 1 is achieved approximately 48 weeks after the start of treatment. In some embodiments, a PGIS-S score of 0 or 1 is achieved within 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 ​​weeks, or 52 weeks after the start of treatment.

[0115] In some embodiments, the methods provided herein are therapeutically effective in achieving “broadly improved” PGIC-AA. In some embodiments, the methods provided herein are therapeutically effective in achieving “slightly improved” PGIC-AA. In some embodiments, the methods provided herein are therapeutically effective in achieving “broadly improved” PGIC-S. In some embodiments, the methods provided herein are therapeutically effective in achieving “slightly improved” PGIC-S. In some embodiments, “broadly improved” or “slightly improved” PGIC-AA and / or PGIC-S are achieved about 16 weeks after the start of treatment. In some embodiments, “broadly improved” or “slightly improved” PGIC-AA and / or PGIC-S are achieved about 24 weeks after the start of treatment. In some embodiments, “broadly improved” or “slightly improved” PGIC-AA and / or PGIC-S are achieved about 32 weeks after the start of treatment. In some embodiments, "significantly improved" or "slightly improved" PGIC-AA and / or PGIC-S is achieved approximately 40 weeks after the start of treatment. In some embodiments, "significantly improved" or "slightly improved" PGIC-AA and / or PGIC-S is achieved approximately 48 weeks after the start of treatment. In some embodiments, "significantly improved" or "slightly improved" PGIC-AA and / or PGIC-S is achieved within 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 ​​weeks, or 52 weeks after the start of treatment.

[0116] In some embodiments, the methods provided herein are therapeutically effective in achieving improvement in AAPPO. In some embodiments, the methods provided herein are therapeutically effective in achieving improvement in HADS. In some embodiments, improvement in AAPPO and / or HADS is achieved about 16 weeks after the start of treatment. In some embodiments, improvement in AAPPO and / or HADS is achieved about 24 weeks after the start of treatment. In some embodiments, improvement in AAPPO and / or HADS is achieved about 32 weeks after the start of treatment. In some embodiments, improvement in AAPPO and / or HADS is achieved about 40 weeks after the start of treatment. In some embodiments, improvement in AAPPO and / or HADS is achieved about 48 weeks after the start of treatment. In some embodiments, improvement in AAPPO and / or HADS is achieved within 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 ​​weeks, or 52 weeks from the start of treatment.

[0117] In some embodiments, the method further includes detecting AA-related biomarkers in a subject. In some embodiments, administration of the anti-OX40 antibody described herein alters the level of AA-related biomarkers in a subject. In some embodiments, the method further includes selecting subjects based on the level of AA-related biomarkers before administering the anti-OX40 antibody described herein to the subject.

[0118] As used herein, the term “AA-related biomarker” means any biological response, cell type, parameter, protein, polypeptide, enzyme, enzyme activity, metabolite, nucleic acid, carbohydrate, or other biomolecule that is present or detectable in patients with AA at levels or amounts different from (e.g., greater or smaller) than the levels or amounts of markers present or detectable in patients without AA. The term “AA-related biomarker” also includes genes or gene probes known in the Art that are differentially expressed in subjects with AA compared to subjects without AA.

[0119] In some embodiments, the biomarker is evaluated using histology. In some embodiments, the biomarker is evaluated using RNA-seq. In some embodiments, the biomarker is evaluated using proteomic analysis. In some embodiments, the biomarker is evaluated using enzyme-linked immunosorbent assay. In some embodiments, the biomarker is evaluated using mass spectrometry. In some embodiments, the biomarker is evaluated using blood samples. In some embodiments, the biomarker is evaluated using serum samples. In some embodiments, the biomarker is evaluated using plasma samples. In some embodiments, the biomarker is evaluated using tissue samples. In some embodiments, the biomarker is evaluated using punch biopsy. In some embodiments, the biomarker is evaluated using tape strips.

[0120] In some embodiments, the biomarker is selected from IL-13, CCL13, IFN-γ, IL-12p40, IL-6, TNF-α, IL-15, sOX40, and CCL17. In some embodiments, the biomarker is selected from at least one of IL-13, CCL13, IFN-γ, IL-12p40, IL-6, TNF-α, IL-15, sOX40, and CCL17. In some embodiments, the biomarker is IL-13. In some embodiments, the biomarker is CCL13. In some embodiments, the biomarker is IFN-γ. In some embodiments, the biomarker is IL-12p40. In some embodiments, the biomarker is IL-6. In some embodiments, the biomarker is TNF-α. In some embodiments, the biomarker is IL-15. In some embodiments, the biomarker is sOX40. In some embodiments, the biomarker is CCL17.

[0121] In some embodiments, the biomarker is a gene expression signature. In some embodiments, the gene expression signature includes gene expression information for one or more of the following gene groups: hair keratin (KRT) related genes, cytotoxic T lymphocyte infiltration (CTL) related genes, and interferon (IFN) related genes. In some embodiments, the KRT related genes include DSG4, HOXC31, KRT31, KRT32, KRT33B, KRT82, PKP1, and / or PKP2. In some embodiments, the CTL related genes include CD8A, GZMB, ICOS, and / or PRF1. In some embodiments, the IFN related genes include CXCL9, CXCL10, CXCL11, STAT1, and / or MX1.

[0122] In some embodiments, the biomarker is selected from OX40-OX40L signaling pathway-related genes. In some embodiments, the OX40-OX40L signaling pathway-related genes include CTLA-4, Foxp3, TGF-β, BLIMP-1, Bcl-XL, Bcl-2, Bcl-6, Bfl-1, Survivin, Aurora B, CD80, CD86, CD64, and / or CD40. In some embodiments, the biomarker is selected from Th1, Th2, Th17, and Th22-related genes. In some embodiments, the Th1-related genes include IL12RB2, IL1B, STAT1, CCR1, CCR2, IL8, CXCL9, CXCL10, CXCL11, IRF1, IL12B, IFNGR1, IL2RA, OASL, CCL5, CCL3, CCL4, IFNGR2, and / or MX1. In some embodiments, Th2-related genes include IL10, CCR4, CCR5, IL7R, TSLP, IL5, IL13, IL4, IL9, CCL26, CCL24, IL33, STAT6, IL31, IL4R, CCL22, CCL17, CCL7, CCL13, and / or CCL18. In some embodiments, Th17-related genes include IL23R, CCL20, CAMP, CXCL1, CXCL3, CXCL2, IL17A, IL17F, CCR6, LCN2, IL23A, STAT3, and / or PI3. In some embodiments, Th22-related genes include FLG, S100A9, S100A8, S100A7, S100P, SERPINB1, AHR, CALML5, KRT1, IL22, IL32, KRT10, and / or SERPINB4. In some embodiments, the biomarker is the level of inflammatory cells infiltrating the scalp. In some embodiments, the biomarker is selected from scalp OX40, OX40L, tryptase, CD4, CD8, KRT35, and MHC-1.

[0123] In some embodiments, the AA-related biomarkers are selected from IL-15, CCL2, CCL3, CXCL10, IL-13, CCL13, CCL17, CCL4, and CCL11, and the levels of the biomarkers in the serum of subjects with AA are elevated compared to the serum of healthy patients. In some embodiments, the AA-related biomarkers are selected from IL-15 and eotaxin / CCL1, and the levels of the biomarkers are associated with the SALT score.

[0124] In some embodiments, AA-related biomarkers indicate the severity of alopecia areata. In some embodiments, AA-related biomarkers indicate the tendency of the subject's response to treatment with the anti-OX40 antibody described herein.

[0125] In some embodiments, subjects treated with the anti-OX40 antibody described herein exhibit elevated levels of one or more AA-related biomarkers. In some embodiments, treatment with the anti-OX40 antibody described herein results in a decrease in the levels of AA-related biomarkers in the subjects.

[0126] In some embodiments, administration of the anti-OX40 antibody described herein reduces the level of at least one AA-related biomarker selected from IL-13, CCL13, IFN-γ, IL-12p40, IL-6, TNF-α, IL-15, and CCL17 in a subject by 15-75% or more. In some embodiments, administration of the anti-OX40 antibody described herein increases the level of at least one KRT-related gene in a subject by 30-90% or more. In some embodiments, administration of the anti-OX40 antibody described herein reduces the level of at least one CTL-related gene in a subject by 15-75% or more. In some embodiments, administration of the anti-OX40 antibody described herein reduces the level of at least one IFN-related gene in a subject by 15-75% or more. In some embodiments, administration of the anti-OX40 antibody described herein reduces the level of at least one OX40-OX40L signaling pathway-related gene in a subject by 15-75% or more. In some embodiments, administration of the anti-OX40 antibody described herein reduces the level of at least one Th1, Th2, Th17, and Th22-related gene in a subject by 15-85% or more. In some embodiments, administration of the anti-OX40 antibody described herein reduces the level of at least one AA-related biomarker in a subject by 15-85% or more. In some embodiments, administration of the anti-OX40 antibody described herein reduces the level of infiltrating inflammatory cells in a subject by 15-75% or more.

[0127] In some embodiments, the methods provided herein further include monitoring for adverse events during administration of the anti-OX40 antibody described herein and optionally interrupting or discontinuing the administration. As used herein and as understood in the art, “adverse event” means an undesirable medical event associated with treatment with the anti-OX40 antibody described herein.

[0128] In some embodiments, the methods provided herein further include monitoring vital signs (including blood pressure, pulse, respiratory rate, and body temperature) and / or physical examination during administration, or monitoring hematology and serological chemistry during the treatment cycle. In some embodiments, heart rate or cardiac signals are monitored. In some embodiments, heart rate or cardiac signals are monitored by electrocardiogram.

[0129] In some embodiments, the methods provided herein reduce the incidence and severity of adverse events resulting from the treatment of the conditions described herein. In some embodiments, the methods provided herein result in no serious adverse events.

[0130] In some embodiments, the methods provided herein do not result in local or systemic infusion-related reactions, including but not limited to fever or chills. In some embodiments, 80%, 70%, 60%, 50%, 40%, 30%, 25%, 20%, 15%, 10%, 8%, 5%, 3%, 2%, or less than 1% of subjects administered with the anti-OX40 antibody described herein report local or systemic infusion-related reactions. In some embodiments, 80%, 70%, 60%, 50%, 40%, 30%, 25%, 20%, 15%, 10%, 8%, 5%, 3%, 2%, or less than 1% of subjects administered with the anti-OX40 antibody described herein report fever or chills.

[0131] 1.3.2 Treatment of Atopic Dermatitis This specification provides a method for treating atopic dermatitis (AD) in a subject in need of treatment for atopic dermatitis (AD), comprising administering a therapeutically effective amount of anti-OX40 antibody as described herein to the subject in need. This specification provides the use of the anti-OX40 antibody disclosed herein for the treatment of AD. In some embodiments, what is provided herein is the use of the anti-OX40 antibody provided herein for the preparation of a drug for the treatment of AD.

[0132] The severity of AD can be measured using criteria and methods known in the field, such as the Eczema Area and Severity Index (EASI), the Treatment Assessment of Atopic Dermatitis (IGA-AD), the Scoring Index for Atopic Dermatitis (SCORAD), the Numerical Rating Scale for Itch and Sleep Quality (NRS), the Patient's Overall Impression of Severity (PGIS), the Patient's Overall Impression of Change (PGIC), and the Dermatological Quality of Life Index (DLQI).

[0133] EASI: The Eczema Area and Severity Index (EASI) is a validated composite scoring system that assesses the mean severity (0: none, 1: mild, 2: moderate, 3: severe) of the four main signs of Alzheimer's disease (AD) (erythema, edema / papules, scratching, and lichenification) on a four-point scale, and is assessed by the investigator based on relevant body regions in four body parts (head and neck, upper extremities, lower extremities, and trunk). (Hanifin JM et al. (2001) The eczema area and severity index (EASI): assessment of reliability in atopic dermatitis. EASI Evaluator Group. Exp Dermatol. 10(1):11-18). Symptoms (e.g., itching) and secondary signs (e.g., dryness, scaling) are excluded from the assessment. The total EEASI score ranges from 0 (no eczema or very mild) to 72 (maximum severity), with higher values ​​indicating a more severe and widespread disease. A score between 0 and 72 will be recorded.

[0134] The EASI scoring system uses a defined process to assess the severity and extent of eczema symptoms.

[0135] 1. Select a body part: Four body parts are considered individually: head and neck, trunk (including genital area), upper limbs, and lower limbs (including buttocks).

[0136] 2. Assess the extent of eczema in the body part: Each body part may be affected up to 100%. Use the table below to assign a score from 0 to 6 to each body part based on the percentage affected. Precise measurement is not required. [Table 7]

[0137] 3. Assess the severity of each of the four signs in the body part: erythema, edema / papules, scratching, and lichenification. Assess the severity of each sign on the following scale: none (0), mild (1), moderate (2), severe (3).

[0138] The evaluated parameters are inserted into the table (the following is an example for individuals aged 8 and over). The final EASI score ranges from 0 to 72. [Table 8] [Table 9]

[0139] IGA-AD The Investigator's Global Assessment (IGA-AD) for Alzheimer's disease (AD) aims to assess the overall or visual "average" severity of the major acute clinical signs of AD (erythema, induration / papules, exudation / crusting (excluding lichenification)). This assessment is based on a 5-point scale, with 0 being "significantly improved (completely cured)," 1 being "somewhat improved," 2 being "mild," 3 being "moderate," and 4 being "severe." The investigator scores the grade from 0 to 4. [Table 10]

[0140] STORADThe validated SCORing Atopic Dermatitis (SCORAD) index uses the Rule of Nine to assess the extent of the disease and determines the severity of the disease based on the following six clinical features: (1) erythema, (2) edema / papules, (3) exudation / crusting, (4) scratching, (5) lichenification, and (6) dryness (European Task Force on Atopic Dermatitis (1993). Assessment of the severity of atopic dermatitis: SCORAD index. Consensus report of the European Task Force on Atopic Dermatitis on atopic dermatitis. Dermatology. 186(1):23-31). The SCORAD index also assesses subjective symptoms such as itching and sleep deprivation. These three domains (extent of the disease, severity of the disease, and subjective symptoms) are combined, with a maximum score of 103.

[0141] BSA Body Surface Area Estimation (BSA) assessment estimates the extent of disease or skin involvement in Alzheimer's disease (AD) and is expressed as a percentage of total body surface area. BSA is measured by the principal investigator using the palm rule, which states that the palm of a patient accounts for 1% of the body surface area. Different anatomical structures are assessed individually. These include: the forehead, occipital region, anterior torso, posterior torso, left forearm, right forearm, left posterior arm, right posterior arm, left foreleg, right foreleg, left hind leg, right hind leg, and genital / perineum.

[0142] NRS The Itch and Sleep Quality Numerical Rating Scale allows participants to rate the worst itching intensity (WI-NRS) and sleep quality (SQ-NRS) associated with Alzheimer's disease (AD) over a 7-day period immediately preceding their scheduled visit.

[0143] The WI-NRS scale defines 0 as "no itchiness at all" and 10 as "the worst itchiness imaginable."

[0144] The SQ-NRS defines 0 as "the best possible sleep" and 10 as "the worst possible sleep."

[0145] PGIS-AD The Patient Global Impression of Severity (PGIS) is used to assess participants' overall impression of the severity of their AD over the past week. It is expressed on a 5-point scale: 0 = "None", 1 = "Mild", 2 = "Moderate", 3 = "Severe", and 4 = "Very Severe".

[0146] PGIC-AD: The Patient-Governmental Change Impression (PGIC) for Alzheimer's Disease (AD) is used by participants to assess changes in their AD, and is expressed on a 5-point scale: 1 = "Greatly improved", 2 = "Slightly improved", 3 = "No change", 4 = "Slightly worsened", and 5 = "Very worsened".

[0147] DLQI The Skin Disease Quality of Life Index (DLQI) is a 10-item questionnaire used to assess the impact of skin disease on a patient's quality of life (QoL) over the past week. The 10 questions cover symptoms, embarrassment, shopping / housework, clothing, social / leisure, sports, work / study, interpersonal relationships, sexual activity, and treatment. The DLQI score ranges from 0 (skin disease does not affect QoL) to 30 (maximum impact on QoL).

[0148] This specification provides a method for treating AD in a subject in need of treatment for AD, comprising administering a therapeutically effective dose of anti-OX40 antibody as described herein to the subject in need. The subject may be a human. The subject may have AD of varying severity. In some embodiments, the subject has severe AD. In some embodiments, the subject has moderate AD. In some embodiments, the subject has mild AD. In some embodiments, the subject has moderate to severe AD. In some embodiments, the subject has chronic AD. In some embodiments, the subject with AD is poorly controlled by topical therapy or is resistant to topical therapy.

[0149] In some embodiments, the subject is evaluated using EASI. In some embodiments, the subject is evaluated using IGA-AD, SCORAD, WI-NRS, SQ-NRS, or any combination thereof. In some embodiments, the subject is evaluated using PGIS-AD, PGIC-AD, DLQI, or any combination thereof.

[0150] In some embodiments, subjects requiring treatment have an EASI score of at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, and at least 20. In some embodiments, subjects requiring treatment have an EASI score of about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, and about 20. In some embodiments, a subject has an EASI score of at least 7. In some embodiments, a subject has an EASI score of at least 8. In some embodiments, a subject has an EASI score of at least 10. A subject may have an EASI score of at least 11. A subject may have an EASI score of at least 12. A subject may have an EASI score of at least 13. A subject may have an EASI score of at least 14. A subject may have an EASI score of at least 15. The subject may have at least 16 EASI scores. The subject may have at least 17 EASI scores. The subject may have at least 18 EASI scores. The subject may have at least 19 EASI scores. The subject may have at least 20 EASI scores. The subject may have approximately 10 EASI scores. The subject may have approximately 15 EASI scores. The subject may have approximately 20 EASI scores.

[0151] In some embodiments, subjects requiring treatment have an EASI score of at least 5. In some embodiments, subjects requiring treatment have an EASI score of at least 8. In some embodiments, subjects requiring treatment have an EASI score of at least 12. In some embodiments, subjects requiring treatment have an EASI score of at least 16.

[0152] In some embodiments, subjects requiring treatment have at least 1, at least 2, at least 3, or 4 IGA-AD scores. A subject may have at least 1 IGA-AD score. A subject may have at least 2 IGA-AD scores. A subject may have at least 3 IGA-AD scores. A subject may have 1 IGA-AD score. A subject may have 2 IGA-AD scores. A subject may have 3 IGA-AD scores. A subject may have 4 IGA-AD scores.

[0153] In some embodiments, subjects requiring treatment have an IGA-AD score of 3.

[0154] In some embodiments, the BSA content of the subject requiring treatment is 5% or more, 10% or more, 15% or more, 20% or more, 25% or more, 30% or more, 35% or more, 40% or more, 45% or more, or 50% or more. The subject may have 5% or more BSA. The subject may have 10% or more BSA. The subject may have 15% or more BSA. The subject may have 20% or more BSA. The subject may have 25% or more BSA. The subject may have 30% or more BSA. The subject may have 35% or more BSA. The subject may have 40% or more BSA. The subject may have 45% or more BSA. The subject may have 50% or more BSA.

[0155] In some embodiments, more than 10% of the subjects may have BSA requiring treatment.

[0156] In some embodiments, subjects treated by the methods disclosed herein have a clinical diagnosis of AD for 6 months or longer, based on the American Academy of Dermatology consensus diagnostic criteria (Eichenfield LF et al. (2014)). In some embodiments, subjects may have a clinical diagnosis of AD for 1 year or longer. Subjects may have a clinical diagnosis of AD for 2 years or longer. Subjects may have a clinical diagnosis of AD for 3 years or longer. Subjects may have a clinical diagnosis of AD for 4 years or longer. Subjects may have a clinical diagnosis of AD for 5 years or longer. Subjects may have a clinical diagnosis of AD for 6 years or longer. Subjects may have a clinical diagnosis of AD for 7 years or longer. Subjects may have a clinical diagnosis of AD for 8 years or longer. Subjects may have a clinical diagnosis of AD for 9 years or longer. Subjects may have a clinical diagnosis of AD for 10 years or longer.

[0157] In some embodiments, subjects administered with the anti-OX40 antibody described herein had previously received at least one therapeutic agent or therapy for the treatment of AD. In some embodiments, the at least one therapeutic agent or therapy previously administered for the treatment of AD was selected from topical corticosteroids (TCS), topical calcineurin inhibitors (TCI), topical phosphodiesterase-4 inhibitors, or topical Janus kinase (JAK) inhibitors.

[0158] In some embodiments, subjects had previously received non-biological systemic (oral or injectable) drugs such as conventional immunosuppressants or immunomodulators (e.g., corticosteroids, methotrexate, cyclosporine, tacrolimus, mycophenolate mofetil, azathioprine, JAK inhibitors), or other approved drugs or investigational drugs with potential immunosuppressive effects. In some embodiments, subjects had previously used phototherapy for AD with ultraviolet (UV) A or UV B. In some embodiments, subjects had previously received topical, intralesional, or systemic corticosteroids. In some embodiments, subjects had previously received systemic glucocorticoids. In some embodiments, subjects had previously received topical calcineurin inhibitors. In some embodiments, subjects had previously received topical prescription drugs for AD. In some embodiments, subjects had previously received systemic glucocorticoids. In some embodiments, subjects had previously received immunoglobulins or blood products. In some embodiments, the subject had previously been administered systemic immunosuppressants and / or immunomodulators, such as cyclosporine, azathioprine, and / or methotrexate. In some embodiments, the subject had previously been administered JAK inhibitors, such as topical or oral JAK inhibitors. In some embodiments, the subject had previously received biological treatment, such as approved or experimental biological products (e.g., antibodies against IL-13, IL-13 receptor, IL-4 receptor α, or experimental antibodies against IL-31 or IL-31 receptor).

[0159] As used herein and as understood in the art, a subject is said to “tolerate” treatment if the administration of treatment to the subject does not result in an unacceptable adverse event or combination of unacceptable adverse events. Those skilled in the art will understand that tolerability is a subjective measure, and what is tolerable to one person may not be tolerable to another. As used herein and as understood in the art, “unacceptable” or “intolerable” means a serious toxicity and / or tolerability issue that leads to a reduction in dosage or discontinuation of treatment.

[0160] In some embodiments, subjects may have responded poorly to, lost efficacy from, developed tolerance to, or developed dependence on other medications for treating AD. In some embodiments, subjects may have responded poorly to, lost efficacy from, developed tolerance to, or developed dependence on other medications for treating AD. In some embodiments, subjects may have responded poorly to, lost efficacy from, developed tolerance to, or developed dependence on one or more topical treatments, such as TCS or TCI. In some embodiments, subjects may have responded poorly to one or more topical treatments, such as TCS or TCI. In some embodiments, subjects may have developed tolerance to one or more topical treatments, such as TCS or TCI.

[0161] In some embodiments, the subject may have responded poorly, lost its response, or was intolerant to the conventional treatment. In some embodiments, the subject may have responded poorly to the conventional treatment. In some embodiments, the subject may have lost its response to the conventional treatment. In some embodiments, the subject may have been intolerant to the conventional treatment. In some embodiments, the conventional treatment is referred to as the previous treatment.

[0162] In some embodiments, the subject may have shown an insufficient response, loss of response, or intolerance to at least one therapeutic agent or treatment. In some embodiments, the subject may have shown an insufficient response, loss of response, or intolerance to at least one therapeutic agent or treatment. In some embodiments, the subject may have shown an insufficient response, loss of response, or intolerance to at least one therapeutic agent or treatment over a period of one month (four weeks). In some embodiments, the subject may have shown an insufficient response, loss of response, or intolerance to at least one therapeutic agent or treatment over a period of two months (eight weeks). In some embodiments, the subject may have shown an insufficient response, loss of response, or intolerance to at least one therapeutic agent or treatment over a period of three months (twelve weeks). In some embodiments, the subject may have shown an insufficient response, loss of response, or intolerance to at least one therapeutic agent or treatment over a period of six months. In some embodiments, the subject may have shown an insufficient response, loss of response, or intolerance to at least one therapeutic agent or treatment over a period of nine months.

[0163] The amount of anti-OX40 antibody administered to a subject according to the methods disclosed herein is generally a therapeutically effective dose. In some embodiments, the therapeutic dose may range from about 1 mg to about 1200 mg. In one embodiment, 300 mg of anti-OX40 antibody is administered. In another embodiment, 600 mg of anti-OX40 antibody is administered.

[0164] The amount of anti-OX40 antibody contained in each dose can also be expressed in milligrams of antibody per kilogram of body weight of the subject (i.e., mg / kg). In certain embodiments, the anti-OX40 antibody used in the method herein can be administered to the subject in doses of about 0.01 to about 100 mg per kg of body weight of the subject. In some embodiments, the method involves administering the anti-OX40 antibody in doses of about 4 mg per kg of body weight of the patient. In some embodiments, the method involves administering the anti-OX40 antibody in doses of about 8 mg per kg of body weight of the patient.

[0165] A treatment cycle may comprise one or more doses of the anti-OX40 antibody described herein. In some embodiments, a treatment cycle may comprise two doses of the anti-OX40 antibody described herein. A treatment cycle may comprise three doses of the anti-OX40 antibody described herein.

[0166] If multiple doses are administered during a treatment cycle, they may be administered at different frequencies. In some embodiments, the method provided herein involves administering a single dose of the anti-OX40 antibody as described herein. In some embodiments, the anti-OX40 antibody is administered multiple times. In some embodiments, the method provided herein involves administering the anti-OX40 antibody to a subject at a frequency of once every two weeks.

[0167] For illustrative purposes, in some embodiments, the method provided herein comprises administering 300 mg of the anti-OX40 antibody described herein every two weeks, with three doses administered within four weeks to complete a treatment cycle. In some embodiments, the method provided herein comprises administering 600 mg of the anti-OX40 antibody described herein every two weeks, with three doses administered within four weeks to complete a treatment cycle.

[0168] All combinations and sequences of dosages and treatment plans described above are expressly intended herein. Dosage and frequency vary depending on the half-life of the anti-OX40 antibody in the patient. In therapeutic use, relatively high doses at relatively short intervals are sometimes required until disease progression is reduced or halted, and until the patient exhibits partial or complete remission of disease symptoms. Actual dose levels of the anti-OX40 antibody described herein may be varied to obtain an amount that is effective in achieving the desired therapeutic response with respect to a particular patient, composition, and mode of administration without being toxic to the patient. The selected dosage level depends on a variety of pharmacokinetic factors, including the activity of the particular composition of the present invention used, or their esters, salts, or amides; the route of administration; the time of administration; the excretion rate of the particular compound used; the duration of treatment; other drugs, compounds, and / or substances used in combination with the particular composition used; the age, sex, weight, body mass index (BMI), condition, overall health status, and prior medical history of the patient being treated, as well as similar factors well known in the medical field.

[0169] In some embodiments, additional therapeutic agents may be administered prior to, simultaneously with, or after the administration of the anti-OX40 antibody described herein.

[0170] In some embodiments, the anti-OX40 antibody described herein is administered in combination with a second therapeutic agent or treatment. In some embodiments, the second therapeutic agent or treatment for atopic dermatitis is selected from emollients such as petrolatum, topical prescription drugs such as topical steroids, oral antihistamines, and / or antibiotics.

[0171] In some embodiments, subjects are not administered topical treatments for AD, such as topical corticosteroids (TCS), topical calcineurin inhibitors (TCI), topical phosphodiesterase 4 inhibitors, or topical Janus kinase (JAK) inhibitors. In some embodiments, subjects are not previously administered non-biological systemic (oral or injectable) agents such as conventional immunosuppressants or immunomodulators (e.g., corticosteroids, methotrexate, cyclosporine, tacrolimus, mycophenolate mofetil, azathioprine, JAK inhibitors), or other approved or investigational drugs with potential immunosuppressive effects. In some embodiments, subjects have not previously used phototherapy for AD with ultraviolet (UV) A or UV B. In some embodiments, subjects have not previously received topical, intralesional, or systemic corticosteroids. In some embodiments, subjects are not administered systemic glucocorticoids. In some embodiments, subjects are not administered topically with calcineurin inhibitors. In some embodiments, subjects are not administered topical prescription drugs for AD. In some embodiments, subjects are not administered systemic glucocorticoids. In some embodiments, subjects are not administered immunoglobulins or blood products. In some embodiments, subjects are not administered systemic immunosuppressants and / or immunomodulators, such as cyclosporine, azathioprine, and / or methotrexate. In some embodiments, subjects are not administered JAK inhibitors, such as topical or oral JAK inhibitors (e.g., abrocitinib (CIBINQO) or upadacitinib (Rinvoq)). In some embodiments, subjects are not administered biological agents, including investigational drugs such as dupilumab (Dupixent), tralokinumab-ldrm (ADBRY), lebrikizumab, locatinlimab, amritelimab, terazolimab, and nemolizumab.

[0172] In some embodiments, the subject is not administered the aforementioned therapeutic agent or therapy prior to the administration of the anti-OX40 antibody disclosed herein. In some embodiments, the subject is not concurrently administered the aforementioned therapeutic agent or therapy during the administration of the anti-OX40 antibody disclosed herein.

[0173] In some embodiments, the treatment methods described herein induce clinical remission of AD. In some embodiments, the treatment methods described herein maintain clinical remission of AD. In some embodiments, the treatment methods described herein induce and maintain clinical remission of AD.

[0174] In some embodiments, the therapeutic methods described herein induce and / or maintain a clinical response. In some embodiments, the therapeutic methods described herein induce a clinical response. In some embodiments, the therapeutic methods described herein maintain a clinical response.

[0175] In some embodiments, the treatment methods described herein reduce the signs and / or symptoms of AD, for example, by lowering the EASI from baseline. In some embodiments, the treatment methods described herein reduce the signs of AD. In some embodiments, the treatment methods described herein reduce the symptoms of AD.

[0176] In some embodiments, the therapeutic effect is observed within 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 10 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 ​​weeks, or 52 weeks from the start of treatment. In some embodiments, the therapeutic effect is observed approximately 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 10 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 ​​weeks, or 52 weeks after the start of treatment. In some embodiments, the start of treatment refers to the first administration of the anti-OX40 antibody disclosed herein.

[0177] In some embodiments, the method provided herein is therapeutically effective in achieving at least a 30% reduction from the baseline EASI score of the subject. In some embodiments, the method provided herein is therapeutically effective in achieving at least a 50% reduction from the baseline EASI score of the subject. In some embodiments, the method provided herein is therapeutically effective in achieving at least a 75% reduction from the baseline EASI score of the subject. In some embodiments, the method provided herein is therapeutically effective in achieving at least a 90% reduction from the baseline EASI score of the subject. In some embodiments, the method is therapeutically effective in achieving at least a 50% reduction from the baseline EASI score of the subject about 12 weeks after the initiation of treatment. In some embodiments, the method is therapeutically effective in achieving at least a 50% reduction from the baseline EASI score of the subject about 16 weeks after the initiation of treatment. In some embodiments, the method is therapeutically effective in achieving at least a 50% reduction from the baseline EASI score of the subject about 24 weeks after the initiation of treatment. In some embodiments, the method is therapeutically effective in achieving at least a 50% reduction from the baseline EASI score of the subject about 36 weeks after the initiation of treatment. In some embodiments, the method is therapeutically effective in achieving at least a 50% reduction from the baseline EASI score within 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 ​​weeks, or 52 weeks from the start of treatment. In some embodiments, the method is therapeutically effective in achieving at least a 75% reduction from the baseline EASI score approximately 12 weeks after the start of treatment. In some embodiments, the method is therapeutically effective in achieving at least a 75% reduction from the baseline EASI score approximately 16 weeks after the start of treatment. In some embodiments, the method is therapeutically effective in achieving at least a 75% reduction from the baseline EASI score approximately 24 weeks after the start of treatment.In some embodiments, the method is therapeutically effective in achieving at least a 75% reduction from the baseline EASI score of the subject approximately 36 weeks after the start of treatment. In some embodiments, the method is therapeutically effective in achieving at least a 75% reduction from the baseline EASI score of the subject within 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 ​​weeks, or 52 weeks after the start of treatment. In some embodiments, the method is therapeutically effective in achieving at least a 90% reduction from the baseline EASI score of the subject approximately 12 weeks after the start of treatment. In some embodiments, the method is therapeutically effective in achieving at least a 90% reduction from the baseline EASI score of the subject approximately 16 weeks after the start of treatment. In some embodiments, the method is therapeutically effective in achieving at least a 90% reduction from the baseline EASI score of the subject approximately 24 weeks after the start of treatment. In some embodiments, the method is therapeutically effective in achieving at least a 90% reduction from the baseline EASI score of the subject approximately 36 weeks after the start of treatment. In some embodiments, the method is therapeutically effective in achieving at least a 90% reduction from the baseline EASI score of the subject within 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 ​​weeks, or 52 weeks after the start of treatment.

[0178] In some embodiments, the method provided herein is therapeutically effective in achieving a reduction of at least 1 point from the baseline IGA-AD score of the subject. In some embodiments, the method provided herein is therapeutically effective in achieving a reduction of at least 2 points from the baseline IGA-AD score of the subject. In some embodiments, the method provided herein is therapeutically effective in achieving a reduction of at least 3 points from the baseline IGA-AD score of the subject. In some embodiments, the reduction in the IGA-AD score is achieved approximately 12 weeks from the start of treatment. In some embodiments, the reduction in the IGA-AD score is achieved approximately 16 weeks from the start of treatment. In some embodiments, the reduction in the IGA-AD score is achieved approximately 24 weeks from the start of treatment. In some embodiments, the reduction in the IGA-AD score is achieved approximately 36 weeks from the start of treatment. In some embodiments, a reduction in the IGA-AD score is achieved within 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 ​​weeks, or 52 weeks from the start of treatment.

[0179] In some embodiments, the methods provided herein are therapeutically effective in achieving an IGA-AD score of 0. In some embodiments, the methods provided herein are therapeutically effective in achieving an IGA-AD score of 1. In some embodiments, an IGA-AD score of 0 or 1 is achieved approximately 12 weeks from the start of treatment. In some embodiments, an IGA-AD score of 0 or 1 is achieved approximately 16 weeks from the start of treatment. In some embodiments, an IGA-AD score of 0 or 1 is achieved approximately 24 weeks from the start of treatment. In some embodiments, an IGA-AD score of 0 or 1 is achieved approximately 36 weeks from the start of treatment. In some embodiments, an IGA-AD score of 0 or 1 is achieved within 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 ​​weeks, or 52 weeks from the start of treatment.

[0180] In some embodiments, the methods provided herein are therapeutically effective in achieving an IGA-AD score of 0, an IGA-AD score of 1, or a reduction of at least 2 points from the baseline IGA-AD score of the subject. In some embodiments, the methods provided herein are therapeutically effective in achieving an IGA-AD score of 0 and a reduction of at least 2 points from the baseline IGA-AD score of the subject. In some embodiments, the methods provided herein are therapeutically effective in achieving an IGA-AD score of 1 and a reduction of at least 2 points from the baseline IGA-AD score of the subject. In some embodiments, the methods provided herein are therapeutically effective in achieving a reduction of at least 30% from the baseline BSA of the subject. In some embodiments, the methods provided herein are therapeutically effective in achieving a reduction of at least 50% from the baseline BSA of the subject. In some embodiments, the methods provided herein are therapeutically effective in achieving a reduction of at least 75% from the baseline BSA of the subject. In some embodiments, the methods provided herein are therapeutically effective in achieving a reduction of at least 90% from the baseline BSA of the subject. In some embodiments, the reduction in the baseline BSA of the subject is achieved approximately 12 weeks after the start of treatment. In some embodiments, the reduction in baseline BSA is achieved approximately 16 weeks after the start of treatment. In some embodiments, the reduction in baseline BSA is achieved approximately 24 weeks after the start of treatment. In some embodiments, the reduction in baseline BSA is achieved approximately 36 weeks after the start of treatment. In some embodiments, the reduction in baseline BSA is achieved within 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 ​​weeks, or 52 weeks after the start of treatment.

[0181] In some embodiments, the methods provided herein are therapeutically effective in achieving at least a 50% reduction from the baseline SCORAD of the subject. In some embodiments, the methods provided herein are therapeutically effective in achieving at least a 75% reduction from the baseline SCORAD of the subject. In some embodiments, the methods provided herein are therapeutically effective in achieving at least a 90% reduction from the baseline SCORAD of the subject. In some embodiments, the reduction from the baseline SCORAD of the subject is achieved approximately 12 weeks after the start of treatment. In some embodiments, the reduction from the baseline SCORAD of the subject is achieved approximately 16 weeks after the start of treatment. In some embodiments, the reduction from the baseline SCORAD of the subject is achieved approximately 24 weeks after the start of treatment. In some embodiments, the reduction from the baseline SCORAD of the subject is achieved approximately 36 weeks after the start of treatment. In some embodiments, the reduction in baseline SCORAD in the subject is achieved within 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 ​​weeks, or 52 weeks from the start of treatment.

[0182] In some embodiments, the methods provided herein are therapeutically effective in achieving a reduction of at least 2 points on the NRS. In some embodiments, the methods provided herein are therapeutically effective in achieving a reduction of at least 3 points on the NRS. In some embodiments, the methods provided herein are therapeutically effective in achieving a reduction of at least 4 points on the NRS. In some embodiments, the methods provided herein are therapeutically effective in achieving a reduction of at least 5 points on the NRS. In some embodiments, the methods provided herein are therapeutically effective in achieving a reduction of at least 6 points on the NRS. In some embodiments, the methods provided herein are therapeutically effective in achieving a reduction of at least 7 points on the NRS.

[0183] In some embodiments, the methods provided herein are therapeutically effective in achieving at least a 30% reduction from the baseline WI-NRS of the subject. In some embodiments, the methods provided herein are therapeutically effective in achieving at least a 50% reduction from the baseline WI-NRS of the subject. In some embodiments, the methods provided herein are therapeutically effective in achieving at least a 75% reduction from the baseline WI-NRS of the subject. In some embodiments, the methods provided herein are therapeutically effective in achieving at least a 90% reduction from the baseline WI-NRS of the subject. In some embodiments, the reduction in the baseline WI-NRS of the subject is achieved approximately 12 weeks after the start of treatment. In some embodiments, the reduction in the baseline WI-NRS of the subject is achieved approximately 16 weeks after the start of treatment. In some embodiments, the reduction in the baseline WI-NRS of the subject is achieved approximately 24 weeks after the start of treatment. In some embodiments, the reduction in the baseline WI-NRS of the subject is achieved approximately 36 weeks after the start of treatment. In some embodiments, the reduction in the subject's baseline WI-NRS is achieved within 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 ​​weeks, or 52 weeks from the start of treatment.

[0184] In some embodiments, the methods provided herein are therapeutically effective in achieving at least a 30% reduction from the baseline SQ-NRS of the subject. In some embodiments, the methods provided herein are therapeutically effective in achieving at least a 50% reduction from the baseline SQ-NRS of the subject. In some embodiments, the methods provided herein are therapeutically effective in achieving at least a 75% reduction from the baseline SQ-NRS of the subject. In some embodiments, the methods provided herein are therapeutically effective in achieving at least a 90% reduction from the baseline SQ-NRS of the subject. In some embodiments, the reduction from the baseline SQ-NR of the subject is achieved approximately 12 weeks after the start of treatment. In some embodiments, the reduction from the baseline SQ-NR of the subject is achieved approximately 16 weeks after the start of treatment. In some embodiments, the reduction from the baseline SQ-NR of the subject is achieved approximately 24 weeks after the start of treatment. In some embodiments, the reduction from the baseline SQ-NR of the subject is achieved approximately 36 weeks after the start of treatment. In some embodiments, the reduction in the baseline SQ-NR of the subject is achieved within 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 ​​weeks, or 52 weeks from the start of treatment.

[0185] In some embodiments, the methods provided herein are therapeutically effective in achieving a PGIS-AD score of 0. In some embodiments, the methods provided herein are therapeutically effective in achieving a PGIS-AD score of 1. In some embodiments, a PGIS-AD score of 0 or 1 is achieved approximately 12 weeks from the start of treatment. In some embodiments, a PGIS-AD score of 0 or 1 is achieved approximately 16 weeks from the start of treatment. In some embodiments, a PGIS-AD score of 0 or 1 is achieved approximately 24 weeks from the start of treatment. In some embodiments, a PGIS-AD score of 0 or 1 is achieved approximately 36 weeks from the start of treatment. In some embodiments, a PGIS-AD score of 0 or 1 is achieved within 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 ​​weeks, or 52 weeks from the start of treatment.

[0186] In some embodiments, the methods provided herein are therapeutically effective in achieving “significantly improved” PGIC-AD. In some embodiments, the methods provided herein are therapeutically effective in achieving “slightly improved” PGIC-AD. In some embodiments, “significantly improved” or “slightly improved” PGIC-AD is achieved approximately 12 weeks after the start of treatment. In some embodiments, “significantly improved” or “slightly improved” PGIC-AD is achieved approximately 16 weeks after the start of treatment. In some embodiments, “significantly improved” or “slightly improved” PGIC-AD is achieved approximately 24 weeks after the start of treatment. In some embodiments, “significantly improved” or “slightly improved” PGIC-AD is achieved approximately 36 weeks after the start of treatment. In some embodiments, "significantly improved" or "slightly improved" PGIC-AD is achieved within 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 ​​weeks, or 52 weeks from the start of treatment.

[0187] In some embodiments, the methods provided herein are therapeutically effective in achieving a change in DLQI. In some embodiments, the methods provided herein are therapeutically effective in achieving a reduction of at least 3 points in DLQI. In some embodiments, the methods provided herein are therapeutically effective in achieving a reduction of at least 4 points in DLQI. In some embodiments, the methods provided herein are therapeutically effective in achieving a reduction of at least 5 points in DLQI. In some embodiments, the methods provided herein are therapeutically effective in achieving a reduction of at least 6 points in DLQI. In some embodiments, the methods provided herein are therapeutically effective in achieving a reduction of at least 7 points in DLQI. In some embodiments, the methods provided herein are therapeutically effective in achieving a reduction of at least 8 points in DLQI. In some embodiments, the change in DLQI is achieved approximately 12 weeks from the start of treatment. In some embodiments, the change in DLQI is achieved approximately 16 weeks from the start of treatment. In some embodiments, the change in DLQI is achieved approximately 24 weeks from the start of treatment. In some embodiments, the change in DLQI is achieved approximately 36 weeks from the start of treatment. In some embodiments, changes in DLQI are achieved within 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 ​​weeks, or 52 weeks from the start of treatment.

[0188] In some embodiments, the method further includes detecting AD-related biomarkers in a subject. In some embodiments, the method further includes selecting a subject based on the level of AD-related biomarkers before administering the anti-OX40 antibody described herein to the subject. In some embodiments, administration of the anti-OX40 antibody described herein alters the level of AD-related biomarkers in the subject.

[0189] As used herein, the term “AD-related biomarker” means any biological response, cell type, parameter, protein, polypeptide, enzyme, enzyme activity, metabolite, nucleic acid, carbohydrate, or other biomolecule that is present or detectable in patients with AD at levels or amounts different from (e.g., greater or smaller) than the levels or amounts of markers present or detectable in patients without AD. The term “AD-related biomarker” also includes genes or gene probes known in the Art that are differentially expressed in subjects with AD compared to subjects without AD.

[0190] In some embodiments, the biomarker is CCL17. In some embodiments, subjects treated with the anti-OX40 antibody described herein show elevated levels of CCL17. In some embodiments, administration of the anti-OX40 antibody described herein reduces the level of CCL17 in subjects by 15-85% or more.

[0191] In some embodiments, the biomarker is evaluated using histology. In some embodiments, the biomarker is evaluated using RNA-seq. In some embodiments, the biomarker is evaluated using proteomic analysis. In some embodiments, the biomarker is evaluated using enzyme-linked immunosorbent assay. In some embodiments, the biomarker is evaluated using mass spectrometry. In some embodiments, the biomarker is evaluated using blood samples. In some embodiments, the biomarker is evaluated using serum samples. In some embodiments, the biomarker is evaluated using plasma samples. In some embodiments, the biomarker is evaluated using tissue samples. In some embodiments, the biomarker is evaluated using punch biopsy. In some embodiments, the biomarker is evaluated using tape strips.

[0192] In some embodiments, the methods provided herein further include monitoring for adverse events during administration of the anti-OX40 antibody described herein and optionally interrupting or discontinuing administration. As used herein and as understood in the art, “adverse event” means an undesirable medical event associated with treatment with the anti-OX40 antibody described herein.

[0193] In some embodiments, the methods provided herein further include monitoring vital signs (including blood pressure, pulse, respiratory rate, and body temperature) and / or physical examination during administration, or monitoring hematology and serological chemistry during the treatment cycle. In some embodiments, heart rate or cardiac signals are monitored. In some embodiments, heart rate or cardiac signals are monitored by electrocardiogram.

[0194] In some embodiments, the methods provided herein reduce the incidence and severity of adverse events resulting from the treatment of the conditions described herein. In some embodiments, the methods provided herein result in no serious adverse events.

[0195] In some embodiments, the methods provided herein do not result in local or systemic infusion-related reactions, including but not limited to fever or chills. In some embodiments, 80%, 70%, 60%, 50%, 40%, 30%, 25%, 20%, 15%, 10%, 8%, 5%, 3%, 2%, or less than 1% of subjects administered with the anti-OX40 antibody described herein report local or systemic infusion-related reactions. In some embodiments, 80%, 70%, 60%, 50%, 40%, 30%, 25%, 20%, 15%, 10%, 8%, 5%, 3%, 2%, or less than 1% of subjects administered with the anti-OX40 antibody described herein report fever or chills.

[0196] 1.4 Exemplary Embodiments Embodiment 1: A method for treating alopecia areata (AA) in a subject requiring treatment for alopecia areata (AA), comprising administering a therapeutically effective amount of an anti-OX40 antibody or its antigen-binding fragment to the subject, wherein the antibody comprises (1) a light chain variable region (VL) comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively, and (2) a heavy chain variable region (VH) comprising VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 4, 5, and 6, respectively.

[0197] Embodiment 2: The method according to Embodiment 1, wherein the anti-OX40 antibody or antigen-binding fragment is a chimeric antibody or antigen-binding fragment, a humanized antibody or antigen-binding fragment, or a human antibody or antigen-binding fragment.

[0198] Embodiment 3: The method according to Embodiment 2, wherein the anti-OX40 antibody or antigen-binding fragment is a humanized antibody or antigen-binding fragment.

[0199] Embodiment 4: (1) The VL has at least 85%, at least 90%, at least 95%, at least 98%, or 100% sequence identity with respect to the amino acid sequence of SEQ ID NO: 7; and / or (2) The method according to Embodiment 3, wherein the VH has at least 85%, at least 90%, at least 95%, at least 98%, or 100% sequence identity with respect to the amino acid sequence of SEQ ID NO: 8.

[0200] Embodiment 5: The method according to Embodiment 4, wherein VL has the amino acid sequence of SEQ ID NO: 7, 9, or 10, and VH has the amino acid sequence of SEQ ID NO: 8, 11, or 12.

[0201] Embodiment 6: The method according to Embodiment 4, wherein VL and VH have the amino acid sequences of SEQ ID NOs: 7 and 8, respectively.

[0202] Embodiment 7: The method according to any one of Embodiments 1 to 6, wherein the anti-OX40 antibody or antigen-binding fragment is selected from the group consisting of Fab, Fab', F(ab')2, Fv, scFv, and (scFv)2.

[0203] Embodiment 8: The method according to any one of Embodiments 1 to 6, wherein the anti-OX40 antibody or antigen-binding fragment is an IgG1 antibody, an IgG2 antibody, an IgG3 antibody, or an IgG4 antibody.

[0204] Embodiment 9: The method according to Embodiment 8, wherein the anti-OX40 antibody is a humanized IgG1 antibody.

[0205] Embodiment 10: The method according to Embodiment 9, wherein the anti-OX40 antibody comprises a light chain constant region (CL) having at least 85% sequence identity with kappa CL (Cκ; SEQ ID NO: 13) or lambda CL (Cλ; SEQ ID NO: 14).

[0206] Embodiment 11: The method according to Embodiment 10, wherein CL is Cκ (SEQ ID NO: 13).

[0207] Embodiment 12: The method according to any one of Embodiments 9 to 11, wherein the anti-OX40 antibody comprises the wild-type heavy chain constant region (CH) of human IgG1 (SEQ ID NO: 16), or a variant thereof in which binding to FcγR is reduced.

[0208] Embodiment 13: The method according to Embodiment 12, wherein the anti-OX40 antibody comprises the CH region of human IgG1 having an N297A substitution.

[0209] Embodiment 14: The method according to Embodiment 9, wherein the anti-OX40 antibody comprises a light chain having the amino acid sequence of SEQ ID NO: 19 and a heavy chain having the amino acid sequence of SEQ ID NO: 20.

[0210] Embodiment 15: The method according to any one of Embodiments 1 to 14, wherein the subject has moderate or severe AA.

[0211] Embodiment 16: The method according to any one of Embodiments 1 to 14, wherein the subject has 50% or more of scalp hair loss, or has a Saliva Severity Tool (SALT) score of at least 50.

[0212] Embodiment 17: The method according to Embodiment 15 or 16, wherein the subject has diffuse alopecia areata, alopecia areata monolocularis, alopecia areata multilocularis, serpentine alopecia, alopecia areata barbae, alopecia areata totalis, or alopecia areata universalis.

[0213] Embodiment 18: The method according to any one of Embodiments 1 to 17, wherein the subject is diagnosed with AA, and the current hair loss episode has lasted for more than 6 months.

[0214] Embodiment 20: The method according to Embodiment 19, wherein the anti-OX40 antibody is administered by intravenous injection.

[0215] Embodiment 21: The method according to any one of Embodiments 1 to 20, comprising an anti-OX40 antibody in doses ranging from approximately 1 mg to approximately 1200 mg.

[0216] Embodiment 23: The method according to Embodiment 21, comprising administering approximately 300 mg of the anti-OX40 antibody to the subject.

[0217] Embodiment 24: The method according to Embodiment 21, comprising administering approximately 600 mg of the anti-OX40 antibody to the subject.

[0218] Embodiment 25: The method according to any one of Embodiments 1 to 24, comprising one or more doses of the anti-OX40 antibody.

[0219] Embodiment 26: The method according to Embodiment 25, comprising three administrations of the anti-OX40 antibody.

[0220] Embodiment 27: The method according to Embodiment 26, wherein the anti-OX40 antibody is administered once every two weeks.

[0221] Embodiment 28: The method according to any one of Embodiments 1 to 27, wherein the method is therapeutically effective in achieving at least a 30% reduction from an individual's baseline SALT score.

[0222] Embodiment 29: The method according to Embodiment 28, wherein the method is therapeutically effective in achieving a reduction in baseline SALT score at approximately 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 ​​weeks, or 52 weeks after the start of treatment.

[0223] Embodiment 30: The method according to Embodiment 29, wherein the method is therapeutically effective in achieving a reduction in baseline SALT score in about 16 weeks.

[0224] Embodiment 31: The method according to Embodiments 1 to 27, wherein the method is therapeutically effective in inducing a SALT score of 10 or less (i.e., inducing hair regeneration in at least 90% of the scalp of subjects suffering from AA), or inducing a SALT score of 20 or less (i.e., inducing hair regeneration in at least 80% of the scalp of subjects suffering from AA).

[0225] Embodiment 32: The method according to any one of Embodiments 1 to 31, wherein the administration does not result in any serious adverse events related to the treatment.

[0226] Embodiment 33: A method for treating atopic dermatitis (AD) in a subject requiring treatment for atopic dermatitis (AD), comprising administering to the subject a therapeutically effective amount of an anti-OX40 antibody or an antigen-binding fragment thereof, the subject comprising: (1) a light chain variable region (VL) comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively; and (2) a heavy chain variable region (VH) comprising VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 4, 5, and 6, respectively.

[0227] Embodiment 34: The method according to Embodiment 33, wherein the anti-OX40 antibody or antigen-binding fragment is a chimeric antibody or antigen-binding fragment, a humanized antibody or antigen-binding fragment, or a human antibody or antigen-binding fragment.

[0228] Embodiment 35: The method according to Embodiment 34, wherein the anti-OX40 antibody or antigen-binding fragment is a humanized antibody or antigen-binding fragment.

[0229] Embodiment 36: (1) The VL has at least 85%, at least 90%, at least 95%, at least 98%, or 100% sequence identity with respect to the amino acid sequence of SEQ ID NO: 7; and / or (2) The method according to Embodiment 35, wherein the VH has at least 85%, at least 90%, at least 95%, at least 98%, or 100% sequence identity with respect to the amino acid sequence of SEQ ID NO: 8.

[0230] Embodiment 37: The method according to Embodiment 36, wherein VL has the amino acid sequence of SEQ ID NO: 7, 9, or 10, and VH has the amino acid sequence of SEQ ID NO: 8, 11, or 12.

[0231] Embodiment 38: The method according to Embodiment 36, wherein VL and VH have the amino acid sequences of SEQ ID NOs. 7 and 8, respectively.

[0232] Embodiment 39: The method according to any one of Embodiments 33 to 38, wherein the anti-OX40 antibody or antigen-binding fragment is selected from the group consisting of Fab, Fab', F(ab')2, Fv, scFv, and (scFv)2.

[0233] Embodiment 40: The method according to any one of Embodiments 33 to 38, wherein the anti-OX40 antibody or antigen-binding fragment is an IgG1 antibody, an IgG2 antibody, an IgG3 antibody, or an IgG4 antibody.

[0234] Embodiment 41: The method according to Embodiment 30, wherein the anti-OX40 antibody is a humanized IgG1 antibody.

[0235] Embodiment 42: The method according to Embodiment 41, wherein the anti-OX40 antibody comprises a light chain constant region (CL) having at least 85% sequence identity with kappa CL (Cκ; SEQ ID NO: 13) or lambda CL (Cλ; SEQ ID NO: 14).

[0236] Embodiment 43: The method according to Embodiment 42, wherein CL is Cκ (SEQ ID NO: 13).

[0237] Embodiment 44: The method according to any one of Embodiments 41 to 43, wherein the anti-OX40 antibody comprises the wild-type heavy chain constant region (CH) of human IgG1 (SEQ ID NO: 16), or a variant thereof in which binding to FcγR is reduced.

[0238] Embodiment 45: The method according to Embodiment 44, wherein the anti-OX40 antibody comprises the CH region of human IgG1 having an N297A substitution.

[0239] Embodiment 46: The method according to Embodiment 45, wherein the anti-OX40 antibody comprises a light chain having the amino acid sequence of SEQ ID NO: 19 and a heavy chain having the amino acid sequence of SEQ ID NO: 20.

[0240] Embodiment 47: The method according to any one of Embodiments 33 to 46, wherein the subject has moderate or severe AD.

[0241] Embodiment 48: The method according to Embodiment 47, wherein the subject has a) at least 12 eczema area and severity index (EASI) scores, b) at least 3 investigator-reported global assessment (IGA)-AD scores, and c) 10% or more of body surface area (BSA).

[0242] Embodiment 49: The method according to Embodiment 48, wherein the subject has at least 16 EASI scores.

[0243] Embodiment 50: The method according to any one of Embodiments 33 to 49, wherein the subject has been diagnosed with AD for at least 6 months.

[0244] Embodiment 51: The method according to Embodiment 50, wherein the anti-OX40 antibody is administered by intravenous injection.

[0245] Embodiment 52: The method according to Embodiments 33 to 51, comprising administering approximately 1 mg to approximately 1200 mg of anti-OX40 antibody to the subject.

[0246] Embodiment 53: The method according to Embodiment 52, comprising administering approximately 300 mg of the anti-OX40 antibody to the subject.

[0247] Embodiment 54: The method according to Embodiment 52, comprising administering approximately 600 mg of the anti-OX40 antibody to the subject.

[0248] Embodiment 55: The method according to any one of Embodiments 33 to 54, comprising one or more doses of the anti-OX40 antibody.

[0249] Embodiment 56: The method according to Embodiment 55, comprising three administrations of the anti-OX40 antibody.

[0250] Embodiment 57: The method according to Embodiment 56, wherein the anti-OX40 antibody is administered once every two weeks.

[0251] Embodiment 58: The method according to Embodiment 55, comprising administering the anti-OX40 antibody three times at two-week intervals.

[0252] Embodiment 59: The method according to any one of Embodiments 33 to 58, wherein the method is therapeutically effective in a) achieving a reduction of at least 75% from an individual's baseline EASI score, b) achieving a reduction of at least 90% from an individual's baseline EASI score, c) achieving a reduction of at least 4 points in the DLQI score, or d) achieving an IGA-AD score of 0 or 1, thereby achieving a reduction of at least 2 points from the baseline IGA-AD score.

[0253] Embodiment 60: The method according to Embodiment 59, wherein the method is therapeutically effective in achieving a reduction at approximately 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 ​​weeks, or 52 weeks from the start of treatment.

[0254] Embodiment 61: The method according to Embodiment 60, wherein the method is therapeutically effective in achieving a reduction in about 12 weeks.

[0255] Embodiment 62: The method according to any one of Embodiments 33 to 61, wherein the administration does not result in any serious adverse events related to the treatment.

[0256] Unless otherwise indicated, the implementation of this specification will utilize conventional techniques in molecular biology, cell biology, microbiology, genetic analysis, recombinant DNA, organic chemistry, biochemistry, PCR, oligonucleotide synthesis and modification, nucleic acid hybridization, and related fields within the art. These techniques are described in and fully explained in the references cited herein.For example, Maniatis et al. (1982) Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press; Sambrook et al. (1989), Molecular Cloning: A Laboratory Manual, Second Edition, Cold Spring Harbor Laboratory Press; Sambrook et al. (2001) Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY; Ausubel et al., Current Protocols in Molecular Biology,John Wiley&Sons (1987 and annual updates) al.(eds.)(1999) Genome Analysis:A Laboratory See Manual, Cold Spring Harbor Laboratory Press; Borrebaeck (ed.) (1995) Antibody Engineering, Second Edition, Oxford University Press; Lo (ed.) (2006) Antibody Engineering: Methods and Protocols (Methods in Molecular Biology); Vol. 248, Humana Press, Inc. Each of these is incorporated herein by reference in its entirety.

[0257] 1.5 Experiment The examples provided below are for illustrative purposes only and are not limiting unless otherwise specified. Therefore, the present invention should be construed as encompassing any variations that become apparent as a result of the teachings provided herein, rather than being limited to the following examples.

[0258] The active pharmaceutical ingredient investigated in the research described below is a humanized anti-OX40 IgG1 monoclonal antibody, whose light chain has the amino acid sequence of SEQ ID NO: 19 and whose heavy chain has the amino acid sequence of SEQ ID NO: 20 (hereinafter referred to as "API").

[0259] In short, the results of the studies described below show that APIs are safe and effective in treating AA and AD.

[0260] Example 1: Phase 1b / 2a trial in adult participants with alopecia areata (AA) This Phase 1b / 2a trial aims to evaluate the safety, pharmacokinetics (PK), efficacy, and pharmacodynamics (PD) of AP in AA participants. Approximately 30 participants are expected.

[0261] Study group The study population includes adults with AA. Inclusion criteria include: 1) Males or females aged 18 to 65 years (inclusive) at the time of signing the consent form. 2) Willingness to participate in and abide by all study procedures and restrictions and to provide written informed consent to participate in the study. 3) Having a clinical diagnosis of AA and a current episode of hair loss between 6 months and 8 years prior to screening. 4) No evidence of terminal hair regrowth within 6 months prior to the screening and baseline (day 1) visit. 5) Having AA (including AT and AU) covering 50% or more of the scalp, defined as a SALT score of 50 or higher (out of a total of 100) at the screening and baseline (day 1) visit.

[0262] Research period : Each treatment cohort consists of three periods: a screening period of up to 5 weeks, a treatment period of 16 weeks, and a follow-up period of 8 weeks.

[0263] The treatment period is from day 1 (baseline) to day 113 (16 weeks). Participants who meet all eligibility criteria are enrolled and receive three IV infusions of API 300 mg or 600 mg at two-week intervals at the baseline (day 1), week 2 (day 15), and week 4 (day 29) visits.

[0264] Participants receive additional examinations at week 1 (day 8), week 6 (day 43), week 8 (day 57), week 12 (day 85), and week 16 (day 113) / end of treatment (EOT).

[0265] Therapeutic administration:

[0266] [[ID=1,6]] API is prepared according to the desired dosage, diluted with isotonic saline (commercially available 0.9% sodium chloride), and then administered via an IV infusion solution. The dosages are as follows. [[ID=1,9]] Cohort 1 (6 participants): Infuse API 300 mg Q2W three times within 4 weeks. Cohort 2 (24 participants): Infuse API 600 mg Q2W three times within 4 weeks.

[0267] Test evaluation : At least the following evaluations are performed during the trial.

[0268] Safety evaluation: Treatment-emergent adverse events (TEAEs), treatment-emergent serious adverse events (SAEs), and TEAEs leading to treatment discontinuation.

[0269] Efficacy evaluation: In-hospital evaluation by the principal investigator: Principal investigator evaluation of SALT score, Principal investigator evaluation of target scalp lesions (IATS), Principal investigator overall evaluation of eyebrows (IGA-EB), Principal investigator overall evaluation of eyelashes (IGA-EL), Principal investigator overall evaluation of nails (IGA-FN). In-hospital evaluation by participants: Patient overall impression (PGIS) regarding the severity of AA (PGIS-AA) and AA on the scalp (PGIS-S), eyebrows (PGIS-EB), eyelashes (PGIS-EL), and fingernails (PGIS-FN). Patient overall impression (PGIC) regarding changes in AA (PGIC-AA) and AA on the scalp (PGIC-S), eyebrows (PGIC-EB), eyelashes (PGIC-EL), and fingernails (PGIC-FN). Priority outcome for alopecia areata patients (AAPPO). Hospital Anxiety and Depression Scale (HADS). Scalp photographs from four planes / views (left, right, top, posterior) and the targeted scalp lesion.

[0270] Pharmacodynamic evaluation: Blood samples are taken for analysis of inflammation-related proteins. Scalp biopsy samples are collected for biopsy, transcriptome analysis, and immunohistochemical staining for tissue biomarkers.

[0271] Test endpoints : Incidence of TEAE, PK: Central compartment clearance (CL) and central compartment volume (Vc) of API, and percentage change in SALT from baseline to 16 weeks.

[0272] Example 2: Phase 1b / 2a study in adult patients with atopic dermatitis (AD) This Phase 1b / 2a open-label trial aims to evaluate the safety, tolerability, pharmacokinetics (PK), efficacy, and pharmacodynamics (PD) of multiple doses of API in patients with Alzheimer's disease (AD). Approximately 24 participants are expected.

[0273] This study consists of two dose cohorts, which are started sequentially in ascending order of dose. Cohort 1 So, at least 10 participants will receive three IV infusions of 300 mg of API over a four-week period. Cohort 2So, at least 12 participants will receive three IV infusions of API 600mg over a four-week period.

[0274] Study group The study population includes adults with moderate or severe Alzheimer's disease (AD). The inclusion criteria are as follows: 1) Males or females aged 18 to under 75 years. 2) Willingness to participate in and abide by all study procedures and restrictions and to provide written informed consent to participate in the study. 3) At the time of the screening visit, diagnosed with A at least 6 months prior to the screening visit, according to the consensus diagnostic criteria of the American Academy of Dermatology. 4) Criteria defined as moderate to severe AD: a) EASI score of 12 or higher at the screening visit and 16 or higher at the baseline visit. b) IGA of 3 or higher at both the screening and baseline visits. c) Body surface area (BSA) of 10% or higher at both the screening and baseline visits. 5) Prior to the screening visit, the patient has been evaluated by a knowledge physician for an inadequate response to or lack of tolerance to one or more stable regimens (4 weeks or longer) of topical treatment, such as topical corticosteroids (TCS) or topical calcineurin inhibitors (TCI), or has a record of being deemed unsuitable for topical treatment. 6) The patient agrees to apply a stable dose of non-medicinal emollient (moisturizer) twice daily from at least one week before the baseline visit throughout the trial period.

[0275] Research period: Each treatment cohort consists of three periods: a screening period of up to 5 weeks, a treatment period of 12 weeks, and a follow-up period of 12 weeks.

[0276] Treatment period: The study period is from day 1 (baseline) to day 85 (12 weeks). Participants who meet all eligibility criteria are enrolled and receive three IV infusions of API 300 mg or 600 mg at 2-week intervals during visits at baseline (day 1), week 2 (day 15), and week 4 (day 29).

[0277] Participants will receive additional consultations in Week 1 (Day 8), Week 6 (Day 43), Week 8 (Day 57), and Week 12 (Day 85) / End of Treatment (EOT).

[0278] Therapeutic administration:

[0279] The API is prepared to the desired dosage, diluted with isotonic saline (commercially available 0.9% sodium chloride), and then administered via IV infusion. For Cohort 1: 300 mg of API is administered intravenously three times within four weeks at Q2W. For Cohort 2: API 600 mg is administered intravenously three times within 4 weeks at Q2W.

[0280] Test evaluation During the test, at least the following evaluations will be performed:

[0281] Safety evaluation: Treatment-induced adverse events (TEAEs), treatment-induced serious adverse events (SAEs), and TEAEs leading to discontinuation of treatment.

[0282] Efficacy evaluation: In-hospital evaluation by the principal investigator (Eczema Area and Severity Index (EASI), Principal Investigator's Overall Assessment (IGA), Atopic Dermatitis Scoring Index (SCORAD), Body Surface Area (BSA), etc.). In-hospital evaluation by the patient (Most severe itching and sleep quality due to atopic dermatitis in the 7 days immediately preceding the scheduled visit, Patient's General Impression of Atopic Dermatitis Severity (PGIS), Patient's General Impression of Changes in Atopic Dermatitis (PGIC), Dermatological Quality of Life Index (DLQI), Patient's Numerical Rating Scale for Itching and Sleep Quality (NRS), Photographs of Atopic Dermatitis Lesions (optional), etc.).

[0283] PD assessment: Measure levels of inflammatory markers such as thymus and activating regulatory chemokines (TARCs), OX40 receptor occupancy in blood samples, and tissue biomarkers related to OX40-OX40 ligand signaling and AD pathophysiology (skin lesion biopsy is optional).

[0284] Test endpoints : Incidence of TEAE, PK: Central compartment clearance (CL) and central compartment volume (Vc) of API, and rate of change of EASI from baseline to 12 weeks.

[0285] 1.6 References One of the specifications was developed in the following manner: Bai S et al. (2012)Clin Pharmacokinet.51(2):119-135;Bieber T.(2021).Nat Rev Drug Discov.21(1):21-40;Eichenfield LF et al.(2014).J Am Acad Dermatol.70(2):338-351;Elsner J et al.(2020).Acta Derm Venereol.100(6):1-5;European Task Force on Atopic Dermatitis.(1993)Dermatology 186(1):23-31;Fu Y et al.(2020)Acta Pharm Sin B.10(3):414-433;Furihata K et al.(2021)Clin Pharmacol Drug Dev.10(8):870-883;Guttman-Yassky E et al.(2019)J Allergy Clin Immunol.144(2):482-493.e7;Guttman-Yassky E.(2021). et al. (2023).Lancet.401(10372):204-214;Hanifin JM et al.(2001).EASI Evaluator Group.Exp Dermatol.10(1):11-18;Kunz B et al.(1997)Dermatology.195(1):10-19;Nakagawa H et al.(2020)J Dermatol Sci.99(2):82-89;Renert-Yuval Y and Guttman-Yassky E.(2020)Ann Allergy Asthma Immunol.124(1):28-35;Rosenberg AS and Worobec A.(2004)Biopharm International. 17(11):22-26;Sampson HA et al.(2006)J Allergy Clin Immunol.117(2):391-397;Shah D K, Betts A M.(2013)MAbs.5(2),297-305;Sher L. (2021)Society of Investigative Dermatology Annual Meeting,8 May 2021;Webb GJ et al. (2016)Clin Rev Allergy Immunol.50(3):312-332;Bertolini M et al.(2014) PLoS One.9(5):e94260;Bulfone-Paus S, Bahri R.(2015)Front Immunol.6:394;Czarnowicki T et al.(2018)Allergy 73(3):713-723;Glickman JW et al.(2021) Allergy.76(10):3053-3065;Glickman JW et al.(2021)J Am Acad Dermatol.84(2):370-380;Harries M et al.(2022)Br J Dermatol.186(2):257-265;Iriki H et al.(2023)J Invest Dermatol.143(4):545-553;King B et al.(2021) J Am Acad Dermatol.85(4):847-853;King B et al.(2022) N Engl J Med.386(18):1687-1699;King BA et al.(2022)Dermatol Ther(Heidelb). 12(4):825-834;King BA et al.(2022)J Am Acad Dermatol.86(2):359-364;Lee S et al.(2019)J Am Acad Dermatol.80(2):466-477.e16.Meah N et al.(2020)J Am Acad Dermatol.83(1):123-130;Mesinkovska N et al.(2020)J Investig Dermatol Symp Proc.20(1):S62-S68;Mostaghimi A et al.(2023)JAMA Dermatol.159(4):411-418;Nakae S et al.(2005)Proc Natl Acad Sci US A.102(18):6467-6472;Olayinka JJT,Richmond JM (2021)Curr Res Immunol.2:7-11;Olsen EA et al.(2004)J Am Acad Dermatol.51(3):440-447;Pratt CH et al.(2017)Night Rev Dis Primers 3:17011;Redler S et al.(2015)J Invest Dermatol.135(3):919-921;Winnette R et al.(2021)Dermatol Ther(Heidelb).11(2):599-613;Wyrwich KW et al.(2022)Dermatol Ther(Heidelb).12(1):149-166;Zigmond AS(1983).Acta Psychiatr Scand.67(6):361-370.

Claims

1. A method for treating alopecia areata (AA) in a subject requiring treatment for alopecia areata (AA), comprising administering to the subject a therapeutically effective amount of an anti-OX40 antibody or an antigen-binding fragment thereof, the subject having (1) a light chain variable region (VL) comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively, and (2) a heavy chain variable region (VH) comprising VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 4, 5, and 6, respectively.

2. The method according to claim 1, wherein the anti-OX40 antibody or antigen-binding fragment is a chimeric antibody or antigen-binding fragment, a humanized antibody or antigen-binding fragment, or a human antibody or antigen-binding fragment.

3. The method according to claim 2, wherein the anti-OX40 antibody or antigen-binding fragment is a humanized antibody or antigen-binding fragment.

4. The method according to claim 3, wherein (1) VL has at least 85%, at least 90%, at least 95%, at least 98%, or 100% sequence identity with respect to the amino acid sequence of SEQ ID NO: 7; and / or (2) VH has at least 85%, at least 90%, at least 95%, at least 98%, or 100% sequence identity with respect to the amino acid sequence of SEQ ID NO:

8.

5. The method according to claim 4, wherein VL has the amino acid sequence of SEQ ID NO: 7, 9, or 10, and VH has the amino acid sequence of SEQ ID NO: 8, 11, or 12.

6. The method according to claim 4, wherein VL and VH each have the amino acid sequences of SEQ ID NOs: 7 and 8, respectively.

7. The anti-OX40 antibody or antigen-binding fragment is Fab, Fab', F(ab') ２ , Fv, scFv, and (scFv) ２ A method according to any one of claims 1 to 6, selected from the group consisting of the following.

8. The method according to any one of claims 1 to 6, wherein the anti-OX40 antibody or antigen-binding fragment is an IgG1 antibody, an IgG2 antibody, an IgG3 antibody, or an IgG4 antibody.

9. The method according to claim 8, wherein the anti-OX40 antibody is a humanized IgG1 antibody.

10. The method according to claim 9, wherein the anti-OX40 antibody comprises a light chain constant region (CL) having at least 85% sequence identity with kappa CL (Cκ; SEQ ID NO: 13) or lambda CL (Cλ; SEQ ID NO: 14).

11. The method according to claim 10, wherein CL is Cκ (SEQ ID NO: 13).

12. The method according to any one of claims 9 to 11, wherein the anti-OX40 antibody comprises the wild-type heavy chain constant region (CH) of human IgG1 (SEQ ID NO: 16), or a variant thereof in which binding to FcγR is reduced.

13. The method according to claim 12, wherein the anti-OX40 antibody comprises the CH region of human IgG1 having the N297A substitution.

14. The method according to claim 9, wherein the anti-OX40 antibody comprises a light chain having the amino acid sequence of SEQ ID NO: 19 and a heavy chain having the amino acid sequence of SEQ ID NO:

20.

15. The method according to any one of claims 1 to 14, wherein the subject has moderate or severe AA.

16. The method according to any one of claims 1 to 14, wherein the subject has 50% or more of the scalp affected by hair loss, or has an Alopecia Severity Tool (SALT) score of at least 50.

17. The method according to claim 15 or 16, wherein the subject is diffuse alopecia areata, monolocular alopecia areata (alopecia areata monolocularis), multiple alopecia areata (alopecia areata multilocularis), serpentine alopecia, beard alopecia areata (alopecia areata barbae), alopecia totalis (alopecia areata totalis), or alopecia universalis (alopecia areata universalis).

18. The method according to any one of claims 1 to 17, wherein the subject is diagnosed with AA, in which the current hair loss episode has lasted for more than six months.

19. The method according to claims 1 to 18, wherein the anti-OX40 antibody is administered by intravenous injection.

20. The method according to any one of claims 1 to 19, comprising an anti-OX40 antibody in doses ranging from approximately 1 mg to approximately 1200 mg.

21. The method according to claim 20, comprising administering approximately 300 mg of the anti-OX40 antibody to the subject.

22. The method according to claim 20, comprising administering approximately 600 mg of the anti-OX40 antibody to the subject.

23. The method according to any one of claims 1 to 22, comprising one or more administrations of the anti-OX40 antibody.

24. The method according to claim 23, comprising three administrations of the anti-OX40 antibody.

25. The method according to claim 23, wherein the anti-OX40 antibody is administered once every two weeks.

26. The method according to claim 23, comprising administering the anti-OX40 antibody three times at two-week intervals.

27. The method according to any one of claims 1 to 26, wherein the method is therapeutically effective in achieving a reduction of at least 30% from an individual's baseline SALT score.

28. The method according to claim 27, wherein the method is therapeutically effective in achieving a reduction in the baseline SALT score at approximately 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 ​​weeks, or 52 weeks from the start of treatment.

29. The method according to claim 28, wherein the method is therapeutically effective in achieving a reduction in baseline SALT score in about 16 weeks.

30. The method according to any one of claims 1 to 26, wherein the method is therapeutically effective in 1) inducing a SALT score of 10 or less (i.e., inducing hair regeneration in at least 90% of the scalp of a subject suffering from AA), or 2) inducing a SALT score of 20 or less (i.e., inducing hair regeneration in at least 80% of the scalp of a subject suffering from AA).

31. The method according to any one of claims 1 to 30, wherein the aforementioned administration does not result in any serious adverse events related to treatment.

32. A method for treating atopic dermatitis (AD) in a person who requires treatment for atopic dermatitis (AD), The method comprising administering to the subject a therapeutically effective amount of an anti-OX40 antibody or an antigen-binding fragment thereof, comprising: (1) a light chain variable region (VL) comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively; and (2) a heavy chain variable region (VH) comprising VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 4, 5, and 6, respectively.

33. The method according to claim 32, wherein the anti-OX40 antibody or antigen-binding fragment is a chimeric antibody or antigen-binding fragment, a humanized antibody or antigen-binding fragment, or a human antibody or antigen-binding fragment.

34. The method according to claim 33, wherein the anti-OX40 antibody or antigen-binding fragment is a humanized antibody or antigen-binding fragment.

35. The method according to claim 34, wherein (1) VL has at least 85%, at least 90%, at least 95%, at least 98%, or 100% sequence identity with respect to the amino acid sequence of SEQ ID NO: 7; and / or (2) VH has at least 85%, at least 90%, at least 95%, at least 98%, or 100% sequence identity with respect to the amino acid sequence of SEQ ID NO:

8.

36. The method according to claim 35, wherein VL has the amino acid sequence of SEQ ID NO: 7, 9, or 10, and VH has the amino acid sequence of SEQ ID NO: 8, 11, or 12.

37. The method according to claim 34, wherein VL and VH each have the amino acid sequences of SEQ ID NOs: 7 and 8, respectively.

38. The anti-OX40 antibody or antigen-binding fragment is Fab, Fab', F(ab') ２ , Fv, scFv, and (scFv) ２ The method according to any one of claims 32 to 37, selected from the group consisting of the following.

39. The method according to any one of claims 32 to 37, wherein the anti-OX40 antibody or antigen-binding fragment is an IgG1 antibody, an IgG2 antibody, an IgG3 antibody, or an IgG4 antibody.

40. The method according to claim 39, wherein the anti-OX40 antibody is a humanized IgG1 antibody.

41. The method according to claim 40, wherein the anti-OX40 antibody comprises a light chain constant region (CL) having at least 85% sequence identity with kappa CL (Cκ; SEQ ID NO: 13) or lambda CL (Cλ; SEQ ID NO: 14).

42. The method according to claim 41, wherein CL is Cκ (SEQ ID NO: 13).

43. The method according to any one of claims 40 to 42, wherein the anti-OX40 antibody comprises the wild-type heavy chain constant region (CH) of human IgG1 (SEQ ID NO: 16), or a variant thereof in which binding to FcγR is reduced.

44. The method according to claim 43, wherein the anti-OX40 antibody comprises the CH region of human IgG1 having the N297A substitution.

45. The method according to claim 44, wherein the anti-OX40 antibody comprises a light chain having the amino acid sequence of SEQ ID NO: 19 and a heavy chain having the amino acid sequence of SEQ ID NO:

20.

46. The method according to any one of claims 32 to 45, wherein the subject has moderate to severe AD.

47. The method according to claim 46, wherein the subject has a) at least 12 eczema area and severity index (EASI) scores, b) at least 3 investigator-generalized assessment (IGA)-AD scores, and c) body surface area (BSA) of 10% or more.

48. The method according to claim 47, wherein the subject has at least 16 EASI scores.

49. The method according to any one of claims 32 to 48, wherein the subject has been diagnosed with AD for at least six months.

50. The method according to claim 49, wherein the anti-OX40 antibody is administered by intravenous injection.

51. The method according to claims 32 to 50, comprising administering approximately 1 mg to approximately 1200 mg of anti-OX40 antibody to the subject.

52. The method according to claim 51, comprising administering approximately 300 mg of the anti-OX40 antibody to the subject.

53. The method according to claim 51, comprising administering approximately 600 mg of the anti-OX40 antibody to the subject.

54. The method according to any one of claims 32 to 53, comprising one or more administrations of the anti-OX40 antibody.

55. The method according to claim 54, comprising three administrations of the anti-OX40 antibody.

56. The method according to claim 55, wherein the anti-OX40 antibody is administered once every two weeks.

57. The method according to claim 55, comprising administering the anti-OX40 antibody three times at two-week intervals.

58. The method according to any one of claims 32 to 57, wherein the method is therapeutically effective in a) achieving a reduction of at least 75% from the individual's baseline EASI score, b) achieving a reduction of at least 90% from the individual's baseline EASI score, c) achieving a reduction of at least 4 points in the DLQI score, or d) achieving an IGA-AD score of 0 or 1, thereby achieving a reduction of at least 2 points from the baseline IGA-AD score.

59. The method according to claim 58, wherein the method is therapeutically effective in achieving a reduction at approximately 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 ​​weeks, or 52 weeks from the start of treatment.

60. The method according to claim 59, wherein the method is therapeutically effective in achieving a reduction in about 12 weeks.

61. The method according to any one of claims 32 to 60, wherein the aforementioned administration does not result in any serious treatment-related adverse events.

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