Methods for treating cardiovascular disease

Abstract

The present disclosure provides a method for treating cardiovascular disease, comprising subcutaneously administering a therapeutically effective dose of an anti-interleukin-6 (anti-IL-6) antibody or antibody fragment to a patient in need thereof. Further provided herein are pharmacologically active agents, compositions, methods and / or administration schedules for the treatment of cardiovascular disease.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 383,429, filed November 11, 2022, and U.S. Provisional Patent Application No. 63 / 586,027, filed September 28, 2023, each of which is incorporated by reference in its entirety for all purposes.

[0002]

[0002] Reference to Electronic Sequence Listing The contents of the electronic sequence listing (Tour_004_02WO_SeqList_ST26.xml, size: 14,173 bytes, and creation date: November 3, 2023) are incorporated herein by reference in their entirety.

[0003]

[0003] This disclosure relates to therapeutic antibody molecules and treatments for cardiovascular disease. [Background technology]

[0004]

[0004] Cardiovascular disease is the leading cause of death in the United States and many Western countries. It is estimated that more than 70 million people in the United States alone suffer from cardiovascular diseases or disorders, including, but not limited to, hypertension, coronary heart disease, dyslipidemia, congestive heart failure, and stroke.

[0005]

[0005] Interleukin-6 (IL-6) is a widely expressed cytokine that causes inflammation and oxidative stress, which further lead to cardiac damage. Increased expression of IL-6 is closely associated with atherosclerosis, myocardial infarction, heart failure, and ischemic stroke. Lipid lowering is the primary treatment for atherosclerosis. However, cardiovascular risk remains elevated even in patients with optimal lipid management.

[0006] IL-6 inhibition has been investigated as a therapeutic strategy to reduce the risk of cardiovascular (CV) morbidity and mortality. A phase II clinical trial of the human anti-IL-6 monoclonal antibody diltibekimab has shown that diltibekimab substantially reduces various inflammatory biomarkers associated with atherosclerosis in patients with advanced chronic kidney disease (CKD) (NCT03926117). However, anti-drug antibodies were detected in 12.5% ​​of patients receiving 2 mg diltibekimab, 6.3% of patients receiving 6 mg diltibekimab, and 12.5% ​​of patients receiving 20 mg diltibekimab. Summary of the Invention [Problem to be solved by the invention]

[0007]

[0007] Individuals with moderate chronic kidney disease and elevated IL-6 or C-reactive protein have significantly increased incidence of major adverse cardiovascular events and constitute a group with substantial unmet need for treatment. [Means for solving the problem]

[0008]

[0008] Provided herein is a method for treating cardiovascular disease, comprising administering to a patient in need thereof a therapeutically effective dose of an anti-interleukin-6 (anti-IL-6) antibody or antibody fragment having variable heavy (VH) CDRs defined in SEQ ID NOs: 2, 3, and 4 and variable light (VL) CDRs defined in SEQ ID NOs: 8, 9, and 10.

[0009] In some embodiments, the anti-IL-6 antibody or antibody fragment comprises a heavy chain polypeptide comprising a polypeptide having at least about 98% identity to SEQ ID NO: 1 and a light chain polypeptide comprising a polypeptide having at least about 98% identity to SEQ ID NO: 7. In one aspect, the anti-IL-6 antibody or antibody fragment comprises a heavy chain polypeptide having the sequence of SEQ ID NO: 1 and a light chain polypeptide having the sequence of SEQ ID NO: 7.

[0010]

[0010] In some embodiments, patients treated according to the methods of the present disclosure are at least 18 years of age.

[0011] In some embodiments, the patient treated according to the methods of the present disclosure has chronic kidney disease (CKD). In one embodiment, the patient has anemia of CKD. In another embodiment, the patient has Kidney Disease Outcome Improvement Initiative (KDOQI) Stages 1-5 CKD. In another embodiment, the patient has Kidney Disease Outcome Improvement Initiative (KDOQI) Stages 3-5 CKD. In yet another embodiment, the patient has an estimated glomerular filtration rate (eGFR) CKD-Epidemiology Collaboration (CKD-EPI) of less than 60 mL / min / 1.73 m^2.

[0011]

[0012] In some embodiments, the patient treated according to the methods of the present disclosure has atherosclerotic cardiovascular disease (ASCVD), coronary artery disease (CAD), or peripheral artery disease (PAD).

[0012]

[0013] In some embodiments, the patient has clonal hematopoiesis of unspecified potential (CHIP). In some embodiments, the patient has one or more mutations in DNMT3A, TET2, ASXL1, PPM1D, TP53, JAK2, SF3B1, or SRSF2.

[0013]

[0014] In some embodiments, the patient has risk factors for developing cardiovascular disease. For example, but not limited to, risk factors for developing cardiovascular disease include: (a) diabetes (type I or type II), (b) metabolic syndrome; (c) hypertension; (d) age greater than about 55 years for men or greater than about 65 years for women; (e) dyslipidemia; (f) family history of cardiovascular disease; (g) history of stroke or transient ischemic attack; (h) smoking (currently active or history); (i) homocysteinemia; (j) hyperuricemia; (k) HDL-C levels of less than or equal to about 40 mg / dL for men or less than or equal to about 50 mg / dL for women, (l) renal dysfunction (e.g., creatinine clearance ("CrCL") greater than about 30 mL / min and less than about 60 mL / min); (m) retinopathy (e.g., non-proliferative retinopathy, pre-proliferative retinopathy, proliferative retinopathy, , maculopathy, advanced diabetic eye disease, or history of photocoagulation); (n) microalbuminuria (e.g., a positive micro or other strip test, an albumin / creatinine ratio of about 2.5 mg / mmol or greater, or an albumin excretion rate of about 20 mg / min or greater on at least two consecutive scheduled collections); (o) macroalbuminuria (e.g., albatics or other dipstick evidence of crude proteinuria, an albumin / creatinine ratio of about 25 mg / mmol or greater, or an albumin excretion rate of about 200 mg / min or greater on at least two consecutive scheduled collections); and / or (p) ankle-brachial index of less than about 0.9 in the absence of symptoms of intermittent claudication.

[0014]

[0015] In some embodiments, the patient treated according to the methods of the present disclosure has anemia of chronic inflammation, anemia of chronic disease, or iron-restricted anemia. In some embodiments, the patient has functional iron deficiency or iron restriction. In some embodiments, the patient has elevated serum hepcidin or urinary hepcidin. In some embodiments, the patient has a red blood cell distribution width (RDW) of greater than about 13%, or an RDW in the highest quartile of the overall population. In some embodiments, the patient has a white blood cell count (WBC) of greater than 9000 per microliter of blood, or an WBC in the highest quartile of the overall population.

[0015]

[0016] In some embodiments, the patient has had a recent infection within the past month, three months, six months, or one year. In some embodiments, the patient has had a recent COVID-19 (SARS-CoV-2) infection within the past month, three months, six months, or one year. In some embodiments, the patient has had a recent surgical procedure within the past month, three months, six months, or one year. In some embodiments, the patient has periodontal disease.

[0016]

[0017] In some embodiments, the patient receives 2.0 x 10 per L 9 In some embodiments, patients have an absolute neutrophil count of 120 x 10 per L or greater. 9 In some embodiments, the patient has a spot urine to creatine ratio of 4 or greater.

[0017]

[0018] In some embodiments, the patient is negative for active tuberculosis, HIV, or hepatitis B or C. In some embodiments, the patient is not undergoing long-term use of immunosuppressive therapy.

[0018]

[0019] In some embodiments, the cardiovascular disease is selected from the group consisting of non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death. In one embodiment, the cardiovascular disease is heart failure.

[0019]

[0020] In some embodiments, a therapeutically effective dose of the present disclosure is about 5 mg to about 200 mg, hi some embodiments, a therapeutically effective dose is about 5, about 7.5, about 10, about 15, about 20, about 25, about 30, about 50, about 60, about 70, about 80, about 90, or about 100 mg of anti-IL-6 antibody or antibody fragment.

[0020]

[0021] In some embodiments, the therapeutically effective dose is about 50 mg every 90 days. In one embodiment, the total therapeutically effective dose is about 100 mg. In some embodiments, the therapeutically effective dose is about 25 mg every 90 days. In one embodiment, the total therapeutically effective dose is about 50 mg. In some embodiments, the therapeutically effective dose is about 15 mg every 30 days. In one embodiment, the total therapeutically effective dose is about 90 mg.

[0021]

[0022] In one embodiment, the therapeutically effective dose is administered subcutaneously.

[0023] In some embodiments, the administration schedule of the anti-IL-6 antibody or antibody fragment is every week to every 24 weeks. In one embodiment, a therapeutically effective dose is administered every 4 weeks, every 8 weeks, every 12 weeks, or every 24 weeks. In some embodiments, a therapeutically effective dose is administered every 30 days to every 90 days. In one embodiment, a therapeutically effective dose is administered every 30 days. In one embodiment, a therapeutically effective dose is administered every 90 days.

[0022]

[0024] In some embodiments, the methods of the present disclosure comprise: (a) administering a loading dose of an anti-IL-6 antibody or antibody fragment subcutaneously to a patient for at least the first two doses during a loading regimen; and (b) subsequently administering a maintenance dose of an anti-IL-6 antibody or antibody fragment subcutaneously to a patient during a maintenance regimen. In some embodiments, the loading regimen comprises administering the loading dose every week, every two weeks, or every four weeks. In some embodiments, the maintenance regimen comprises administering a maintenance dose every four weeks, every eight weeks, every twelve weeks, or every twenty-four weeks. In some embodiments, the methods of the present disclosure comprise: (a) administering a loading dose of an anti-IL-6 antibody or antibody fragment subcutaneously to a patient for the first two doses every four weeks during the loading regimen; and (b) subsequently administering a maintenance dose of an anti-IL-6 antibody or antibody fragment subcutaneously to a patient every eight weeks or every twelve weeks during the maintenance regimen. In some embodiments, the loading dose is equal to or greater than the maintenance dose. In some embodiments, the loading dose is between 5 mg and 200 mg. In some embodiments, the maintenance dose is between 5 mg and 200 mg.

[0023]

[0025] In some embodiments, the patient has inflammation. In one embodiment, the patient has IL-6-mediated inflammation. In some embodiments, the treatment of the present disclosure is sufficient to reduce inflammation without causing immunosuppression.

[0024]

[0026] In some embodiments, immunosuppression is measured by absolute neutrophil count (ANC). In some embodiments, the post-treatment ANC is at least 500 cells / pL. In some embodiments, the post-treatment ANC is at least 1000 cells / pL. In some embodiments, the post-treatment ANC is at least 1500 cells / pL. In some embodiments, the post-treatment ANC is at least 2000 cells / pL. In some embodiments, the ANC is reduced by 2000 cells / pL or less compared to pre-treatment levels. In some embodiments, the ANC is reduced by 1500 cells / pL or less compared to pre-treatment levels. In some embodiments, the ANC is reduced by 1000 cells / pL or less compared to pre-treatment levels. In some embodiments, the ANC is reduced by 500 cells / pL or less compared to pre-treatment levels. In some embodiments, the ANC is reduced by about 50% or less compared to pre-treatment levels. In some embodiments, the ANC is reduced by about 40% or less compared to pre-treatment levels. In some embodiments, the ANC is reduced by about 30% or less compared to pre-treatment levels. In some embodiments, the ANC is reduced by no more than about 20% compared to pre-treatment levels, in some embodiments, the ANC is reduced by no more than about 10% compared to pre-treatment levels, in some embodiments, the ANC is not reduced compared to pre-treatment levels.

[0025]

[0027] In some embodiments, inflammation is measured by high-sensitivity C-reactive protein (hsCRP) levels. In some embodiments, the patient has elevated pre-treatment hsCRP levels. In some embodiments, the patient's pre-treatment hsCRP level is at least 2 mg / L. In some embodiments, the patient's pre-treatment hsCRP level is at least 4 mg / L. In some embodiments, the patient's pre-treatment hsCRP level is at least 6 mg / L. In some embodiments, the patient's pre-treatment hsCRP level is at least 10 mg / L. In some embodiments, the patient's pre-treatment hsCRP level is 2 mg / L or less. In some embodiments, the patient's pre-treatment hsCRP level is 1 mg / L or less. In some embodiments, the post-treatment hsCRP level is 2 mg / L or less. In some embodiments, the post-treatment hsCRP level is 1 mg / L or less. In some embodiments, the hsCRP level is reduced by at least about 50% compared to pre-treatment levels. In some embodiments, the hsCRP level is reduced by at least about 60% compared to pre-treatment levels. In some embodiments, hsCRP levels are reduced by at least about 70% compared to pre-treatment levels. In some embodiments, hsCRP levels are reduced by at least about 80% compared to pre-treatment levels. In some embodiments, hsCRP levels are reduced by at least about 90% compared to pre-treatment levels. In some embodiments, treatment results in hsCRP reduction within about 4 weeks, about 8 weeks, about 12 weeks, or about 24 weeks of treatment. In some embodiments, treatment results in hsCRP reduction after about 180 days of treatment. In some embodiments, treatment is sufficient to maintain a reduction in hsCRP for at least 24 weeks or 48 weeks.

[0026]

[0028] In some embodiments, treatment is sufficient to reduce fibrinogen, haptoglobin, serum amyloid A (SAA), secretory phospholipase A2 (sPLA2), lipoprotein(a), or neutrophil-to-lymphocyte ratio (NLR) by at least about 15%, about 30%, or about 50%.

[0027]

[0029] In some embodiments, the treatment is sufficient to reduce the incidence of one or more cardiovascular events by at least about 10%, about 15%, about 20%, about 25%, about 30%, about 40%, or about 50%. In some embodiments, the adverse cardiovascular event is selected from the group consisting of death, cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, unstable angina requiring urgent coronary revascularization, heart failure (new, worsening, or acute), ventricular arrhythmia due to ischemia, ischemic damage to a heart valve, increased N-terminal pro-brain natriuretic peptide (NT-pro-BNP), increased cardiac markers of damage (such as troponin or creatine kinase-MB), a decrease in left ventricular ejection fraction of at least about 5%, atrial fibrillation or other ventricular arrhythmia, intestinal ischemia (small intestine or colon), new-onset or worsening peripheral arterial disease, critical limb ischemia, atheroembolism (cholesterol embolism), new-onset or worsening thromboangiitis obliterans, a worsening of the New York Heart Association (NYHA) classification of heart failure by one or more degrees, a worsening score on the Kansas City Cardiomyopathy Questionnaire, and a change in the Short Form 36-item (SF-36) Physical Component Score (PCS).

[0028]

[0030] In some embodiments, the methods described herein further comprise treating the subject with an additional form of therapy. In some embodiments, the additional form of therapy comprises administering one or more therapeutic agents in addition to the anti-IL-6 antibody or antibody fragment described herein. Therapeutic agents include a second antibody (e.g., an anti-IL-1 antibody, an anti-IGF-1 receptor antibody, an anti-VEGF antibody, and / or an anti-IL17a antibody), a soluble receptor (e.g., a soluble IL-1 receptor, a soluble TNF-α receptor), an anti-inflammatory agent (e.g., paclitaxel, docetaxel, cisplatin, doxorubicin, prednisone, mitomycin, progesterone, tamoxifen, or fluorouracil), or a cardiovascular risk modifier (e.g., an adrenergic blocking agent, an angiotensin-converting enzyme inhibitor ... These include, but are not limited to, antihypertensive drugs such as otensin II receptor blockers and calcium channel blockers; lipid-lowering drugs such as statins, fibrates, PCSK9 inhibitors, bile acid resins, niacin, selective cholesterol absorption inhibitors, omega-3 fatty acids and fatty acid esters, and adenosine triphosphate citrate lyase (ACL) inhibitors; antidiabetic drugs such as metformin; or antiplatelet drugs such as aspirin, clopidogrel, ticlopidine, ticagrelor, prasugrel, and cangrelor.

[0029]

[0031] In some embodiments, the anti-IL-6 antibody or antibody fragment comprising the CDRs described herein is comprised in a pharmaceutical composition comprising the anti-IL-6 antibody or antibody fragment and a pharmaceutically acceptable carrier.

[0030]

[0032] In some embodiments, provided are pharmacologically active agents, compositions, methods and / or administration schedules that have certain advantages over currently used and / or known in the art, such that they can be administered less frequently or at lower doses to achieve comparable efficacy in inhibiting IL-6-mediated signaling. [Brief explanation of the drawings]

[0031] [Figure 1]

[0033] Schematic of the Phase II randomized, double-blind, placebo-controlled study of TOUR006. DETAILED DESCRIPTION OF THE INVENTION

[0032]

[0034] Provided herein is a method for treating cardiovascular disease, comprising subcutaneously administering a therapeutically effective dose of an anti-interleukin-6 (anti-IL-6) antibody or antibody fragment to a patient in need thereof.

[0033]

[0035] Further provided herein are pharmacologically active agents, compositions, methods and / or administration schedules for the treatment of cardiovascular disease.

[0036] antibody Provided herein are antibodies and antigen-binding fragments thereof that specifically bind to IL-6. The antibodies and antigen-binding fragments disclosed herein specifically bind to human IL-6. In some embodiments, the antibodies may be specific only for human IL-6 and may not exhibit non-human cross-reactivity.

[0034]

[0037] Throughout this disclosure, the term "about" may be used in conjunction with numerical values ​​and / or ranges. The term "about" is understood to encompass values ​​that are close to the recited value and within the acceptable degree of error in the art. For example, "about 40 units" may mean ±10%, ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2%, ±10%, ±1%, less than ±1%, or a value or range of values ​​within or below that range.

[0035]

[0038] As used herein, the term "antibody" refers to immunoglobulin (Ig) molecules and immunologically active portions or fragments of immunoglobulin molecules, i.e., molecules that contain an antigen-binding site that specifically binds (immunoreacts with) an antigen (e.g., IL-6). "Specifically binds" or "immunoreacts" means that the antibody reacts with one or more antigenic determinants of a desired antigen and not with other polypeptides. In some embodiments, an antibody is said to specifically bind an antigen when it preferentially recognizes its target antigen in a complex mixture of proteins and / or macromolecules. In some embodiments, an antibody "specifically binds" to IL-6 if it binds to IL-6 with higher affinity, higher avidity, more readily, and / or for a longer duration than it binds to other polypeptides.

[0036]

[0039] The term "antibody" generally refers broadly to an immunoglobulin (Ig) molecule comprising four polypeptide chains, two heavy (H) chains and two light (L) chains, or any functional fragment, mutant, variant, or derivative thereof that retains the essential target-binding properties of an Ig molecule. Such mutant, variant, or derivative antibody formats are known in the art.

[0037]

[0040] In a full-length antibody, each heavy chain comprises a heavy chain variable domain (abbreviated herein as VH) and a heavy chain constant region. The heavy chain constant region comprises three domains, namely CH1, CH2, and CH3. Each light chain comprises a light chain variable domain (abbreviated herein as VL) and a light chain constant region. The light chain constant region comprises one domain, namely CL. The VH and VL domains are further divided into regions of hypervariability called complementarity-determining regions (CDRs), interspersed with more conserved regions called framework regions (FRs). Each VH and VL domain is composed of three CDRs and four FRs, arranged from the amino terminus to the carboxyl terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.

[0038]

[0041] The term "Fc region" is used to define the C-terminal region of an immunoglobulin heavy chain. The "Fc region" may be a native-sequence Fc region or a variant Fc region. Although the boundaries of the Fc region of an immunoglobulin heavy chain can vary, the human IgG heavy chain Fc region is usually defined to stretch from the amino acid residue at position Cys226, or from Pro230, to the carboxyl terminus. The numbering of residues in the Fc region follows the EU numbering system. The Fc region of an immunoglobulin generally contains two constant domains, CH2 and CH3. The Fc region may exist in a dimeric or monomeric form. The Fc region binds to various cellular receptors, such as Fc receptors, and other immune molecules, such as complement proteins.

[0039]

[0042] Immunoglobulin molecules can be of any type (e.g., IgG, IgE, IgM, IgD, IgA, or IgY) and class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, or IgA2) or subclass. IgG, IgD, and IgE antibodies generally comprise two identical heavy chains and two identical light chains, and two antigen-binding domains (each composed of a VH and a VL). IgA antibodies generally comprise two monomers, each composed of two heavy chains and two light chains (for IgG, IgD, and IgE antibodies). Thus, an IgA molecule has four antigen-binding domains, each also composed of a VH and a VL. Certain IgA antibodies are monomeric in that they are composed of two heavy chains and two light chains. Secreted IgM antibodies are generally composed of five monomers, each composed of two heavy chains and two light chains (for IgG and IgE antibodies). Thus, an IgM molecule has 10 antigen-binding domains, each similarly composed of a VH and a VL. The cell surface form of IgM has a two heavy chain / two light chain structure similar to IgG, IgD, and IgE antibodies.

[0040]

[0043] As used herein, the term "antigen-binding portion" or "antigen-binding fragment" of an antibody (or "antibody portion" or "antibody fragment") refers to one or more fragments of an antibody that retain the ability to specifically bind to an antigen (e.g., IL-6). It has been shown that the antigen-binding function of an antibody can be performed by portions or fragments of a full-length antibody. Examples of binding fragments encompassed by the term "antigen-binding portion" of an antibody include: (i) a Fab fragment, i.e., a monovalent fragment consisting of the VL, VH, CL, and CH1 domains; (ii) a F(ab')2 fragment, i.e., a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; (iii) a Fd fragment consisting of the VH and CH1 domains; (iv) a Fv fragment consisting of the VL and VH domains of a single antibody arm; (v) a dAb (domain antibody) fragment comprising a single variable domain (Ward et al., Nature 341:544-546 (1989); WO 90 / 05144 A1, each of which is incorporated herein by reference in its entirety); and (vi) an isolated complementarity-determining region (CDR). The present disclosure also encompasses Fab' fragments. Fab' fragments may be formed by reduction of F(ab')2 fragments. Fab' is derived from F(ab')2, and thus Fab' may contain a portion of Fc. Furthermore, although the two domains of the Fv fragment, i.e., VL and VH, are encoded by separate genes, they can be joined by a synthetic linker, allowing them to be produced as a single protein chain using recombinant methods, where the VL and VH domains pair to form a monovalent molecule (known as single-chain Fv (scFv)). See, e.g., Bird et al. (1988) Science 242:423-426; Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85:5879-5883. Such single-chain antibodies are also intended to be encompassed by the term "antigen-binding portion" of an antibody. In some embodiments, scFv molecules can be incorporated into fusion proteins. In some embodiments, provided herein are single-chain camelid antibodies.In some embodiments, provided herein are shark heavy chain antibodies (V-NARs). See English et al. (2020) Antibody Therapeutics, 3(1):1-9. Examples of antigen-binding moieties are known in the art (Kontermann and Dubel eds., Antibody Engineering (2001) Springer-Verlag. New York. 790pp.). In some embodiments, provided herein are single-domain antibodies. In general, as used herein, the term "antibody" encompasses "antibody fragments." Antibody fragments generally retain the antigen-binding properties of full-length antibodies.

[0041]

[0044] The antibodies and antibody portions provided herein may be in a multispecific (e.g., bispecific or trispecific) format. Such multispecific molecules specifically bind to two or more different molecular targets or epitopes. In some embodiments, the antibody or antigen-binding portion is a bispecific molecule that specifically binds to a first antigen and a second antigen, where the first antigen is IL-6 and the second antigen is not IL-6. In some embodiments, the antibody or antigen-binding portion is a diabody. Diabodies are bivalent, bispecific antibodies in which the VH and VL domains are expressed on a single polypeptide chain but pair with complementary domains on another chain to form two antigen-binding sites, using a linker that is too short to allow pairing between the two domains on the same chain (see, e.g., Holliger et al. (1993) Proc. Natl. Acad. Sci. USA 90:6444-6448; Poljak et al. (1994) Structure 2:1121-1123). In some embodiments, the antibody or antigen-binding portion is a triabody, tetrabody, bis-scFv, or tandem scFv. In some embodiments, the antibody or antigen-binding portion is a dual affinity retargeting protein.

[0042]

[0045] In some embodiments, the anti-IL-6 antigen binding portion disclosed herein is a Fab, F(ab')2, Fab', Fv, scFv, Fd, single domain antibody, single chain camelid antibody, diabody, triabody, tetrabody, or bis-scFv.

[0043]

[0046] As used herein, the terms "immunological binding" and "immunological binding properties" refer to the type of non-covalent interaction that occurs between an immunoglobulin molecule (e.g., an antibody or antigen-binding portion thereof) and the antigen for which that immunoglobulin is specific. The strength or affinity of an immunological binding interaction is determined by the dissociation constant (K d ) and can be expressed in terms of smaller K d represents a greater affinity. The immunological binding properties of a selected polypeptide can be quantified by methods well known in the art. One such method involves measuring the rates of antigen-binding site / antigen complex formation and dissociation, which depend on the concentrations of the complex partners, the affinity of the interaction, and geometric parameters that affect the rate equally in both directions. Thus, the "on-rate constant" (K on ) and "off rate constant" (K off Both K and K can be determined by calculating the concentration and the actual rates of association and dissociation. (See Malmqvist, Nature 361:186-187 (1993)). off / K on The ratio of α to β allows for the release of all parameters not related to affinity and gives the dissociation constant K d (See Davies et al. (1990) Annual Rev Biochem 59:439-473.) The antibodies or antigen-binding portions provided herein have an equilibrium binding constant (K d ) is said to specifically bind to IL-6 when it is 10 μM or less, preferably 10 nM or less, more preferably 10 nM or less, and most preferably 100 pM to about 1 pM, as measured by an assay such as a radioligand binding assay or similar assay known to those of skill in the art.

[0044]

[0047] In some embodiments, the anti-IL-6 antibodies or antigen-binding portions provided herein are monovalent or bivalent and comprise a single chain or two chains. Functionally, the binding affinity of the antibodies or antigen-binding portions is about 10 -5 M~10 -12 For example, the binding affinity of an antibody or antigen-binding portion may be in the range of about 10 -6 M~10 -12 M, about 10 -7 M~10 -12 M, about 10 -8 M~10 -12 M, about 10 -9 M~10 -12 M, about 10 -5 M~10 -11 M, about 10 -6 M~10 -11 M, about 10 -7 M~10 -11 M, about 10 -8 M~10 -11 M, about 10 -9 M~10 -11 M, about 10 -10 M~10 -11 M, about 10 -5 M~10 -10 M, about 10 -6 M~10 -10 M, about 10 -7 M~10 -10 M, about 10 -8 M~10 -10 M, about 10 -9 M~10 -10 M, about 10 -5 M~10 -9 M, about 10 -6 M~10 -9 M, about 10 -7 M~10 -9 M, about 10 -8 M~10 -9 M, about 10 -5 M~10 -8 M, about 10 -6 M~10 -8 M, about 10 -7 M~10 -8 M, about 10 -5 M~10 -7 M, about 10 -6 M~10-7 M, or about 10 -5 M~10 -6 I am M.

[0045]

[0048] The human anti-IL-6 monoclonal antibody (PF-04236921) is described in U.S. Pat. No. 8,188,235, the entire contents of which are incorporated herein by reference. The human anti-IL-6 monoclonal antibody is a fully human immunoglobulin G2 monoclonal antibody that binds to human IL-6 and has a half-life of 36 to 51 days. In phase I studies (protocols B0151001, NCT00838565, and NCT01166555) in healthy volunteers and patients with rheumatoid arthritis, the human anti-IL-6 monoclonal antibody (PF-04236921) was well tolerated and caused sustained suppression of C-reactive protein (CRP), a marker of inflammation transcriptionally regulated by IL-6. PF-04236921 is also being investigated in a phase II study in patients with systemic lupus erythematosus (SLE; NCT01405196). Although the study did not meet its primary endpoint, improvements in the primary and key secondary endpoints were observed at the 10 mg dose. Overall, the human anti-IL-6 monoclonal antibody demonstrated favorable pharmacokinetic (PK) and pharmacodynamic (PD) properties supporting durable target inhibition, as well as a low incidence of immunogenicity following single and multiple dose administration. See Danese, et al., Randomized trial and open-label extension study of an anti-interleukin-6 antibody in Crohn's disease (ANDANTE I and II), Gut 2019;68:40-48; Li et al., Pharmacokinetics and C-reactive protein modeling of anti-interleukin-6 antibody (PF-04236921) in healthy volunteers and patients with autoimmune disease, Br J Clin Pharmacol. 2018Sep;84(9):2059-2074.

[0046]

[0049] The amino acid sequence and nucleic acid sequence of the human anti-IL-6 antibody (TOUR006) are shown in Table 1.

[0047] [Table 1-1]

[0048] [Table 1-2]

[0049] [Table 1-3]

[0050] Provided herein are methods for treating cardiovascular disease, comprising subcutaneously administering to a patient in need thereof a therapeutically effective dose of an anti-interleukin-6 (anti-IL-6) antibody or antibody fragment having variable heavy (VH) CDRs defined in SEQ ID NOs:2, 3, and 4 and variable light (VL) CDRs defined in SEQ ID NOs:8, 9, and 10. In some embodiments, the antibody or antibody fragment comprises a heavy chain polypeptide comprising a polypeptide having at least about 95%, about 96%, about 97%, about 98%, or about 99% identity to SEQ ID NO:1, and a light chain polypeptide comprising a polypeptide having at least about 95%, about 96%, about 97%, about 98%, or about 99% identity to SEQ ID NO:7. In some embodiments, the antibody or antibody fragment comprises a heavy chain polypeptide comprising a polypeptide having the sequence of SEQ ID NO:1, and a light chain polypeptide comprising a polypeptide having the sequence of SEQ ID NO:7. In some embodiments, the anti-IL-6 antibody or antigen-binding portion comprises a human IgG2 constant region.

[0051] As used herein, the term "conservative substitution" refers to the substitution of one amino acid with another amino acid that does not significantly adversely alter functional activity. A preferred example of a "conservative substitution" is the substitution of one amino acid with another amino acid that has a value of 0 or greater in the following BLOSUM 62 substitution matrix (see Henikoff & Henikoff, 1992, PNAS 89:10915-10919):

[0052] [Table 2]

[0053] Calculations of sequence homology or sequence identity between sequences (the terms are used interchangeably herein) can be performed as follows. To determine the percent identity of two amino acid sequences or two nucleic acid sequences, the sequences are aligned for optimal comparison purposes (e.g., gaps can be introduced into one or both of the first and second amino acid or nucleic acid sequences for optimal alignment, and non-homologous sequences can be ignored for comparison purposes). In a preferred embodiment, the length of the reference sequence aligned for comparison purposes is at least about 30%, preferably at least about 40%, more preferably at least about 50%, even more preferably at least about 60%, and even more preferably at least about 70%, about 75%, about 80%, about 82%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100% of the length of the reference sequence. The amino acid residues or nucleotides at corresponding amino acid positions or nucleotide positions are then compared. When a position in the first sequence is occupied by the same amino acid residue or nucleotide as the corresponding position in the second sequence, the molecules are identical at that position (as used herein, amino acid or nucleic acid "identity" is equivalent to amino acid or nucleic acid "homology"). The percent identity between two sequences is a function of the number of identical positions shared by the sequences, taking into account the number of gaps and the length of each gap that need to be introduced for optimal alignment of the two sequences.

[0054] Comparison of sequences and determination of percent identity between two sequences can be performed using a mathematical algorithm. In some embodiments, percent identity between two amino acid sequences is determined using the Needleman et al. ((1970) J. Mol. Biol. 48:444-453) algorithm incorporated into the GAP program of the GCG software package, with either a BLOSUM 62 matrix or a PAM250 matrix, using a gap weight of 16, 14, 12, 10, 8, 6, or 4, and a length weight of 1, 2, 3, 4, 5, or 6. In some embodiments, percent identity between two nucleotide sequences is determined using the GAP program of the GCG software package, with a NWSgapdna.CMP62 matrix, using a gap weight of 40, 50, 60, 70, or 80, and a length weight of 1, 2, 3, 4, 5, or 6. One set of parameters (and one that can be used if the practitioner is unsure which parameters to apply to determine whether a molecule falls within the sequence identity or sequence homology limits of the invention) is the BLOSUM 62 scoring matrix, with a gap penalty of 12, a gap extension penalty of 4, and a frameshift gap penalty of 5.

[0055]

[0055] In some embodiments, the percent identity between two amino acid or nucleotide sequences can be determined using the algorithm of Meyers et al. ((1989) CABIOS 4:11-17) as incorporated into the ALIGN program (version 2.0), using a PAM120 weight residue table, a gap length penalty of 12, and a gap penalty of 4.

[0056]

[0056] In some embodiments, the anti-IL-6 antibodies or antigen-binding portions provided herein are monoclonal.

[0057] In some embodiments, the anti-IL-6 antibodies or antigen-binding portions provided herein are chimeric. The term "chimeric" is intended to refer to an antibody molecule, or antigen-binding portion thereof, in which the variable domain sequences are derived from one species and at least one constant region sequence is derived from another species. For example, one or all of the variable domains of the light chain(s) and / or one or all of the variable domains of the heavy chain(s) of a murine antibody (e.g., a murine monoclonal antibody) can each be linked to a human constant region, such as, but not limited to, the human constant region of IgG1, IgG2, or IgG4. Examples of chimeric antibodies and suitable techniques for their production are provided in US 4,816,567, US 4,975,369, and US 4,816,397, each of which is incorporated herein by reference in its entirety.

[0057]

[0058] In some embodiments, the anti-IL-6 antibodies or antigen-binding portions thereof provided herein are humanized. The term "humanized" is intended to refer to an antibody, or antigen-binding portion thereof, that has been engineered to contain one or more human framework regions in the variable domains along with non-human (e.g., mouse, rat, or hamster) CDRs in the heavy and / or light chains. In some embodiments, a humanized antibody comprises sequences that are fully human except for the CDRs. In some embodiments, the VH domain, VL domain, or both the VH and VL domains of an anti-IL-6 antibody or antigen-binding portion provided herein comprise one or more human framework region amino acid sequences. In some embodiments, a humanized antibody comprises sequences that are fully human except for the CDRs that are the CDRs of antibody 32G8H6. Examples of humanized antibodies and suitable techniques for their production are described in Hwang et al., Methods 36:35, 2005; Queen et al., Proc. Natl. Acad. Sci. USA, 86:10029-10033, 1989; Jones et al., Nature, 321:522-25, 1986; Riechmann et al., Nature, 332:323-27, 1988; Verhoeyen et al., Science, 239:1534-36, 1988; Orlandi et al., Proc. Natl. Acad. Sci. USA, 86:10029-10033, 1989. USA, 86:3833-37, 1989; US 5,225,539; US 5,530,101; US ​​5,585,089; US 5,693,761; US ​​5,693,762; US 6,180,370; and WO 90 / 07861, each of which is incorporated herein by reference in its entirety.

[0058]

[0059] In some embodiments, humanization involves the removal of post-translational modification (PTM) sites in the variable domain sequences of a non-human antibody (e.g., in the CDR or framework sequences). For example, one or more PTM sites within a CDR sequence can be removed by substituting specific amino acid residues. In some embodiments, humanization involves CDR grafting and backmutation.

[0059]

[0060] In some embodiments, the anti-IL-6 antibody, or antigen-binding portion thereof, comprises an immunoglobulin constant region. In some embodiments, the immunoglobulin constant region is IgG, IgE, IgM, IgD, IgA, or IgY. In some embodiments, the immunoglobulin constant region is IgG1, IgG2, IgG3, IgG4, IgA1, or IgA2. In some embodiments, the immunoglobulin constant region is immunologically inert. In some embodiments, the immunoglobulin constant region comprises one or more mutations that reduce or prevent FcγR binding, antibody-dependent cell-mediated cytotoxicity, and / or complement-dependent cytotoxicity. In some embodiments, the immunoglobulin constant region is a wild-type human IgG1 constant region, a wild-type human IgG2 constant region, a wild-type human IgG4 constant region, a human IgG1 constant region comprising the amino acid substitutions L234A, L235A, and G237A, a human IgG1 constant region comprising the amino acid substitutions L234A, L235A, G237A, and P331S, or a human IgG4 constant region comprising the amino acid substitution S228P, where numbering is according to the EU numbering system. In some embodiments, amino acid residue positions within the constant region of an immunoglobulin molecule are numbered according to EU nomenclature (Ward et al., 1995 Therap. Immunol. 2:77-94).

[0060]

[0061] In some embodiments, the anti-IL-6 antibody, or antigen-binding portion thereof, can comprise an immunoglobulin light chain constant region that is a kappa light chain constant region or a lambda light chain constant region.

[0061]

[0062] In some embodiments, the anti-IL-6 antibody, or antigen-binding portion thereof, may comprise a human IgG4 constant region and a kappa light chain constant region comprising the amino acid substitution S228P.

[0063] Further provided herein are immunoconjugates comprising an anti-IL-6 antibody or antigen-binding portion linked to a therapeutic agent. In some embodiments, the therapeutic agent is a small molecule therapeutic agent.

[0062]

[0064] Pharmaceutical Composition The anti-IL-6 antibodies and antigen-binding portions (also referred to herein as "active compounds") described herein can be incorporated into pharmaceutical compositions suitable for administration. Such compositions typically comprise an anti-IL-6 antibody or antigen-binding portion (or an immunoconjugate comprising said antibody or portion) and a pharmaceutically acceptable carrier, diluent, or excipient. As used herein, the term "pharmaceutically acceptable" refers to molecular entities and compositions that generally do not produce allergic or other serious adverse reactions when administered using routes well known in the art. Molecular entities and compositions approved by federal or state regulatory agencies or listed in the United States Pharmacopoeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans, are considered "pharmaceutically acceptable." As used herein, the term "pharmaceutically acceptable carrier" is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, that are compatible with pharmaceutical compositions. Suitable carriers are described in the latest edition of Remington's Pharmaceutical Sciences, a standard reference textbook in this field, and are incorporated herein by reference.Some examples of such carriers or diluents include, but are not limited to, water, saline, Ringer's solution, dextrose solution, and 5% human serum albumin.Non-aqueous media such as liposomes and fixed oils can also be used.The use of such media and agents for pharmaceutical active substances is well known in the art.Except where any conventional media or agent is incompatible with the active compound, its use in the composition is contemplated.Auxiliary active compounds can also be incorporated into the composition.

[0063]

[0065] Provided herein is a pharmaceutical composition comprising: (i) an anti-IL-6 antibody or antigen-binding portion thereof (the antibody or antigen-binding portion comprises a VH domain and a VL domain, wherein (a) the amino acid sequence of the VH domain comprises an HCDR1 of SEQ ID NO: 2, an HCDR2 of SEQ ID NO: 3, and an HCDR3 of SEQ ID NO: 4, and the amino acid sequence of the VL domain comprises an LCDR1 of SEQ ID NO: 8, an LCDR2 of SEQ ID NO: 9, and an LCDR3 of SEQ ID NO: 10), and (ii) a pharmaceutically acceptable carrier, diluent, or excipient.

[0064]

[0066] The pharmaceutical compositions disclosed herein are formulated to be compatible with their intended route of administration. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (i.e., topical), transmucosal, and rectal administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous application may contain the following components: a sterile diluent such as water for injection, saline, fixed oils, polyethylene glycol, glycerin, propylene glycol, or other synthetic solvents; an antibacterial agent such as benzyl alcohol or methylparaben; an antioxidant such as ascorbic acid or sodium bisulfate; a chelating agent such as ethylenediaminetetraacetic acid (EDTA); a buffer such as acetate, citrate, or phosphate, and an agent for adjusting tonicity such as sodium chloride or dextrose. pH can be adjusted with acids or bases such as hydrochloric acid or sodium hydroxide. Parenteral formulations can be enclosed in ampoules, disposable syringes, or multiple-dose vials made of glass or plastic.

[0065]

[0067] Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL® (BASF, Parsippany, NJ), or phosphate-buffered saline (PBS). In all cases, the composition must be sterile and fluid to the extent that easy syringability exists. It should be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. Prevention of the action of microorganisms can also be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, sodium chloride in the composition. Prolonged absorption of injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.

[0066]

[0068] Sterile injectable solution can be prepared by incorporating the required amount of active compound into suitable solvent, and optionally with one or combination of the above-listed ingredients, and then filter sterilization.Generally, dispersion agent is prepared by mixing active compound into a sterile vehicle that contains basic dispersion medium and other ingredients that are required from the above-listed ingredients.For the preparation of sterile powder for sterile injectable solution, the preparation method is vacuum drying and freeze-drying, which can obtain the powder of active compound and any additional desired ingredients from the solution that has been previously sterile-filtered.

[0067]

[0069] Oral compositions generally contain an inert diluent or an edible carrier. They can be enclosed in gelatin capsules or compressed into tablets. For oral therapeutic administration, the active compound can be incorporated with an excipient and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, in which the compound in the liquid carrier is orally applied, swished in the mouth, and expectorated or swallowed. Pharmaceutically compatible binders and / or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel®, or cornstarch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, orange flavor, and the like.

[0068]

[0070] For administration by inhalation, the compounds can be delivered in the form of an aerosol spray from pressured container or dispenser which contains a suitable propellant, eg, a gas such as carbon dioxide, or a nebulizer.

[0069]

[0071] Systemic administration can also be by transmucosal or transdermal means.For transmucosal or transdermal administration, a penetrant suitable for the barrier to be permeated is used in the formulation.Such penetrants are well known in the art, and for example, for transmucosal administration, surfactants, bile salts, and fusidic acid derivatives are included.Transmucosal administration can be achieved by using nasal sprays or suppositories.For transdermal administration, the active compound is formulated into ointments, salves, gels, or creams well known in the art.

[0070]

[0072] The medications can also be prepared in the form of suppositories (e.g., with conventional suppository bases such as cocoa butter and other glycerides) or retention enemas for rectal delivery.

[0073] In some embodiments, the active compound is prepared with a carrier that protects the compound from rapid elimination from the body, for example, a controlled release formulation, including implants and microencapsulated delivery systems.Biodegradable biocompatible polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid can be used.Methods for preparing such formulations will be clear to those skilled in the art.Materials are also commercially available.Liposomal suspensions can also be used as pharmaceutically acceptable carriers.

[0071]

[0074] In order to facilitate administration and make dosage uniform, it is particularly advantageous to prepare oral or parenteral compositions into unit dosage form.As used herein, unit dosage form refers to a physically separate unit that is suitable as a single dose for the subject to be treated, and each unit contains a predetermined amount of active compound that is calculated to produce desired therapeutic effect in association with required pharmaceutical carrier.The specification of the unit dosage form of the present invention is influenced by and directly depends on the inherent characteristics of active compound and the specific therapeutic effect that is to be achieved, and the limitations inherent in the field of preparing this active compound for individual treatment.

[0072]

[0075] The pharmaceutical compositions provided herein can be included in a container, pack, or dispenser together with instructions for administration.

[0076] Use of antibodies Provided herein are methods and uses of anti-IL-6 antibodies, anti-IL-6 antigen-binding portions, immunoconjugates, and pharmaceutical compositions described herein for providing a therapeutic benefit to a subject having a condition associated with IL-6 expression. In some embodiments, the condition is elevated cardiovascular risk. In some embodiments, the condition is chronic kidney disease (CKD) accompanied by elevated cardiovascular risk. In some embodiments, the condition is cardiovascular disease, including, but not limited to, non-fatal myocardial infarction, non-fatal stroke, cardiovascular death, and heart failure.

[0073]

[0077] In some embodiments, the methods described herein further comprise treating the subject with an additional form of therapy. In some embodiments, the additional form of therapy comprises administering one or more therapeutic agents in addition to the anti-IL-6 antibody or antibody fragment described herein. Therapeutic agents include a second antibody (e.g., an anti-IL-1 antibody, an anti-IGF-1 receptor antibody, an anti-VEGF antibody, and / or an anti-IL17a antibody), a soluble receptor (e.g., a soluble IL-1 receptor, a soluble TNF-α receptor), an anti-inflammatory agent (e.g., paclitaxel, docetaxel, cisplatin, doxorubicin, prednisone, mitomycin, progesterone, tamoxifen, or fluorouracil), or a cardiovascular risk modifier (e.g., an adrenergic blocking agent, an angiotensin-converting enzyme inhibitor ... These include, but are not limited to, antihypertensive drugs such as otensin II receptor blockers and calcium channel blockers; lipid-lowering drugs such as statins, fibrates, PCSK9 inhibitors, bile acid resins, niacin, selective cholesterol absorption inhibitors, omega-3 fatty acids and fatty acid esters, and adenosine triphosphate citrate lyase (ACL) inhibitors; antidiabetic drugs such as metformin; or antiplatelet drugs such as aspirin, clopidogrel, ticlopidine, ticagrelor, prasugrel, and cangrelor.

[0074]

[0078] Provided herein is an anti-IL-6 antibody or anti-IL-6 antigen-binding portion, immunoconjugate, or pharmaceutical composition described herein for use as a medicament.

[0079] As used herein, the terms "effective amount" or "therapeutically effective amount" refer to an amount of a pharmaceutical agent, e.g., an anti-IL-6 antibody or antigen-binding portion thereof, sufficient to reduce or alleviate the severity and / or duration of a disorder, e.g., cardiovascular disease, or one or more symptoms thereof, prevent progression of the disorder, cause regression of the disorder, prevent the recurrence, onset, onset, or progression of one or more symptoms associated with the disorder, detect the disorder, or enhance or improve the prophylactic or therapeutic efficacy of another therapy (e.g., a prophylactic or therapeutic agent). In some embodiments, a therapeutically effective dose of the anti-IL-6 antibody or antibody fragment is effective to alter one or more biomarkers of IL-6-mediated signaling, including, but not limited to, total sIL-6R, total IL-6, C-reactive protein (CRP), and / or autoantibodies, for an unexpectedly long period of time.

[0075]

[0080] As used herein, terms such as "treat," "treating," and "treatment" refer to reducing or ameliorating a disorder and / or its associated signs or symptoms, or slowing or halting its progression. It is understood that treating a disorder or condition does not prevent, but does not require, the associated disorder, condition, or symptoms to be completely eliminated.

[0076]

[0081] As used herein, "pre-treatment" means before the first administration of an anti-IL-6 antibody according to the methods described herein. Pre-treatment does not exclude, and in many cases will include, prior administration of a therapeutic agent other than an anti-IL-6 antibody.

[0077]

[0082] As used herein, "post-treatment" means after administration of an anti-IL-6 antibody according to the methods described herein. Post-treatment includes after any administration of an anti-IL-6 antibody at any dosage described herein. Post-treatment also includes after a treatment phase with an anti-IL-6 antibody.

[0078]

[0083] The actual amount administered, its rate of administration, and its duration will depend on the nature and severity of the condition being treated, the particular injury being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the injury, the site of delivery of the composition, the method of administration, the administration schedule, and other factors known to medical professionals. Prescribing treatment, e.g., determining dosage, is within the responsibility of general practitioners and other physicians and may depend on the severity of the condition and / or the progression of the disease being treated. Appropriate dosages for antibody molecules are well known in the art (Ledermann JA et al., 1991, Int. J. Cancer 47:659-664; Bagshawe KD et al., 1991, Antibody, Immunoconjugates and Radiopharmaceuticals 4:915-922). Specific dosages, depending on the type of medication being administered, are described herein or in the Physician's Desk Reference (2003) and can be used. A therapeutically effective amount or appropriate dosage of an antibody molecule can be determined by comparing its in vitro activity with its in vivo activity in animal models. Methods for extrapolating effective dosages in mice and other test animals to humans are known. The exact dosage will depend on many factors, including whether the antibody is prophylactic or therapeutic, the size and location of the area to be treated, the precise nature of the antibody (e.g., whole antibody, fragment), and the nature of any detectable label or other molecule attached to the antibody.

[0079]

[0084] Typical antibody doses range from 100 μg to 1 g for systemic use and from 1 μg to 1 mg for intradermal injection. An initial higher loading dose can be administered, followed by one or more lower doses. In some embodiments, the antibody is a whole antibody, e.g., an IgG1, IgG2, or IgG4 isotype. This dose is for a single treatment of an adult subject and can be adjusted proportionally for children and infants, and for other antibody formats proportionally based on molecular weight. Treatment can be repeated at daily, twice-weekly, weekly, or monthly intervals, at the physician's discretion. The treatment schedule for a subject can depend on the pharmacokinetic and pharmacodynamic properties of the antibody composition, the route of administration, and the nature of the condition being treated. In some embodiments, dosages of the present disclosure include an anti-IL-6 antibody or antibody fragment in an amount of at least about 10 mg, or at least about 20 mg, or at least about 30 mg, or at least about 40 mg, or at least about 50 mg.

[0080]

[0085] Treatment can be periodic, with the period between administrations being about 2 weeks or more, e.g., about 3 weeks or more, about 4 weeks or more, about monthly or more, about 5 weeks or more, or about 6 weeks or more. For example, treatment can be every 2 to 4 weeks or every 4 to 8 weeks. Treatment can be administered before and / or after surgery and / or administered or applied directly to the anatomical site of the surgical or invasive procedure. Suitable formulations and routes of administration are described above. In some embodiments, the administration schedule for the anti-IL-6 antibody or antibody fragment is once every 4 weeks or once every 8 weeks for a total of up to about 52 weeks.

[0081]

[0086] In some embodiments, the subject is a human, a non-human primate, a pig, a horse, a cow, a dog, a cat, a guinea pig, a mouse, or a rat. In some embodiments, the subject is an adult human. In some embodiments, the subject is a pediatric human. In some embodiments, the patient has previously received or is concurrently receiving prednisone or the like at the time of initiation of the treatment. In one aspect, the dosage of prednisone or the like is 10 mg to 60 mg per day.

[0082]

[0087] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. All documents or portions of documents cited herein, including, but not limited to, patents, patent applications, articles, books, and treatises, are expressly incorporated herein by reference in their entirety for all purposes. In the event that one or more of the incorporated documents or portions of documents defines a term that contradicts a term's definition in this application, the definition set forth in this application shall prevail. However, the mention of any references, papers, publications, patents, patent publications, and patent applications cited herein is not, and should not be construed as, an acknowledgment or any form of suggestion that they constitute valid prior art or form part of the general knowledge in any country in the world.

[0083]

[0088] In describing the present invention, any concentration range, percentage range, ratio range, or integer range is understood to include any integer value within the recited range, and, where appropriate, fractions thereof (such as 1 / 10 and 1 / 100 of an integer), unless otherwise specified. As used herein, the terms "a" and "an" should be understood to refer to "one or more" of the recited components, unless otherwise specified. The use of alternatives (e.g., "or") should be understood to mean either one, both, or any combination thereof of the alternatives. As used herein, the terms "include" and "comprise" are used interchangeably.

[0084]

[0089] The present disclosure will be further clarified by the following examples, which are intended to be purely illustrative of the disclosure and not limiting in any way. [Example]

[0085]

[0090] Example 1: Clinical evaluation of human anti-IL6 antibodies in patients with cardiovascular disease A Phase II clinical trial of the human anti-IL6 antibody TOUR006 disclosed herein is being conducted in patients at increased risk for cardiovascular events, including chronic kidney disease (CKD). The trial is a randomized, double-blind, placebo-controlled study designed to evaluate the anti-inflammatory effects of TOUR006 at three dosing regimens in participants at high cardiovascular risk (identified as hsCRP ≥ 2.0 mg / L at baseline and diagnosed with CKD).

[0086]

[0091] Selection Criteria To be included in this study, participants must meet all of the following criteria: 1) Age ≥ 18 years at the time of signing the informed consent form (ICF). 2) Serum hsCRP level ≥ 2.0 mg / L at the screening visit. 3) Diagnosis of CKD (estimated glomerular filtration rate [eGFR] ≥ 15 and < 60 mL / min / 1.73 m 2 ) and is not expected to require dialysis during the course of the study. 4) Received a COVID-19 vaccine (completed the primary series) at least 30 days prior to the screening visit and / or had a previous COVID-19 infection (excluding COVID-19 infection within 30 days prior to the screening visit [see exclusion criterion #19]). 5) Agreement to adhere to contraception and reproductive restrictions: a. Male participants must be surgically sterilized or, if sexually active with a female partner of childbearing potential, must agree to use condoms during the study and for 4 months after completing study medication. b. Female participants of childbearing potential (those who were menopausal less than 2 years prior to the screening visit, had non-treatment-induced amenorrhea within 12 months prior to the screening visit, or are not surgically sterilized (absence of ovaries and / or uterus and / or both fallopian tubes) must have a negative serum pregnancy test at the screening visit, a negative urine pregnancy test at all protocol-specified time points, and agree to use at least one acceptable method of contraception throughout the study and for 32 weeks after the last dose of study medication.

[0087]

[0092] Exclusion criteria Participants will be excluded from the study if they meet any of the following criteria: Test values 1) Hemoglobin level at screening examination is 8.0 g / dL or less. 2) Transferrin saturation <15.0% at screening examination. 3) Absolute neutrophil count at screening examination of 2.0 × 10 9 / L or less. 4) Platelet count at screening examination is 120 x 10 9 / L or less. 5) Urine protein-to-creatinine ratio >3000 mg / g (3.0 g / g) at screening examination. 6) Serum albumin <3.0 g / dL at screening examination. 7) Serum total IgG >700 mg / dL at screening examination. 8) Uncontrolled diabetes with HbA1c >9% at screening visit. 9) Fasting low-density lipoprotein >130 mg / dL at screening visit. 10) Fasting triglycerides >200 mg / dL at screening visit. 11) Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) greater than 2.5 times the upper limit of normal at the screening visit. 12) Test positive for tuberculosis at the screening visit. A blood test (e.g., QuantiFERON) is preferred, but a purified protein derivative (PPD) skin test, read by a qualified medical professional within 48-72 hours, may also be administered. If a participant tests positive for PPD but negative for QuantiFERON, they are eligible to enroll in the study. 13) Evidence of human immunodeficiency virus (HIV)-1 or HIV-2 infection by serology at the time of the screening visit. 14) Evidence of hepatitis B or C by serologic testing at the time of the screening visit (e.g., positive hepatitis B surface antigen or hepatitis C antibody). 15) Serum vitamin B-12 and folate levels below the lower limit of normal laboratory limits at the time of the screening visit (known or suspected cause of anemia other than CKD). medical condition or illness 16) Acute coronary syndrome, ischemic stroke, transient ischemic attack, or other thrombotic or thromboembolic event within 6 months prior to randomization. 17) Participants with an indwelling urethral or intravenous catheter. 18) Clinical evidence or suspicion of active infection. 19) History of major gastrointestinal bleeding (excluding hemorrhoidal bleeding) within 6 months prior to randomization. 20) History of active colitis or gastrointestinal abscess within 12 months prior to randomization. 21) History of clinically active inflammatory bowel disease within 12 months prior to randomization. 22) Uncontrolled hypertension (defined as a mean of three systolic blood pressure measurements >160 mmHg or a mean diastolic blood pressure >100 mmHg before randomization). If antihypertensive therapy is initiated or increased as a result of an initial screening blood pressure that is out of range, participants may be reassessed for this criterion at the investigator's discretion. 23) Planned coronary revascularization (percutaneous coronary intervention or coronary artery bypass graft) or other major surgical procedure during the study period. 24) History of major cardiac surgery, noncardiac surgery, or major endoscopic procedure within 6 months prior to randomization. 25) New York Heart Association Grade IV congestive heart failure. 26) History of hospitalization due to worsening heart failure within 3 months prior to randomization. 27) Untreated cardiac arrhythmias, including: A hemodynamically significant arrhythmia b. Atrial fibrillation or atrial flutter and an uncontrollable resting heart rate (>100 bpm) c. Other arrhythmias, as determined by the investigator, that may affect participant safety or confound the interpretation of safety data in this study. 28) QTcF >450 msec in men or >470 msec in women 29) Diagnosis of cachexia and / or unintentional weight loss >5% within 3 months prior to randomization. 30) Diagnosis of protein-losing enteropathy. 31) Actively treated or aggressive malignancy within 12 months prior to randomization. 32) History of bone marrow or solid organ transplant or planned to undergo bone marrow or solid organ transplant during study participation. 33) Immunodeficiency (inherited or acquired, e.g., acquired immunodeficiency syndrome, common variable immunodeficiency, etc.). 34) Serious infection within the past 12 months before screening or multiple such episodes within 36 months before randomization (infections requiring hospitalization and / or treatment with intravenous [IV] antibiotics, IV antifungals, or IV antivirals, and / or infections with clinical symptoms deemed by the investigator to be consistent with a serious infection). 35) Active or occurring COVID-19 infection (including mild or asymptomatic) within 30 days prior to randomization. 36) History (past or current) of any serious opportunistic infection (e.g., thrush not localized due to corticosteroid therapy). 37) History of or clinical suspicion of systemic lupus erythematosus. 38) Any live attenuated vaccination planned during the study period. 39) Known allergy to the study drug or any of its components. 40) History of any substance use disorder, including alcohol abuse. 41) History of seizures within 10 years prior to randomization. 42) History of psychiatric illness. 43) Significant cognitive impairment. Previous or current medications 44) Received an investigational drug within 30 days (or 5 half-lives of the investigational drug administered, whichever is longer) prior to randomization. 45) Previous treatment with any immunomodulatory or immunosuppressive agent, including systemic corticosteroids, within 5 half-lives (or 3 months, whichever is longer) of the drug prior to randomization, or anticipated use of such medications at any time during the study. Note: Use of otic, ophthalmic, inhaled, and topical corticosteroids or topical corticosteroid injections is not excluded. 46) Treatment with hypoxia-inducible factor stabilizers (e.g., molidusat, roxadustat) or erythropoietin mimetics (e.g., erythropoietin alfa or beta, darbopoietin alfa, or continuous erythropoietin receptor activators) within 6 weeks prior to randomization. 47) Scheduled to receive either the investigational drug or a protocol-specified excluded drug during the treatment or safety follow-up period. 48) Use of systemic antibiotics, antivirals, or antifungals ("systemic" defined as oral or IV medications absorbed into the circulation) within 14 days prior to randomization. General exclusion 49) Currently breastfeeding. 50) It is anticipated that blood transfusions will be required during the study period. 51) Any condition that may interfere with the conduct of the study or the interpretation of the study results, that may interfere with the conduct of the study or the interpretation of the study results, or that in the opinion of the investigator may increase the risks of participating in the study. 52) Expected life expectancy of less than 2 years.

[0088]

[0093] Key inclusion criteria include chronic kidney disease (CKD) and a pretreatment hsCRP level of 2 mg / L or higher. For example, eligible patients include, but are not limited to, patients with a pretreatment hsCRP level of 2 mg / L or higher, CKD, anemia associated with CKD, Kidney Disease Outcome Improvement Initiative (KDOQI) stages 1-5 CKD, an estimated glomerular filtration rate (eGFR) of less than 60 mL / min / 1.73 m² (CKD-Epidemiology Collaborative Study (CKD-EPI)), and / or a clonal hematopoietic phenotype (CHIP) signature. The CHIP signature includes, but is not limited to, one or more mutations in DNMT3A, TET2, ASXL1, PPM1D, TP53, JAK2, SF3B1, or SRSF2 found in blood or bone marrow cells.

[0089]

[0094] The study also includes patients with established cardiovascular disease (CVD). For example, but not limited to, eligible patients include those with atherosclerotic cardiovascular disease (ASCVD), coronary artery disease (CAD), or peripheral artery disease (PAD).

[0090]

[0095] Additionally, this study includes patients with risk factors for developing cardiovascular disease, regardless of whether they have CKD. For example, but without limitation, risk factors for developing cardiovascular disease include: (a) diabetes (type I or type II); (b) metabolic syndrome; (c) hypertension; (d) age greater than about 55 years for men and greater than about 65 years for women; (e) dyslipidemia; (f) family history of cardiovascular disease; (g) history of stroke or transient ischemic attack; (h) smoking (current or former); (i) homocysteinemia; (j) hyperuricemia; (k) HDL-C levels of less than about 40 mg / dL for men and less than about 50 mg / dL for women; (l) renal dysfunction (e.g., creatinine clearance ("CrCL") greater than about 30 mL / min and less than about 60 mL / min); (m) retinopathy (e.g., non-proliferative retinopathy, pre-proliferative retinopathy, proliferative retinopathy, or proliferative retinopathy). (n) microalbuminuria (e.g., a positive micro or other strip test, an albumin / creatinine ratio of about 2.5 mg / mmol or greater, or an albumin excretion rate of about 20 mg / min or greater on at least two consecutive scheduled collections); (o) macroalbuminuria (e.g., albatics or other dipstick evidence of crude proteinuria, an albumin / creatinine ratio of about 25 mg / mmol or greater, or an albumin excretion rate of about 200 mg / min or greater on at least two consecutive scheduled collections); (p) an ankle-brachial index of less than about 0.9, without symptoms of intermittent claudication.

[0091]

[0096] The study may also include patients with anemia of chronic inflammation, anemia of chronic disease, or iron-restricted anemia; functional iron deficiency or iron restriction; elevated hepcidin (serum or urine); a red blood cell distribution width (RDW) greater than about 13% or an RDW in the highest quartile of the overall population, and / or a white blood cell count (WBC) greater than 9000 per microliter of blood or a WBC in the highest quartile of the overall population.

[0092]

[0097] The study may also include patients who have had a recent infection within the past month, three months, six months, or year; who have had a recent COVID-19 (SARS-CoV-2) infection within the past month, three months, six months, or year; who have had recent surgery within the past month, three months, six months, or year; and / or who have periodontal disease.

[0093]

[0098] This test involves 2.0 x 10 per liter. 9 Absolute neutrophil count of 120 x 10 per L or greater 9 Patients with a spot urine to creatine ratio of 4 or greater may also be included.

[0094]

[0099] The study will exclude individuals who have tested positive for active tuberculosis, HIV, or hepatitis B or C. The study will also exclude individuals who have received long-term immunosuppressive therapy.

[0100] Dosing regimen A study schematic is shown in Figure 1. Eligible patients will be randomized 1:1:1:1 to one of three dosing regimens of TOUR006 or placebo (see treatment arms below). To mitigate imbalances in background safety risks due to CKD, participants will be stratified by CKD stage to ensure balanced randomization. Treatment arms are as follows: Treatment group A (50 mg of TOUR006 administered subcutaneously every 90 days) Participants will receive a 50 mg injection of TOUR006 on study days 1 and 90. Matching placebo injections will be administered on study days 30, 60, 120, and 150. Total cumulative TOUR006 dose: 100 mg Treatment arm B (25 mg of TOUR006 administered subcutaneously every 90 days) Participants will receive 25 mg injections of TOUR006 on study days 1 and 90. Matching placebo injections will be administered on study days 30, 60, 120, and 150. Total cumulative TOUR006 dose: 50mg Treatment group C (TOUR006 15 mg administered subcutaneously every 30 days) Participants will receive a 15mg injection of TOUR006 on study days 1, 30, 60, 90, 120, and 150. Total cumulative TOUR006 dose: 90mg Placebo: Subcutaneous administration every 30 days

[0101] Approximately 120 participants (30 per each treatment group) will be randomized. After a screening period, randomized participants will receive TOUR006 or placebo every 30 days (participants in Groups A and B will receive placebo on study days 30, 60, 120, and 150 to align with the 30-day dosing regimen). Participants will be followed for pharmacokinetic and pharmacodynamic endpoints through study day 180 and for safety through study day 365. The primary pharmacodynamic endpoint will be assessed on study day 180.

[0095]

[0102] The additional TOUR006 dosing regimen includes three dose levels ranging from 5 mg to 200 mg. For example, effective doses are 5, 7.5, 10, 15, 20, 25, 30, or 50 mg of TOUR006 antibody. TOUR006 may be administered subcutaneously every 4, 8, 12, or 24 weeks. The total study duration for each patient is approximately 24 weeks.

[0096]

[0103] Further dosing regimens include (a) administering a loading dose of TOUR006 subcutaneously to the patient for at least the first two administrations during the loading regimen; and (b) thereafter administering a maintenance dose of TOUR006 subcutaneously to the patient during the maintenance regimen. The loading regimen includes administering the loading dose every week, every two weeks, or every four weeks. The maintenance regimen includes administering the maintenance dose every four weeks, every eight weeks, every 12 weeks, or every 24 weeks. The loading dose can be equal to or greater than the maintenance dose. The loading dose is 5 mg to 200 mg, and the maintenance dose is 5 mg to 200 mg.

[0097]

[0104] Evaluation items: Clinically relevant parameters may be recorded during the study, including, but not limited to, high-sensitivity C-reactive protein (hsCRP), absolute neutrophil count (ANC), fibrinogen, haptoglobin, serum amyloid A (SAA), secretory phospholipase A2 (sPLA2), lipoprotein (a) levels, neutrophil-to-lymphocyte ratio (NLR), red blood cell distribution width (RDW), LDL levels, APOB, APOA1, hemoglobin, transferrin saturation (TSAT), reticulocyte hemoglobin count (Ch), total iron-binding capacity (TIBC), serum ferritin, albumin, erythropoiesis resistance index (ERI), handgrip, NT-proBNP, and cardiac MRI. Details of these clinically relevant parameters are described in US8,906,964, US11,369,582, and US11,384,143, the contents of each of which are expressly incorporated herein by reference in their entirety for all purposes.

[0098]

[0105] The primary endpoint of this study is the change from baseline in hsCRP after 180 days of treatment. Additionally, the primary endpoint is the reduction in hsCRP from week 12 to week 24 of treatment, for example, week 12, week 16, or week 24 of treatment. Enrolled patients have inflammation or IL6-mediated inflammation. C-reactive protein (CRP) is a marker of inflammation. CRP levels rise in response to inflammation and can be measured with an hsCRP (high-sensitivity C-reactive protein) test. Patients typically have pre-treatment hsCRP levels greater than 2 mg / L. Under certain circumstances, patients have pre-treatment hsCRP levels of 1 mg / L or less. Treatment is sufficient to reduce hsCRP levels. For example, post-treatment hsCRP levels are 2 mg / L or less. The treatment is sufficient to reduce hsCRP levels by at least about 50%, about 60%, about 70%, about 80%, or about 90% compared to pre-treatment (baseline). The treatment results in a reduction in hsCRP within 4, 8, 12, 16, or 24 weeks of treatment. Furthermore, the treatment is sufficient to sustain the reduction in hsCRP for at least 24 weeks or 48 weeks.

[0099]

[0106] One secondary endpoint is the proportion of participants achieving an hsCRP response (greater than 90% reduction from baseline and / or hsCRP<2.0 mg / L) after 180 days of treatment. Other secondary endpoints are serum drug concentrations of TOUR006 at baseline and after 30, 60, 90, 120, 150, and 180 days of treatment, and at 210, 270, 330, and 365 days.

[0100]

[0107] To assess the safety and tolerability of TOUR006 in participants with elevated cardiovascular risk and CKD, safety endpoints will include the proportion of participants with adverse events (AEs), serious AEs (SAEs), severe AEs, and AEs leading to discontinuation; description and frequency of events of particular interest by treatment group; and description of additional safety assessments by treatment group and dose, e.g., vital signs, electrocardiogram, and anti-drug antibodies.

[0101]

[0108] To investigate the effect of TOUR006 on markers of inflammation, exploratory endpoints include change from baseline in serum amyloid A (SAA); change from baseline in lipoprotein(a); change from baseline in neutrophil-to-lymphocyte ratio (NLR); and change from baseline in secretory phospholipase (sPLA2). To evaluate the effect of TOUR006 on functional iron deficiency and anemia, additional endpoints include change from baseline in red blood cell distribution width (RDW); change from baseline in hemoglobin, and change from baseline in transferrin saturation (TSAT), reticulocyte hemoglobin count (Ch), total iron-binding capacity (TIBC), and serum ferritin.

[0102]

[0109] This treatment is sufficient to reduce inflammation without causing immunosuppression. Immunosuppression is measured by absolute neutrophil count (ANC). The normal range for ANC is approximately 500-7000 cells / pL. Post-treatment ANC is at least 500, 1000, 1500, or 2000 cells / pL compared to pre-treatment levels. Under certain circumstances, ANC is reduced by approximately 50%, 40%, 30%, 20%, or 10% or less compared to pre-treatment levels. Under certain circumstances, ANC is not reduced compared to pre-treatment levels.

[0103]

[0110] Other secondary endpoints of the study include the incidence of one or more cardiovascular events, and the treatment reduces the incidence of one or more cardiovascular events by at least about 10%, about 15%, about 20%, about 25%, about 30%, about 40%, or about 50%. Adverse cardiovascular events include, but are not limited to, death, cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, unstable angina requiring urgent coronary revascularization, heart failure (new, worsening, or acute), ventricular arrhythmias due to ischemia, ischemic damage to a heart valve, increased N-terminal pro-brain natriuretic peptide (NT-pro-BNP), increased cardiac markers of damage (such as troponin or creatine kinase-MB), a decrease in left ventricular ejection fraction of at least about 5%, atrial fibrillation or other ventricular arrhythmias, intestinal ischemia (small bowel or colon), new-onset or worsening peripheral arterial disease, critical limb ischemia, atheroembolism (cholesterol embolism), new-onset or worsening thromboangiitis obliterans, a worsening of New York Heart Association (NYHA) heart failure classification by one or more degrees, worsening Kansas City Cardiomyopathy Questionnaire score, and a change in the Short Form 36 (SF-36) Physical Component Score (PCS).

[0104]

[0111] The study will consist of three phases: (i) screening and randomization, (ii) treatment, and (iii) follow-up. During screening, each potential subject will provide informed consent before beginning any study-specific procedures. Randomization of subjects into study arms will be performed centrally by an interactive web response system (IWRS) using a randomization scheme reviewed and approved by an independent statistician. During the treatment period, randomized subjects will receive treatment and evaluations according to the protocol. Follow-up will occur 8, 12, 16, 24, or 36 weeks after the end of treatment.

[0105]

[0112] Incorporation by Reference All references, articles, publications, patents, patent publications, and patent applications cited herein are incorporated herein by reference in their entirety for all purposes. However, mention of any reference, article, publication, patent, patent publication, or patent application cited herein is not, and should not be construed as, an acknowledgment or any form of suggestion that they constitute valid prior art or form part of the general knowledge in any country in the world.

Claims

1. A method for treating cardiovascular disease, comprising administering to a patient in need thereof a therapeutically effective dose of an anti-interleukin-6 (anti-IL-6) antibody or antibody fragment having variable heavy (VH) CDRs defined in SEQ ID NOs: 2, 3, and 4 and variable light (VL) CDRs defined in SEQ ID NOs: 8, 9, and 10.

2. 2. The method of claim 1, wherein the antibody or antibody fragment comprises a heavy chain polypeptide comprising a polypeptide having at least 98% identity to SEQ ID NO: 1 and a light chain polypeptide comprising a polypeptide having at least 98% identity to SEQ ID NO:

7.

3. 2. The method of claim 1, wherein the antibody or antibody fragment comprises a heavy chain polypeptide having the sequence of SEQ ID NO:1 and a light chain polypeptide having the sequence of SEQ ID NO:

7.

4. The method of any one of claims 1 to 3, wherein the patient is at least 18 years old.

5. The method of any one of claims 1 to 4, wherein the patient has chronic kidney disease (CKD).

6. The method of any one of claims 1 to 4, wherein the patient has anemia of CKD.

7. 7. The method of claim 5 or 6, wherein the patient has Kidney Disease Outcome Improvement Initiative (KDOQI) stage 3-5 CKD.

8. 7. The method of claim 5 or 6, wherein the patient has an estimated glomerular filtration rate (eGFR) CKD-Epidemiology Collaboration (CKD-EPI) formula of less than 60 mL / min / 1.73 m^2.

9. The method of any one of claims 1 to 4, wherein the patient has atherosclerotic cardiovascular disease (ASCVD), coronary artery disease (CAD), or peripheral arterial disease (PAD).

10. The method of any one of claims 1 to 9, wherein the patient has a risk factor for developing cardiovascular disease.

11. 11. The method of claim 10, wherein the risk factors for developing cardiovascular disease are selected from the group consisting of: (a) type I or type II diabetes; (b) metabolic syndrome; (c) hypertension; (d) age 55 or older for men and age 65 or older for women; (e) dyslipidemia; (f) a family history of cardiovascular disease; (g) a history of stroke or transient ischemic attack; (h) current or former smoking; (i) homocysteinemia; (j) hyperuricemia; (k) an HDL-C level of about 40 mg / dL or less for men and about 50 mg / dL or less for women; (l) impaired renal function; (m) retinopathy; (n) microalbuminuria; (o) macroalbuminuria; and (p) an ankle-brachial index of less than about 0.9 in the absence of symptoms of intermittent claudication.

12. The method of any one of claims 1 to 11, wherein the patient has anemia of chronic inflammation, anemia of chronic disease, or iron-restricted anemia.

13. The method of any one of claims 1 to 12, wherein the patient has functional iron deficiency or iron restriction.

14. The method of any one of claims 1 to 13, wherein the patient has elevated serum or urinary hepcidin.

15. The method of any one of claims 1 to 14, wherein the patient has a red blood cell distribution width (RDW) of greater than 13% or an RDW in the highest quartile.

16. 16. The method of any one of claims 1 to 15, wherein the patient has a white blood cell count (WBC) of greater than 9000 cells per microliter of blood or a WBC in the highest quartile.

17. The patient receives 2.0 x 10 per liter ９ The method of any one of claims 1 to 16, wherein the patient has an absolute neutrophil count of at least 100 mg / kg.

18. The patient is given 120 x 10 per L ９ The method according to any one of claims 1 to 17, wherein the patient has a platelet count of at least 100 mg / kg.

19. 19. The method of any one of claims 1 to 18, wherein the patient has a spot urine to creatine ratio of 4 or greater.

20. The method of any one of claims 1 to 19, wherein the patient is negative for active tuberculosis.

21. The method of any one of claims 1 to 20, wherein the patient is HIV negative.

22. The method of any one of claims 1 to 21, wherein the patient is negative for hepatitis B or hepatitis C.

23. 23. The method of any one of claims 1 to 22, wherein the cardiovascular disease is selected from the group consisting of non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death.

24. The method of any one of claims 1 to 22, wherein the cardiovascular disease is heart failure.

25. 25. The method of any one of claims 1 to 24, wherein the therapeutically effective dose is from about 5 mg to about 200 mg.

26. 26. The method of claim 25, wherein the therapeutically effective dose is about 5 mg, about 7.5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, or about 100 mg.

27. 27. The method of claim 26, wherein the therapeutically effective dose is about 50 mg every 90 days.

28. 28. The method of claim 27, wherein the total therapeutically effective dose is about 100 mg.

29. 27. The method of claim 26, wherein the therapeutically effective dose is about 25 mg every 90 days.

30. 30. The method of claim 29, wherein the total therapeutically effective dose is about 50 mg.

31. 27. The method of claim 26, wherein the therapeutically effective dose is about 15 mg every 30 days.

32. 32. The method of claim 31, wherein the total therapeutically effective dose is about 90 mg.

33. 33. The method of any one of claims 1 to 32, wherein the therapeutically effective dose is administered subcutaneously.

34. 27. The method of any one of claims 1 to 26, wherein the therapeutically effective dose is administered every week to every 24 weeks.

35. 27. The method of claim 26, wherein the therapeutically effective dose is administered every 4 weeks, every 8 weeks, every 12 weeks, or every 24 weeks.

36. 27. The method of any one of claims 1 to 26, wherein the therapeutically effective dose is administered every 30 days to every 90 days.

37. 37. The method of claim 36, wherein the therapeutically effective dose is administered every 30 days.

38. 37. The method of claim 36, wherein the therapeutically effective dose is administered every 90 days.

39. a) administering to said patient a loading dose of said anti-IL-6 antibody or antibody fragment in at least the first two administrations of a loading regimen; b) thereafter administering to said patient a maintenance dose of said anti-IL-6 antibody or antibody fragment during a maintenance regimen; The method of any one of claims 1 to 26, further comprising:

40. 40. The method of claim 39, wherein the loading regimen comprises administering the loading dose every week, every two weeks, or every four weeks.

41. 40. The method of claim 39, wherein the maintenance regimen comprises administering the maintenance dose every 4 weeks, every 8 weeks, every 12 weeks, or every 24 weeks.

42. (a) administering to said patient a loading dose of said anti-IL-6 antibody or antibody fragment in the first two administrations four weeks apart during a loading regimen; (b) thereafter administering to the patient a maintenance dose of the anti-IL-6 antibody or antibody fragment every 8 weeks or every 12 weeks during a maintenance regimen; 40. The method of claim 39, further comprising:

43. 43. The method of any one of claims 39 to 42, wherein the loading dose is equal to or greater than the maintenance dose.

44. The method of any one of claims 1 to 43, wherein the patient has inflammation.

45. 45. The method of claim 44, wherein the patient has IL-6 mediated inflammation.

46. 46. ​​The method of claim 44 or 45, wherein the treatment is sufficient to reduce the inflammation without causing immunosuppression.

47. 45. The method of claim 44, wherein the immunosuppression is measured by absolute neutrophil count (ANC).

48. 48. The method of claim 47, wherein the post-treatment ANC is at least 500, 1000, 1500, or 2000 cells / pL.

49. 48. The method of claim 47, wherein the post-treatment ANC is reduced by no more than 50%, 40%, 30%, 20%, or 10% compared to pre-treatment levels.

50. 48. The method of claim 47, wherein the ANC is not decreased compared to pre-treatment levels.

51. 51. The method of any one of claims 44 to 50, wherein the inflammation is measured by high sensitivity C-reactive protein (hsCRP) levels.

52. 52. The method of claim 51, wherein the patient has a pre-treatment hsCRP level greater than 2 mg / L.

53. 52. The method of claim 51, wherein the patient has a pre-treatment hsCRP level of 2 mg / L or less.

54. 52. The method of claim 51, wherein the patient has a pre-treatment hsCRP level of 1 mg / L or less.

55. 52. The method of claim 51, wherein the treatment is sufficient to reduce the hsCRP level to 2 mg / L or less.

56. 52. The method of claim 51, wherein the treatment is sufficient to reduce the hsCRP level to 1 mg / L or less.

57. 57. The method of any one of claims 51-56, wherein the treatment is sufficient to reduce the hsCRP level by at least 50%, 60%, 70%, 80%, or 90% compared to pre-treatment levels.

58. 58. The method of claim 57, wherein the treatment results in a reduction in hsCRP within 4, 8, or 12 weeks of treatment.

59. 58. The method of claim 57, wherein the treatment is sufficient to maintain the reduction in hsCRP for at least 24 or 48 weeks.

60. 58. The method of claim 55 or 57, wherein the treatment results in a decrease in hsCRP after about 180 days of treatment.

61. 61. The method of any one of claims 1-60, wherein the treatment is sufficient to reduce fibrinogen, haptoglobin, serum amyloid A (SAA), secretory phospholipase A2 (sPLA2), lipoprotein(a), or neutrophil-to-lymphocyte ratio (NLR) by at least 15%, 30%, or 50%.

62. 62. The method of any one of claims 1-61, wherein said treatment is sufficient to reduce the incidence of one or more cardiovascular events by at least about 10%, about 15%, about 20%, about 25%, about 30%, about 40%, or about 50%.

63. 63. The method of claim 62, wherein the adverse cardiovascular event is selected from the group consisting of death, cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, unstable angina requiring urgent coronary revascularization, new heart failure, worsening heart failure, acute heart failure, ventricular arrhythmia due to ischemia, ischemic damage to a heart valve, increased N-terminal pro-brain natriuretic peptide (NT-pro-BNP), increased cardiac markers of damage, a decrease in left ventricular ejection fraction of at least 5%, atrial fibrillation, ventricular arrhythmia, small bowel ischemia, colonic ischemia, new-onset or worsening peripheral arterial disease, critical limb ischemia, atheroembolism, cholesterol embolism, new-onset or worsening thromboangiitis obliterans, a worsening of one or more New York Heart Association (NYHA) classification of heart failure, a worsening score on the Kansas City Cardiomyopathy Questionnaire, and a change in the Short Form-36 (SF-36) Physical Component Score (PCS).

64. 64. The method of claim 63, wherein the cardiac marker of injury is troponin or creatine kinase-MB.

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