Compositions and methods for treating psoriasis

Abstract

Provided are compositions and methods for treating subjects with psoriasis, comprising an inhibitor of oxidized low-density lipoprotein (LDL), a malondialdehyde-modified epitope in LDL, or native LDL for administration. Exemplary inhibitors of oxidized LDL or malondialdehyde-modified LDL include oticumab, a variant antibody or peptide capable of binding to oxidized LDL or malondialdehyde-modified LDL, which improves psoriatic disease even in patients refractory to ultraviolet A / B therapy and topical steroids.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Patent Application No. 62 / 677,590, filed May 29, 2018, the entire contents of which are hereby incorporated by reference. Technical Field

[0003] The present invention relates to the treatment of psoriasis in patients and the treatment of atherosclerosis in patients with psoriasis. Background Art

[0004] All publications herein are incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated as being incorporated by reference. The following description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, nor is it an admission that any publication specifically or implicitly referenced is prior art.

[0005] Psoriasis is a chronic inflammatory disease manifested as scaly plaques on the skin, which occurs due to excessive proliferation of keratinocytes and activated immune cells. Treatment generally involves immune mediation, such as the use of anti-inflammatory agents (including topical corticosteroids), ultraviolet (UV) A and B light therapy or cytotoxic agents. In patients who are refractory to topical treatment and / or UVA / B therapy, anti-inflammatory biological therapy is started, such as monoclonal antibodies to TNFα, IL-12 / 23 and IL-17 or antibodies only to IL-23.

[0006] Many systemic treatments for psoriasis have adverse cardiovascular effects, such as dyslipidemia and hypertension. The highly oxidative environment generated by psoriatic inflammation promotes LDL oxidation and endothelial dysfunction, two key factors in the development of atherosclerosis.

[0007] When LDL infiltrates the subendothelial space in the arterial wall and contacts with reactive oxygen species that are highly upregulated in psoriasis, oxidized LDL (oxLDL) is formed. Through the LDL oxidation process, various adducts (e.g., malondialdehyde [MDA]) are formed, which further modify LDL (i.e., MDA-LDL). Oxidized / modified LDL works in countless ways that support inflammation and atherosclerosis. Without being bound by any theory, such molecules may affect the proliferation and migration of vascular smooth muscle cells (VSMC) by binding to lectin-type oxidized LDL receptor 1 (LOX-1), which is a key event in the progression of atherosclerotic plaques. Oxidized / modified LDL is also absorbed by macrophages, which become foam cells and stimulate a proinflammatory response that causes the accumulation of necrotic cores in vascular plaques and the recruitment of additional monocytes to the plaques. This process provides a chronic inflammatory feedforward loop that causes plaque growth and plaque instability. Elevated levels of oxLDL, MDA-LDL, and LOX-1 have been found in both plaque and plasma in patients at risk for developing CVD and inflammation.

[0008] It is therefore an object of the present invention to provide compositions and methods for treating, reducing the severity of, or the likelihood of psoriasis in a subject. Summary of the Invention

[0009] The following embodiments and aspects thereof are described and illustrated in conjunction with compositions and methods, which are intended to be exemplary and illustrative, not limiting in scope.

[0010] Provided are methods for treating, reducing the severity of, slowing the progression of, or inhibiting psoriasis in a subject in need thereof, comprising administering to the subject an effective amount of an antibody or antibody fragment capable of binding to a fragment of apolipoprotein B100 (ApoB100), wherein the fragment of ApoB100 comprises the amino acid sequence of SEQ ID No.: 1 or its active site, and wherein the antibody comprises one, two, or three heavy chain complementary determining regions (HCDRs) selected from the group consisting of HCDR 1 (HCDR1), HCDR 2 (HCDR2), and HCDR 3 (HCDR3) sequences of SEQ ID Nos. 2, 3, and 4, respectively, and one, two, or three light chain complementary determining regions (LCDRs) selected from the group consisting of LCDR 1 (LCDR1), LCDR 2 (LCDR2), and LCDR 3 (LCDR3) sequences of SEQ ID Nos. 5, 6, and 7, respectively.

[0011] Additional embodiments provide methods for treating psoriasis, reducing the severity or likelihood of psoriasis, comprising administering one or more therapeutic agents in combination (e.g., sequentially or simultaneously) with an antibody fragment that binds to an epitope of SEQ ID No. 1 of ApoB100. Exemplary additional therapeutic agents or therapies for inhibitors of oxLDL or malondialdehyde-modified LDL include corticosteroids, ultraviolet (UV) A therapy, UV B therapy, anti-TNFα antibodies, anti-IL-12 / 23 antibodies, or anti-IL-23 antibodies that bind only to IL-23, and anti-IL-17 antibodies. In other embodiments, the composition does not contain these additional therapeutic agents or therapies.

[0012] The subject can be diagnosed with psoriasis, characterized by elevated levels of tumor necrosis factor-α (TNFα), interleukin 6 (IL-6), C-reactive protein (CRP), or a combination thereof, compared to a control subject without psoriasis. In other aspects, the subject is diagnosed with plaque psoriasis and does not have or display symptoms of non-plaque psoriasis.

[0013] Various embodiments of the disclosed methods include subcutaneously administering an antibody (eg, orticumab) or antibody fragment to an adult human subject at about 330 mg at approximately monthly intervals to treat psoriasis or provide passive immunity.

[0014] Other embodiments provide for administering an effective amount of an anti-LDL or anti-oxLDL antibody in the methods described herein at an initial dose of at least 5 mg / kg or preferably at least 8 mg / kg. In some embodiments, the initial dose is sufficient to improve and treat the patient's psoriasis. In another embodiment, the method further comprises administering multiple subsequent doses of the composition in an amount of at least about 2 mg / kg / week, at least about 2.5 mg / kg / two weeks, or at least about 6 mg / kg / month. Typically, the effective amount of the anti-LDL antibody or anti-oxLDL antibody in the method results in an antibody amount of at least 4 μg / mL in the circulation, preferably at least 12 μg / mL in the circulation; the effective amount of the anti-LDL antibody or anti-oxLDL antibody includes multiple doses, and the multiple doses result in an antibody amount of at least 4 μg / mL in the circulation, preferably at least 12 μg / mL in the circulation, for an extended period of time (e.g., at least 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 1 day, 2 days, 3 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, or 3 months). In some aspects, the amount of each of the subsequent doses is about the same as or less than the initial dose, wherein the subsequent doses are separated in time from each other by at least 3 days, 5 days, 7 days, 2 weeks, 3 weeks, or 1 month.

[0015] Another exemplary embodiment provides for the administration of escalating doses of an antibody directed against native or oxidized LDL to treat psoriasis. In this embodiment, an exemplary (starting) dose of an antibody directed against native or oxidized LDL (e.g., otikumab) for a single dose administration is 0.005 to 0.01 mg / kg (e.g., intravenously); and other exemplary dose levels to be administered in a single dose administration are 0.01 to 0.15, 0.15 to 0.75, 0.75 to 2.5, 2.5 to 7.5, and 7.5 to 30 mg / kg (e.g., intravenously). For example, in a single dose intravenous administration, the starting dose of otikumab is 0.007 mg / kg; and in subsequent single dose intravenous administrations, other exemplary doses may be 0.05, 0.25, 1.25, 5.0, or 15.0 mg / kg. In another embodiment, the single dose of the antibody for natural or oxidized LDL is 0.5 to 6 mg / kg subcutaneously, and the multiple doses are also 0.5 to 6 mg / kg subcutaneously. For example, 1.25 mg / kg of the antibody for natural or oxidized LDL is administered subcutaneously. In various embodiments, the dose is administered within a specified hour range of the day in each administration, and each dose in the multiple dose treatment (e.g., 4 doses, 3 doses, 5 doses or 6 doses) is administered at weekly intervals in a time window of 1 day. In another example, an antibody for natural or oxidized LDL (such as otikumab) is administered to a human subject at 300 mg to 450 mg (such as 360 mg), optionally followed by another dose of 300 mg to 450 mg (such as 360 mg) to the human subject, wherein the second dose is at least 70 days (up to 91 days) apart from the first dose. Antibodies (such as oticumab) can be formulated at a concentration of 100-170 mg / mL (e.g., 150 mg / mL) and administered subcutaneously without further dilution or diluted to a large volume for intravenous infusion.

[0016] Other features and advantages of the invention will become apparent from the following detailed description, taken in conjunction with the accompanying drawings, which illustrate, by way of example, various features of embodiments of the invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Exemplary embodiments are shown in the accompanying drawings.It is intended that the embodiments and figures disclosed herein be considered illustrative rather than restrictive.

[0018] Figure 1 Depicted are simulated human pharmacokinetic (PK) curves (solid lines) following a subcutaneous (SC) loading dose of 8 mg / kg followed by weekly SC dosing of 2 mg / kg. Dashed lines indicate two expected thresholds for serum concentrations of oticumab (4 μg / mL, typically the lowest line, and 12 μg / mL, the upper dashed line).

[0019] Figure 2A and Figure 2B The simulated human PK curve based on SC administration is depicted. Figure 2A In the diagram, the highest solid line from 0 to 96 hours indicates dosing at a weekly frequency of 2 mg / kg; typically, the middle solid line from 24 to 96 hours indicates dosing at a biweekly frequency of 2 mg / kg; and typically, the lowest solid line indicates dosing at a monthly frequency of 2 mg / kg. Figure 2B In the figure, the solid line indicates a loading dose of 5 mg / kg and subsequent doses of 2 mg / kg every two weeks. Generally, the lower dashed line indicates a desired threshold value of 4 μg / mL for the serum concentration of oticumab. Generally, the upper dashed line indicates a desired threshold value of 12 μg / mL for the serum concentration of oticumab.

[0020] Figure 3 Depicted are simulated human PK profiles following weekly SC dosing, using PK parameters from Phase I data. The solid lines from low to high in the figure represent doses of 0.5, 1, 1.25, 2, 2.5, 4, or 6 mg / kg.

[0021] Figure 4 Depicted are simulated human PK profiles following biweekly SC dosing, using PK parameters from Phase I data. The solid lines from low to high in the figure represent doses of 1, 1.5, 2, or 2.5 mg / kg.

[0022] Figure 5 Depicted are simulated human PK profiles following monthly SC dosing, using parameters from Phase I data. The solid lines from low to high in the figure represent doses of 2, 3, 4, or 6 mg / kg. DETAILED DESCRIPTION

[0023] All references cited herein are incorporated by reference in their entirety as if fully set forth. Unless otherwise defined, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Singleton et al., Dictionary of Microbiology and Molecular Biology 3rd ed., Revised, J. Wiley & Sons (New York, NY 2006); March, Advanced Organic Chemistry Reactions, Mechanisms and Structure 7th ed., J. Wiley & Sons (New York, NY 2013); and Sambrook and Russell, Molecular Cloning: A Laboratory Manual 4th ed., Cold Spring Harbor Laboratory Press (Cold Spring Harbor, NY 2012) provide those skilled in the art with a general guide to many of the terms used in this application. For references on how to make antibodies, see D. Lane, Antibodies: A Laboratory Manual 2nd ed. (Cold Spring Harbor Press, Cold Spring Harbor NY, 2013); Kohler and Milstein, (1976) Eur. J. Immunol. 6:511; Queen et al., U.S. Pat. No. 5,585,089; and Riechmann et al., Nature 332:323 (1988); U.S. Pat. No. 4,946,778; Bird, Science 242:423-42 (1988); Huston et al., Proc. Natl. Acad. Sci. USA 85:5879-5883 (1988); Ward et al., Nature 334:544-54 (1989); Tomlinson I. and Holliger P. (2000) Methods Enzymol, 326, 461-479; Holliger P. (2005) Nat. Biotechnol. Sep; 23(9):1126-36).

[0024] Those skilled in the art will recognize many methods and materials similar or equivalent to the methods and materials described herein that can be used in the practice of the present invention. In fact, the present invention is in no way limited to the methods and materials described. For purposes of the present invention, the following terms are defined below.

[0025] As used herein, the term "antibody" or "antibodies" refers broadly to and includes immunoglobulin molecules, including polyclonal antibodies, monoclonal antibodies (including murine monoclonal antibodies, human monoclonal antibodies, human-adapted monoclonal antibodies, humanized monoclonal antibodies, and chimeric monoclonal antibodies), antibody fragments, bispecific or multispecific antibodies, dimers, tetramers or multimeric antibodies, and single-chain antibodies.

[0026] Depending on the amino acid sequence of the heavy chain constant domain, immunoglobulins can be assigned to five major classes, namely IgA, IgD, IgE, IgG and IgM. IgA and IgG are further subclassified into isotypes IgA1, IgA2, IgG1, IgG2, IgG3 and IgG4. The light chains of antibodies from any vertebrate species can be assigned to one of two clearly distinct types, i.e., kappa (κ) and lambda (λ), based on the amino acid sequence of their constant domains.

[0027] The term "antibody fragment" refers to a portion of an immunoglobulin molecule that retains the heavy and / or light chain antigen binding sites, such as the heavy chain complementarity determining regions (HCDRs) 1, 2, and 3, the light chain complementarity determining regions (LCDRs) 1, 2, and 3, the heavy chain variable region (V H ), or light chain variable region (V L ). Antibody fragments include Fab fragments, which are composed of V L 、V H 、C L and C HI a monovalent fragment consisting of a V domain; a F(ab)2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge in the hinge region; and a Fd fragment consisting of a V domain. H and C HI domain; Fv fragment, which consists of the V L and V H Domain composition; domain antibody (dAb) fragments (Ward et al. (1989) Nature 341:544-546), which are composed of V H The structural domain is composed of V H and V L Domains were engineered and linked together via synthetic linkers to form various types of single-chain antibody designs, where V H / V L Domains within or between molecules (in V H and V LIn some embodiments, the antibody fragments are paired (in the case where the domains are expressed by separate single-chain antibody constructs) to form a monovalent antigen-binding site, such as a single-chain Fv (scFv) or a diabody; which is described, for example, in PCT International Publication Nos. WO 1998 / 44001, WO 1988 / 01649, WO 1994 / 13804, and WO 1992 / 01047. These antibody fragments are obtained using well-known techniques known to those skilled in the art, and the fragments are screened for utility in the same manner as full-length antibodies.

[0028] The variable region of an antibody consists of a "framework" region interrupted by three "antigen binding sites." Antigen binding sites are defined using various terms such as: complementarity determining regions (CDRs), which are V H Three of them (HCDR1, HCDR2, HCDR3) and V L The three (LCDR1, LCDR2, LCDR3) of the human genomic DNA sequence are categorized based on sequence variability (Wu and Kabat J Exp Med 132:211-50, 1970; Kabat et al., Sequences of Proteins of Immunological Interest, 5th ed., Public Health Service, National Institutes of Health, Bethesda, Md., 1991), or "hypervariable regions," "HVRs," or "HVs," i.e., V H Three of them (H1, H2, H3) and V L The three (L1, L2, L3) of the variable domains refer to the structurally hypervariable regions of the antibody variable domains as defined by Chothia and Lesk (Chothia and Lesk Mol Biol 196:901-17, 1987). Other terms include "IMGT-CDR" (Lefranc et al., Dev Comparat Immunol 27:55-77, 2003) and "Specificity Determining Residue Usage" (SDRU) (Almagro, Mol Recognit 17:132-43, 2004). The International ImMunoGeneTics (IMGT) database provides standardized numbering and definitions of antigen binding sites. The correspondence between CDR, HV, and IMGT delineations is described in Lefran et al., Dev Comparat Immunol 27:55-77, 2003.

[0029] "Framework" or "framework sequence" is the remaining sequence of the variable region other than those defined as the antigen binding site. Since the antigen binding site can be defined by various terms as described above, the precise amino acid sequence of the framework depends on how the antigen binding site is defined.

[0030] "Humanized antibodies" refer to antibodies in which the antigen-binding site is derived from a non-human species and the variable region framework is derived from a human immunoglobulin sequence. Humanized antibodies may include substitutions in the framework region so that the framework is not an exact copy of an expressed human immunoglobulin or germline gene sequence.

[0031] A "human-adapted" antibody or "human framework-adapted (HFA)" antibody refers to a humanized antibody adapted according to the methods described in U.S. Patent Publication No. US2009 / 0118127. Human-adapted antibodies are humanized by selecting an acceptor human framework based on maximum CDR and FR similarity, length compatibility, and sequence similarity to the CDR1 and CDR2 loops and a portion of the light chain CDR3 loop.

[0032] "Human antibody" refers to an antibody having a heavy chain variable region and a light chain variable region, wherein both the framework and the antigen binding site are derived from sequences derived from human sources. If the antibody contains a constant region, the constant region is also derived from sequences of human origin.

[0033] Human antibodies include heavy or light chain variable regions of sequences "derived from" human sources, wherein the variable regions of the antibodies are obtained from a system using human germline immunoglobulins or rearranged immunoglobulin genes. Such systems include human immunoglobulin gene libraries displayed on phages, and transgenic non-human animals, such as mice carrying human immunoglobulin loci as described herein. When "human antibodies" are compared with human germline or rearranged immunoglobulin sequences, they may contain amino acid differences, which are attributed to, for example, naturally occurring somatic mutations or intentional introduction of substitutions in the framework or antigen binding site. Typically, human antibodies are at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequences encoded by human germline or rearranged immunoglobulin genes. In some cases, a "human antibody" may contain a consensus framework sequence derived from human framework sequence analysis, e.g., as described in Knappik et al., J Mol Biol 296:57-86, 2000; or a synthetic HCDR3 incorporated into a human immunoglobulin gene library displayed on phage, e.g., as described in Shi et al., J Mol Biol 397:385-96, 2010 and International Patent Publication No. WO2009 / 085462. Antibodies whose antigen-binding sites are derived from non-human species are not included in the definition of a human antibody.

[0034] The term "recombinant antibody" as used herein includes all antibodies prepared, expressed, created, or isolated by recombinant means, such as antibodies isolated from animals (such as mice) that are transgenic or transchromosomal for human immunoglobulin genes or hybridomas prepared therefrom (described further below), antibodies isolated from host cells transformed to express the antibodies, antibodies isolated from recombinant, combinatorial antibody libraries, as well as antibodies prepared, expressed, created, or isolated by any other means involving splicing of human immunoglobulin gene sequences to other DNA sequences, or antibodies generated in vitro using Fab arm exchange, such as bispecific antibodies.

[0035] The term "monoclonal antibody" as used herein refers to a preparation of antibody molecules of single molecular composition. A monoclonal antibody composition displays a single binding specificity and affinity for a particular epitope, or in the case of a bispecific monoclonal antibody, dual binding specificities for two different epitopes.

[0036] As used herein, the term "epitope" refers to a portion of an antigen to which an antibody specifically binds. An epitope is typically composed of chemically active (such as polar, nonpolar or hydrophobic) surface groups or polysaccharide side chains of a portion (such as an amino acid) and may have specific three-dimensional structural characteristics as well as specific charge characteristics. An epitope may be composed of continuous and / or discontinuous amino acids that form a unit of conformational space. For discontinuous epitopes, amino acids from different parts of the linear sequence of an antigen are brought into close proximity in 3-dimensional space by the folding of the protein molecule.

[0037] As used herein, "variant" refers to a polypeptide or polynucleotide that differs from a reference polypeptide or reference polynucleotide by one or more modifications (eg, substitutions, insertions, or deletions).

[0038] As used herein, "administering" and / or "administering" refer to any route for delivering a pharmaceutical composition to a patient. Routes of delivery can include non-invasive oral (by mouth), topical (dermal), transmucosal (nasal, buccal / sublingual, vaginal, ocular, and rectal) and inhalation routes, as well as parenteral routes and other methods known in the art. Parenteral refers to a delivery route generally associated with injection including intraorbital, infusion, intraarterial, intracarotid, intracapsular, intracardiac, intradermal, intramuscular, intraperitoneal, intrapulmonary, intraspinal, intrasternal, intrathecal, intrauterine, intravenous, subarachnoid, subcapsular, subcutaneous, transmucosal, or transtracheal. Via the parenteral route, the composition can be in the form of a solution or suspension for infusion or injection, or as a lyophilized powder.

[0039] "Beneficial results" may include, but are in no way limited to, lessening or alleviating the severity of a disease condition, preventing a disease condition from worsening, curing a disease condition, preventing a disease condition from developing, reducing a patient's chance of developing a disease condition, and / or extending a patient's life span or life expectancy. In some embodiments, the disease condition is psoriasis, or a combination of psoriasis and atherosclerosis.

[0040] As used herein, the term "effective amount" refers to an amount of a pharmaceutical composition that reduces at least one or more symptoms of a disease or condition, and relates to a sufficient amount of a pharmacological composition to provide the desired effect. As used herein, the phrase "therapeutically effective amount" means a sufficient amount of a composition to treat a condition at a reasonable benefit / risk ratio applicable to any medical treatment. In various embodiments, the pharmaceutical compositions described herein further comprise a pharmaceutically acceptable carrier. In some embodiments, the therapeutic pharmaceutical compositions are used, for example, to treat psoriasis or a combination of psoriasis and atherosclerosis and / or related symptoms in a subject in need thereof, to inhibit psoriasis or a combination of psoriasis and atherosclerosis and / or related symptoms, to reduce the severity of psoriasis or a combination of psoriasis and atherosclerosis and / or related symptoms, and / or to shorten the duration of psoriasis or a combination of psoriasis and atherosclerosis and / or related symptoms.

[0041] A significant reduction in the treatment or prevention of symptoms is, for example, at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100% or more of a measured parameter, compared to a control or non-treated subject or the state of the subject before administration of the compositions described herein. Measured or measurable parameters include clinically detectable markers of disease, e.g., elevated or depressed biomarker levels, and parameters associated with clinically accepted scales for symptoms or markers of psoriasis and / or atherosclerosis. However, it should be understood that the total daily usage of the compositions and formulations disclosed herein will be determined by the attending physician within the scope of sound medical judgment. The precise amount required will vary depending on factors such as the type of disease being treated, the sex, age, and weight of the subject. An "ineffective" treatment refers to an improvement in symptoms of less than 1%, 2%, 3%, 4%, or 5% when the treatment is administered to the subject.

[0042] "Subject" or "individual" or "animal" or "patient" or "mammal" means any subject, particularly a mammalian subject, for whom diagnosis, prognosis, or therapy is desired. Mammalian subjects include, but are not limited to, humans, livestock, farm animals, zoo animals, sports animals, pet animals, such as dogs, cats, guinea pigs, rabbits, rats, mice, horses, cattle, cows; primates, such as apes, monkeys, gorillas, and chimpanzees; canines, such as dogs and wolves; felines, such as cats, lions, and tigers; equines, such as horses, donkeys, and zebras; food animals, such as cattle, pigs, and sheep; ungulates, such as deer and giraffes; rodents, such as mice, rats, hamsters, and guinea pigs; and the like. In certain embodiments, a mammal is a human subject.

[0043] As used herein, the terms "treat," "treatment," "treating," or "improvement" refer to therapeutic treatments and preventative or prophylactic measures when used to refer to a disease, disorder, or medical condition, wherein the purpose is to prevent, reverse, alleviate, improve, inhibit, mitigate, slow down, or stop the progression or severity of a symptom or condition. The term "treat" includes reducing or alleviating at least one adverse effect or symptom of a condition. A treatment is generally "effective" if one or more symptoms or clinical markers are reduced. Alternatively, a treatment is "effective" if the progression of a disease state is reduced or stopped. That is, "treatment" includes not only the improvement of symptoms or markers, but also the stopping or at least slowing down of the progression or worsening of symptoms that would be expected in the absence of treatment. In addition, "treatment" can mean pursuing or obtaining beneficial results, or reducing the chance of an individual developing a condition, even if the treatment is ultimately unsuccessful. Those in need of treatment include those already suffering from the condition, as well as those susceptible to the condition or those to be prevented from developing the condition. For example, Example 3 describes an embodiment for measuring therapeutic efficacy (e.g., symptom improvement). In one aspect, a decrease in the Psoriasis Area and Severity Index (PASI) score from baseline indicates improvement. In another aspect, a two-point improvement in the 5-point Investigator Global Assessment (IGA) scale, as well as achieving the designation "clear" or "almost clear," indicates improvement compared to baseline.

[0044] The term "statistically significant" or "significant" refers to statistical evidence of a difference. It is defined as the probability of rejecting the null hypothesis when it is actually true. This decision is often made using a p-value.

[0045] As used herein, "cardiovascular disease" refers to disorders of the heart and blood vessels, and includes disorders of the arteries, veins, arterioles, venules, and capillaries. Non-limiting examples of cardiovascular disease include congestive heart failure, arrhythmias, pericarditis, acute myocardial infarction, infarcted myocardium, coronary artery disease, coronary heart disease, ischemic heart disease, cardiomyopathy, stroke, hypertensive heart disease, heart failure, cor pulmonale, ischemic syndrome, coronary microvascular disease, dysrhythmia, rheumatic heart disease, aortic aneurysm, atrial fibrillation, congenital heart disease, endocarditis, inflammatory heart disease, endocarditis, inflammatory cardiac hypertrophy, myocarditis, valvular heart disease, cerebrovascular disease, and peripheral arterial disease, or any combination thereof.

[0046] "Psoriasis" refers to an immune-mediated disease that causes raised, red, scaly patches to appear on the skin. As a skin condition, psoriasis accelerates the life cycle of skin cells, causing them to rapidly accumulate on the skin's surface and sometimes causing itching and pain. There are different types of psoriasis. For example, plaque psoriasis (or psoriasis vulgaris) is the most common form of the disease and manifests as raised, red patches covered with a silvery-white accumulation of dead skin cells or scales. These patches or plaques often appear on the scalp, knees, elbows, and lower back. Another form is guttate psoriasis, which appears on the skin as small, red spots, often on the trunk and limbs, but can also appear on the face and scalp. The spots are usually not as thick as those in plaque psoriasis, but can develop into plaque psoriasis over time. Flexural psoriasis, or inverse psoriasis, is another form of psoriasis that often appears in skinfolds, such as under the breasts or in the armpits or groin area. This type of psoriasis is red and often shiny and smooth. Sweat and moisture from the skinfolds prevent this form of psoriasis from shedding skin scales. Pustular psoriasis is a severe form of psoriasis that rapidly develops as numerous white pustules surrounded by red skin. The three types of pustular psoriasis, acute generalized (von Zumbusch) pustular psoriasis, palmoplantar pustulosis, and acropustulosis, can have different symptoms and severity. In addition, erythrodermic psoriasis or exfoliative psoriasis is a rare type of psoriasis that looks like a severe burn. This form of psoriasis is widespread, red, and scaly. This serious condition can cause the patient to lose control of their body temperature.

[0047] "Psoriatic arthritis" is a form of inflammatory arthritis that affects some people who have psoriasis, a condition characterized by red patches of skin covered with silvery scales. With psoriatic arthritis, most people first develop psoriasis and are later diagnosed with psoriatic arthritis, but joint problems can sometimes begin before skin lesions appear.

[0048] "Binding," "selectively binding," or "specifically binding" with respect to the interaction between an antibody and an epitope refers to the antibodies or antibody fragments thereof described herein that bind to an epitope in the following manner: D Ability to bind to a target (such as a molecule present on the surface of a cell): 10 -5 M (10000nM) or less, for example, 10 -6 M, 10 -7 M, 10 -8 M, 10 -9 M, 10 -10 M, 10 -11 M, 10 -12 The specific binding can be affected by, for example, the affinity and avidity of the polypeptide reagent and the concentration of the polypeptide agent. Those of ordinary skill in the art can use any suitable method, such as titrating the polypeptide agent in a suitable cell-binding assay, to determine the appropriate conditions under which the polypeptide agent as described herein selectively binds to the target.

[0049] As used herein, the term "in combination with" means that two or more therapeutic agents may be administered to a subject together in a mixture, simultaneously as a single agent, or sequentially in any order as a single agent.

[0050] Methods and systems

[0051] Various embodiments provide methods of treating or reducing the severity of psoriasis by administering to a subject an antibody or antibody fragment that binds to at least one fragment of apolipoprotein B100 (apoB100). In various embodiments, the methods provide for treatment of psoriasis by passive immunization.

[0052] Various embodiments provide methods of reducing the likelihood of a subject developing psoriasis by administering to the subject an antibody or antibody fragment that binds to at least one fragment of apolipoprotein B100 (apoB100). In various embodiments, the method provides passive immunity to the subject to reduce the likelihood of developing psoriasis.

[0053] Various embodiments provide that the antibodies or antibody fragments of the methods disclosed herein bind to the native and / or oxidized epitope P45 of apoB100. Various embodiments provide that the antibodies or antibody fragments of the methods disclosed herein bind only to the native and / or oxidized epitope P45 of apoB100. P45 of apoB100 has a polypeptide sequence of IEIGLEGKGFEPTLEALFGK (SEQ ID No.: 1). Oxidized epitopes or oxidized lipoproteins include, but are not limited to, modifications of epitopes or lipoproteins carrying malondialdehyde (MDA) groups on lysine and histidine, modifications induced by copper oxidation (e.g., CuOxLDL), modifications carrying hydroxynonenal, or modifications carrying aldehyde haptens. Another embodiment provides that the antibodies or antibody fragments of the methods disclosed herein further bind to one or more fragments of apoB100.

[0054] ApoBlOO contains peptide fragments identifiable as P1-P302 with overlapping amino acids between adjacent peptides, as described in U.S. Patent Application Publication No. US / 2017 / 0340702 and U.S. Patent Nos. 7,468,183 and 7,704,499, which are incorporated herein by reference in their entireties.

[0055] Various embodiments provide methods of treating or reducing the severity of psoriasis in a subject including, but not limited to, administering Optikunmab or an Optikunmab variant having the same heavy and / or light chain as Optikunmab or the same complementarity determining regions as Optikunmab, which are also described in detail below.

[0056] Various embodiments provide methods for reducing the likelihood of developing psoriasis in a subject, including but not limited to administering Optikunmab or an Optikunmab variant having the same heavy and / or light chains as Optikunmab or the same complementarity determining regions as Optikunmab, which are also described in detail below. In yet another aspect, the methods provide passive immunization to the subject to reduce the likelihood of developing psoriasis.

[0057] Various embodiments of the methods disclosed herein include clear or almost clear psoriasis plaques or a ≥ 2-point improvement in a psoriasis measure in the treated subject compared to pre-treatment according to one or more of the 5-point static Investigator's Global Assessment (2011 revised) (sIGA), the Physician's Global Assessment (PGA) scale, and the Pustular Symptom Score (PSS).

[0058] Various embodiments provide methods disclosed herein including that the subject after treatment has reduced plaque areas in one or more of four body regions (i.e., head and neck, upper limbs, trunk, and lower limbs) compared to before treatment. Other embodiments provide methods disclosed herein including that the subject has a reduced Psoriasis Area and Severity Index (PASI) after treatment. PASI combines assessments of four body regions: head and neck (H), upper limbs (UL), trunk (T), and lower limbs (LL). The percentage of skin affected by psoriasis in each region is given a numerical score representing the percentage involved: 1 (0–9%), 2 (10–29%), 3 (30–49%), 4 (50–69%), 5 (70–89%), or 6 (90–100%). The severity of the three plaque signs (erythema (E), thickness / induration (I), and scaling / scaling (D)) within each area (H, UL, T, LL) was assessed on a 5-point scale: 0 (none), 1 (mild), 2 (moderate), 3 (severe), or 4 (very severe).

[0059] Optikumab is a human monoclonal antibody containing heavy chain complementarity determining regions (HCDRs) 1 (HCDR1), 2 (HCDR2), and 3 (HCDR3) as shown in SEQ ID Nos: 2, 3, and 4, respectively; and light chain complementarity determining regions (LCDRs) 1 (LCDR1), 2 (LCDR2), and 3 (LCDR3) as shown in SEQ ID Nos: 5, 6, and 7, respectively. Optikumab contains a variable heavy chain region (V H ) amino acid sequence, the variable light chain region (light region) of SEQ ID No: 9 (V L ) amino acid sequence. Otikumab contains the heavy chain amino acid sequence of SEQ ID No: 10 and the light chain amino acid sequence of SEQ ID No: 11.

[0060] HCDR1, SEQ ID No.: 2, is: FSNAWMSWVRQAPG.

[0061] HCDR2, SEQ ID No.: 3, is: SSISVGGHRTYYADSVKGR.

[0062] HCDR3, SEQ ID No.: 4, is: ARIRVGPSGGAFDY.

[0063] LCDR1, SEQ ID No.: 5, is: CSGSNTNIGKNYVS.

[0064] LCDR2, SEQ ID No.: 6, is: ANSNRPS.

[0065] LCDR3, SEQ ID No.: 7, is: CASWDASLNGWV.

[0066] Variable heavy chain region (V H ), i.e., SEQ ID No.: 8, as shown below:

[0067] EVQLLESGGG LVQPGGSLRL SCAASGFTFS NAWMSWVRQA PGKGLEWVSS ISVGGHRTYYADSVKGRSTI SRDNSKNTLY LQMNSLRAED TAVYYCARIR VGPSGGAFDY WGQGTLVTVS.

[0068] Variable light chain region (V L ), i.e., SEQ ID No.: 9, as shown below:

[0069] QSVLTQPPSA SGTPGQRVTI SCSGSNTNIG KNYVSWYQQL PGTAPKLLIY ANSNRPSGVPDRFSGSKSGT SASLAISGLR SEDEADYYCA SWDASLNGWV FGGGTKLTVL.

[0070] The heavy chain, SEQ ID No.: 10, is shown below:

[0071] EVQLLESGGG LVQPGGSLRL SCAASGFTFS NAWMSWVRQA PGKGLEWVSS ISVGGHRTYYADSVKGRSTI SRDNSKNTLY LQMNSLRAED TAVYYCARIR VGPSGGAFDY WGQGTLVTVS SASTKGPSVFPLAPSSKSTS GGTAALGCLV KDYFPEPVTV SWNSGALTSG VHTFPAVLQS SGLYSLSSVV TVPSSSLGTQTYICNVNHKP SNTKVDKKVE PKSCDKTHTC PPCPAPELLG GPSVFLFPPK PKDTLMISRT PEVTCVVVDVSHEDPEVKFN WYVDGVEVHN AKTKPREEQY NSTYRVVSVL TVLHQDWLNG KEYKCKVSNK ALPAPIEKTISKAKGQPREP QVYTLPPSRD ELTKNQVSLT CLVKGFYPSD ​​IAVEWESNGQ PENNYKTTPP VLDSDGSFFLYSKLTVDKSR WQQGNVFSCS VMHEALHNHY TQKSLSLSPG K.

[0072] The light chain, SEQ ID No.: 11, is shown below:

[0073] QSVLTQPPSA SGTPGQRVTI SCSGSNTNIG KNYVSWYQQL PGTAPKLLIY ANSNRPSGVPDRFSGSKSGT SASLAISGLR SEDEADYYCA SWDASLNGWV FGGGTKLTVL GQPKAAPSVT LFPPSSEELQANKATLVCLI SDFYPGAVTV AWKADSPVK AGVETTTPSK QSNNKYAASS YLSLTPEQWK SHRSYSCQVTHEGSTVEKTV APTECS.

[0074] Provided are methods for treating or reducing the severity of psoriasis in a subject, comprising administering to the subject an effective amount of an antibody or antibody fragment that binds to the fragment of apoB100 shown in SEQ ID No.: 1, and wherein the antibody contains one or more of HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 as shown in SEQ ID No.: 2-7.

[0075] Also provided is a method for treating or reducing the severity of psoriasis in a subject, comprising administering to the subject an effective amount of an antibody or antibody fragment that binds to the fragment of apoB100 shown in SEQ ID No.: 1, and wherein the antibody contains one or more of HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 as shown in SEQ ID No.: 2-7.

[0076] An antibody containing "one or more of HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3" encompasses embodiments in which the antibody contains one, any two, any three, any four, any five, or all six CDRs (i.e., HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3). One aspect of the present invention provides an antibody comprising at least one complementarity determining region (CDR) having the amino acid sequence of the corresponding CDR of the antibody oticumumab; more preferably, the antibody has two or three or four or five CDRs having the sequence of the corresponding CDR of the antibody oticumumab; if the antibody has three or four CDRs having the sequence of the corresponding CDR of the antibody oticumumab, then preferably, the antibody has all three heavy chain or all three light chain CDRs, and the all three heavy chain or all three light chain CDRs have the sequence of the corresponding CDR of the antibody oticumumab; therefore, this aspect of the present invention includes an antibody comprising three light chain CDRs having the sequence of the corresponding three light chain CDRs of the antibody oticumumab, or three heavy chain CDRs having the sequence of the corresponding three heavy chain CDRs of the antibody oticumumab; even more preferably, the antibody comprises three light chain CDRs and three heavy chain CDRs. R, the three light chain CDRs and the three heavy chain CDRs have the sequences of the corresponding CDRs of the antibody Optikunmab; if the antibody does not comprise all six CDRs having the sequences of the corresponding CDRs of the antibody Optikunmab, it is preferred that some or all of the 1, 2, 3, 4 or 5 "non-identical" CDRs comprise variants of the sequences of the corresponding CDRs of the antibody Optikunmab ("variant" includes the following meanings: the variant has at least 50%, more preferably at least 70%, even more preferably at least 80% or at least 90% or at least 95% sequence identity with the sequence of the corresponding CDR; most preferably, the variant has 96% or 97% or 98% or 99% sequence identity with the sequence of the corresponding CDR of the antibody Optikunmab; typically, the "variant" CDR sequence has 5 or 4 or 3 or 2 or only 1 amino acid residue difference with the sequence of the corresponding CDR of the antibody Optikunmab); and this aspect of the invention includes the antibody Optikunmab. For example, one aspect of the embodiment provides that the antibody administered comprises a HCDR1 as set forth in SEQ ID No.: 2. Another aspect provides that the antibody administered comprises a HCDR2 as set forth in SEQ ID No.: 3. Another aspect provides that the antibody administered comprises a HCDR3 as set forth in SEQ ID No.: 4. Another aspect provides that the antibody administered comprises a LCDR1 as set forth in SEQ ID No.: 5. Another aspect provides that the antibody administered comprises a LCDR2 as set forth in SEQ ID No.: 6.In another aspect, the antibody administered comprises a LCDR3 as set forth in SEQ ID No.: 7. In yet another aspect, the antibody administered comprises a HCDR1 as set forth in SEQ ID No.: 2 and a HCDR2 as set forth in SEQ ID No.: 3. In another aspect, the antibody administered comprises a HCDR1 as set forth in SEQ ID No.: 2 and a HCDR3 as set forth in SEQ ID No.: 4. In another aspect, the antibody administered comprises a HCDR1 as set forth in SEQ ID No.: 2 and a LCDR1 as set forth in SEQ ID No.: 5. In another aspect, the antibody administered comprises a HCDR1 as set forth in SEQ ID No.: 2 and a LCDR2 as set forth in SEQ ID No.: 6. In another aspect, the antibody administered comprises a HCDR1 as set forth in SEQ ID No.: 2 and a LCDR3 as set forth in SEQ ID No.: 7. In another aspect, the antibody administered comprises a HCDR2 as set forth in SEQ ID No.: 3 and a HCDR3 as set forth in SEQ ID No.: 4. In another aspect, the antibody administered comprises the HCDR2 as set forth in SEQ ID No.: 3 and the LCDR1 as set forth in SEQ ID No.: 5. In another aspect, the antibody administered comprises the HCDR2 as set forth in SEQ ID No.: 3 and the LCDR2 as set forth in SEQ ID No.: 6. In another aspect, the antibody administered comprises the HCDR2 as set forth in SEQ ID No.: 3 and the LCDR3 as set forth in SEQ ID No.: 7. In another aspect, the antibody administered comprises the HCDR3 as set forth in SEQ ID No.: 4 and the LCDR1 as set forth in SEQ ID No.: 5. In another aspect, the antibody administered comprises the HCDR3 as set forth in SEQ ID No.: 4 and the LCDR2 as set forth in SEQ ID No.: 6. In another aspect, the antibody administered comprises the HCDR3 as set forth in SEQ ID No.: 4 and the LCDR3 as set forth in SEQ ID No.: 7. In another aspect, the antibody administered comprises the LCDR1 as set forth in SEQ ID No.: 5 and the LCDR2 as set forth in SEQ ID No.: 6. Another aspect provides that the administered antibody contains LCDR1 as shown in SEQ ID No.: 5 and LCDR3 as shown in SEQ ID No.: 7. Another aspect provides that the administered antibody contains LCDR2 as shown in SEQ ID No.: 6 and LCDR3 as shown in SEQ ID No.: 7.In another aspect, the antibodies administered contain the HCDR1, HCDR2, and HCDR3 as set forth in SEQ ID Nos.: 2-4, respectively. In another aspect, the antibodies administered contain the HCDR1, HCDR2, and LCDR1 as set forth in SEQ ID Nos.: 2, 3, and 5, respectively. In another aspect, the antibodies administered contain the HCDR1, HCDR2, and LCDR2 as set forth in SEQ ID Nos.: 2, 3, and 6, respectively. In another aspect, the antibodies administered contain the HCDR1, HCDR2, and LCDR3 as set forth in SEQ ID Nos.: 2, 3, and 7, respectively. In another aspect, the antibodies administered contain the HCDR1, HCDR3, and LCDR1 as set forth in SEQ ID Nos.: 2, 4, and 5, respectively. In another aspect, the antibodies administered contain the HCDR1, HCDR3, and LCDR2 as set forth in SEQ ID Nos.: 2, 4, and 6, respectively. In another aspect, the antibodies administered contain the HCDR1, HCDR3, and LCDR3 as set forth in SEQ ID Nos.: 2, 4, and 7, respectively. In another aspect, the antibodies administered contain HCDR1, LCDR1, and LCDR2 as set forth in SEQ ID Nos.: 2, 5, and 6, respectively. In another aspect, the antibodies administered contain HCDR1, LCDR1, and LCDR3 as set forth in SEQ ID Nos.: 2, 5, and 7, respectively. In another aspect, the antibodies administered contain HCDR1, LCDR2, and LCDR3 as set forth in SEQ ID Nos.: 2, 6, and 7, respectively. In another aspect, the antibodies administered contain HCDR2, HCDR3, and LCDR1 as set forth in SEQ ID Nos.: 3, 4, and 5, respectively. In another aspect, the antibodies administered contain HCDR2, HCDR3, and LCDR2 as set forth in SEQ ID Nos.: 3, 4, and 6, respectively. In another aspect, the antibodies administered contain HCDR2, HCDR3, and LCDR3 as set forth in SEQ ID Nos.: 3, 4, and 7, respectively. In another aspect, the antibodies administered contain HCDR2, LCDR1, and LCDR2 as set forth in SEQ ID Nos.: 3, 5, and 6, respectively. In another aspect, the antibodies administered contain HCDR2, LCDR1, and LCDR3 as shown in SEQ ID No.: 3, 5, and 7, respectively. In another aspect, the antibodies administered contain HCDR2, LCDR2, and LCDR3 as shown in SEQ ID No.: 3, 6, and 7, respectively. In another aspect, the antibodies administered contain HCDR3, LCDR1, and LCDR2 as shown in SEQ ID No.: 4, 5, and 6, respectively.In another aspect, the antibodies administered contain HCDR3, LCDR1, and LCDR3 as set forth in SEQ ID Nos.: 4, 5, and 7, respectively. In another aspect, the antibodies administered contain HCDR3, LCDR2, and LCDR3 as set forth in SEQ ID Nos.: 4, 6, and 7, respectively. In another aspect, the antibodies administered contain LCDR1, LCDR2, and LCDR3 as set forth in SEQ ID Nos.: 5-7, respectively. In yet another aspect, the antibodies administered contain HCDR1, HCDR2, HCDR3, and LCDR1 as set forth in SEQ ID Nos.: 2-5, respectively. In another aspect, the antibodies administered contain HCDR1, HCDR2, HCDR3, and LCDR2 as set forth in SEQ ID Nos.: 2-4 and 6, respectively. In another aspect, the antibodies administered contain HCDR1, HCDR2, HCDR3, and LCDR3 as set forth in SEQ ID Nos.: 2-4 and 7, respectively. In another aspect, the antibodies administered contain HCDR1, HCDR2, LCDR1, and LCDR2 as set forth in SEQ ID Nos.: 2, 3, 5, and 6, respectively. In another aspect, the antibodies administered contain HCDR1, HCDR2, LCDR1, and LCDR3 as set forth in SEQ ID Nos.: 2, 3, 5, and 7, respectively. In another aspect, the antibodies administered contain HCDR1, HCDR2, LCDR2, and LCDR3 as set forth in SEQ ID Nos.: 2, 3, 6, and 7, respectively. In another aspect, the antibodies administered contain HCDR1, HCDR3, LCDR1, and LCDR2 as set forth in SEQ ID Nos.: 2, 4, 5, and 6, respectively. In another aspect, the antibodies administered contain HCDR1, HCDR3, LCDR1, and LCDR3 as set forth in SEQ ID Nos.: 2, 4, 5, and 7, respectively. In another aspect, the antibodies administered contain HCDR1, HCDR3, LCDR2, and LCDR3 as set forth in SEQ ID Nos.: 2, 4, 6, and 7, respectively. In another aspect, the antibodies administered contain HCDR1, LCDR1, LCDR2, and LCDR3 as shown in SEQ ID Nos.: 2, 5, 6, and 7, respectively. In another aspect, the antibodies administered contain HCDR2, HCDR3, LCDR1, and LCDR2 as shown in SEQ ID Nos.: 3-6, respectively. In another aspect, the antibodies administered contain HCDR2, HCDR3, LCDR1, and LCDR3 as shown in SEQ ID Nos.: 3-5 and 7, respectively. In another aspect, the antibodies administered contain HCDR2, HCDR3, LCDR2, and LCDR3 as shown in SEQ ID Nos.: 3, 4, 6, and 7, respectively.In another aspect, the antibodies administered contain HCDR2, LCDR1, LCDR2, and LCDR3 as set forth in SEQ ID Nos.: 3, 5, 6, and 7, respectively. In another aspect, the antibodies administered contain HCDR3, LCDR1, LCDR2, and LCDR3 as set forth in SEQ ID Nos.: 4, 5, 6, and 7, respectively. In yet another aspect, the antibodies administered contain HCDR1, HCDR2, HCDR3, LCDR1, and LCDR2 as set forth in SEQ ID Nos.: 2-6, respectively. In another aspect, the antibodies administered contain HCDR1, HCDR2, HCDR3, LCDR1, and LCDR3 as set forth in SEQ ID Nos.: 2-5 and 7, respectively. In another aspect, the antibodies administered contain HCDR1, HCDR2, HCDR3, LCDR2, and LCDR3 as set forth in SEQ ID Nos.: 2, 3, 4, 6, and 7, respectively. In another aspect, the antibodies administered contain HCDR1, HCDR2, LCDR1, LCDR2, and LCDR3 as shown in SEQ ID No.: 2, 3, 5-7, respectively. In another aspect, the antibodies administered contain HCDR1, HCDR3, LCDR1, LCDR2, and LCDR3 as shown in SEQ ID No.: 2, 4-7, respectively. In another aspect, the antibodies administered contain HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 as shown in SEQ ID No.: 3-7, respectively. In yet another aspect, the antibodies administered contain HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 as shown in SEQ ID No.: 2-7, respectively.

[0077] Yet another aspect of the present invention provides a method for treating psoriasis, reducing the severity of psoriasis, or providing passive immunity against psoriasis to a subject, comprising administering to the subject an effective amount of an antibody or antibody fragment that binds to the fragment of apoB100 shown in SEQ ID No.: 1, and the antibody contains HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 as shown in SEQ ID No.: 2-7, respectively.

[0078] Provided is a method for treating psoriasis or reducing the severity of psoriasis, comprising administering to a subject an effective amount of an antibody or antibody fragment that binds to a fragment of apoB100 as shown in SEQ ID No.: 1, and wherein the antibody contains a variable heavy chain region (V H ) and the variable light chain region (V L), wherein the variable light domain comprises LCDR1, LCDR2 and LCDR3 as shown in SEQ ID No.: 5-7, respectively. In another aspect, a method for treating psoriasis or reducing the severity of psoriasis and / or providing passive immunity is provided, comprising administering to the subject an effective amount of an antibody or antibody fragment that binds to the fragment of apoB100 shown in SEQ ID No.: 1, and wherein the antibody comprises a variable light chain region (V L ) and the variable heavy chain region (V H ), wherein the variable heavy chain region comprises HCDR1, HCDR2 and HCDR3 as shown in SEQ ID No.: 2-4, respectively. Another aspect of the present invention provides a method for treating psoriasis, reducing the severity of psoriasis and / or reducing the likelihood of psoriasis in a subject, comprising administering to the subject an effective amount of an antibody or antibody fragment that binds to the fragment of apoB100 shown in SEQ ID No.: 1, and wherein the antibody comprises a variable heavy chain region (V H ) and the variable light chain region (V L ).

[0079] Provided is a method for reducing the likelihood of psoriasis or providing passive immunity against psoriasis to a subject, comprising administering to the subject an effective amount of an antibody or antibody fragment that binds to a fragment of apoB100 as shown in SEQ ID No.: 1, and wherein the antibody contains a variable heavy chain region (V H ) and the variable light chain region (V L ), wherein the variable light domain comprises LCDR1, LCDR2 and LCDR3 as shown in SEQ ID No.: 5-7, respectively. In another aspect, a method for treating psoriasis, reducing the severity of psoriasis and / or reducing the likelihood of psoriasis in a subject is provided, comprising administering to the subject an effective amount of an antibody or antibody fragment that binds to the fragment of apoB100 shown in SEQ ID No.: 1, and wherein the antibody comprises a variable light chain region (V L ) and the variable heavy chain region (V H ), wherein the variable heavy chain region comprises HCDR1, HCDR2 and HCDR3 as shown in SEQ ID No.: 2-4, respectively. Another aspect of the present invention provides a method for treating psoriasis, reducing the severity of psoriasis and / or reducing the likelihood of developing psoriasis in a subject, comprising administering to the subject an effective amount of an antibody or antibody fragment that binds to the fragment of apoB100 shown in SEQ ID No.: 1, and wherein the antibody comprises a variable heavy chain region (V H) and the variable light chain region (V L ).

[0080] Also provided is a method for treating or reducing the severity of psoriasis, comprising administering to a subject an effective amount of an antibody or antibody fragment that binds to a fragment of apoB100 as shown in SEQ ID No.: 1, and the antibody comprises a heavy chain and a light chain of SEQ ID No.: 10, wherein the light chain comprises LCDR1, LCDR2, and LCDR3 as shown in SEQ ID No.: 5-7, respectively. Yet another aspect of the embodiment provides that the method comprises administering to the subject an effective amount of an antibody or antibody fragment that binds to a fragment of apoB100 as shown in SEQ ID No.: 1, wherein the antibody comprises a heavy chain and a light chain of SEQ ID No.: 10, wherein the light chain comprises a variable light chain region (V) of SEQ ID No.: 9. L ). Another aspect of the present invention provides the method comprising administering to the subject an effective amount of an antibody or antibody fragment that binds to the fragment of SEQ ID No.: 1 of apoB100, and the antibody comprises a light chain and a heavy chain of SEQ ID No.: 11, and the heavy chain comprises HCDR1, HCDR2, and HCDR3 as shown in SEQ ID No.: 2-4, respectively. Still another aspect provides the method comprising administering to the subject an effective amount of an antibody or antibody fragment that binds to the fragment of SEQ ID No.: 1 of apoB100, and the antibody comprises a light chain and a heavy chain of SEQ ID No.: 11, and the heavy chain comprises a variable heavy chain region (V) of SEQ ID No.: 8. H Alternatively, the method comprises administering to the subject an effective amount of an antibody or antibody fragment that binds to the fragment of apoB100 shown in SEQ ID No.: 1, and the antibody comprises a heavy chain of SEQ ID No.: 10 and a light chain of SEQ ID No.: 11.

[0081] Also provided are methods for reducing the likelihood of psoriasis or providing passive immunity against psoriasis to a subject, comprising administering to the subject an effective amount of an antibody or antibody fragment that binds to the fragment of apoB100 shown in SEQ ID No.: 1, and the antibody comprises a heavy chain and a light chain of SEQ ID No.: 10, wherein the light chain comprises LCDR1, LCDR2, and LCDR3 as shown in SEQ ID No.: 5-7, respectively. Yet another aspect of the embodiment provides that the method comprises administering to the subject an effective amount of an antibody or antibody fragment that binds to the fragment of apoB100 shown in SEQ ID No.: 1, wherein the antibody comprises a heavy chain and a light chain of SEQ ID No.: 10, wherein the light chain comprises a variable light chain region (V) of SEQ ID No.: 9. L ). Another aspect of the present invention provides the method comprising administering to the subject an effective amount of an antibody or antibody fragment that binds to the fragment of SEQ ID No.: 1 of apoB100, and the antibody comprises a light chain and a heavy chain of SEQ ID No.: 11, and the heavy chain comprises HCDR1, HCDR2, and HCDR3 as shown in SEQ ID No.: 2-4, respectively. Still another aspect provides the method comprising administering to the subject an effective amount of an antibody or antibody fragment that binds to the fragment of SEQ ID No.: 1 of apoB100, and the antibody comprises a light chain and a heavy chain of SEQ ID No.: 11, and the heavy chain comprises a variable heavy chain region (V) of SEQ ID No.: 8. H Alternatively, the method comprises administering to the subject an effective amount of an antibody or antibody fragment that binds to the fragment of apoB100 shown in SEQ ID No.: 1, and the antibody comprises a heavy chain of SEQ ID No.: 10 and a light chain of SEQ ID No.: 11.

[0082] Additional embodiments of the method include administering to the subject an inhibitor of native LDL, oxidized LDL (oxLDL), or MDA-modified LDL, which is suitable for treating subjects diagnosed with psoriasis and reducing the severity of psoriasis, and optionally also reducing the severity of atherosclerosis or the likelihood of developing atherosclerosis. In one embodiment, the inhibitor is an anti-oxLDL antibody or antigen-binding fragment thereof that is capable of binding to an oxidized fragment of apolipoprotein B100. In another embodiment, the inhibitor of oxidized LDL is a small molecule, polypeptide, peptide, or nucleic acid molecule that is capable of binding to an oxidized fragment of apolipoprotein B100. In other embodiments, the inhibitor of oxidized LDL is an antibody or antigen-binding fragment that is capable of binding to malondialdehyde-modified LDL. In an exemplary embodiment, the inhibitor of oxidized LDL or malondialdehyde-modified LDL is a monoclonal antibody that targets an oxidized form or an MDA-modified form of LDL, such as otekumab.

[0083] Patient selection

[0084] In some embodiments, the methods disclosed herein comprise treating or inhibiting one or more forms of psoriasis by administering an effective amount of oticumab to a subject in need thereof.

[0085] Some embodiments provided in the disclosed methods further include selecting a subject who exhibits symptoms of psoriasis or has been diagnosed with psoriasis. For example, a subject with psoriasis may be characterized by elevated levels of tumor necrosis factor-α (TNFα), interleukin 6 (IL-6), C-reactive protein (CRP), or a combination thereof, compared to a control subject without psoriasis. In some aspects, the methods are used to treat subjects who are refractory to typical therapies for psoriasis (e.g., UVA or UVB therapy; topical steroids).

[0086] In other embodiments, methods of treating plaque psoriasis or inhibiting the development of plaque psoriasis are provided, wherein an effective amount of oticumab is administered to a subject having plaque psoriasis, and the subject, at least at the time of administration, does not have a non-plaque form of psoriasis, such as erythrodermic psoriasis, guttate psoriasis, or pustular psoriasis.

[0087] Various embodiments provide that the psoriasis in the methods disclosed herein is plaque psoriasis, and excludes non-plaque forms of psoriasis, such as erythrodermic psoriasis, guttate psoriasis, or pustular psoriasis.

[0088] Other embodiments of the method of treating or reducing the severity of psoriasis include selecting a subject exhibiting symptoms of or diagnosed with plaque psoriasis, and administering to the subject an antibody or antibody fragment thereof according to any of the above-described antibody characteristics.

[0089] Yet another aspect of the present invention provides a method of treating psoriasis, reducing the severity of psoriasis, and / or reducing the likelihood of psoriasis comprising administering an antibody or antibody fragment thereof according to any of the above-described antibody characteristics to a subject, wherein the subject exhibits symptoms of plaque psoriasis or has been diagnosed with plaque psoriasis but does not show symptoms of erythrodermic psoriasis, guttate psoriasis, or pustular psoriasis.

[0090] Still other embodiments provide methods disclosed herein in which the subject has been further diagnosed with atherosclerosis or exhibits symptoms of atherosclerosis, and the method further reduces symptoms of atherosclerosis other than plaque psoriasis. For example, a method for treating or reducing the severity of psoriasis and atherosclerosis comprises administering to the subject an effective amount of an antibody or antibody fragment that binds to the epitope set forth in SEQ ID No.: 1, wherein the antibody is otikumab or an antigen-binding fragment thereof, and wherein the subject exhibits symptoms of plaque psoriasis and atherosclerosis.

[0091] Also provided are embodiments of the method wherein the subject does not have atherosclerosis, has not been diagnosed with atherosclerosis, or does not display symptoms of atherosclerosis.

[0092] Other embodiments of the present invention provide methods for treating psoriatic arthritis or inhibiting the progression of psoriatic arthritis by administering an effective amount of oticumab to a subject in need thereof. In some embodiments, the subject has been diagnosed with psoriatic arthritis, exhibits symptoms of psoriatic arthritis, or has psoriatic arthritis.

[0093] In some embodiments, the above methods for treating, reducing the severity of, slowing the progression of, or inhibiting a combination of psoriasis and atherosclerosis in a subject in need thereof are characterized in that after administration of an anti-oxLDL antibody of SEQ ID No.: 1 that binds ApoB100, the amount of plaque psoriasis in the subject is reduced compared to those levels before administration of the anti-oxLDL antibody.

[0094] Combination therapy

[0095] Additional embodiments provide methods of treating psoriasis or reducing the severity of psoriasis comprising administering to a subject an effective amount of an antibody or antibody fragment in combination with another therapeutic agent. Also provided are embodiments of methods of reducing the likelihood of psoriasis in a subject comprising administering to the subject an effective amount of an antibody or antibody fragment in combination with another therapeutic agent. Exemplary therapeutic agents for use in this combination include corticosteroids (e.g., Cortisol, corticosterone, cortisone, aldosterone), vitamin D analogs (e.g., calcipotriol, maxacalcitol, tacalcitol, and calcitriol), retinoids (e.g., soriatane, acitretin, and tazarotene), keratolytics (e.g., salicylic acid), coal tar, ultraviolet (UV) A therapy, UV B therapy, TNFα inhibitors (e.g., anti-TNFα antibodies such as infliximab, adalimumab, certolizumab pegol), golimumab, etanercept; thalidomide, lenalidomide, pomalidomide; xanthine derivatives such as pentoxifylline; bupropion), anti-IL-12 / 23 antibodies (e.g., ustekinumab, sedano, ), anti-IL-23 antibodies that bind only to IL-23 but not to IL-12 (e.g., risankizumab, guselkumab, tildrakizumab), and anti-IL-17 antibodies (e.g., secukinumab, ixekizumab, brodalumab).

[0096] The method may further comprise administering an antibody or antibody fragment that binds to SEQ ID No.: 1, another therapeutic agent, and a commonly used adjuvant to enhance absorption of the antibody or antibody mixture.

[0097] In various embodiments, the composition to be used in the disclosed method is formulated for delivery via any route of administration. For example, the method includes administration via aerosol, nasal, oral, transmucosal, transdermal, parenteral or enteral routes. "Parenteral" refers to routes of administration generally associated with injections including intraorbital, infusion, intraarterial, intracapsular, intracardiac, intradermal, intramuscular, intraperitoneal, intrapulmonary, intraspinal, intrasternal, intrathecal, intrauterine, intravenous, subarachnoid, subcapsular, subcutaneous, transmucosal or transtracheal. By parenteral route, the composition can be in the form of a solution or suspension for infusion or injection, or as a lyophilized powder. By parenteral route, the composition can be in the form of a solution or suspension for infusion or injection. By enteral route, the pharmaceutical composition can be in the form of tablets, gel capsules, sugar-coated tablets, syrups, suspensions, solutions, powders, granules, emulsions, microspheres or nanospheres or lipid vesicles or polymer vesicles that allow controlled release. Typically, the composition is administered by injection.

[0098] dose

[0099] Typically, in the methods disclosed herein, an effective amount of an anti-oxLDL or anti-LDL antibody, or an antibody that binds SEQ ID No.: 1, results in a plasma concentration in the subject of at least 4 μg / mL, preferably at least 12 μg / mL.

[0100] Embodiments provide methods of treating or reducing the severity of psoriasis in a subject comprising subcutaneously administering to the subject an antibody or antibody fragment disclosed above at about 330 mg / month for about 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months or longer, wherein the subject is an adult.

[0101] Other embodiments provide for administering the antibody or antibody fragment at least 8 mg of Optikunmab / kg patient (e.g., 664 mg for an average 83 kg human patient) to treat psoriasis or provide passive immunity. Some embodiments provide for administering the antibody or antibody fragment at 5 mg of Optikunmab / kg patient (e.g., 415 mg for an average 83 kg human patient) to 8 mg / kg. Some embodiments provide for administering Optikunmab at the above doses on a monthly dosing schedule.

[0102] Other embodiments provide for weekly administration of the antibody or antibody fragment at no less than 2 mg / kg / week (166 mg for an average 83 kg human patient); preferably 4 mg / kg / week (332 mg for an average 83 kg human patient) to treat psoriasis. In another aspect, the composition of the anti-oxLDL antibody is administered every two weeks at >2.5 mg / kg / two weeks (e.g., 208 mg for an average 83 kg human patient). In yet another aspect, the composition of the anti-oxLDL antibody is administered monthly at about 6 mg / kg / month (e.g., about 498 mg for an average 83 kg human patient). For example, monthly dosing can be performed for 12 months or 3 months.

[0103] Still other embodiments provide for the administration of an antibody or antibody fragment to treat psoriasis, with an initial dose of at least 800-900 mg, 900-1000 mg, 1000-1100 mg, 1100-1200 mg, 1200-1300 mg, 1300-1400 mg, 1400-1500 mg, or 1500-1600 mg. In some aspects, the effective amount of the methods described herein comprises an initial dose of approximately 1000-1500 mg of oticumab, followed by subsequent doses of 700-900 mg of the antibody administered weekly for 2, 3, 4, or 5 weeks and / or even monthly for 1, 2, or 3 months.

[0104] Other embodiments provide for the administration of escalating doses of an antibody directed against native or oxidized LDL (e.g., binding to SEQ ID No.: 1). In this embodiment, an exemplary (starting) dose for a single dose of an antibody directed against native or oxidized LDL (e.g., otikumab) is 0.005 to 0.01 mg / kg (e.g., intravenously); and other exemplary dose levels to be administered in a single dose are 0.01 to 0.15, 0.15 to 0.75, 0.75 to 2.5, 2.5 to 7.5, and 7.5 to 30 mg / kg (e.g., intravenously). For example, in a single intravenous dose, the starting dose of otikumab is 0.007 mg / kg; and in subsequent single intravenous doses, other exemplary doses may be 0.05, 0.25, 1.25, 5.0, or 15.0 mg / kg. In another embodiment, the single dose of the antibody for natural or oxidized LDL is 0.5 to 5 mg / kg subcutaneously, and the multiple doses are also 0.5 to 5 mg / kg subcutaneously. For example, 1.25 mg / kg of the antibody for natural or oxidized LDL is administered subcutaneously. In various embodiments, the dosage is administered within a specified hour range of the day in each administration, and each dose in the multiple dose treatment (e.g., 4 doses, 3 doses, 5 doses, or 6 doses) is administered at weekly intervals in a time window of 1 day. In another example, an antibody for natural or oxidized LDL (such as otikumab) is administered to a human subject at 300 mg to 450 mg (such as 360 mg), optionally followed by another dose of 300 mg to 450 mg (such as 360 mg) to the human subject, wherein the second dose is at least 70 days (up to 91 days) apart from the first dose. Antibodies (such as oticumab) can be formulated at a concentration of 100-170 mg / mL (e.g., 150 mg / mL) and administered subcutaneously without further dilution or diluted to a large volume for intravenous infusion.

[0105] Additional embodiments include administering to a subject an effective amount of an antibody or antibody fragment that binds to SEQ ID No.: 1 and has a sequence of one or more of SEQ ID Nos.: 2-11, the effective amount being in the range of about 10-50 μg / session, 50-100 μg / session, 100-150 μg / session, 150-200 μg / session, 100-200 μg / session, 200-300 μg / session, 300-400 μg / session, 400-500 μg / session, 500-600 μg / session, 600-700 μg / session, 700-800 μg / session, 800-900 μg / session, 900-1000 μg / session, 1000-1100 μg / session, 1100-1200 μg / session, 1200-1300 μg / session, 1300-1400 μg / period, 1400-1500 μg / period, 1500-1600 μg / period, 1600-1700 μg / period, 1700-1800 μg / period, 1800-1900 μg / period, 1900-2000 μg / period, 2000-2100 μg / period, 2100-2200 μg / period, 2200-2300 μg / period, 2300-2400 μg / period, 2400-2500 μg / period, 2500-2600 μg / period, 2600-2700 μg / period, 2700-2800 μg / period, 2800-2900 μg / period or 2900-3000 μg / period. A period is one day, one week, one month, or another length of time. One aspect is administration of the antibody (eg, oticumab) at a weekly, biweekly, or monthly frequency of any of the above dosages per period.

[0106] In some embodiments, the method comprises administering an inhibitor of oxidized LDL (e.g., otikumab) to the subject for 1-5 days, 1-5 weeks, 1-5 months, or 1-5 years. For example, the antibody is administered to the subject in 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 doses, each dose separated by at least 3 days, 5 days, one week, two weeks, one month, two months, or a combination thereof. In other embodiments, the second dose is administered about 2-3 weeks or about 3 weeks after the first dose, and the third dose is administered about 5-6 weeks or about 6 weeks after the first dose, and so on. In another embodiment, the second dose is administered about 2-3 months, about 2 months, about 3 months, or about 4 months after the first dose, and the third dose is administered about 4-6 months, about 5-6 months, about 5 months, or about 6 months after the first dose.

[0107] Other embodiments provide for the administration of escalating doses of antibodies to native or oxidized LDL to treat psoriasis or provide passive immunity. In this embodiment, an exemplary (starting) dose of a single dose of an antibody to native or oxidized LDL (e.g., otikumab) is 0.005 to 0.01 mg / kg (e.g., intravenously); and other exemplary dose levels to be administered in a single dose are 0.01 to 0.15, 0.15 to 0.75, 0.75 to 2.5, 2.5 to 7.5, and 7.5 to 30 mg / kg (e.g., intravenously). For example, in a single dose intravenous administration, the starting dose of otikumab is 0.007 mg / kg; and in subsequent single dose intravenous administrations, other exemplary doses may be 0.05, 0.25, 1.25, 5.0, or 15.0 mg / kg. In another embodiment, the single dose of the antibody for natural or oxidized LDL is 0.5 to 5 mg / kg subcutaneously, and the multiple doses are also 0.5 to 5 mg / kg subcutaneously. For example, 1.25 mg / kg of the antibody for natural or oxidized LDL is administered subcutaneously. In various embodiments, the dosage is administered within a specified hour range of the day in each administration, and each dose in the multiple dose treatment (e.g., 4 doses, 3 doses, 5 doses, or 6 doses) is administered at weekly intervals in a time window of 1 day. In another example, an antibody for natural or oxidized LDL (such as otikumab) is administered to a human subject at 300 mg to 450 mg (such as 360 mg), optionally followed by another dose of 300 mg to 450 mg (such as 360 mg) to the human subject, wherein the second dose is at least 70 days (up to 91 days) apart from the first dose. Antibodies (such as oticumab) can be formulated at a concentration of 100-170 mg / mL (e.g., 150 mg / mL) and administered subcutaneously without further dilution or diluted to a large volume for intravenous infusion. In some embodiments, a therapeutically effective amount of an anti-LDL antibody or anti-oxLDL antibody, or an analog, pharmaceutical equivalent, or peptidomimetic thereof, for use in the methods described herein is 1-10 μg / kg of subject, 10-100 μg / kg of subject, 100-500 μg / kg of subject, 200-500 μg / kg of subject, 300-500 μg / kg of subject, 400-500 μg / kg of subject, 1-5 mg / kg of subject, 5-10 mg / kg of subject, 10-15 mg / kg of subject, 15-20 mg / kg of subject, 20-25 mg / kg of subject, 25-50 mg / kg of subject, 50-75 mg / kg of subject per dose; wherein each dose is administered daily, weekly, monthly, or at other intervals.

[0108] In some embodiments, in addition to one or more vials / dose of an antibody or antibody fragment for treating psoriasis, an instruction manual, a vial for diluent, or both are included in the kit.

[0109] Composition or medicine

[0110] In various embodiments, the present invention provides pharmaceutical compositions for use in the methods described herein for treating psoriasis, reducing the severity of psoriasis, and / or reducing the likelihood of psoriasis. The pharmaceutical compositions comprise an inhibitor of oxidized LDL (such as an anti-oxLDL antibody that binds to the epitope of SEQ ID No.: 1 of ApoB100) and a pharmaceutically acceptable carrier. Another embodiment provides a composition or medicament for treating psoriasis, reducing the severity of psoriasis, or promoting prevention against psoriasis in a subject exhibiting symptoms of psoriasis or having been diagnosed with psoriasis, or treating psoriasis, reducing the severity of psoriasis, or promoting prevention against atherosclerosis, wherein the composition or medicament contains an anti-oxLDL antibody that binds to the epitope of SEQ ID No.: 1 of ApoB100 as disclosed above, in an amount of 300 mg to 400 mg, preferably about 330 mg, per dose (or vial); optionally with a pharmaceutically acceptable carrier, each (e.g., for monthly subcutaneous administration to a subject) for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 months or longer. Other embodiments provide compositions or medicaments containing an anti-oxLDL antibody that binds to the epitope of SEQ ID No.: 1 of ApoB100 as disclosed above, in an amount of at least 5, 6, 7, or 8 mg of otikumab per kg of patient, divided into one dose (or vial) and optionally multiple doses (or vials) of at least 2 mg / kg per week, at least 2.5 mg / kg per two weeks, or at least 6 mg / kg per month for 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 months or longer. Additional embodiments provide compositions or medicaments containing an antibody (such as otikumab) at a concentration of 100-170 mg / mL (e.g., 150 mg / mL) and for subcutaneous administration without further dilution or diluted to a large volume for intravenous infusion.

[0111] As used herein, "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, composition, or vehicle that is involved in carrying or transporting a target compound from one tissue, organ, or part of the body to another. For example, a carrier can be a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, or a combination thereof. Examples of excipients include, but are not limited to, starch, sugar, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrants, wetting agents, emulsifiers, colorants, release agents, coating agents, sweeteners, flavorings, fragrances, preservatives, antioxidants, plasticizers, gelling agents, thickeners, hardeners, coagulants, suspending agents, surfactants, wetting agents, carriers, stabilizers, and combinations thereof. Generally, each component of a carrier must be "pharmaceutically acceptable" in that it must be compatible with the other ingredients of the formulation. It must also be suitable for use in contact with any tissue or organ with which it may come into contact, meaning that it must not carry the risk of toxicity, irritation, allergic reaction, immunogenicity, or any other complications that would outweigh its therapeutic benefits.

[0112] According to the present invention, pharmaceutical compositions can be delivered in a therapeutically effective amount. An accurate therapeutically effective amount is the amount of the composition that will produce the most effective results in a given subject in terms of therapeutic effect. This amount will vary depending on a variety of factors, including but not limited to the properties of the therapeutic compound (including activity, pharmacokinetics, pharmacodynamics, and bioavailability), the subject's physiological condition (including age, sex, disease type and stage, general physical condition, responsiveness to a given dose, and drug type), the properties of one or more pharmaceutically acceptable carriers in the preparation, and the route of administration. Those skilled in the art of clinical and pharmacological medicine will be able to determine the therapeutically effective amount by routine experiments (e.g., by monitoring the subject's response to the compound and adjusting the dosage accordingly). For further guidance, see Remington: The Science and Practice of Pharmacy (Gennaro, ed., 20th edition, Williams & Wilkins PA, USA) (2000).

[0113] Preparation of antibodies in the method

[0114] In some embodiments, the above method relates to antibodies that bind to specific antigenic epitopes, wherein the antibodies contain one or more defined sequences. For example, modern recombinant library technology is used to prepare therapeutic antibodies against natural ApoB, oxidized ApoB, or MDA-modified ApoB. Although mouse hybridoma cells produce a large number of identical antibodies, these non-human antibodies are recognized as foreign by the human body. Therefore, in addition to inducing allergic reactions, their efficacy and plasma half-life are also reduced. To solve this problem, one method is to prepare chimeric antibodies, wherein the mouse variable domains of the antibody are transferred to the human constant region, producing mainly human antibodies. A further improvement of this method is to develop humanized antibodies, wherein the region of the mouse antibody contacting the antigen (the so-called complementary determining region (CDR)) is transferred to the human antibody framework to produce humanized antibodies. Another method is to use recombinant technology to produce completely human antibodies, which does not rely on immunizing animals to generate specific antibodies. Instead, recombinant libraries contain a large number of pre-made antibody variants, and the library may have at least one antibody specific for any antigen. Phage display systems can be used, in which antibody fragments are expressed and displayed on the surface of filamentous phage particles as fusions with phage coat proteins, and phage display systems carry the genetic information of the displayed molecules encoded simultaneously. Phages displaying antibody fragments specific to a particular antigen can be selected by combining the antigen in question. The phage separated can then be amplified, and the genes encoding the selected antibody variable domains can optionally be converted to other antibody forms, such as full-length immunoglobulins, and expressed in high amounts using appropriate vectors and host cells well known in the art. The specific forms of the antibodies displayed on the phage particles can be different. The most commonly used forms are Fab and single chain (scFv), both of which contain the variable antigen binding domains of antibodies. The single chain form is connected to a variable light domain (V) via a flexible linker. L ) of the variable heavy domain (V H ) composition. Prior to use as an analytical reagent or therapeutic agent, the displayed antibody specificity is converted to a soluble form, for example, Fab or scFv, and analyzed as such. In a subsequent step, antibody fragments identified as having the desired characteristics can be converted to other forms, such as full-length antibodies.

[0115] Antibody production using hybridomas

[0116] Cell fusions are achieved by standard procedures well known to those skilled in the art of immunology. Fusion partner cell lines and methods for fusing and selecting hybridomas and screening mAbs are well known in the art. See, for example, Ausubel, hereinafter, Harlow, hereinafter, and Colligan, hereinafter, the contents of which are incorporated herein by reference in their entirety.

[0117] Anti-oxidized LDL antibodies can be produced in large quantities by injecting antibody-secreting hybridoma or transfectoma cells into the peritoneal cavity of mice and, after an appropriate period of time, harvesting ascites fluid containing high titers of mAb and isolating the mAb therefrom. For such in vivo production of mAb using non-mouse hybridomas (e.g., rat or human), it is preferred to grow the hybridoma cells in irradiated or athymic nude mice. Alternatively, the antibodies can be produced recombinantly in eukaryotic or prokaryotic cells by culturing hybridoma or transfectoma cells in vitro and isolating the secreted mAb from the cell culture medium.

[0118] Recombinant expression of anti-oxidized LDL antibodies

[0119] Recombinant mouse or chimeric mouse-human or human-human antibodies that inhibit oxidized LDL can be provided according to the present invention using known techniques based on the teachings provided herein. See, for example, Ausubel et al., eds., Current Protocols in Molecular Biology, Wiley Interscience, NY (1987, 1992, 1993); and Sambrook et al., Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press (1989).

[0120] The DNA encoding the anti-oxidized LDL antibody can be a genomic DNA or cDNA encoding at least one of the heavy chain constant region (Hc), the heavy chain variable region (Hc), the light chain variable region (Lv) and the light chain constant region (Lc). A convenient alternative to using chromosomal gene fragments as a source of DNA encoding the murine V region antigen-binding fragment is to use cDNA for constructing chimeric immunoglobulin genes, for example, as reported by Liu et al. (Proc. Natl. Acad. Sci., USA 84: 3439 (1987) and J. Immunology 139: 3521 (1987). The use of cDNA requires that gene expression elements suitable for host cells be combined with genes to achieve the synthesis of the desired protein. The use of cDNA sequences is superior to genomic sequences (which contain introns) because cDNA sequences can be expressed in bacteria or other hosts that lack appropriate RNA splicing systems.

[0121] Example

[0122] The following examples are provided to better illustrate the claimed invention and should not be construed as limiting the scope of the invention. Specific materials mentioned are for illustrative purposes only and are not intended to limit the invention. Those skilled in the art may develop equivalent means or reactants without exercising their inventive abilities and without departing from the scope of the invention.

[0123] Example 1. Improved psoriasis symptoms in human patients receiving oticumab.

[0124] In a Phase 2a study testing Optikunmab (a human monoclonal IgG1 antibody directed against an MDA-modified epitope in LDL) in patients with stable atherosclerosis, four of the enrolled patients had a medical history of psoriasis. Optikunmab was administered intravenously (IV) to three of the four patients (initial dose 1245 mg, followed by 830 mg weekly x 3, then 830 mg monthly x 2), while the fourth patient received a placebo. During the course of the study, no patients received concomitant medication for psoriasis. Of the three patients treated with Optikunmab, two experienced improvement in their psoriasis. One patient reported improvement after the first dose. The second patient, who was refractory to UVA / B and topical steroids, reported improvement in both elbow and knee plaques. These results show that treatment with Optikunmab, an anti-inflammatory molecule that targets the oxidized form of LDL, demonstrates therapeutic value in patients with psoriasis.

[0125] Example 2. Simulated and actual pharmacokinetics (PK)

[0126] The ability of oticumab to shut down macrophage proinflammatory activity locally in plaques has become a focus, as it is considered a potentially important mechanism of its therapeutic activity. The initial hypothesis for the use of oticumab was related to neutralization of oxLDL from the systemic compartment, which required 4 μg / mL = approximately 28 nM = 11 mg of oticumab to neutralize 90% of systemic oxLDL. Further in vitro assays provided insight into the minimum effective concentration of oticumab required to achieve 50% or 90% inhibition of oxLDL-mediated cytokine release (i.e., inhibition of monocyte chemoattractant protein 1, MCP-1):

[0127] IC of MCP-1 inhibition 50 : About 10nM = 1.5μg / mL = about 4mg

[0128] IC of MCP-1 inhibition 90 : about 30-80nM = 4.5-12μg / mL = 12.4-33mg.

[0129] IC 90 Compared with the lower range of (12.4 mg of oticumab), the doses in the clinical trial of Example 1 (initial dose 1245 mg, followed by 830 mg weekly × 3, then 830 mg monthly × 2) are 67 times and 100 times larger. 90 Compared to the higher range of α-tekumab (33 mg of α-tekumab), the doses in the clinical trial of Example 1 were 25-fold and 38-fold greater.

[0130] In patients with atherosclerosis, increased endothelial permeability to macromolecules has been reported, where uptake of injected macromolecules into the arterial wall is rapid and linear over time, reaching equilibrium with circulating blood flow within 1 hour (Ross et al., NEJM 1999).

[0131] Based on this background information, we proposed a loading dose that would produce a steady-state plasma concentration of at least 12 μg / mL of oticumab for up to 96 hours in the simulation model ( Figure 1 The loading dose was 8 mg / kg (664 mg for an average 83 kg patient), followed by 2 mg / kg (166 mg) subcutaneous (SC) administration every two weeks to weekly. This loading dose was 1 / 1.9 of the loading dose in Example 1, and the weekly dosing was 1 / 5 of the weekly dosing in Example 1.

[0132] In another set of simulations based on SC administration:

[0133] (1) On days 2-4, a threshold of 12 μg / mL was achieved with weekly dosing of 2 mg / kg (166 mg) Figure 2A );

[0134] (2) On days 1-6, the 12 μg / mL threshold was not achieved at 2 mg / kg every two weeks, but the 4 μg / mL threshold was achieved ( Figure 2A );

[0135] (3) Monthly dosing at 2 mg / kg did not achieve sustained exposure below the 4 μg / mL threshold ( Figure 2A );

[0136] (4) A loading dose of 5 mg / kg (415 mg) followed by 2 mg / kg every two weeks did not achieve the 12 μg / mL threshold through day 6, but maintained exposure above 4 μg / mL ( Figure 2B ).

[0137] In clinical trials of oticumab, the PK data are summarized in Tables 1-4 below.

[0138] Table 1. PK data from a "FIH" study using a single dose.

[0139]

[0140] Table 2. PK data from a "FIH" study conducted with multiple dosing.

[0141]

[0142] Table 3. PK data from a "Ph1" study comparing subcutaneous (SC) and intravenous (IV) administration using a single dose.

[0143]

[0144]

[0145] Table 4. PK data from the "Ph2" trial.

[0146]

[0147] Cmax, single dose of 1.25 mg / kg: 1.25 mg / kg = 104 mg, maximum exposure with IV administration was 6.9 times the maximum exposure with SC administration (half-life was 20 days for both); the SC dose did not reach the 4-12 μg / mL threshold.

[0148] Cmax, single dose of 360 mg: 360 mg = 4.34 mg / kg (3.5 times that of the FIH study), maximum exposure with IV administration was 9.2 times that of SC administration (half-life of 33.5 days for IV versus 24.3 days for SC); SC doses fell within the range of 4-12 μg / mL.

[0149] Therefore, based on simulated and actual PK data, 8 mg / kg (664 mg) is optimal, but 5 mg / kg (415 mg) may be sufficient. Monthly dosing is reasonable based on the half-life of a single dose in clinical studies (i.e., 24 days for a single SC dose of 360 mg).

[0150] In another study of oticumab:

[0151] (1) Weekly SC doses of 1 mg / kg and above maintain concentrations above 4 μg / mL at steady state. Figure 3 Simulated human PK profiles are depicted following weekly SC dosing, using PK parameters from Phase I data. Bioavailability following SC dosing was 70%.

[0152] (2) Biweekly SC doses of 1.5 mg / kg and above maintained concentrations above 4 μg / mL at steady state. Figure 4 Simulated human PK profiles following biweekly SC dosing are depicted, using PK parameters from Phase I data.

[0153] (3) Monthly SC doses of approximately 3 to 4 mg / kg and above maintain concentrations above 4 μg / mL. Figure 5 Simulated human PK profiles following monthly SC dosing are depicted, using parameters from Phase I data.

[0154] Based on the simulated PK data, and targeting a plasma concentration of 12 μg / mL threshold for the greatest chance of success, weekly dosing should be no less than 2 mg / kg (166 mg); 4 mg / kg (332) would be preferred; biweekly dosing must be >2.5 mg / kg (208 mg); no higher doses were simulated; and monthly dosing should be 6 mg / kg (498 mg). In some embodiments, the final recommendation is 500 mg per month via SC injection. Monthly dosing of 500 mg per month can be administered for 12 doses over a 12-month dosing regimen, or for 3 doses over a 3-month dosing regimen. Monthly dosing of 330 mg per month (to meet the minimum 4 μg / mL plasma concentration threshold) can be administered for 12 doses over a 12-month dosing regimen, or for 3 doses over a 3-month dosing regimen.

[0155] Example 3. A multicenter, randomized, double-blind, placebo-controlled, Phase 2 study to evaluate the efficacy, safety, tolerability, pharmacokinetics, and pharmacodynamics of monthly administered oticumab in patients with chronic plaque psoriasis and coronary artery disease.

[0156] Patients with psoriasis have accelerated atherosclerosis and are at increased risk for developing cardiovascular disease (CVD). Both psoriasis and atherosclerosis share common inflammatory mediators such as IL-6, TNFα, and C-reactive protein (CRP).

[0157] It has been reported that MDA-LDL and oxLDL are significantly increased in patients with psoriasis. Importantly, oxLDL is found specifically in psoriatic skin lesions, while non-lesional skin from the same patients does not contain oxLDL. In addition, antibodies against oxLDL are thought to be associated with disease severity (Psoriasis Area and Severity Index [PASI] score) as well as total cholesterol, LDL, oxLDL, and CRP in patients with psoriasis. However, prior to the applicant's invention, it was unknown how the administration of autoantibodies against oxLDL might affect psoriasis.

[0158] The primary objective of this study was to evaluate the superiority of otikumab compared to placebo in reducing the area, severity, and improvement of psoriasis. Secondary objectives included evaluating the safety and tolerability of subcutaneous otikumab in adult subjects with moderate plaque psoriasis; evaluating the efficacy of subcutaneous otikumab in adult subjects with moderate plaque psoriasis; evaluating changes in psoriasis severity and area in subjects with moderate plaque psoriasis; evaluating changes in coronary artery inflammation by mapping spatial changes in perivascular fat attenuation using coronary computed tomography angiography (CCTA) in subjects with moderate plaque psoriasis; evaluating changes in coronary artery plaque volume, assessed by CCTA, in subjects with moderate plaque psoriasis; evaluating the pharmacokinetics of otikumab in adults with moderate plaque psoriasis using sparse blood sampling; and evaluating the plasma concentrations and pharmacodynamic effects of otikumab in subjects with moderate plaque psoriasis.

[0159] The primary outcome measures included the percentage of subjects with psoriasis who achieved treatment success (clear = 0 or almost clear = 1) based on the 5-point static Investigator's Global Assessment (2011 revised) (sIGA) and an improvement from baseline greater than or equal to (>=) 2 points (baseline to Week 16).

[0160] Secondary outcome measures included the percentage of subjects who achieved a 75% or greater reduction in PASI score from baseline to Week 16 (PASI 75); the percentage of subjects who achieved a PASI 90 [timeframe: at least a 90% reduction in PASI score from baseline at Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52 + / - 3 days (PASI 90 response)]; the percentage of subjects who achieved a PASI 75 [timeframe: at least a 70% reduction in PASI score from baseline at Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52 + / - 3 days (PASI 75 response)]. the percentage of participants who achieved a 50% reduction from baseline in PASI score (PASI 50 response) at Weeks 2, 4, 6, 8, 8, 10, 12, and 16 + / - 3 days [Time Frame: Week 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52 + / - 3 days]; the percentage of participants who achieved a 50% reduction from baseline in PASI score (PASI 50 response) at Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52 + / - 3 days]. Mean change from baseline in PASI score at Week 52 + / - 3 days [Time frame: baseline, Week 4, Week 8, Week 12, Week 16, Week 20, Week 24, Week 28, Week 32, Week 36, Week 40, Week 44, Week 48, and Week 52 + / - 3 days]; Mean change from baseline in PASI score at Week 4, Week 8, Week 12, Week 16, Week 20, Week 24, Week 28, Week 32, Week 36, Week 40, Week 44, Week 48, and Week 52 + / - 3 days [Time frame: baseline, Week 4, Week 8, Week 12, Week 16, Week 20, Week 24, Week 28, Week 32, Week 36, Week 40, Week 44, Week 48, and Week 52 + / - 3 days 8 and 52 + / - 3 days] sIGA (2011 revision); Mean change in sIGA (2011 revision) at Week 4, Week 8, Week 12, Week 16, Week 20, Week 24, Week 28, Week 32, Week 36, Week 40, Week 44, Week 48, and Week 52 + / - 3 days [Time Frame: Week 4, Week 8, Week 12 and Week 16, Week 20, Week 24, Week 28, Week 32, Week 36, Week 40, Week 44, Week 48, and Week 52 + / - 3 days]; Percentage of subjects achieving an improvement from baseline of greater than or equal to (>=) 2 points on the sIGA (2011 revision) for participants with a score of 3 at baseline;Participants who achieved clear = 0 or almost clear = 1 on a 5-point sIGA score of 3 at baseline were eligible for the treatment of nausea and vomiting at Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52 + / - 3 days [Timeframe: Weeks 2, 4, 8, 12, and 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52 + / - 3 days]. Percentage of participants who achieved clear = 0 or almost clear = 1 based on the 5-point sIGA at Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52 + / - 3 days [Time Frame: Weeks 4, 8, 12 and 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52 + / - 3 days] for participants with a score of 3 at baseline; as well asPercentage of subjects with an improvement of greater than or equal to (>=) 2 points from baseline; Mean change from baseline in the Numerical Rating Scale score for Itch at Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52 + / - 3 days [Time Frame: Baseline, Week 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52 + / - 3 days]; Dermatology Life Quality Index. Changes in the DLQI (mean change in DLQI total score from baseline to Week 16 and Week 52 + / - 3 days) [Timeframe: baseline, Week 16, and Week 52 + / - 3 days]; changes in body surface area (BSA) (mean change in BSA from baseline to Week 16 and Week 52 + / - 3 days) [Timeframe: baseline, Week 16, and Week 52 + / - 3 days]; changes in cholesterol and lipid profiles (mean change from baseline to Week 16 and Week 52 + / - 3 days); changes in high-sensitivity C-reactive protein (mean change from baseline to Week 16 and Week 52 + / - 3 days); changes in oxidatively modified lipids; LDL, lipoprotein ( a) Changes in oxLDL and oxHDL (mean change from baseline to Week 16 and Week 52 + / - 3 days); Number and percentage of participants with one or more treatment-emergent adverse events (AEs) or any serious AEs [Time range: baseline to up to Week 52 + / - 3 days]; Changes in hemodynamic and EKG parameters [Time range: baseline to up to Week 52 + / - 3 days]; Changes in blood chemistries and hematology [Time range: baseline to up to Week 52 + / - 3 days]; Effects on weight and BMI [Time range: baseline to up to Week 52 + / - 3 days]; Changes in physical examinations [Time range: baseline to up to Week 52 + / - 3 days];

[0161] Exploratory measures included change in coronary perivascular fat attenuation index (FAI) measured by CT angiography at screening for subjects with -190 Hounsfield units to -30 Hounsfield units; mean change from screening to week 52 + / - 3 days [time frame: screening to week 52 + / - 3 days] around the proximal right coronary artery, proximal left anterior descending artery, and left circumflex artery; change in coronary perivascular fat attenuation index (FAI) measured by CT angiography at screening for subjects with -30 to -70 Hounsfield units (HU) (low group); mean change from screening to week 52 + / - 3 days around the proximal right coronary artery, proximal left anterior descending artery, and left circumflex artery; and mean change from screening to week 52 + / - 3 days around the proximal right coronary artery, proximal left anterior descending artery, and left circumflex artery. mean change from screening to week 52 + / - 3 days [time frame: screening to week 52 + / - 3 days]; change in coronary perivascular fat attenuation index (FAI) measured by CT angiography at screening for subjects with -71 Hounsfield units (HU) to -110 Hounsfield units (HU) (mid group); mean change from screening to week 52 + / - 3 days [time frame: screening to week 52 + / - 3 days] around the proximal right coronary artery, proximal left anterior descending artery, and left circumflex artery; mean change from screening to week 52 + / - 3 days [time frame: screening to week 52 + / - 3 days] around the proximal right coronary artery, proximal left anterior descending artery, and left circumflex artery; mean change from screening to week 52 + / - 3 days [time frame: screening to week 52 + / - 3 days] around the proximal right coronary artery, proximal left anterior descending artery, and left circumflex artery; change in perivascular fat attenuation index (FAI) measured by CT angiography at screening in subjects with <70 Hounsfield units (HU) and in subjects with >70 Hounsfield units (HU) (high group); mean ... Indicators of atherosclerosis: Change in non-calcified and low-attenuation coronary plaque volume; mean change from screening to Week 52 + / - 3 days [time frame: screening to Week 52 + / - 3 days]; Change in coronary artery calcium score; mean change from screening to Week 52 + / - 3 days [time frame: screening to Week 52 + / - 3 days]; Change in total plaque volume (non-calcified plus dense calcium plaque); mean change from screening to Week 52 + / - 3 days [time frame: screening to Week 52 + / - 3 days]; Change in fibrous plaque volume; mean change from screening to Week 52 + / - 3 days [time frame: screening to Week 52 + / - 3 days]; change in low-attenuation plaque volume and fibro-fatty plaque volume;Mean change from screening to week 52 + / - 3 days [time frame: screening to week 52 + / - 3 days]; and change in dense calcified plaque burden (DCB); change in non-calcified plaque burden (NCB).

[0162] Study Design

[0163] Following the screening period (Table 5), subjects will be recruited into one of two groups (330 mg / month subcutaneous (sc) (1.1 ml x 2 sc injections) of oticumab or matching placebo). Each subject will receive monthly oticumab or placebo treatment for up to 48 weeks. Subjects will be randomized equally in each group to oticumab or matching placebo (approximately 50 subjects will take oticumab and 50 subjects will take matching placebo). Single-use prefilled vials and matching placebo will be provided by Abcentra, LLC. Participants will receive subcutaneous oticumab or matching placebo. An estimated 100 participants are planned for recruitment: male and female subjects with moderate chronic plaque psoriasis - 50 subjects in the first group and 50 subjects in the second group.

[0164] Every effort will be made to randomize at least 20 women in each group, and every effort will be made to randomize an equal number of subjects taking statins to each treatment group. In addition, randomization will be based on screening computed tomographic angiography, stratified by Hounsfield unit scale, so that subjects will be randomized approximately equally to high, medium, and low groups in both treatment groups.

[0165] The planned treatment is monthly subcutaneous injections of 330 mg sc (1.1 ml x 2 sc injections) of oticumab or matching placebo. Blinded safety, tolerability, and efficacy data will be reviewed by the Internal Safety Review Committee (ISRC) starting after the first five subjects have completed 2 weeks of dosing, every 2 weeks until week 16, and then monthly (+ / - 1 week) thereafter, or sooner as needed.

[0166] From Week 16 to Week 52 (Table 6), the Internal Safety Review Committee (ISRC) will review blinded safety, tolerability, and efficacy data at least monthly until Week 52, or earlier as needed.

[0167] The safety monitoring plan will be completed before the start of the study and will be followed until the last subject has completed his or her last visit. Stopping criteria will be utilized in this study based on laboratory values, vital signs, physical examination, electrocardiogram (EKG), and adverse events (AEs).

[0168] Rescue Medication - After Week 16, any subject who, in the opinion of the investigator, requires medication for psoriasis (in addition to current blinded therapy) may take topical corticosteroids, vitamin D analogs, topical retinoids, keratolytics, coal tar, calcipotriol, anthralin, or any prescription or over-the-counter medications in any combination. local Psoriasis treatment, which, in the medical judgment of the Investigator, will be safe and potentially effective in treating the subject's psoriasis for any period of time that may be considered necessary during the study. The Investigator and qualified staff must supervise the administration of these medications, and relevant logs will be provided by the Sponsor for completion by the site.

[0169] Once all subjects have completed 16 weeks of participation in their group (i.e., have completed all 16 weeks of treatment or withdrawn early), a primary efficacy analysis will be conducted to assess the efficacy of oticumab. The purpose of the Week 16 analysis will be to provide the sponsor with an early indication of the efficacy and safety of the trial while minimizing the impact of changes to the conduct of the study. Investigators and subjects will remain blinded to treatment assignment and to the results of the open-label efficacy and safety assessments.

[0170] Participation in each group will continue during the implementation of the Week 16 analysis, as time will be consumed to retrieve all 16-week data, resolve all data queries, finalize the database, unblind the database, and analyze it. Although the study is not planned to be stopped for efficacy, it may be stopped for futility or the sample size may be revised based on the results of the Week 16 analysis. Details of the analyses to be conducted will be provided in the Statistical Analysis Plan (SAP).

[0171] Research group

[0172] Inclusion

[0173] Men or women aged 18-75 years at the time of consent.

[0174] Female subjects, unless postmenopausal (defined as 12 months of amenorrhea with no alternative medical reason and confirmed by follicle-stimulating hormone [FSH] > 40 mIU / mL) and / or surgically sterilized (hysterectomy or bilateral oophorectomy), are advised to use one of the following contraceptive methods during the study and for 4 months after the last dose of study drug:

[0175] Combined (estrogen and progestogen) oral, vaginal, or transdermal hormonal contraception associated with ovulation suppression

[0176] Oral, injectable, or implantable progestin-only hormonal contraception associated with ovulation suppression

[0177] Intrauterine device

[0178] intrauterine hormone-releasing system

[0179] Bilateral tubal ligation / occlusion

[0180] Vasectomized partners

[0181] Sexual abstinence (no sexual intercourse)

[0182] If men with female partners of fertile potential become sexually active during the study and for 4 months after the study, they must agree to the double barrier method. Male subjects must not donate sperm for 4 months after their participation in the study.

[0183] Must have been a candidate for or previously received topical therapy and / or phototherapy

[0184] Patients must have been diagnosed with plaque psoriasis at least 6 months prior to screening. Patients must meet all of the following criteria:

[0185] Stable plaque psoriasis at screening and randomization

[0186] At screening and baseline, plaque coverage of 3% to 10% of body surface area (BSA)

[0187] PASI ≥ 4.5 but less than PASI 12

[0188] sIGA score of 3-moderate (5-point scale) at screening and baseline

[0189] Coronary perivascular fat attenuation index (FAI) measured by CT angiography was screened within the range of -190 Hounsfield units to -30 Hounsfield units.

[0190] Able to communicate well with researchers, understand and comply with study requirements. Understand and sign the written informed consent form.

[0191] Vital signs must be within the following ranges and stable.

[0192] Systolic blood pressure, 90-150 mm Hg

[0193] Diastolic blood pressure, 50-90 mm Hg

[0194] Pulse rate, 40-100 bpm

[0195] Blood pressure (≤150 / 90 mmHg); may include stable doses (≥45 days of use) of up to two antihypertensive medications intended to be maintained at stable doses during the regimen.

[0196] Results of screening clinical laboratory tests (CBC and platelets with differential and chemistry profile) must be within normal ranges or, if outside normal ranges, must be accepted by the investigator and sponsor as not clinically significant.

[0197] Subjects were allowed to take stable doses of chronic concomitant medications at the time of study enrollment, as long as these medications did not interfere with the interpretation of the primary and key secondary endpoints and were not listed as excluded medications in the protocol. Stable dosing was defined as no change in medication type for at least 60 days prior to Day 1 (baseline) and no change in dose for at least 45 days prior to Day 1 (baseline), and no planned changes in concomitant medications during the course of the study.

[0198] Subjects who were on stable lipid-lowering therapy or a lipid-modifying diet before baseline could be included as long as there was no plan to change their lipid-lowering therapy or diet during the trial.

[0199] exclude

[0200] Any non-plaque form of psoriasis at screening or baseline: erythrodermic, guttate, or pustular

[0201] Subjects with psoriasis of the scalp, palms, or soles only.

[0202] Severe psoriasis PASI >10

[0203] Have drug-induced psoriasis (e.g., new onset or worsening of psoriasis caused by beta-blockers, calcium channel blockers, or lithium).

[0204] Treatment with other biologic therapies or immunosuppressants (such as, but not limited to, cyclosporine, mycophenolate, pimecrolimus, or tacrolimus) within 3 months prior to baseline.

[0205] The following minimum washout period will be required for patients to be eligible for the trial.

[0206] Washout 3 months prior to screening for biologic therapy (such as etanercept, adalimumab, infliximab, or other biologics)

[0207] Washout 1 month prior to screening for immunosuppressants including but not limited to cyclosporine, mycophenolate mofetil, tacrolimus, and any systemic immunosuppressants including but not limited to methotrexate, azathioprine, thioguanine prednisone, mercaptopurine, hydroxyurea, and mycophenolate mofetil

[0208] A 2-week washout period before screening was performed for the following: systemic retinoids, phototherapy or photochemotherapy, high-potency topical corticosteroids, "alternative medicine" treatments for psoriasis, and prolonged sun exposure or tanning bed use, which the investigators believed might alter disease activity.

[0209] Topical treatment within 1 week prior to the start of study treatment and for the duration of the study with agents such as, but not limited to, topical corticosteroids, vitamin D analogs and topical retinoids, keratolytics, coal tar, and anthralin

[0210] History of allergic / hypersensitivity reaction to systemically administered biological agents or their excipients.

[0211] Subjects with a history of hypersensitivity or allergy to oticumab or any of the contents of the SC formulation

[0212] Participation in any clinical study using study drug / device within 2 months prior to the first day of dosing.

[0213] Have underlying conditions that predispose to infection (e.g., immunodeficiency, history of poorly controlled diabetes, splenectomy).

[0214] Are an immediate family member, study center employee, or have a dependent relationship (e.g., spouse, parent, child, sibling) with a study center employee involved in the conduct of this study, or may have given consent under duress.

[0215] Chronic or acute hepatitis B and C, or carrier status. Patients with anti-HBc Ab and undetectable anti-HBs Ab should also be excluded.

[0216] History of human immunodeficiency virus (HIV) positivity

[0217] History of tuberculosis, tuberculosis, or a positive tuberculin skin test (TST) for tuberculosis. Subjects who have previously received BCG vaccination may participate in the study after showing a negative response in an interferon-gamma release assay (IGRA).

[0218] History of recurrent infection

[0219] History of malignancy or suspected active malignancy in the past 5 years other than treated squamous cell carcinoma or basal cell carcinoma of the skin and treated carcinoma in situ of the cervix.

[0220] Intake of restricted medications or other medications that are considered to be potentially interfering with the safe conduct of the study

[0221] A diagnosis of major depressive disorder, schizophrenia, bipolar disorder, personality disorder, or other DSM-V disorder that the investigator believes will significantly interfere with study compliance.

[0222] Suicidal thoughts within 1 year before the screening visit

[0223] Clinically significant disease as determined by the investigator within 8 weeks prior to screening.

[0224] Hepatic, renal, pulmonary, cardiac, neoplastic, or GI disease that, in the opinion of the investigator, is clinically significant or may interfere with safe laboratory interpretation, physical examination, or interpretation of potential adverse events.

[0225] Liver disease or liver damage, as indicated by abnormal liver function tests, SGOT (AST), alkaline phosphatase, or serum bilirubin (>1.5×ULN for any of these tests), or a history of cirrhosis.

[0226] History or presence of impaired renal function as indicated by clinically significant abnormalities in creatinine, BUN, or urine components (e.g., proteinuria), or moderate to severe renal insufficiency as defined by the Cockroft Gault equation (GFR <60 mL / min).

[0227] History of significant drug or solvent abuse within the year prior to screening, or a positive drug of abuse (DOA) test at screening;

[0228] Subjects who are legally using medications that might otherwise be considered drugs of abuse under medical supervision may be enrolled at the investigator's discretion after the investigator has documented the justification for enrollment and reviewed the justification with the sponsor;

[0229] History of alcohol abuse in the past year before screening, or current drinking of more than 21 units per week (3 drinks or units / day).

[0230] exclusions related to coronary computed tomographic angiography;

[0231] previous coronary artery surgery, including stent placement;

[0232] Conditions that increase the risk of the procedure (estimated glomerular filtration rate <60 mL / min / 1.73 m2 or known allergy to iodinated contrast media);

[0233] Factors making the procedure technically infeasible (weight >136 kg, inability to hold breath for 10 seconds, current or previous (within the past year) diagnosis of tachycardia or irregular heart rhythm [e.g., atrial fibrillation]).

[0234] The researcher considers the subject to be unsuitable for study participation.

[0235] Clinically significant blood loss or donation of >500 mL within 3 months.

[0236] Inadequate venous access.

[0237] Study Drug: Otikumab is a fully humanized recombinant monoclonal antibody directed against a specific oxidized low-density lipoprotein (malondialdehyde-modified human ApoB100). It is designed to exert an anti-inflammatory effect in subjects with plaque psoriasis and coronary artery inflammation.

[0238] Study Duration: This study will take approximately 14.5 months and will include a 4-week screening period, 48 weeks of drug or matching placebo administration, one end-of-treatment evaluation visit (Week 52 + / - 3 days), and 2 weeks for subjects in each group to return for their follow-up visit after their last treatment visit.

[0239] Subject Duration: Subjects will each take approximately 58 weeks (14.5 months) to complete all study visits, including screening (4 weeks), treatment (48 weeks), one end-of-treatment evaluation visit (Week 52 + / - 3 days), and follow-up (2 weeks).

[0240] Study Procedure:

[0241] Screening (Day -30 to Day 1) (See also Table 5 for the assessment schedule). Informed consent will be obtained and subjects will undergo a procedure to determine eligibility. Eligible male and female subjects who have given informed consent to participate in the trial and have met all screening inclusion criteria and have no screening exclusions will undergo coronary computed tomography angiography during the screening period, which will serve as their baseline reading.

[0242] Baseline (Day 1, Week 1, Visit 1)

[0243] Following reconfirmation of eligibility and baseline efficacy and safety assessments on Day 1, eligible male and female subjects will be randomized to 330 mg of oticumab or matching placebo. Subjects will receive 330 mg of oticumab or matching placebo administered as two 1.1 ml subcutaneous injections monthly for 48 weeks + / - 3 days of treatment. Safety and tolerability will be monitored by physical examination, assessment of AEs and concomitant medications, suicidality, assessment of vital signs, safety laboratory tests (hematology [including coagulation], chemistry, urinalysis), and ECG.

[0244] The following measurements will be obtained prior to dosing at the Baseline Visit (see also Table 5 for assessment schedule).

[0245] Psoriasis Area and Severity Index - PASI

[0246] Percentage of body surface area (BSA) covered by psoriasis

[0247] Investigator Global Assessment (sIGA)

[0248] Patient Global Assessment (PtGA)

[0249] Intensive Numerical Rating Scale (INRS)

[0250] Dermatology Life Quality Index – DLQI

[0251] Perform, read, and interpret screening coronary computed tomography angiography

[0252] Body surface area (excluding head and groin) – Standardized digital photographs of selected areas

[0253] Psoriatic Arthritis Questionnaire.

[0254] Treatment phase [week 1 to week 16 (visits 1-9)]

[0255] All subjects enrolled will be reviewed for safety, tolerability, and efficacy by an Internal Safety Review Committee (ISRC) after the first five subjects have completed 2 weeks of treatment, and monthly + / - 1 week thereafter or sooner as needed. Individual and study stopping criteria will be utilized in this study based on laboratory values, vital signs, electrocardiogram (ECG), adverse events (AEs), and physical examinations.

[0256] The following measurements will be obtained at Weeks 4, 8, 12, and 16 + / - 3 days (see also Table 5 for assessment schedule).

[0257] Psoriasis Area and Severity Index - PASI

[0258] Investigator Global Assessment (sIGA)

[0259] Intensive Numerical Rating Scale (INRS)

[0260] The following will also be obtained at Week 16 + / - 3 days (see also Table 5 for assessment schedule).

[0261] Patient Global Assessment (PtGA)

[0262] Dermatology Life Quality Index-DLQI

[0263] Body surface area affected by psoriasis (%)

[0264] Medication Inventory

[0265] Physical examination

[0266] pregnancy test

[0267] Laboratory evaluation

[0268] 12-lead ECG in triplicate

[0269] Body surface area (excluding head and groin) – Standardized digital photographs of selected areas

[0270] Psoriatic Arthritis Questionnaire

[0271] Treatment phase [week 20 to week 52 (visits 10-19)]

[0272] All subjects enrolled will be reviewed for safety, tolerability, and efficacy at least monthly by an Internal Safety Review Committee (ISRC). Individual and study stopping criteria will be utilized in this study based on laboratory values, vital signs, electrocardiogram (ECG), and adverse events (AEs).

[0273] The following measurements will be obtained at Weeks 20, 24, 28, 32, 36, 40, 44, 48, and 52 + / - 3 days (see also Table 6 for assessment schedule).

[0274] Psoriasis Area and Severity Index - PASI

[0275] Investigator Global Assessment (sIGA)

[0276] Intensive Numerical Rating Scale (INRS)

[0277] Body surface area affected by psoriasis (%)

[0278] Medication Inventory

[0279] The following will also be obtained at Weeks 28, 36, and 52 + / - 3 days (see also Table 6 for assessment schedule).

[0280] Patient Global Assessment (PtGA)

[0281] Physical examination

[0282] Laboratory evaluation

[0283] 12-lead ECG in triplicate

[0284] The following will also be obtained at Week 52 + / - 3 days (see also Table 6 for assessment schedule).

[0285] Dermatology Life Quality Index – DLQI

[0286] pregnancy test

[0287] Coronary computed tomography angiography (CCTA)

[0288] Body surface area (excluding head and groin) – Standardized digital photographs of selected areas

[0289] Psoriatic Arthritis Questionnaire

[0290] Follow-up visit - 54 weeks after screening (Visit 20)

[0291] The following will be obtained at Week 54 + / - 3 days (see also Table 5 for assessment schedule): Vital signs.

[0292] Statistical methods

[0293] Sample size considerations:

[0294] In previous studies, the placebo response rate for the primary endpoint ranged from 0% to 10%. Assuming a true placebo response rate of 10%, and based on a two-sided, two-sample comparison using binomial proportions at a significance level of α = 0.05, a sample size of 100 subjects (50 subjects per group) would provide 90% power to detect an improvement of 27 percentage points, i.e., a true response rate of 37% in the active group. No formal statistical assessment of the population PK estimates was performed with respect to sample size.

[0295] Every effort will be made to evenly distribute subjects receiving lipid-lowering therapy between the placebo and active treatment groups.

[0296] Main efficacy analysis:

[0297] The primary analysis and all other efficacy analyses will be performed in the Intent-to-Treat (ITT) analysis group, which is defined as all randomized subjects. The active and placebo groups will be compared using a two-sided Cochran-Mantel-Haenszel statistic (stratified by the randomization stratification variable) at a significance level of α=0.05.

[0298] Key secondary efficacy analyses:

[0299] If the primary efficacy analysis is statistically significant (p < 0.05), the key secondary endpoints will be analyzed using the Cochran-Mantel-Haenszel statistic (stratified by the randomization stratification variable) at a (two-sided) significance level of α = 0.05. However, if the primary analysis is not statistically significant, the results of the key secondary analyses will be exploratory rather than confirmatory.

[0300] Data presentation / descriptive statistics:

[0301] All demographic, safety, PK, and efficacy data will be presented and summarized in a tabular format and, where appropriate, by descriptive statistics. Pharmacokinetic and efficacy data will also be presented graphically, where appropriate. Paired comparisons of PK and efficacy parameters will also be reported. Exploratory analyses may be performed to compare between groups.

[0302] Statistical model:

[0303] In general, any statistical model will be summarized using estimates and confidence intervals for the model effects. Geometric mean ratios and interval estimates will be reported for C troughs compared across time points.

[0304] Outcome measures

[0305] Psoriasis Area and Severity Index (PASI) - The PASI combines assessments of four body regions: head and neck (H), upper extremities (UL), trunk (T), and lower extremities (LL). The percentage of skin affected by psoriasis in each region is given a numerical score representing the percentage involved: 1 (0–9%), 2 (10–29%), 3 (30–49%), 4 (50–69%), 5 (70–89%), or 6 (90–100%). The severity of three plaque signs (erythema (E), thickness / induration (I), and scaling / desquamation (D)) within each region (H, UL, T, LL) is assessed on a 5-point scale: 0 (none), 1 (mild), 2 (moderate), 3 (severe), or 4 (very severe).

[0306] Assessments of lesion severity and affected area are combined into a single score. The final PASI will be = the sum of the severity parameters for each region × area score × region weight (where head: 0.1, arms: 0.2, body: 0.3, legs: 0.4); the total possible score range is: 0 = no disease to 72 = maximum disease.

[0307] The maximum measurable PASI score will be <72, as the PASI assessment will exclude the scalp, palms, fingernails, soles, and toenails.

[0308] Trial researchers participating in this assessment will be required to undergo video training

[0309] The final PASI score will be calculated using the following formula:

[0310] PASI=0.1(EH+IH+HH)AH+0.2(EUL+IUL+HUL)AUL+0.3(ET+IT+HT)AT+0.4(ELL+ILL+HLL)ALL

[0311] A decrease in PASI score from baseline indicates improvement. The percent change will be calculated by subtracting the Week 16 and Week 52 values ​​from the baseline value. The percent change will be calculated for each overall treatment group (not for each participant). A positive percent change from baseline will indicate improvement.

[0312] Trial researchers involved in this assessment will have to undergo training

[0313] Body surface area - scored as the percentage of body surface area affected by psoriasis; 0–100%. A common method for estimating the body surface area of ​​psoriatic lesions is the "rule of nines," which was originally developed to estimate the surface area of ​​burns. It is defined as 9% coverage of the head and neck, 9% of each arm, 9% of the front and back legs, and 9% of each of the four trunk quadrants, with the remaining genitals accounting for 1%. BSA can also be estimated by the number of areas of a patient's hands affected, assuming that one "handprint" reflects approximately 1% of BSA.

[0314] Trial researchers involved in this assessment will have to undergo training

[0315] The Investigator Global Assessment - IGA is a 5-category scale consisting of "0 = clear," "1 = almost clear," "2 = mild," "3 = moderate," or "4 = severe" that instructs the physician to assess the overall severity of psoriasis, focusing on induration, erythema, and scaling. Treatment success of "clear" or "almost clear" includes no signs of psoriasis or normal to pink lesions, no plaque thickening, and no to minimal scaling of lesions. The IGA collects and categorizes a global assessment of all clinical signs and symptoms of the disease. The scale is scored as a static assessment; that is, it does not take into account previous assessments. To achieve a success on the IGA, a patient must have an indication of "clear" or "almost clear" and demonstrate a two-point improvement from baseline. Therefore, if a patient had "mild" disease at baseline, he / she must achieve "clear." If a patient had "moderate" disease at baseline, he / she must achieve "almost clear." And, if a patient was classified as "severe" at baseline, he / she must still achieve "almost clear," even if this requires a three-point improvement.

[0316] Trial researchers involved in this assessment will have to undergo training

[0317] The Pruritus Numeric Rating Scale (NRS) is a self-administered patient-reported outcome questionnaire completed during protocol-specified clinic visits. Subjects indicate pruritus severity by circling the integer that best describes the worst level of pruritus due to psoriasis in the past 24 hours on an 11-point scale anchored by 0 (no itch) and 10 (worst itch imaginable).

[0318] Dermatology Life Quality Index (DLQI) - The DLQI is a dermatology-specific quality of life measure for the psoriasis population. The 10-item questionnaire assesses participants' health-related quality of life (daily activities, relationships, symptoms and feelings, leisure, work and school, and treatment). Participants rate the DLQI questions from 0 (not relevant at all / not relevant) to 3 (very relevant), with a total score ranging from 0 (best) to 30 (worst); higher scores indicate poor quality of life.

[0319] Patient Global Assessment (PtGA) - The PtGA asks participants to rate overall skin disease at that time point on a single 5-point scale (0 = clear; 1 = almost clear; 2 = mild; 3 = moderate; 4 = severe).

[0320] Coronary perivascular fat attenuation index (FAI) - measured by CT angiography.

[0321] Table 5 Evaluation schedule

[0322]

[0323]

[0324] PK = pharmacokinetics; ECG = electrocardiogram; ET = premature termination; F / U = follow-up; Psoriasis Area and Severity Index (PASI); BSA = percentage of body surface area affected by psoriasis; static Researchers Global Assessment (sIGA); Patient Global Assessment (PtGA); Clinically Based Itch Numerical Rating Scale (INRS); Dermatology Life Quality Index (DLQI); Coronary Computed Tomography Angiography (CCTA)

[0325] a Unscheduled visits may be performed at any time for safety reasons and / or for any other reason. Safety laboratories, EKG and physical examinations, and other assessments may be performed at the discretion of the investigator.

[0326] b Visits should be conducted within ±3 days.

[0327] c Hematology and coagulation tests including hsCRP; SMA25 (Comprehensive Metabolic Profile (CMP) (including eGFR): (A:G ratio; serum albumin; serum alkaline phosphatase; ALT (SGPT); AST (SGOT); total bilirubin; BUN; BUN:creatinine ratio; serum calcium; total carbon dioxide; serum chloride; serum creatinine; total globulin; serum glucose; serum potassium; serum total protein; serum sodium); serum total creatine kinase (CK); serum gamma glutamyl transpeptidase (GGT); lactate dehydrogenase (LDH); lactate; plasma lipid panel: total cholesterol; high-density lipoprotein (HDL) cholesterol; low-density lipoprotein (LDL) cholesterol (calculated); triglycerides; very low-density lipoprotein (VLDL), lipoprotein(a) oxLDL, and oxHDL; serum magnesium; serum phosphorus; serum uric acid

[0328] In addition, urinalysis will be performed at all indicated visits. A urine drug screen will also be performed at screening. Only a hepatitis panel will be performed at screening, and an FSH screen will be performed at screening in postmenopausal women. Only a Mantoux tuberculin skin test will be performed at screening (interferon-gamma release assay (IGRA) can be offered for subjects who have already had the Bacille Calmette-Guerin (BCG) vaccine).

[0329] d For women of childbearing potential, a serum pregnancy test was performed at Screening (central laboratory) and a urine pregnancy test was performed at all other recorded visits (clinical center).

[0330] e This includes a supine position (at least 5 minutes) for blood pressure, pulse rate, respiratory rate, and temperature, and a standing position (after 1 and 3 minutes) for blood pressure and pulse rate. Height will be measured once at screening. The weight will be measured at the 1st, 4th, 7th and 9th Pounds (lbs) measured at visit 1 and recorded on the CRF and BMI records

[0331] f Electrocardiograms were recorded in triplicate after the subjects rested quietly in the supine position for 5 minutes.

[0332] g Baseline dermatologic examination at screening and before dosing must reveal the presence of moderate Plaque psoriasis , characterized by raised, inflamed lesions covered with silvery-white scales. The scales may be scraped off to reveal the inflamed skin underneath.

[0333] Table 6 Evaluation schedule

[0334]

[0335]

[0336] PK = pharmacokinetics; ECG = electrocardiogram; ET = premature termination; F / U = follow-up; Psoriasis Area and Severity Index (PASI); BSA = percentage of body surface area affected by psoriasis; static Researchers sIGA; Patient Global Assessment (PtGA); Investigator Global Assessment (sIGA); Clinician-Based Itch Numerical Rating Scale (INRS); Dermatology Life Quality Index (DLQI); Coronary Computed Tomography Angiography (CCTA)

[0337] a Unscheduled visits may be performed at any time for safety reasons and / or for any other reason. Safety laboratories, EKG and physical examinations, and other assessments may be performed at the discretion of the investigator.

[0338] b Visits should be conducted within ±3 days.

[0339] c Hematology and coagulation tests included hsCRP; SMA25 (comprehensive metabolic profile (CMP) of serum amylase (including eGFR): (A:G ratio; serum albumin; serum alkaline phosphatase; ALT (SGPT); AST (SGOT); total bilirubin; BUN; BUN:creatinine ratio; serum calcium; total carbon dioxide; serum chloride; serum creatinine; total globulin; serum glucose; serum potassium; serum total protein; serum sodium); serum total creatine kinase (CK); serum gamma glutamyl transpeptidase (GGT); lactate dehydrogenase (LDH); lactate; plasma lipid profile: total cholesterol; high-density lipoprotein (HDL) cholesterol; low-density lipoprotein (LDL) cholesterol (calculated); triglycerides; very low-density lipoprotein (VLDL) cholesterol (calculated); lipoprotein(a); serum magnesium; serum phosphorus; serum uric acid

[0340] In addition, urinalysis will be performed at all indicated visits. A urine drug screen will also be performed at Screening. Only a hepatitis panel will be performed at Screening, and FSH screening will be performed at Screening in postmenopausal women. Only a Mantoux tuberculin skin test will be performed at Screening (for subjects who have already had the Bacillus Calmette-Guérin (BCG) vaccine, an interferon-gamma release assay (IGRA) may be offered).

[0341] d For women of childbearing potential, a serum pregnancy test was performed at Screening (central laboratory) and a urine pregnancy test was performed at all other recorded visits (clinical center).

[0342] e This will include a supine position (at least 5 minutes) for blood pressure, pulse rate, respiratory rate, and temperature, and a standing position (after 1 and 3 minutes) for blood pressure and pulse rate. Height will be measured once at Screening. Weight will be measured at Visits 10, 14, 19, and 20 and recorded in pounds (lbs) and BMI on the CRF.

[0343] f Electrocardiograms were recorded in triplicate after the subjects rested quietly in the supine position for 5 minutes.

[0344] Various embodiments of the present invention have been described above in the detailed description. Although these descriptions directly describe the above-mentioned embodiments, it should be understood that modifications and / or variations of the specific embodiments shown and described herein may be envisioned by those skilled in the art. Any such modifications or variations that fall within the scope of this description are also intended to be included therein. Unless otherwise specified, it is the inventor's intention that the words and phrases in the specification and claims are given their ordinary and customary meanings to those skilled in the applicable art.

[0345] The foregoing description of various embodiments of the present invention known to the applicant at the time of filing this application has been presented and is intended for the purpose of illustration and description. This description is not intended to be exhaustive, nor is it intended to limit the invention to the precise form disclosed, and many modifications and variations are possible in light of the above teachings. The described embodiments are intended to explain the principles of the present invention and its practical application so that those skilled in the art can utilize different embodiments of the present invention and different modifications to suit the specific use contemplated. Therefore, it is intended that the present invention is not limited to the specific embodiments disclosed for implementing the present invention.

[0346] While specific embodiments of the present invention have been shown and described, it will be apparent to those skilled in the art that changes and modifications may be made based on the teachings herein without departing from the present invention and its broader aspects, and therefore, the appended claims are intended to cover within their scope all such changes and modifications as are within the true spirit and scope of the invention. It will be understood by those skilled in the art that, in general, the terms used herein are generally intended to be "open" terms (e.g., the term "including" should be interpreted as "including but not limited to," the term "having" should be interpreted as "at least having," the term "includes" should be interpreted as "includes but is not limited to," etc.).

[0347] As used herein, the terms "comprising" or "comprises" are used to refer to compositions, methods, and respective components thereof that are useful for the embodiments, but also include unspecified elements, whether useful or not. Those skilled in the art will understand that, in general, the terms used herein are generally intended to be "open" terms (e.g., the term "including" should be interpreted as "including but not limited to," the term "having" should be interpreted as "having at least," the term "includes" should be interpreted as "includes but is not limited to," etc.). Although the open term "comprising" is used herein as a synonym for terms such as including, containing, or having to describe and claim the present invention, the present invention or its embodiments may alternatively be described using alternative terms such as "consisting of" or "consisting essentially of."

Claims

1. Use of an antibody or antibody fragment in the preparation of a medicament for treating psoriasis in a subject in need thereof, wherein the antibody or antibody fragment comprises a heavy chain complementarity determining region (HCDR) 1 consisting of the sequence of SEQ ID No: 2, a HCDR 2 (HCDR2) consisting of the sequence of SEQ ID No: 3, and a HCDR 3 (HCDR3) consisting of the sequence of SEQ ID No: 4, and a light chain complementarity determining region (LCDR) 1 consisting of the sequence of SEQ ID No: 5, a LCDR 2 (LCDR2) consisting of the sequence of SEQ ID No: 6, and a LCDR 3 (LCDR3) consisting of the sequence of SEQ ID No:

7.

2. The method of claim 1, wherein the antibody comprises a variable heavy chain region (V H ), the variable light chain region (V L ) or both.

3. The method of claim 2, wherein the antibody comprises a heavy chain as shown in SEQ ID No.: 10, a light chain as shown in SEQ ID No.: 11, or both. The method according to claim 1 , wherein the antibody is oticumab.

5. The use according to claim 1, wherein the psoriasis is plaque psoriasis.

6. The use of claim 5, wherein the subject does not have a non-plaque form of psoriasis, wherein the non-plaque form comprises erythrodermic psoriasis, guttate psoriasis, or pustular psoriasis.

7. The use of claim 1, wherein the subject is a human, the antibody is oticumab, and oticumab is administered subcutaneously at a dose of 330 mg / month for 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months.

8. The use of claim 1, wherein the antibody is oticumab and is administered intravenously at an initial dose of at least 5 mg / kg, followed by multiple subsequent doses.

9. The use of claim 8, wherein the subsequent doses are each at least 2 mg / kg / week.

10. The use of claim 8, wherein the subsequent doses are each at least 2.5 mg / kg every two weeks.

11. The use of claim 8, wherein the subsequent doses are each at least 6 mg / kg / month.

12. The use of claim 1, wherein the antibody or antibody fragment is administered at 1-10 μg / kg.

13. The use of claim 1, wherein the antibody or antibody fragment is administered at 10-100 μg / kg.

14. The use of claim 1, wherein the antibody or antibody fragment is administered at 100-500 μg / kg.

15. The use of claim 1, wherein the antibody or antibody fragment is administered at 200-500 μg / kg.

16. The use of claim 1, wherein the antibody or antibody fragment is administered at 300-500 μg / kg.

17. The use of claim 1, wherein the antibody or antibody fragment is administered at 400-500 μg / kg.

18. The use of claim 1, wherein the antibody or antibody fragment is administered at 1-5 mg / kg.

19. The use of claim 1, wherein the antibody or antibody fragment is administered at 5-10 mg / kg.

20. The use of claim 1, wherein the antibody or antibody fragment is administered at 10-15 mg / kg.

21. The use of claim 1, wherein the antibody or antibody fragment is administered at 15-20 mg / kg.

22. The use of claim 1, wherein the antibody or antibody fragment is administered at 20-25 mg / kg.

23. The use of claim 1, wherein the antibody or antibody fragment is administered at 25-50 mg / kg.

24. The use of claim 1, wherein the antibody or antibody fragment is administered at 50-75 mg / kg.

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