Treatment of myocarditis by administration of anti-interleukin-6 antibody

Abstract

The present disclosure relates to the use of anti-IL-6 antibodies for the treatment of myocarditis and for managing the symptoms of myocarditis, particularly for (sub)acute myocarditis. The present disclosure also relates to the use of anti-interleukin-6 (IL-6) antibodies for the prevention of chronic myocarditis. In some embodiments, the myocarditis is caused by a viral infection or an autoimmune disease.

Description

[Technical Field]

[0001] Related application data This application claims priority to U.S. Patent Application No. 63 / 435,149, filed December 23, 2022, and U.S. Patent Application No. 63 / 513,463, filed July 13, 2023, the entire contents of which are incorporated herein by reference.

[0002] Sequence Listing This application is filed with an electronic Sequence Listing, the entire contents of which are incorporated herein by reference.

[0003] Field The present disclosure relates to the use of anti-interleukin-6 (IL-6) antibodies, such as clazakizumab, for the treatment of myocarditis and for managing the symptoms of myocarditis, particularly for (sub)acute myocarditis. The present disclosure also relates to the use of anti-interleukin-6 (IL-6) antibodies for the prevention of chronic myocarditis. In some embodiments, the myocarditis is caused by a viral infection or an autoimmune disease. [Background technology]

[0004] Interleukin-6 (hereinafter "IL-6") (also known as interferon-beta 2; B-cell differentiation factor; B-cell stimulating factor-2; hepatocyte stimulating factor; hybridoma growth factor; and plasmacytoma growth factor) is a multifunctional cytokine involved in numerous biological processes, such as regulation of acute inflammatory responses, modulation of specific immune responses including B-cell and T-cell differentiation, bone metabolism, thrombopoiesis, epidermal proliferation, menstruation, neuronal differentiation, neuroprotection, aging, cancer, and the inflammatory responses occurring in Alzheimer's disease. See Non-Patent Document 1.

[0005] Interleukin-6 (IL-6) is a member of a family of cytokines that promotes cellular responses through a receptor complex consisting of at least one subunit of the signaling glycoprotein gp130 and the IL-6 receptor ("IL-6R") (also known as gp80). IL-6R can also exist in a soluble form ("sIL-6R"). IL-6 binds to IL-6R and subsequently dimerizes the signaling receptor gp130. See Non-Patent Document 2. In humans, the gene encoding IL-6 consists of five exons and four introns and maps to 7p21 on the short arm of chromosome 7. Translation and post-translational processing of IL-6 RNA result in the formation of a 21-28 kDa protein with 184 amino acids in its mature form (see Non-Patent Document 1).

[0006] IL-6 inhibitors have been developed to treat certain inflammatory disorders in which IL-6 has been shown to contribute significantly to the pathogenesis of the disease. For example, the anti-IL-6 receptor (anti-IL-6R) antibody tocilizumab (ACTEMRA®) has been approved for the treatment of rheumatoid arthritis, giant cell arteritis, polyarticular juvenile idiopathic arthritis, systemic juvenile idiopathic arthritis, and iatrogenic cytokine release syndrome. The anti-IL-6R antibody sarilumab (KEVZARA®) has been approved for the treatment of adult patients with moderate to severe active rheumatoid arthritis. Other exemplary anti-IL6R antibodies include bovalilizumab and revalimuab (BCD-089). For example, the IL-6 antibody clazakizumab (BMS-945429, ALD518) is a humanized rabbit anti-IL-6 antibody that also acts as an IL-6 inhibitor. Other exemplary anti-IL-6 antibodies include ziltibeximab, siltuximab (SYLVIANT™), olokizumab (CDP6038), elcilimomab, and sirukumab (CNTO 136).

[0007] Myocarditis is inflammation of the myocardium (myocardium). Histopathologically, myocarditis is characterized by inflammatory cell infiltration (which may be focal or diffuse) with or without myocardial cell injury. See, for example, Non-Patent Document 3; Non-Patent Document 4. Myocarditis has various causes, such as viral infections or autoimmune conditions, as well as certain drug or vaccine regimens. After exposure to a causative agent or condition, (sub)acute myocarditis may occur in some cases within the first few weeks or months. Acute or subacute myocarditis may progress to chronic myocarditis in some cases.

[0008] To the applicant's knowledge, no clinical trials have been reported using anti-IL-6 antibodies to treat myocarditis, particularly acute or subacute myocarditis, or to prevent chronic myocarditis. [Prior art documents] [Non-patent literature]

[0009] [Non-Patent Document 1] Papassotiropoulos et al., Neurobiology of Aging, 22:863-871 (2001) [Non-patent document 2] Jones, SA, J.Immunology, 175:3463~3468 (2005) [Non-patent document 3] Aretz et al., Myocarditis. A histopathologic definition and classification, Am J Cardiovasc Pathol, pp. 1:3-14 (1987) [Non-patent document 4] Ammirati et al., Management of acute myocarditis and chronic inflammatory cardiomyopathy: an expert consensus document. Circ Heart Fail pp. 663-87 (2020) Summary of the Invention [Problem to be solved by the invention]

[0010] There is a need in the art for improved methods for treating myocarditis, particularly acute and subacute myocarditis. Interleukin-6 (IL-6) is a cytokine that has a strong stimulatory effect on B cells and plasma cells, and in cooperation with other cytokines, is responsible for normal antibody production. IL-6 also has a strong stimulatory effect on T cell-mediated inflammatory processes. The present disclosure relates to the use of anti-IL-6 monoclonal antibodies (mAbs), such as clazakizumab or diltibekimab, or anti-IL6R antibodies, for the treatment of myocarditis. [Means for solving the problem]

[0011] The present disclosure provides, inter alia, a method for treating myocarditis in a human subject in need thereof, comprising subcutaneously or intravenously administering a therapeutically effective amount of an anti-IL-6 antibody to the human subject once every four weeks or once monthly.

[0012] The present disclosure also provides the use of an anti-IL-6 antibody for treating myocarditis in a human subject in need thereof, wherein a therapeutically effective amount of the antibody is administered subcutaneously or intravenously to the human subject once every four weeks or once a month.

[0013] In some embodiments, the antibody comprises a variable light chain (VL) polypeptide comprising the complementarity determining regions (CDRs) of SEQ ID NOs: 4, 5, and 6, and a variable heavy chain (VH) polypeptide comprising the CDRs of SEQ ID NOs: 7, 8, or 120, and 9.

[0014] In some embodiments, the antibody comprises a heavy chain polypeptide of SEQ ID NO:704 and a light chain polypeptide of SEQ ID NO:702.

[0015] In some embodiments, the antibody comprises a human IgG1 constant region.

[0016] In some embodiments, the antibody is clazakizumab.

[0017] In some embodiments, the antibody is administered subcutaneously.

[0018] In some embodiments, the antibody is administered intravenously.

[0019] In some embodiments, the antibody is administered at a dose of 0.3 to 100 mg, 1 to 60 mg, 2 to 25 mg, 3 to 15 mg, or 5 to 10 mg.

[0020] In some embodiments, the antibody is administered at a dose of 3, 4, 5, 6, 7, 8, 9, 10, 12, 12.5, 15, 20, 24, 25, 36, 40, 60 or 100 mg.

[0021] In some embodiments, the antibody is administered at a dose of 5 mg, 10 mg, 12.5 mg, or 25 mg.

[0022] In some embodiments, the antibody is administered for at least 4, 6, 9, 10, 12, 14, 16, 18, 20, 22, 24, or 36 months.

[0023] In some embodiments, the antibody is clazakizumab and is administered subcutaneously or intravenously at a dose of 5 to 12.5 mg every four weeks or monthly, optionally for a period of at least three months, at least six months, at least nine months, at least one year, or at least two years.

[0024] In some embodiments, the human subject has elevated serum C-reactive protein (CRP) levels before treatment, optionally the CRP levels are determined by an hs-CRP test.

[0025] In some embodiments, the human subject has a pre-treatment CRP level of at least 2, 4, 6, or 10 mg / L.

[0026] In some embodiments, the human subject has elevated serum IL-6 levels before treatment.

[0027] In some embodiments, the pre-treatment serum IL-6 level is at least 2, 4, 5, or 10 ng / L.

[0028] In some embodiments, post-treatment CRP levels are reduced by at least 50%, 70%, 80%, or 90% compared to pre-treatment CRP levels.

[0029] In some embodiments, the method or use further comprises determining the level of serum IL-6 or serum CRP at least once after treatment.

[0030] In some embodiments, the human subject prior to treatment has been diagnosed with reduced ejection fraction (less than or equal to 45%), ventricular arrhythmia such as sustained ventricular arrhythmia, heart failure, chest pain, and / or cardiogenic shock.

[0031] In some embodiments, the method further comprises administration of at least one other therapeutic agent.

[0032] In some embodiments, the at least one other therapeutic agent comprises a corticosteroid, an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin II receptor blocker (ARB), a beta-blocker, intravenous IgG (IVIG), subcutaneous IgG (SCIG), and / or a diuretic.

[0033] In some embodiments, the myocarditis is caused by one or more of a viral infection, a bacterial infection, a fungal infection, a parasite, one or more medicines, drugs, toxins or chemicals, radiation, an autoimmune disease or other inflammatory disease, or an insect or other animal bite or sting.

[0034] In some embodiments, the myocarditis is caused by a viral infection.

[0035] In some embodiments, the myocarditis is caused by an autoimmune disease.

[0036] In some embodiments, the myocarditis is (sub)acute myocarditis and / or early myocarditis, in particular early sub(acute) myocarditis.

[0037] In some embodiments, the myocarditis is acute myocarditis.

[0038] In some embodiments, the myocarditis is subacute myocarditis.

[0039] In some embodiments, the human subject does not have an active viral infection.

[0040] The present disclosure also provides a method of treating acute or subacute myocarditis (i.e., (sub)acute myocarditis) caused by a viral infection or an autoimmune disease in a human subject in need thereof, comprising subcutaneously or intravenously administering clazakizumab at a dose of less than 30 mg to the human subject every four weeks or monthly.

[0041] In some embodiments, the dose of clazakizumab is less than or equal to 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 12.5, 15, 20, or 25 mg.

[0042] In some embodiments, the dose of clazakizumab is 5 to 25 mg or 5 to 12.5 mg.

[0043] In some embodiments, clazakizumab is administered for a period of at least 3 months, at least 6 months, at least 9 months, or at least 1 year.

[0044] In some embodiments, the human subject prior to treatment has been diagnosed with reduced ejection fraction (less than or equal to 45%), ventricular arrhythmia (such as sustained ventricular arrhythmia), heart failure, chest pain, and / or cardiogenic shock.

[0045] In some embodiments, treatment includes long-term care.

[0046] In some embodiments, the human subject does not have an active viral infection.

[0047] It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the scope of the claims. [Brief explanation of the drawings]

[0048] [Figure 1] This figure shows an outline of an experiment in a mouse model of experimental autoimmune myocarditis (EAM) in disease-susceptible BALB / c mice. Mice received subcutaneous booster immunizations of 100 μg of MyHCα 614-629 emulsified in CFA on days 0 and 7, as previously described. See Cihacova et al., Am J Pathol. 2008 May; 172(5):1195-1208. Randomized mice were treated with an isotype control (25 mg / kg) or a mouse anti-IL-6 antibody (5 mg / kg or 25 mg / kg) on ​​days 7, 10, 14, 21, 28, and 35 and sacrificed on day 42 after the first immunization. Echocardiography was performed on days 0, 7, 14, 21, 28, 35, and 42 after immunization. [Figure 2]Percent change in body weight over time (days 0–43) is shown for BALB / c mice treated with 5 mg / kg or 25 mg / kg anti-IL-6 compared to isotype control. Statistical test: two-way ANOVA with Dunnett's multiple comparisons. Asterisks indicate significant differences compared to isotype control in post-hoc analysis (***P<0.001, **P=0.001, *P=0.01). The first row of underlined asterisks corresponds to the 5 mg / kg anti-IL-6 treatment group, and the second row of asterisks corresponds to the 25 mg / kg anti-IL-6 treatment group, which are statistically significantly different compared to isotype in post-hoc analysis. Based on percent change in body weight compared to day 0, treatment with either dose of anti-IL-6 significantly prevents weight loss on days 10 and 14 (i.e., during the acute phase of disease) in the EAM model. Treatment with low dose anti-IL-6 (5 mg / kg) significantly prevents weight loss on day 21 in EAM. [Figure 3-1] Figures 3A-3E show typical measurements of heart weight (HW) per body weight (BW) (Figure 3A), HW per tibia length (TL) (Figure 3B), HW per spleen weight (SPL) (Figure 3C), SPL per BW (Figure 3D), and SPL per TL (Figure 3E) for the 5 or 25 mg / kg anti-IL-6 groups compared to the isotype control (*P<0.05, **P<0.01, Tukey's multiple comparison test). [Figure 3-2] Same as above. [Figure 4] Semiquantitative assessment of myocardial fibrosis at day 42 in mice treated with 5 mg / kg or 25 mg / kg anti-IL-6 antibody compared to isotype control treatment is shown. [Figure 5A] Ejection fraction (EF) (Figure 5A) and fractional shortening (FS) (Figure 5B) measured by echocardiography are shown, respectively. Asterisks indicate significant differences in post-hoc analysis comparing the 5 mg / kg and 25 mg / kg anti-IL-6 groups with the isotype control (*P<0.05, **P≤0.01, ***P≤0.001). [Figure 5B]Ejection fraction (EF) (Figure 5A) and fractional shortening (FS) (Figure 5B) measured by echocardiography are shown, respectively. Asterisks indicate significant differences in post-hoc analysis comparing the 5 mg / kg and 25 mg / kg anti-IL-6 groups with the isotype control (*P<0.05, **P≤0.01, ***P≤0.001). [Figure 6A] Multiple comparisons of left ventricular diameter (LVID) are shown. Figure 6A shows the change in end-diastolic LVID (LVID; d) from day 0 to day 42 in all treatment groups, and Figure 6B shows the change in end-systolic LVID (LVID; s). Asterisks indicate significant differences in post-hoc analysis comparing the 5 mg / kg and 25 mg / kg anti-IL-6 groups with the isotype control (*P<0.05, **P≦0.01). [Figure 6B] Multiple comparisons of left ventricular diameter (LVID) are shown. Figure 6A shows the change in end-diastolic LVID (LVID; d) from day 0 to day 42 in all treatment groups, and Figure 6B shows the change in end-systolic LVID (LVID; s). Asterisks indicate significant differences in post-hoc analysis comparing the 5 mg / kg and 25 mg / kg anti-IL-6 groups with the isotype control (*P<0.05, **P≦0.01). [Figure 7A] Multiple comparisons are shown for end-diastolic (IVS; d) (Figure 7A) and end-systolic (IVS; s) (Figure 7B) interventricular septum (IVS) changes in all treatment groups from day 0 to day 42. Asterisks indicate significant differences in the 5 mg / kg anti-IL-6 group compared to the isotype control in post-hoc analysis in Figure 7B (*P<0.05, **P≦0.01, ***P≦0.001). [Figure 7B] Multiple comparisons are shown for end-diastolic (IVS; d) (Figure 7A) and end-systolic (IVS; s) (Figure 7B) interventricular septum (IVS) changes in all treatment groups from day 0 to day 42. Asterisks indicate significant differences in the 5 mg / kg anti-IL-6 group compared to the isotype control in post-hoc analysis in Figure 7B (*P<0.05, **P≦0.01, ***P≦0.001). [Figure 8A]Multiple comparisons of left ventricular posterior wall (LVPW) thickness at end-diastole (LVPW; d) (FIG. 8A) and end-systole (LVPW; s) (FIG. 8B) across all treatment groups are shown. No differences were observed in LVPW following treatment with anti-IL-6 antibody. [Figure 8B] Multiple comparisons of left ventricular posterior wall (LVPW) thickness at end-diastole (LVPW; d) (FIG. 8A) and end-systole (LVPW; s) (FIG. 8B) across all treatment groups are shown. No differences were observed in LVPW following treatment with anti-IL-6 antibody. [Figure 9] Plasma levels of mouse IL-6 after treatment with isotype control or anti-IL-6 antibody are shown (****P<0.0001). [Figure 10-1] Figures 10A-10D show plasma levels of C-reactive protein (CRP, a surrogate marker for IL-6) (Figure 10A), anti-myosin IgG (Figure 10B), serum amyloid A (SAA) (Figure 10C), and anti-troponin IgG (Figure 10D) (**P<0.01, ***P<0.001, ****P<0.0001). [Figure 10-2] Same as above. [Figure 11-1] Figures 11A-11D show plasma levels of the inflammatory cytokines granulocyte-macrophage colony-stimulating factor (GM-CSF) (Figure 11A), interleukin-1A (IL-1A) (Figure 11B), IL-1B (Figure 11C), and TNFα (Figure 11D) (***P≦0.001). [Figure 11-2] Same as above. [Figure 12] 12A-12C show plasma levels of T cell cytokines IL-2 (FIG. 12A), IL-7 (FIG. 12B), and IL-10 (FIG. 12C). [Figure 13A]Figure 13 shows plasma levels of helper T cell cytokines. Figure 13A shows plasma levels of type 1 helper T cell-associated cytokines IFNγ and IL-12, Figure 13B shows plasma levels of type 2 helper T cell-associated cytokines IL-4, IL-5, and IL-13, and Figure 13C shows plasma levels of type 3 helper T cell-associated cytokine IL-17A (*P<0.05, ***P<0.001). [Figure 13B] Figure 13 shows plasma levels of helper T cell cytokines. Figure 13A shows plasma levels of type 1 helper T cell-associated cytokines IFNγ and IL-12, Figure 13B shows plasma levels of type 2 helper T cell-associated cytokines IL-4, IL-5, and IL-13, and Figure 13C shows plasma levels of type 3 helper T cell-associated cytokine IL-17A (*P<0.05, ***P<0.001). [Figure 13C] Figure 13 shows plasma levels of helper T cell cytokines. Figure 13A shows plasma levels of type 1 helper T cell-associated cytokines IFNγ and IL-12, Figure 13B shows plasma levels of type 2 helper T cell-associated cytokines IL-4, IL-5, and IL-13, and Figure 13C shows plasma levels of type 3 helper T cell-associated cytokine IL-17A (*P<0.05, ***P<0.001). [Figure 14-1] Figures 14A-14E show plasma levels of the chemokines CXCL1 (KC) (Figure 14A), CXCL2 (MIP-2) (Figure 14B), CXCL5 (LIX) (Figure 14C), CCL2 (MCP-1) (Figure 14D), and CXCL16 (Figure 14E). [Figure 14-2] Same as above. [Figure 15-1] 15A-15D show plasma levels of follistatin (FIG. 15A), placental growth factor 2 (PlGF-2) (FIG. 15B), NT-proBNP (FIG. 15C), and fibrinogen (FIG. 15D). [Figure 15-2] Same as above. DETAILED DESCRIPTION OF THE INVENTION

[0049] As outlined above, there is a need in the art for improved methods for treating myocarditis. Interleukin-6 (IL-6) is a cytokine that has a potent stimulatory effect on B cells and plasma cells, and in conjunction with other cytokines, is responsible for normal antibody production. IL-6 also has a potent stimulatory effect on T cell-mediated inflammatory processes. The present disclosure relates to the use of anti-IL-6 antibodies (mAbs), such as clazakizumab or diltibekimab, or anti-IL-6R antibodies, for the treatment of myocarditis.

[0050] definition It is understood that this disclosure is not limited to the particular methodology, protocols, cell lines, animal species or genera, and reagents described, as these may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the disclosure, which will be limited only by the appended claims.

[0051] As used herein, the term "about" refers to numerical values, including, for example, integers, fractions, and percentages, whether or not explicitly stated. The term "about" generally refers to a range of numerical values ​​(e.g., + / - 5 to 10% of the recited range) that one of ordinary skill in the art would consider equivalent to the recited value (e.g., having the same function or result). When a term such as "at least" or "about" appears before a list of numerical values ​​or ranges, the term modifies all of the values ​​or ranges provided in the list. In some instances, the term "about" may include numerical values ​​rounded to the nearest significant figure.

[0052] As used herein, the singular forms "a," "and," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, a reference to "a cell" includes a plurality of such cells, and a reference to "the protein" includes a reference to one or more proteins and equivalents thereof known to those skilled in the art, and so forth. All technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs, unless clearly indicated otherwise.

[0053] In this disclosure, the words "comprises," "comprising," "containing," "having," "includes," "including," and linguistic variations thereof have the meanings given them in U.S. patent law and permit the presence of additional components other than those expressly listed.

[0054] In this application, the use of "or" means "and / or" unless specifically stated otherwise. In the context of a multiple dependent claim, the use of "or" refers back to two or more preceding independent or dependent claims, in the alternative only. Also, terms such as "element" or "component" encompass both elements and components comprising a single unit and elements and components comprising two or more subunits, unless specifically stated otherwise.

[0055] As used herein, "myocarditis" refers to inflammation of the heart muscle (myocardium). Myocarditis can be divided into subtypes, such as acute myocarditis, subacute myocarditis, and chronic myocarditis.

[0056] "Acute myocarditis" is defined by Caforio, Eur. Heart J., 34:2636-48 (2013) as the first stage of myocarditis progression (see, e.g., Figure 2 of Caforio, which refers to Stage I) that occurs after exposure to a causative agent or condition. One type of acute myocarditis is "fulminant myocarditis" (FM), which is characterized by rapid, severe, diffuse myocarditis and requires hemodynamic support.

[0057] "Subacute myocarditis" is the second stage of myocarditis progression, characterized, for example, by progressive inflammation, in some cases driven by an adaptive immune response (see Figure 2 of Caforio, which refers to Stage II; see also Sozzi et al., Frontiers Cardiovasc. Med. Vol. 9, Article 908663 (2022) doi:10.3389 / fcvm.2022.908663).

[0058] "(Sub)acute myocarditis" is used herein as a general term to refer to subacute myocarditis and / or acute myocarditis, ie to encompass both of these forms of myocarditis.

[0059] Furthermore, the term "early myocarditis" is used herein to refer to myocarditis (regardless of the type of myocarditis) characterized by a time period from symptom onset to diagnosis of less than six months, particularly less than three months. The present disclosure also particularly relates to the treatment of (sub)acute early myocarditis (also referred to as "early subacute myocarditis"). In some embodiments, the early myocarditis can be acute myocarditis. In some embodiments, treatment continues beyond the period of early myocarditis, for example, at least six months, at least nine months, at least one year, or at least two years, or longer.

[0060] When myocarditis symptoms persist for an extended period of time (eg, more than six months from symptom onset), the disease process can be considered "chronic myocarditis" or "chronic inflammatory cardiomyopathy."

[0061] As used herein, the terms "treat," "treating," "treatment," and the like include alleviating, managing, or ameliorating a disorder, such as myocarditis, and / or at least one sign or symptom associated therewith, or slowing or halting the progression of the disorder or one or more of its signs or symptoms. It will be understood that treating a disorder or condition does not require, but does not preclude, the complete elimination of the disorder, condition, or symptom associated therewith. It will also be understood that treatment is often initiated after the onset of myocarditis, particularly after a diagnosis of subacute or acute myocarditis. In some embodiments, treatment may also include "long-term care," which, as described herein, is understood as medical care or treatment for more than six months, particularly more than one year (as opposed to acute care, which involves short-term administration of a few days or weeks, i.e., less than six months). Treatment of a first condition may encompass prevention of another condition; for example, treatment in the acute phase may prevent progression of myocarditis to the chronic phase. Treatment may also, in some cases, include prevention of progression to chronic myocarditis.

[0062] As used herein, the terms "prevent", "preventing", "prevention", "prophylaxis" and the like refer to reducing or delaying, particularly avoiding, the occurrence of myocarditis or a type or stage of myocarditis or the appearance of at least one symptom.In some cases, in subjects with acute or subacute myocarditis, this may be, for example, the prevention of chronic myocarditis, dilated cardiomyopathy or heart failure.In other cases, for example, in subjects with viral disease or autoimmune disease, prevention may include preventing the appearance of one or more symptoms or signs of myocarditis or a specific stage of myocarditis.

[0063] A "therapeutically effective amount" refers to the amount of a drug sufficient to provide a therapeutic effect in a human subject, e.g., alleviating at least one symptom of a condition or disease, reducing or slowing its progression, or preventing the onset of at least one symptom thereof. A "prophylactically effective amount" refers to the amount of a drug sufficient to provide a prophylactic effect, e.g., preventing the onset of at least one symptom of a condition or disease in a subject at risk of developing the condition or disease.

[0064] A "subject" or "patient" or "individual" to be treated herein refers to a human who has either been diagnosed with myocarditis or has risk factors for developing myocarditis, such as a viral disease or suspected viral disease or an autoimmune disease.

[0065] As used herein, "pre-treatment," e.g., in the context of measuring the level of a marker in a patient, e.g., C-reactive protein (CRP), high-sensitivity CRP (hs-CRP), or determining some other indicator of the patient's condition, means before the first administration of an IL-6 antibody according to the methods described herein. Pre-treatment does not exclude, and in many cases includes, prior administration of a treatment separate from the IL-6 antibody.

[0066] As used herein, "post-treatment" in this context means after administration of an IL-6 antibody according to the methods described herein. Post-treatment includes after any administration of an IL-6 antibody at any dosage described herein. Post-treatment also includes after the IL-6 antibody treatment phase.

[0067] The term "biological sample" refers to any tissue, cell, body fluid, or other material derived from an organism (e.g., a human subject). In certain embodiments, the biological sample is serum or blood.

[0068] The term "antibody" as used herein refers to a molecule comprising at least complementarity-determining regions (CDRs) 1, 2, and 3 of a heavy chain and at least CDRs 1, 2, and 3 of a light chain, and capable of binding to an antigen. This term is used in the broadest sense and encompasses a variety of antibody structures, including, but not limited to, monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies, diabodies, etc.), full-length antibodies, single-chain antibodies, antibody conjugates, and antibody fragments, so long as they exhibit the desired TREM2-specific binding activity. Thus, the term "antibody" includes "antibody fragments" or "antigen-binding fragments," as well as full-length antibodies of any immunoglobulin class, and bispecific or multispecific antibodies. For example, the term "antibody" is intended to include any polypeptide chain-containing molecular structure having a specific shape that adapts to and recognizes an epitope, where one or more noncovalent interactions stabilize the complex between the molecular structure and the epitope. The prototypical antibody molecule is an immunoglobulin, and all types of immunoglobulins, IgG, IgM, IgA, IgE, IgD, etc., from all sources, e.g., human, rodent, rabbit, bovine, ovine, porcine, canine, other mammalian, chicken, other avian, etc., are considered to be "antibodies." Examples include chimeric antibodies, humanized antibodies, single-chain antibodies such as scFv, camelbodies, nanobodies, IgNAR (single-chain antibody derived from shark), small modular immunotherapeutics (SMIPs), and F ab , F ab’ , F (ab’)2Examples include antibody fragments such as those described above. Streltsov et al., "Structure of a shark IgNAR antibody variable domain and modeling of an early-developmental isotype," Protein Sci. 2005 November;14(11):2901-2909. Epub 2005 September 30; Greenberg et al., "A new antigen receptor gene family that undergoes rearrangement and extensive somatic diversification in sharks," Nature. 1995 March 9;374(6518):168-73; Nuttall et al., "Isolation of the new antigen receptor from wobbegong sharks and use as a scaffold for the display of protein loop libraries," Mol Immunol. 2001 August;38(4):313-26; Hamers-Casterman et al., "Naturally occurring antibodies devoid of light chains," Nature. 1993 Jun 3;363(6428):446-8; and Gill et al., Biopharmaceutical drug discovery using novel protein scaffolds, Curr Opin Biotechnol. 2006 Dec;17(6):653-8. Epub 2006 Oct 19. Unless otherwise specified, numbering of antibody constant region residues is according to the EU index as in Kabat.

[0069] As used herein, an "anti-interleukin-6 antibody" (used interchangeably: "anti-IL-6 antibody" and "IL-6 antibody") is an antibody that has the ability to bind to and antagonize IL-6, particularly human IL-6. Similarly, as used herein, an "anti-interleukin-6R antibody" (used interchangeably: "anti-IL-6R antibody" and "IL-6R antibody") is an antibody that has the ability to inhibit IL-6 signaling through the IL-6 receptor by binding to IL-6R, particularly human IL-6R. Both anti-IL-6 antibodies and anti-IL-6R antibodies antagonize IL-6 signaling. When the present disclosure refers to an "antibody," it is an anti-IL-6 antibody or an anti-IL-6R antibody, particularly an anti-IL-6 antibody, unless expressly specified otherwise or unless the context dictates so.

[0070] For example, antibodies (including antibody fragments or antigen-binding fragments) can be produced by genetic engineering. Similar to other methods, this technique involves sensitizing antibody-producing cells to the desired antigen or immunogen. Messenger RNA isolated from the antibody-producing cells is used as a template to generate cDNA using PCR amplification. A library of vectors containing one heavy chain gene and one light chain gene, each retaining the original antigen specificity, is created by inserting appropriate segments of the amplified immunoglobulin cDNA into an expression vector. A combinatorial library is constructed by combining the heavy chain gene library with the light chain gene library. This results in a library of clones co-expressing heavy and light chains (similar to Fab fragments or antigen-binding fragments of antibody molecules). The vectors carrying these genes are co-transfected into host cells. Upon induction of antibody gene synthesis in the transfected host, the heavy and light chain proteins self-assemble to generate active antibodies that can be detected by screening with the antigen or immunogen.

[0071] Antibody coding sequences of interest include those encoded by native sequences, as well as nucleic acids that are not identical in sequence to the disclosed nucleic acids due to the degeneracy of the genetic code, and variants thereof. Variant polypeptides may contain amino acid (aa) substitutions, additions, or deletions. Amino acid substitutions may be conservative or may be substitutions to eliminate non-essential amino acids, for example, to alter glycosylation sites or to minimize misfolding by substituting or deleting one or more cysteine ​​residues not required for function. Variants can be designed to retain or have enhanced biological activity of specific regions of the protein (e.g., functional domains, catalytic amino acid residues, etc.). Variants also include fragments of the polypeptides disclosed herein, particularly biologically active fragments and / or fragments corresponding to functional domains. Techniques for in vitro mutagenesis of cloned genes are known. Polypeptides modified using routine molecular biology techniques to improve their resistance to proteolysis, optimize solubility properties, or make them more suitable as therapeutic agents are also included in the present disclosure.

[0072] Chimeric antibodies can be produced by recombinant means by combining variable light and heavy chain regions (VL and VH) obtained from antibody-producing cells of one species with constant light and heavy chain regions from another species. Typically, chimeric antibodies utilize rodent or rabbit variable regions and human constant regions to produce an antibody with primarily human domains. The production of such chimeric antibodies is well known in the art and can be accomplished by standard means (e.g., as described in U.S. Pat. No. 5,624,659, incorporated herein by reference in its entirety). It is further envisioned that the human constant region of the chimeric antibodies of the present disclosure will be selected from IgG1, IgG2, IgG3, IgG4, IgG5, IgG6, IgG7, IgG8, IgG9, IgG10, IgG11, IgG12, IgG13, IgG14, IgG15, IgG16, IgG17, IgG18, or IgG19 constant regions.

[0073] Humanized antibodies are engineered to contain more human-like immunoglobulin domains and incorporate only the complementarity-determining regions of the animal-derived antibody. This is accomplished by carefully examining the sequence of the hypervariable loops of the variable regions of a monoclonal antibody and adapting it to the structure of human antibody chains. While superficially complex, the process is actually straightforward. See, for example, U.S. Patent No. 6,187,287, incorporated herein by reference in its entirety.

[0074] In addition to whole immunoglobulins (or their recombinant counterparts), immunoglobulin fragments (e.g., Fab', F(ab')2, or other fragments) containing epitope-binding sites can also be synthesized. "Fragments" or minimal immunoglobulins can be engineered using recombinant immunoglobulin technology. For example, "Fv" immunoglobulins for use in the present disclosure can be made by synthesizing fused variable light and heavy chain regions. Combinations of antibodies, such as diabodies containing two different Fv specificities, are also of interest. In another embodiment of the present disclosure, SMIPs (small molecule immunopharmaceuticals), camelbodies, nanobodies, and IgNARs are included in the scope of immunoglobulin fragments.

[0075] Immunoglobulins and fragments thereof can be post-translationally modified to add, for example, effector moieties such as chemical linkers, detectable moieties such as fluorochromes, enzymes, toxins, substrates, bioluminescent, radioactive, chemiluminescent moieties, or specific binding moieties such as streptavidin, avidin, or biotin, and can be utilized in the methods and compositions of the disclosure. Additional exemplary effector molecules are provided below.

[0076] The general structure of antibodies in vertebrates is now well understood. See Edelman, GM, Ann. NY Acad. Sci., 190:5 (1971). Antibodies consist of two identical light polypeptide chains ("light chains") with a molecular weight of approximately 23,000 daltons and two identical heavy chains ("heavy chains") with a molecular weight of 53,000-70,000. The four chains are linked by disulfide bonds in a "Y" configuration, with the light chains beginning at the open end of the "Y" configuration and sandwiching the heavy chains. The "branch" portion of the "Y" configuration is called the Fab region; the stem portion of the "Y" configuration is called the Fc region. The amino acid sequence runs from the N-terminus at the top of the "Y" configuration to the C-terminus at the bottom of each chain. The N-terminus contains a variable region with specificity for the antigen that elicited it; it is approximately 100 amino acids in length and varies slightly between light and heavy chains and from antibody to antibody.

[0077] The variable region is joined in each chain to a constant region that extends the remainder of the chain and does not vary with the specificity of the antibody (i.e., the antigen that elicited it) within a particular class of antibody. Five major classes of constant regions are known that determine the class of immunoglobulin molecule (IgG, IgM, IgA, IgD, and IgE, corresponding to the γ, μ, α, δ, and ε (gamma, mu, alpha, delta, or epsilon) heavy chain constant regions). The constant region or class determines the antibody's subsequent effector functions, including complement activation (Kabat, E. A., Structural Concepts in Immunology and Immunochemistry, 2nd ed., pp. 413-436; Holt, Rinehart, and Winston (1976)) and other cellular responses (Andrews et al., Clinical Immunobiology, pp. 1-18; W. B. Sanders (1980); Kohl et al., Immunology, 48:187 (1983)); whereas, the variable region determines the antigen with which it reacts. Light chains are classified as either kappa (κ) or lambda (λ). Each heavy chain class can pair with either kappa or lambda light chains. Light and heavy chains are covalently linked to each other, and when immunoglobulins are produced by either hybridomas or B cells, the "tail" portions of the two heavy chains are linked to each other by covalent disulfide bonds.

[0078] The term "variable region" or "VR" refers to the domain within each pair of light and heavy chains in an antibody that is directly involved in binding the antibody to an antigen. Each heavy chain has a variable domain (VH) at one end followed by several constant domains. Each light chain has a variable domain (VL) at one end and a constant domain at the other end; the constant domain of the light chain is aligned with the first constant domain of the heavy chain, and the light chain variable domain is aligned with the variable domain of the heavy chain.

[0079] The terms "complementarity-determining region," "hypervariable region," or "CDR" refer to one or more hypervariable or complementarity-determining regions (CDRs) found in the variable region of an antibody's light or heavy chain. See Kabat et al., "Sequences of Proteins of Immunological Interest," National Institutes of Health, Bethesda, MD (1987). These terms include the hypervariable regions as defined by Kabat et al. ("Sequences of Proteins of Immunological Interest," Kabat E. et al., US Dept. of Health and Human Services, 1983), or the hypervariable loops in the three-dimensional structure of an antibody (Chothia and Lesk, J. Mol. Biol. 196:901-917 (1987)). The CDRs of each chain are held in close proximity by framework regions and, together with the CDRs from the other chain, contribute to the formation of the antigen-binding site. Within the CDRs are selective amino acids described as selectivity determining regions (SDRs), which are important contact residues used by the CDRs in antibody-antigen interactions (see Kashmiri, S., Methods, 36:25-34 (2005)).

[0080] The terms "framework region" or "FR" refer to one or more of the framework regions in the light and heavy chain variable regions of an antibody. See Kabat et al., Sequences of Proteins of Immunological Interest, National Institutes of Health, Bethesda, MD (1987). These terms include the amino acid sequence regions intervening between the CDRs in the light and heavy chain variable regions of an antibody. Generally, each heavy and light chain variable region comprises the following series of FR and CDR elements: FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4. Antigen-binding fragments, such as Fvs and others, typically comprise all three CDRs, as well as the intervening framework regions FR2 and FR3, and at least a portion of FR1 and / or FR4.

[0081] An "isolated" antibody is one that has been separated from a component of its natural environment. In some embodiments, the antibody is purified to, for example, greater than 95% or greater than 99% purity, as determined, for example, by electrophoretic (e.g., SDS-PAGE, isoelectric focusing (IEF), capillary electrophoresis) or chromatographic (e.g., ion exchange or reverse-phase HPLC) methods. For a review of methods for assessing antibody purity, see, e.g., Flatman et al., J. Chromatogr. B 848:79-87 (2007).

[0082] "Interleukin-6 (IL-6)" is an indicator of systemic inflammation and metabolic dysfunction. The term refers to the naturally occurring human protein, unless otherwise clearly indicated. Wild-type human interleukin-6 (IL-6) is synthesized as a 212 amino acid precursor protein, which is subsequently cleaved to its active form. It is also understood that any pre-pro, pro, and mature forms of human IL-6 that have IL-6 biological activity, as well as naturally occurring mutants and variants, including allelic variants, are included within the scope of "interleukin-6 (IL-6)."

[0083] An exemplary 212 amino acid precursor sequence of human IL-6 is found in Uniprot No. P05231 (see the uniprot "dot" org website). This sequence is as follows: MNSFSTSAFGPVAFSLGLLLVLPAAFPAPVPPGEDSKDVAAPHRQPLTSSERIDKQIRYILDGISALRKETCNKSNMCESSKEALAENNLNLPKMAEKDGCFQSGFNEETCLVKIITGLLEFEVYLEYLQNRFESSEEQARAVQMSTKVLIQFLQKKAKNLDAITTPDPTTNASLLTKLQAQNQWLQDMTTHLILRSFKEFLQSSLRALRQM (SEQ ID NO: 647)

[0084] "Interleukin-6 receptor" or (IL-6R), as used herein, refers to a polypeptide comprising the amino acid sequence of a naturally occurring human IL-6R subunit a polypeptide or comprising the amino acid sequence of a naturally occurring human IL-6R subunit b (also referred to as glycoprotein 130 or gp130 or IL6ST) and / or IL-6R subunit a polypeptide, as well as naturally occurring mutants and variants, including allelic variants, of these sequences that have IL-6Ra and / or IL-6Rb activity. Exemplary biological activities of IL-6Ra include binding to IL-6, binding to glycoprotein 130 (gp130), and regulating cell proliferation and differentiation. Exemplary biological activities of IL-6Rb include binding to IL-6Ra, IL-6 receptor signaling activity, and regulating cell proliferation, differentiation, hepcidin expression, and the like. An exemplary amino acid sequence of human IL-6Ra is provided in NCBI Accession Nos. NP_000556 or NP_852004. An exemplary IL-6Ra sequence is provided in Uniprot P08887 and is as follows: MLAVGCALLAALLAAPGAALAPRRCPAQEVARGVLTSLPGDSVTLTCPGVEPEDNATVHWVLRKPAAGSHPSRWAGMGRRLLLRSVQLHDSGNYSCYRAGRPAGTVHLLVDVPPEEPQL SCFRKSPLSNVVCEWGPRSTPSLTTKAVLLVRKFQNSPAEDFQEPCQYSQESQKFSCQLAVPEGDSSFYIVSMCVASSVGSKFSKTQTFQGCGILQPDPPANITVTAVARNPRWLSVTW QDPHSWNSSFYRLRFELRYRAERSKTFTTWMVKDLQHHCVIHDAWSGLRHVVQLRAQEEFGQGEWSEWSPEAMGTPWTESRSPPAENEVSTPMQALTTNKDDDNILFRDSANATSLPVQDSSSVPLPTFLVAGGSLAFGTLLCIAIVLRFKKTWKLRALKEGKTSMHPPYSLGQLVPERPRPTPVLVPLISPPVSPSSLGSDNTSSHNRPDARDPRSPYDISNTDYFFPR (SEQ ID NO: 648)

[0085] The amino acid sequence of an exemplary human "glycoprotein 130 (gp130)" or "interleukin-6 receptor subunit b (IL-6Rb) polypeptide" is provided in NCBI accession numbers NP_002175, NP_786943, or NP_001 177910. An exemplary IL-6Rb amino acid sequence is provided in Uniprot P40189-1, which is as follows: (SEQ ID NO: 649)

[0086] Unless otherwise specified, "IL-6 antagonist" refers to an agent capable of reducing the biological activity of IL-6. IL-6 antagonists include agents that reduce serum IL-6 polypeptide levels, including agents that reduce the expression of IL-6 polypeptide or nucleic acid; agents that reduce the ability of IL-6 to bind to IL-6R; agents that reduce IL-6R expression; and agents that reduce signaling by the IL-6R receptor when IL-6 is bound. In some embodiments, the IL-6 antagonist reduces the biological activity of IL-6 by at least about 10%, 20%, 30%, 50%, 70%, 80%, 90%, 95%, or even 100%. As described further below, IL-6 antagonists include IL-6-binding polypeptides, such as anti-IL-6 antibodies and their antigen-binding fragments or derivatives; IL-6R-binding polypeptides, such as anti-IL-6R antibodies and their antigen-binding fragments or derivatives; and synthetic chemical molecules, such as JAK1 and JAK3 inhibitors. In some embodiments, the anti-IL-6 or anti-IL-6R antibody prevents the formation of a complex between IL-6 and IL-6R or one of its subunits, and / or prevents the formation of a complex between IL-6Ra and IL-6Rb. As used herein, "interleukin-6 receptor (IL-6R) complex" refers to the IL-6Ra-IL-6Rb complex. In some embodiments, the administered IL-6 antagonist antibody blocks the binding of IL-6 to the IL-6 receptor, gp130, or both the IL-6 receptor and gp130.

[0087] The term "C-reactive protein" or "CRP" refers to human CRP. CRP levels are elevated in response to inflammation and can be measured with the hsCRP (high sensitivity C-reactive protein) test. An exemplary CRP sequence is provided in NCBI accession number NP_000558.

[0088] In some embodiments, a human subject "does not have an active viral infection." As used herein, "does not have an active viral infection" refers to a subject that does not have a continuously detectable amount of viral activity. For example, in some embodiments, the subject does not have a detectable amount of infection involving adenovirus, SARS-CoV-2, hepatitis B and C, parvovirus, herpes simplex virus, or a combination thereof. In some embodiments, the subject does not have a detectable amount of adenovirus, parvovirus B19, coxsackievirus, rubella virus, poliovirus, Epstein-Barr virus, hepatitis C virus, influenza virus, and SARS-CoV-2 virus.

[0089] In some embodiments, the myocarditis is caused by a viral infection, but the virus level in the subject is decreasing and / or there is no active viral infection. In some embodiments, the myocarditis is caused by a viral infection, but the virus level in the subject has decreased by at least 10-fold from the peak level. In some embodiments, the subject is no longer contagious. In some embodiments, the myocarditis is not caused by a viral infection.

[0090] Treatment of myocarditis Myocarditis is inflammation of the heart muscle (myocardium). It can be caused by one or more of the following: a viral infection, a bacterial infection, a fungal infection, a parasite, one or more medicines, drugs, toxins, or chemicals, radiation, an autoimmune disease or other inflammatory disease, or an insect or other animal bite or sting. Symptoms of myocarditis include, but are not limited to, chest pain, fatigue, a fast or abnormal heart rhythm (arrhythmia), signs of infection, diarrhea, headache, fever, muscle pain, sore throat, shortness of breath, and swelling in the legs. Myocarditis can affect people of all ages. In some embodiments, the subject is an adult between the ages of 18 and 50. Myocarditis patients can also be adults (i.e., 18 years of age or older) or older, for example, over 18, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, or 75 years of age. In other embodiments, the subject is a pediatric subject (ie, under 18 years of age) with pediatric myocarditis.

[0091] Diagnosis of myocarditis is aided by, for example, blood tests, chest x-ray, electrocardiogram (ECG), echocardiogram, cardiac MRI, delayed gadolinium enhancement (LGE), and / or endomyocardial biopsy.

[0092] Myocarditis can exist in acute, subacute, and chronic forms. For example, in some subjects, acute or subacute myocarditis is characterized by a reduced ejection fraction (e.g., 45% or less), the presence of sustained ventricular arrhythmias, the presence of anti-cardiac antibodies (e.g., anti-myosin antibodies), elevated troponin (troponin I and T) levels, heart failure, chest pain, and / or cardiogenic shock. At the histopathological level, myocarditis is characterized by inflammatory cell infiltration (which may be focal or diffuse) with or without myocardial cell injury. Aretz et al., Myocarditis. A histopathologic definition and classification., Am J Cardiovasc Pathol, 1:3-14 (1987). The type of cellular infiltration can be used to classify myocarditis: - Lymphocytic myocarditis - associated with a range of pathogens (mainly viruses), drugs, radiation exposure and autoimmune disorders. -Eosinophilic myocarditis - a relatively rare form associated with parasitic infections, hypersensitivity reactions to various drugs, eosinophilic inflammatory disorders, and rarely neoplastic processes. -Giant cell myocarditis - Most cases are idiopathic, but may also be associated with certain autoimmune disorders, including autoimmune thyroid disease and inflammatory bowel disease. -Granulomatous myocarditis - associated with sarcoidosis.

[0093] See Ammirati et al., Management of acute myocarditis and chronic inflammatory cardio-myopathy: an expert consensus document. Circ Heart Fail, pp. 663-87 (2020). While myocarditis can be diagnosed or confirmed by such histological analysis of cardiac tissue (e.g., by biopsy) using a microscope to detect the presence of specific inflammatory cells, it should be understood that myocarditis can be (and often is) diagnosed based on symptoms, cardiac MRI, and other means as described above, without the need to obtain a sample of cardiac tissue.

[0094] In some cases, myocarditis, as used herein, occurs in conjunction with pericarditis, which is swelling and / or inflammation of the pericardium. In other cases, myocarditis is not accompanied by pericarditis.

[0095] Acute and subacute myocarditis are also associated with Th1 and Th17 immune responses in patients, as well as elevated serum levels of certain cytokines, such as IL-6, TGF-beta, IL-17, and GM-CSF, which may contribute to the Th17 immune response, compared to normal subjects. See, for example, Myers et al., JCI Insight 1(9):e85851 (2016); Savvatis et al., Basic Res Cardiology 109:449 (2014); Amioka et al., J Cardiology 78:157-65 (2021). In a study of six to seven human patients, IL-6 was also found to be expressed by infiltrating inflammatory cells in myocardial tissue in patients with acute myocarditis, suggesting that IL-6 released from inflammatory cells may cause cardiac damage by inducing and maintaining acute inflammation. Furthermore, serum IL-6 levels correlated with the presence of such infiltrating IL-6-expressing inflammatory cells. See Amioka et al. These studies suggest that IL-6 may be a target to consider in myocarditis, although to the applicant's knowledge, no human trials have been performed.

[0096] The present disclosure relates, inter alia, to a method for treating myocarditis, e.g., acute, subacute, or early myocarditis, by administering a therapeutically effective amount of an anti-IL-6 antibody or anti-IL-6R antibody, particularly an anti-IL-6 antibody. The present disclosure also relates, inter alia, to a method for treating (sub)acute and early myocarditis by administering a therapeutically effective amount of an anti-IL-6 antibody. In some cases, the anti-IL-6 antibody is administered to a subject at risk of developing myocarditis for the purpose of preventing myocarditis, reducing the severity of its symptoms, or delaying the onset of its symptoms.

[0097] In some embodiments, the anti-IL-6 antibody neutralizes IL-6. In some embodiments, the administered antibody is an anti-IL-6 antibody, e.g., an IL-6 antagonist antibody that blocks IL-6 binding to IL-6R (e.g., IL-6Ra or IL-6Rb, also known as gp130) by binding to IL-6. In some embodiments, the anti-IL-6 or IL-6R antibody is administered subcutaneously or intravenously. In some embodiments, the anti-IL-6 antibody is administered once every four weeks or once monthly. Exemplary IL-6 and IL-6R antibodies are described below and throughout this disclosure. In some embodiments, a prophylactically effective amount of an anti-IL-6 antibody or anti-IL-6R antibody, e.g., an anti-IL-6 antibody, can be administered to a human subject at risk of developing myocarditis, e.g., acute or subacute myocarditis, e.g., a subject diagnosed with a viral disease or autoimmune disease, for the purpose of, e.g., preventing the onset of myocarditis, or preventing the onset of at least one symptom of myocarditis, or reducing the severity of myocarditis if myocarditis occurs in the subject. In some embodiments, for example, a prophylactically effective amount of the antibody is administered to a subject with acute or subacute myocarditis to prevent the onset of chronic myocarditis.

[0098] In some cases, the subject being treated has been diagnosed with acute or subacute myocarditis based on tests revealing a reduced ejection fraction (e.g., 45% or less), the presence of sustained ventricular arrhythmias, heart failure, the presence of anti-cardiac antibodies (e.g., anti-myosin antibodies), elevated troponin (troponin I and T) levels, chest pain, and / or cardiogenic shock.

[0099] In some embodiments, an IL-6R antibody, e.g., an IL-6R antagonist antibody, is administered. Examples include tocilizumab (ACTEMRA®), sarilumab (KEVZARA®), isovalizumab, and revalimuab (BCD-089). In some embodiments, an IL-6 antibody, e.g., an IL-6 antagonist antibody, is administered. Exemplary IL-6 antibodies include clazakizumab (BMS-945429, ALD518), ziltibekimab, siltuximab (SYLVANT™), olokizumab (CDP6038), elcilimomab, and sirukumab (CNTO 136). In some embodiments, the antibody used in the method is clazakizumab. In some embodiments, the antibody used in the method is ziltibekimab.

[0100] In some embodiments, the anti-IL-6 antibody used in the claimed treatment methods comprises the VL CDRs of SEQ ID NOs: 4, 5, and 6 and the VH CDRs of SEQ ID NOs: 7, 8, or 120, and 9. In some cases, the antibody comprises the VL polypeptide of SEQ ID NO: 20 and / or the VH polypeptide of SEQ ID NO: 18 or 19, or a sequence at least 90%, at least 95%, or at least 97% identical to the VL polypeptide of SEQ ID NO: 20 and / or the VH polypeptide of SEQ ID NO: 18 or 19. In some cases, the anti-IL-6 antibody is a full-length antibody. In some cases, it is an antigen-binding fragment. In some cases, the antibody comprises a human IgG1 constant region. In some cases, the antibody comprises a light chain constant region polypeptide sequence comprising SEQ ID NO: 586 and a heavy chain constant region polypeptide sequence comprising SEQ ID NO: 588.

[0101] In some embodiments, the antibody is clazakizumab, which comprises the heavy and light chain sequences shown below: (Heavy chain) SEQ ID NO: 704 EVQLVESGGGLVQPGGSLRLSCAASGFSLSNYYVTWVRQAPGKGLEWVGIIYGSDETAYATSAIGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDDSSDWDAKFNLWGQ GTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDK THTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEK TISKAKGQPREPQVYTLPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (Light chain) SEQ ID NO: 702 AIQMTQSPSSLSASVGDRVTITCQASQSINNELSWYQQKPGKAPKLLIYRASTLASGVPSRFSGSGSGTDFLTISSLQPDDFATYYCQQGYSLRNIDNAFGGGTKVE IKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0102] Alternatively, in any of the treatment or detection methods of the present invention, the anti-IL-6 antibody may comprise the same CDRs as an anti-IL-6 antibody selected from the group consisting of Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, Ab20, Ab21, Ab22, Ab23, Ab24, Ab25, Ab26, Ab27, Ab28, Ab29, Ab30, Ab31, Ab32, Ab33, Ab34, Ab35, and Ab36 (described in the next section). For example, the anti-IL-6 antibody may comprise at least one VH polypeptide sequence selected from the group consisting of SEQ ID NOs: 3, 18, 19, 22, 38, 54, 70, 86, 102, 117, 118, 123, 139, 155, 171, 187, 203, 219, 235, 251, 267, 283, 299, 315, 331, 347, 363, 379, 395, 411, 427, 443, 459, 475, 491, 507, 523, 539, 555, and SEQ ID NO: 571; and SEQ ID NOs: 2, 20, 21, 37, 53, 69, 85, 101, 119, 122, 138, 154, 170, 186, 202, 218, 220, 222, 224, 226, 228, 229, 230, 231, 232, 233, 234, 235, 240, 242, 244, 246, 248, 249, 250, 252, 254, 256, 258, 260, 261, 262, 263, 264, 265, 266, 267, 283, 299, 315, 331, 347, 363, 379, 395, 411, 427 and SEQ ID NO: 570, or it comprises a humanized variant of any of the foregoing comprising at least one VH polypeptide and at least one VL polypeptide having at least 80, 90, 96, 96, 97, 98, 99 percent sequence identity to any of the foregoing VH or VL polypeptides.

[0103] In some embodiments, the anti-IL-6 antibody is administered subcutaneously, while in other embodiments, the anti-IL-6 antibody is administered intravenously. In some embodiments, the anti-IL-6 antibody is administered at a dose of 0.3 to 100 mg, 1 to 60 mg, 2 to 25 mg, 4 to 25 mg, 5 to 25 mg, 4 to 12.5 mg, or 5 to 12.5 mg. In some embodiments, the anti-IL-6 antibody is administered at a dose of 3, 4, 5, 6, 7, 8, 9, 10, 12, 12.5, 15, 20, 24, 25, 36, 40, 60, or 100 mg. In some embodiments, the anti-IL-6 antibody is administered at a dose of 4 to 25 mg. In some cases, the anti-IL-6 antibody is administered at a dose of 5 to 25 mg. In some embodiments, the anti-IL-6 antibody is administered at a dose of 5 mg, 12.5, or 25 mg. In some cases, the anti-IL-6 antibody is administered every 2 weeks, every 3 weeks, every 4 weeks, or every month, every 5 weeks, or every 6 weeks. In some cases, the antibody is administered every 4 weeks or every month. In some embodiments, the anti-IL-6 antibody in the above administration regimen is clazakizumab or diltibekimab.

[0104] In some cases, the anti-IL-6 antibody is clazakizumab and is administered subcutaneously or intravenously at a dose of 4 to 12.5 mg every four weeks or monthly. In some cases, the anti-IL-6 antibody is clazakizumab and is administered subcutaneously or intravenously at a dose of 5 to 25 mg every four weeks or monthly. In some cases, the anti-IL-6 antibody is clazakizumab and is administered subcutaneously or intravenously at a dose of 5 to 12.5 mg every four weeks or monthly. In some cases, the administration is continued for at least three months, at least six months, at least nine months, at least one year, or at least two years. In some cases, the administration is continued for at least one year. In some embodiments, clazakizumab is administered subcutaneously or intravenously at a dose of 0.3 to 25 mg every four weeks or monthly for at least six months, particularly at least one year. In some embodiments, doses of up to 15 mg are administered subcutaneously or intravenously every four weeks or monthly for at least six months, particularly at least one year.

[0105] The anti-IL-6 antibody may also be diltibekimab. In some embodiments, diltibekimab is administered subcutaneously or intravenously at a dose of 1 to 50 mg every four weeks or monthly. In some embodiments, diltibekimab is administered subcutaneously or intravenously at a dose of 2.5 to 25 mg every four weeks or monthly. In some embodiments, diltibekimab is administered subcutaneously or intravenously at a dose of 5 to 15 mg every four weeks or monthly. In some embodiments, administration of diltibekimab is continued for at least three months, at least six months, at least nine months, at least one year, or at least two years. In some embodiments, administration of diltibekimab is continued for at least one year. In some embodiments, diltibekimab is administered subcutaneously or intravenously at a dose of 1 to 20 mg every four weeks or monthly for at least six months, particularly at least one year. In some embodiments, ziltibekimab is administered subcutaneously or intravenously at a dose of 5-15 mg every four weeks or monthly for at least six months, particularly at least one year.

[0106] In some embodiments, the myocarditis is caused by one or more of a viral infection, a bacterial infection, a fungal infection, a parasite, one or more medicines, drugs, toxins or chemicals, radiation, an autoimmune disease or other inflammatory disease, or an insect or other animal bite or sting. In some cases, it is caused by a viral infection. In some cases, it is caused by an autoimmune disease. In some cases, it is acute myocarditis caused by, for example, a viral disease. In some cases, it is subacute myocarditis caused by, for example, an autoimmune condition.

[0107] In some embodiments, the method further includes determining the levels of IL-6 and / or C-reactive protein (CRP) (e.g., measured by a high-sensitivity CRP or hs-CRP test or other available test), leptin, IL-17, TGT-beta, GM-CSF, troponin (e.g., troponin-I and troponin-T), N-terminal pro-b-natriuretic peptide (NT-proBNP), specific cardiac autoantibodies, and / or TNF-alpha in a blood or serum sample from the patient. These levels can be detected in a subject-derived biological sample by known methods and compared with known levels in normal subjects. In some cases, myocarditis patients exhibit elevated pre-treatment IL-6 levels, e.g., elevated serum IL-6 levels. In some embodiments, the pre-treatment serum IL-6 level is at least 2, at least 4, at least 5, or at least 10 ng / L. In some embodiments, the serum level before treatment is at least 10%, at least 20%, at least 30% or more higher than normal, or even 0.5, 1, 1.5, 2, 3, 4, 5, 10 ng / L or more higher than normal. In some embodiments, an increase in the serum IL-6 level before treatment indicates that the patient should receive treatment with an anti-IL-6 antibody or an anti-IL-6R antibody. In some cases, the serum IL-6 level is determined not only before treatment but also after treatment, for example, once a week, once every two weeks, or once a month for 4 weeks after the start of treatment. In some cases, the serum IL-6 level decreases after treatment with an anti-IL-6 antibody or an anti-IL-6R antibody.

[0108] In addition, myocarditis patients may also have elevated C-reactive protein (CRP) (e.g., hs-CRP), elevated leptin, IL-17, TGT-beta, GM-CSF, troponin (e.g., troponin-I and troponin-T), NT-proBNP, specific cardiac autoantibodies, and / or elevated TNF-α levels in, for example, serum or blood samples. These proteins can also be detected in subject-derived biological samples by known methods, for example, ELISA assays, and the detected levels can be compared with normal levels. In some cases, CRP levels are determined not only before treatment but also after treatment, for example, once a week, once every two weeks, or once a month for 4 weeks after the start of treatment. In some cases, CRP levels decrease after treatment with anti-IL-6 antibody or anti-IL-6R antibody. In some cases, CRP levels after treatment are reduced by at least 50%, 70%, 80%, or 90% compared to pre-treatment CRP levels.

[0109] Any of the methods may further include administration of another antimyocarditis drug, such as a corticosteroid, an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin II receptor blocker (ARB), a beta-blocker, intravenous IgG (IVIG) or subcutaneous IgG (SCIG), and / or a diuretic. In some embodiments, the subject is further receiving an additional myocarditis treatment, such as mechanical support. Mechanical support includes, but is not limited to, extracorporeal membrane oxygenation (ECMO), an intra-aortic balloon pump (IABP), and / or hemodynamic stabilization (e.g., using a heart pump such as the IMPELLA® device (ABIOMED®, Massachusetts)).

[0110] In some embodiments, treatment of subacute or acute myocarditis encompasses prevention of chronic myocarditis. For example, in some cases, treatment of patients with (sub)acute and / or early myocarditis is intended to prevent the onset of chronic myocarditis or its sequelae.

[0111] Exemplary Anti-IL-6 Antibodies In addition to the anti-IL-6 and anti-IL-6R antibodies discussed above, the present disclosure includes antibodies that have binding specificity for IL-6 and have a variable light chain sequence comprising the sequence shown below: MDTRAPTQLLGLLLLWLPGARCAYDMTQTPASVSAAVGGTVTIKCQASQSINNELSWYQQKPGQRPKLLIYRASTLASGVSSRFKGSGSGTEFTLTISDLECADAATYYCQQGYSLRNIDNAFGGGTEVVVKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNN (SEQ ID NO: 2)

[0112] The present disclosure also includes antibodies that have binding specificity for IL-6 and have a variable heavy chain sequence comprising the sequence shown below: METGLRWLLLVAVLKGVQCQSLEESGGRLVTPGTPLTLTCTASGFSLSNYYVTWVRQAPGKGLEWIGIIYGSDETAYATWAIGRFTISKTSTTVDLKMTSLTAADTATYFCARDDSSDWDAKFNLWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVK (SEQ ID NO: 3)

[0113] The present disclosure further contemplates antibodies comprising one or more of the polypeptide sequences of SEQ ID NO:4; SEQ ID NO:5; and SEQ ID NO:6, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO:2, and / or one or more of the polypeptide sequences of SEQ ID NO:7; SEQ ID NO:8; and SEQ ID NO:9, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO:3, or a combination of these polypeptide sequences. In another embodiment of the present disclosure, the antibodies of the present disclosure comprise a combination of the CDR and variable heavy and light chain sequences described above.

[0114] In another embodiment, the present disclosure contemplates other antibodies, e.g., chimeric antibodies, that comprise one or more of the polypeptide sequences of SEQ ID NO:4; SEQ ID NO:5; and SEQ ID NO:6, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO:2, and / or one or more of the polypeptide sequences of SEQ ID NO:7; SEQ ID NO:8; and SEQ ID NO:9, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO:3, or a combination of these polypeptide sequences. In another embodiment of the present disclosure, the antibodies of the present disclosure comprise a combination of the CDRs and variable heavy and light chain sequences described above.

[0115] The present disclosure also contemplates antibody fragments that have binding specificity for IL-6. In one embodiment of the present disclosure, the antibody fragment of the present disclosure comprises, or alternatively consists of, the polypeptide sequence of SEQ ID NO: 2. In another embodiment of the present disclosure, the antibody fragment of the present disclosure comprises, or alternatively consists of, the polypeptide sequence of SEQ ID NO: 3.

[0116] In further embodiments of the present disclosure, antibody fragments having binding specificity for IL-6 comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO:4; SEQ ID NO:5; and SEQ ID NO:6, which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO:2.

[0117] In further embodiments of the present disclosure, antibody fragments having binding specificity for IL-6 comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO:7; SEQ ID NO:8; and SEQ ID NO:9, which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO:3.

[0118] The present disclosure also contemplates antibody fragments comprising one or more of the antibody fragments described herein. In one embodiment of the present disclosure, the antibody fragment having binding specificity to IL-6 comprises, or alternatively consists of, one, two, three, or more, including all, of the following antibody fragments: the variable light chain region of SEQ ID NO: 2; the variable heavy chain region of SEQ ID NO: 3; the complementarity determining regions of the variable light chain region of SEQ ID NO: 2 (SEQ ID NO: 4; SEQ ID NO: 5; and SEQ ID NO: 6); and the complementarity determining regions of the variable heavy chain region of SEQ ID NO: 3 (SEQ ID NO: 7; SEQ ID NO: 8; and SEQ ID NO: 9).

[0119] The present disclosure also contemplates variants in which the heavy chain polypeptide sequence of SEQ ID NO:3 is replaced with either the heavy chain polypeptide sequence of SEQ ID NO:18 or SEQ ID NO:19; the light chain polypeptide sequence of SEQ ID NO:2 is replaced with the light chain polypeptide sequence of SEQ ID NO:20; and the heavy chain CDR sequence of SEQ ID NO:8 is replaced with the heavy chain CDR sequence of SEQ ID NO:120.

[0120] In one embodiment of the present disclosure, the anti-IL-6 antibody is Ab1 comprising SEQ ID NO: 2 and SEQ ID NO: 3, or an alternative SEQ ID NO: shown in paragraph

[0083] above, and having at least one of the biological activities described herein.

[0121] In another embodiment, the present disclosure includes an antibody that has binding specificity for IL-6 and has a variable light chain sequence comprising the sequence shown below: MDTRAPTQLLGLLLLWLPGARCAYDMTQTPASVEVAVGGTVTINCQASETIYSWLSWYQQKPGQPPKLLIYQASDLASGVPSRFSGSGAGTEYTLTISGVQCDDAATYYCQQGYSGSNVDNVFGGGTEVVVKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFY (SEQ ID NO: 21)

[0122] The present disclosure also includes antibodies that have binding specificity for IL-6 and have a variable heavy chain sequence comprising the sequence shown below: METGLRWLLLVAVLKGVQCQEQLKESGGRLVTPGTPLTLTCTASGFSLNDHAMGWVRQAPGKGLEYIGFINSGGSARYASWAEGRFTISRTSTTVDLKMTSLTTEDTATYFCVRGGAVWSIHSFDPWGPGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVK (SEQ ID NO: 22)

[0123] The present disclosure further contemplates antibodies comprising one or more of the polypeptide sequences of SEQ ID NO:23; SEQ ID NO:24; and SEQ ID NO:25, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO:21, and / or one or more of the polypeptide sequences of SEQ ID NO:26; SEQ ID NO:27; and SEQ ID NO:28, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO:22, or a combination of these polypeptide sequences. In another embodiment of the present disclosure, the antibodies of the present disclosure comprise a combination of the CDRs and variable heavy and light chain sequences described above.

[0124] In another embodiment, the present disclosure contemplates other antibodies, e.g., chimeric antibodies, that comprise one or more of the polypeptide sequences of SEQ ID NO:23; SEQ ID NO:24; and SEQ ID NO:25, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO:21, and / or one or more of the polypeptide sequences of SEQ ID NO:26; SEQ ID NO:27; and SEQ ID NO:28, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO:22, or a combination of these polypeptide sequences. In another embodiment of the present disclosure, the antibodies of the present disclosure comprise a combination of the CDRs and variable heavy and light chain sequences described above.

[0125] The present disclosure also contemplates antibody fragments that have binding specificity for IL-6. In one embodiment of the present disclosure, the antibody fragment of the present disclosure comprises, or alternatively consists of, the polypeptide sequence of SEQ ID NO: 21. In another embodiment of the present disclosure, the antibody fragment of the present disclosure comprises, or alternatively consists of, the polypeptide sequence of SEQ ID NO: 22.

[0126] In further embodiments of the present disclosure, the antibody fragment having binding specificity for IL-6 comprises, or alternatively consists of, one or more of the polypeptide sequences of SEQ ID NO:23; SEQ ID NO:24; and SEQ ID NO:25, which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO:21.

[0127] In further embodiments of the present disclosure, antibody fragments having binding specificity for IL-6 comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO:26; SEQ ID NO:27; and SEQ ID NO:28, which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO:22.

[0128] The present disclosure also contemplates antibody fragments comprising one or more of the antibody fragments described herein. In one embodiment of the present disclosure, the antibody fragment having binding specificity to IL-6 comprises, or alternatively consists of, one, two, three, or more, including all, of the following antibody fragments: the variable light chain region of SEQ ID NO:21; the variable heavy chain region of SEQ ID NO:22; the complementarity determining regions of the variable light chain region of SEQ ID NO:21 (SEQ ID NO:23; SEQ ID NO:24; and SEQ ID NO:25); and the complementarity determining regions of the variable heavy chain region of SEQ ID NO:22 (SEQ ID NO:26; SEQ ID NO:27; and SEQ ID NO:28).

[0129] In one embodiment of the present disclosure, the anti-IL-6 antibody is an Ab2 comprising SEQ ID NO:21 and SEQ ID NO:22 and having at least one of the biological activities described herein.

[0130] In another embodiment, the present disclosure includes an antibody that has binding specificity for IL-6 and has a variable light chain sequence comprising the sequence shown below: MDTRAPTQLLGLLLLWLPGATFAAVLTQTPSPVSAAVGGTVSISCQASQSVYDNNYLSWFQQKPGQPPKLLIYGASTLASGVPSRFVGSGSGTQFTLTITDVQCDDAATYYCAGVYDDDSDNAFGGGTEVVVKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNN (SEQ ID NO: 37)

[0131] The present disclosure also includes antibodies that have binding specificity for IL-6 and have a variable heavy chain sequence comprising the sequence shown below: METGLRWLLLVAVLKGVQCQSLEESGGRLVTPGTPLTLTCTASGFSLSVYYMNWVRQAPGKGLEWIGFITMSDNINYASWAKGRFTISKTSTTVDLKMTSPTTEDTATYFCARSRGWGTMGRLDLWGPGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVK (SEQ ID NO: 38)

[0132] The present disclosure further contemplates antibodies comprising one or more of the polypeptide sequences of SEQ ID NO: 39; SEQ ID NO: 40; and SEQ ID NO: 41, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 37, and / or one or more of the polypeptide sequences of SEQ ID NO: 42; SEQ ID NO: 43; and SEQ ID NO: 44, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 38, or a combination of these polypeptide sequences. In another embodiment of the present disclosure, the antibodies of the present disclosure comprise a combination of the CDRs and variable heavy and light chain sequences described above.

[0133] In another embodiment, the present disclosure contemplates other antibodies, e.g., chimeric antibodies, that comprise one or more of the polypeptide sequences of SEQ ID NO: 39; SEQ ID NO: 40; and SEQ ID NO: 41, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 37, and / or one or more of the polypeptide sequences of SEQ ID NO: 42; SEQ ID NO: 43; and SEQ ID NO: 44, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 38, or a combination of these polypeptide sequences. In another embodiment of the present disclosure, the antibodies of the present disclosure comprise a combination of the CDRs and variable heavy and light chain sequences described above.

[0134] The present disclosure also contemplates antibody fragments that have binding specificity for IL-6. In one embodiment of the present disclosure, the antibody fragment of the present disclosure comprises, or alternatively consists of, the polypeptide sequence of SEQ ID NO: 37. In another embodiment of the present disclosure, the antibody fragment of the present disclosure comprises, or alternatively consists of, the polypeptide sequence of SEQ ID NO: 38.

[0135] In further embodiments of the present disclosure, the antibody fragment having binding specificity for IL-6 comprises, or alternatively consists of, one or more of the polypeptide sequences of SEQ ID NO:39; SEQ ID NO:40; and SEQ ID NO:41, which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO:37.

[0136] In further embodiments of the present disclosure, the antibody fragment having binding specificity for IL-6 comprises, or alternatively consists of, one or more of the polypeptide sequences of SEQ ID NO:42; SEQ ID NO:43; and SEQ ID NO:44, which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO:38.

[0137] The present disclosure also contemplates antibody fragments comprising one or more of the antibody fragments described herein. In one embodiment of the present disclosure, the antibody fragment having binding specificity to IL-6 comprises, or alternatively consists of, one, two, three, or more, including all, of the following antibody fragments: the variable light chain region of SEQ ID NO: 37; the variable heavy chain region of SEQ ID NO: 38; the complementarity determining regions of the variable light chain region of SEQ ID NO: 37 (SEQ ID NO: 39; SEQ ID NO: 40; and SEQ ID NO: 41); and the complementarity determining regions of the variable heavy chain region of SEQ ID NO: 38 (SEQ ID NO: 42; SEQ ID NO: 43; and SEQ ID NO: 44).

[0138] In one embodiment of the present disclosure, the anti-IL-6 antibody is an Ab3 comprising SEQ ID NO: 37 and SEQ ID NO: 38 and having at least one of the biological activities described herein.

[0139] In another embodiment, the present disclosure includes an antibody that has binding specificity for IL-6 and has a variable light chain sequence comprising the sequence shown below: MDTRAPTQLLGLLLLWLPGAICDPVLTQTPSPVSAPVGGTVSISCQASQSVYENNYLSWFQQKPGQPPKLLIYGASTLDSGVPSRFKGSGSGTQFTLTITDVQCDDAATYYCAGVYDDDSDDAFGGGTEVVVKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNN (SEQ ID NO: 53)

[0140] The present disclosure also includes antibodies that have binding specificity for IL-6 and have a variable heavy chain sequence comprising the sequence shown below: METGLRWLLLVAVLKGVQCQEQLKESGGGLVTPGGTLTLTCTASGFSLNAYYMNWVRQAPGKGLEWIGFITLNNNVAYANWAKGRFTFSKTSTTVDLKMTSPTPEDTATYFCARSRGWGAMGRLDLWGHGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVK (SEQ ID NO: 54)

[0141] The present disclosure further contemplates antibodies comprising one or more of the polypeptide sequences of SEQ ID NO:55; SEQ ID NO:56; and SEQ ID NO:57, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO:53, and / or one or more of the polypeptide sequences of SEQ ID NO:58; SEQ ID NO:59; and SEQ ID NO:60, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO:54, or a combination of these polypeptide sequences. In another embodiment of the present disclosure, the antibodies of the present disclosure comprise a combination of the CDRs and variable heavy and light chain sequences described above.

[0142] In another embodiment, the present disclosure contemplates other antibodies, e.g., chimeric antibodies, that comprise one or more of the polypeptide sequences of SEQ ID NO:55; SEQ ID NO:56; and SEQ ID NO:57, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO:53, and / or one or more of the polypeptide sequences of SEQ ID NO:58; SEQ ID NO:59; and SEQ ID NO:60, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO:54, or a combination of these polypeptide sequences. In another embodiment of the present disclosure, the antibodies of the present disclosure comprise a combination of the CDRs and variable heavy and light chain sequences described above.

[0143] The present disclosure also contemplates antibody fragments that have binding specificity for IL-6. In one embodiment of the present disclosure, the antibody fragment of the present disclosure comprises, or alternatively consists of, the polypeptide sequence of SEQ ID NO: 53. In another embodiment of the present disclosure, the antibody fragment of the present disclosure comprises, or alternatively consists of, the polypeptide sequence of SEQ ID NO: 54.

[0144] In further embodiments of the present disclosure, the antibody fragment having binding specificity for IL-6 comprises, or alternatively consists of, one or more of the polypeptide sequences of SEQ ID NO:55; SEQ ID NO:56; and SEQ ID NO:57, which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO:53.

[0145] In further embodiments of the present disclosure, antibody fragments having binding specificity for IL-6 comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO:58; SEQ ID NO:59; and SEQ ID NO:60, which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO:54.

[0146] The present disclosure also contemplates antibody fragments comprising one or more of the antibody fragments described herein. In one embodiment of the present disclosure, the antibody fragment having binding specificity to IL-6 comprises, or alternatively consists of, one, two, three, or more, including all, of the following antibody fragments: the variable light chain region of SEQ ID NO: 53; the variable heavy chain region of SEQ ID NO: 54; the complementarity determining regions of the variable light chain region of SEQ ID NO: 53 (SEQ ID NO: 55; SEQ ID NO: 56; and SEQ ID NO: 57); and the complementarity determining regions of the variable heavy chain region of SEQ ID NO: 54 (SEQ ID NO: 58; SEQ ID NO: 59; and SEQ ID NO: 60).

[0147] In one embodiment of the present disclosure, the anti-IL-6 antibody is an Ab4 comprising SEQ ID NO: 53 and SEQ ID NO: 54 and having at least one of the biological activities described herein.

[0148] In another embodiment, the present disclosure includes an antibody that has binding specificity for IL-6 and has a variable light chain sequence comprising the sequence shown below: MDTRAPTQLLGLLLLWLPGATFAQVLTQTPSPVSAAVGGTVTINCQASQSVDDNNWLGWYQQKRGQPPKYLIYSASTLASGVPSRFKGSGSGTQFTLTISDLECDDAATYYCAGGFSGNIFAFGGGTEVVVKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNF (SEQ ID NO: 69)

[0149] The present disclosure also includes antibodies that have binding specificity for IL-6 and have a variable heavy chain sequence comprising the sequence shown below: METGLRWLLLVAVLKGVQCQSVEESGGRLVTPGTPLTLTCTVSGFSLSSYAMSWVRQAPGKGLEWIGIIGGFGTTYYATWAKGRFTISKTSTTVDLRITSPTTEDTATYFCARGGPGNGGDIWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKD (SEQ ID NO: 70)

[0150] The present disclosure further contemplates antibodies comprising one or more of the polypeptide sequences of SEQ ID NO:71; SEQ ID NO:72; and SEQ ID NO:73, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO:69, and / or one or more of the polypeptide sequences of SEQ ID NO:74; SEQ ID NO:75; and SEQ ID NO:76, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO:70, or a combination of these polypeptide sequences. In another embodiment of the present disclosure, the antibodies of the present disclosure comprise a combination of the CDRs and variable heavy and light chain sequences described above.

[0151] In another embodiment, the present disclosure contemplates other antibodies, e.g., chimeric antibodies, that comprise one or more of the polypeptide sequences of SEQ ID NO:71; SEQ ID NO:72; and SEQ ID NO:73, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO:69, and / or one or more of the polypeptide sequences of SEQ ID NO:74; SEQ ID NO:75; and SEQ ID NO:76, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO:70, or a combination of these polypeptide sequences. In another embodiment of the present disclosure, the antibodies of the present disclosure comprise a combination of the CDRs and variable heavy and light chain sequences described above.

[0152] The present disclosure also contemplates antibody fragments that have binding specificity for IL-6. In one embodiment of the present disclosure, the antibody fragment of the present disclosure comprises, or alternatively consists of, the polypeptide sequence of SEQ ID NO: 69. In another embodiment of the present disclosure, the antibody fragment of the present disclosure comprises, or alternatively consists of, the polypeptide sequence of SEQ ID NO: 70.

[0153] In further embodiments of the present disclosure, antibody fragments having binding specificity for IL-6 comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO:71; SEQ ID NO:72; and SEQ ID NO:73, which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO:69.

[0154] In further embodiments of the present disclosure, antibody fragments having binding specificity for IL-6 comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO:74; SEQ ID NO:75; and SEQ ID NO:76, which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO:70.

[0155] The present disclosure also contemplates antibody fragments comprising one or more of the antibody fragments described herein. In one embodiment of the present disclosure, the antibody fragment having binding specificity to IL-6 comprises, or alternatively consists of, one, two, three, or more, including all, of the following antibody fragments: the variable light chain region of SEQ ID NO: 69; the variable heavy chain region of SEQ ID NO: 70; the complementarity determining regions of the variable light chain region of SEQ ID NO: 69 (SEQ ID NO: 71; SEQ ID NO: 72; and SEQ ID NO: 73); and the complementarity determining regions of the variable heavy chain region of SEQ ID NO: 70 (SEQ ID NO: 74; SEQ ID NO: 75; and SEQ ID NO: 76).

[0156] In one embodiment of the present disclosure, the anti-IL-6 antibody is Ab5 comprising SEQ ID NO: 69 and SEQ ID NO: 70 and having at least one of the biological activities described herein.

[0157] In another embodiment, the present disclosure includes an antibody that has binding specificity for IL-6 and has a variable light chain sequence comprising the sequence shown below: MDTRAPTQLLGLLLLWLPGATFAAVLTQTPSPVSVPVGGTVTIKCQSSQSVYNNFLSWYQQKPGQPPKLLIYQASKLASGVPDRFSGSGSGTQFTLTISGVQCDDAATYYCLGGYDDDADNAFGGGTEVVVKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNF (SEQ ID NO: 85)

[0158] The present disclosure also includes antibodies that have binding specificity for IL-6 and have a variable heavy chain sequence comprising the sequence shown below: METGLRWLLLVAVLKGVQCQSVEESGGRLVTPGTPLTLTCTVSGIDLSDYAMSWVRQAPGKGLEWIGIIYAGSGSTWYASWAKGRFTISKTSTTVDLKITSPTTEDTATYFCARDGYDDYGDFDRLDLWGPGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKD (SEQ ID NO: 86)

[0159] The present disclosure further contemplates antibodies comprising one or more of the polypeptide sequences of SEQ ID NO: 87; SEQ ID NO: 88; and SEQ ID NO: 89, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 85, and / or one or more of the polypeptide sequences of SEQ ID NO: 90; SEQ ID NO: 91; and SEQ ID NO: 92, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 86, or a combination of these polypeptide sequences. In another embodiment of the present disclosure, the antibodies of the present disclosure comprise a combination of the CDRs and variable heavy and light chain sequences described above.

[0160] In another embodiment, the present disclosure contemplates other antibodies, e.g., chimeric antibodies, that comprise one or more of the polypeptide sequences of SEQ ID NO:87; SEQ ID NO:88; and SEQ ID NO:89, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO:85, and / or one or more of the polypeptide sequences of SEQ ID NO:90; SEQ ID NO:91; and SEQ ID NO:92, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO:86, or a combination of these polypeptide sequences. In another embodiment of the present disclosure, the antibodies of the present disclosure comprise a combination of the CDRs and variable heavy and light chain sequences described above.

[0161] The present disclosure also contemplates antibody fragments that have binding specificity for IL-6. In one embodiment of the present disclosure, the antibody fragment of the present disclosure comprises, or alternatively consists of, the polypeptide sequence of SEQ ID NO: 85. In another embodiment of the present disclosure, the antibody fragment of the present disclosure comprises, or alternatively consists of, the polypeptide sequence of SEQ ID NO: 86.

[0162] In further embodiments of the present disclosure, antibody fragments having binding specificity for IL-6 comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO:87; SEQ ID NO:88; and SEQ ID NO:89, which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO:85.

[0163] In further embodiments of the present disclosure, antibody fragments having binding specificity for IL-6 comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO:90; SEQ ID NO:91; and SEQ ID NO:92, which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO:86.

[0164] The present disclosure also contemplates antibody fragments comprising one or more of the antibody fragments described herein. In one embodiment of the present disclosure, the antibody fragment having binding specificity to IL-6 comprises, or alternatively consists of, one, two, three, or more, including all, of the following antibody fragments: the variable light chain region of SEQ ID NO: 85; the variable heavy chain region of SEQ ID NO: 86; the complementarity determining regions of the variable light chain region of SEQ ID NO: 85 (SEQ ID NO: 87; SEQ ID NO: 88; and SEQ ID NO: 89); and the complementarity determining regions of the variable heavy chain region of SEQ ID NO: 86 (SEQ ID NO: 90; SEQ ID NO: 91; and SEQ ID NO: 92).

[0165] In one embodiment of the present disclosure, the anti-IL-6 antibody is Ab6 comprising SEQ ID NO: 85 and SEQ ID NO: 86 and having at least one of the biological activities described herein.

[0166] In another embodiment, the present disclosure includes an antibody that has binding specificity for IL-6 and has a variable light chain sequence comprising the sequence shown below: MDTRAPTQLLGLLLLWLPGARCAYDMTQTPASVSAAVGGTVTIKCQASQSINNELSWYQQKSGQRPKLLIYRASTLASGVSSRFKGSGSGTEFTLTISDLECADAATYYCQQGYSLRNIDNAFGGGTEVVVKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNF (SEQ ID NO: 101)

[0167] The present disclosure also includes antibodies that have binding specificity for IL-6 and have a variable heavy chain sequence comprising the sequence shown below: METGLRWLLLVAVLSGVQCQSLEESGGRLVTPGTPLTLTCTASGFSLSNYYMTWVRQAPGKGLEWIGMIYGSDETAYANWAIGRFTISKTSTTVDLKMTSLTAADTATYFCARDDSSDWDAKFNLWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVK (SEQ ID NO: 102)

[0168] The present disclosure further contemplates antibodies comprising one or more of the polypeptide sequences of SEQ ID NO: 103; SEQ ID NO: 104; and SEQ ID NO: 105, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 101, and / or one or more of the polypeptide sequences of SEQ ID NO: 106; SEQ ID NO: 107; and SEQ ID NO: 108, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 102, or a combination of these polypeptide sequences. In another embodiment of the present disclosure, the antibodies of the present disclosure comprise a combination of the CDRs and variable heavy and light chain sequences described above.

[0169] In another embodiment, the present disclosure contemplates other antibodies, e.g., chimeric antibodies, that comprise one or more of the polypeptide sequences of SEQ ID NO: 103; SEQ ID NO: 104; and SEQ ID NO: 105, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 101, and / or one or more of the polypeptide sequences of SEQ ID NO: 106; SEQ ID NO: 107; and SEQ ID NO: 108, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 102, or a combination of these polypeptide sequences. In another embodiment of the present disclosure, the antibodies of the present disclosure comprise a combination of the CDRs and variable heavy and light chain sequences described above.

[0170] The present disclosure also contemplates antibody fragments that have binding specificity for IL-6. In one embodiment of the present disclosure, the antibody fragment of the present disclosure comprises, or alternatively consists of, the polypeptide sequence of SEQ ID NO: 101. In another embodiment of the present disclosure, the antibody fragment of the present disclosure comprises, or alternatively consists of, the polypeptide sequence of SEQ ID NO: 102.

[0171] In further embodiments of the present disclosure, the antibody fragment having binding specificity for IL-6 comprises, or alternatively consists of, one or more of the polypeptide sequences of SEQ ID NO: 103; SEQ ID NO: 104; and SEQ ID NO: 105, which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 101.

[0172] In further embodiments of the present disclosure, the antibody fragment having binding specificity for IL-6 comprises, or alternatively consists of, one or more of the polypeptide sequences of SEQ ID NO: 106; SEQ ID NO: 107; and SEQ ID NO: 108, which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 102.

[0173] The present disclosure also contemplates antibody fragments comprising one or more of the antibody fragments described herein. In one embodiment of the present disclosure, the antibody fragment having binding specificity to IL-6 comprises, or alternatively consists of, one, two, three, or more, including all, of the following antibody fragments: the variable light chain region of SEQ ID NO: 101; the variable heavy chain region of SEQ ID NO: 102; the complementarity determining regions of the variable light chain region of SEQ ID NO: 101 (SEQ ID NO: 103; SEQ ID NO: 104; and SEQ ID NO: 105); and the complementarity determining regions of the variable heavy chain region of SEQ ID NO: 102 (SEQ ID NO: 106; SEQ ID NO: 107; and SEQ ID NO: 108).

[0174] The present disclosure also contemplates variants in which the heavy chain polypeptide sequence of SEQ ID NO: 102 is replaced with either the heavy chain polypeptide sequence of SEQ ID NO: 117 or SEQ ID NO: 118; the light chain polypeptide sequence of SEQ ID NO: 101 is replaced with the light chain polypeptide sequence of SEQ ID NO: 119; and the heavy chain CDR sequence of SEQ ID NO: 107 is replaced with the heavy chain CDR sequence of SEQ ID NO: 121.

[0175] In one embodiment of the present disclosure, the anti-IL-6 antibody is Ab7 comprising SEQ ID NO: 101 and SEQ ID NO: 102, or an alternative SEQ ID NO: set forth in paragraph

[0138] above, and having at least one of the biological activities described herein.

[0176] In another embodiment, the present disclosure includes an antibody that has binding specificity for IL-6 and has a variable light chain sequence comprising the sequence shown below: MDTRAPTQLLGLLLLWLPGATFAAVLTQTPSPVSAAVGGTVTISCQSSQSVGNNQDLSWFQQRPGQPPKLLIYEISKLESGVPSRFSGSGSGTHFTLTISGVQCDDAATYYCLGGYDDDADNA (SEQ ID NO: 122)

[0177] The present disclosure also includes antibodies that have binding specificity for IL-6 and have a variable heavy chain sequence comprising the sequence shown below: METGLRWLLLVAVLKGVQCHSVEESGGRLVTPGTPLTLTCTVSGFSLSSRTMSWVRQAPGKGLEWIGYIWSGGSTYYATWAKGRFTISKTSTTVDLKITSPTTEDTATYFCARLGDTGGHAYATRLNL (SEQ ID NO: 123)

[0178] The present disclosure further contemplates antibodies comprising one or more of the polypeptide sequences of SEQ ID NO: 124; SEQ ID NO: 125; and SEQ ID NO: 126, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 122, and / or one or more of the polypeptide sequences of SEQ ID NO: 127; SEQ ID NO: 128; and SEQ ID NO: 129, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 123, or a combination of these polypeptide sequences. In another embodiment of the present disclosure, the antibodies of the present disclosure comprise a combination of the CDRs and variable heavy and light chain sequences described above.

[0179] In another embodiment, the present disclosure contemplates other antibodies, e.g., chimeric antibodies, that comprise one or more of the polypeptide sequences of SEQ ID NO: 124; SEQ ID NO: 125; and SEQ ID NO: 126, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 122, and / or one or more of the polypeptide sequences of SEQ ID NO: 127; SEQ ID NO: 128; and SEQ ID NO: 129, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 123, or a combination of these polypeptide sequences. In another embodiment of the present disclosure, the antibodies of the present disclosure comprise a combination of the CDRs and variable heavy and light chain sequences described above.

[0180] The present disclosure also contemplates antibody fragments that have binding specificity for IL-6. In one embodiment of the present disclosure, the antibody fragment of the present disclosure comprises, or alternatively consists of, the polypeptide sequence of SEQ ID NO: 122. In another embodiment of the present disclosure, the antibody fragment of the present disclosure comprises, or alternatively consists of, the polypeptide sequence of SEQ ID NO: 123.

[0181] In further embodiments of the present disclosure, antibody fragments having binding specificity for IL-6 comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO: 124; SEQ ID NO: 125; and SEQ ID NO: 126, which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 122.

[0182] In further embodiments of the present disclosure, antibody fragments having binding specificity for IL-6 comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO: 127; SEQ ID NO: 128; and SEQ ID NO: 129, which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 123.

[0183] The present disclosure also contemplates antibody fragments comprising one or more of the antibody fragments described herein. In one embodiment of the present disclosure, the antibody fragment having binding specificity to IL-6 comprises, or alternatively consists of, one, two, three, or more, including all, of the following antibody fragments: the variable light chain region of SEQ ID NO: 122; the variable heavy chain region of SEQ ID NO: 123; the complementarity determining regions of the variable light chain region of SEQ ID NO: 122 (SEQ ID NO: 124; SEQ ID NO: 125; and SEQ ID NO: 126); and the complementarity determining regions of the variable heavy chain region of SEQ ID NO: 123 (SEQ ID NO: 127; SEQ ID NO: 128; and SEQ ID NO: 129).

[0184] In one embodiment of the present disclosure, the anti-IL-6 antibody is Ab8 comprising SEQ ID NO: 122 and SEQ ID NO: 123 and having at least one of the biological activities described herein.

[0185] In another embodiment, the present disclosure includes an antibody that has binding specificity for IL-6 and has a variable light chain sequence comprising the sequence shown below: MDTRAPTQLLGLLLLWLPGATFAAVLTQTPSSVSAAVGGTVSISCQSSQSVYSNKYLAWYQQKPGQPPKLLIYWTSKLASGAPSRFSGSGSGTQFTLTISGVQCDDAATYYCLGAYDDDADNA (SEQ ID NO: 138)

[0186] The present disclosure also includes antibodies that have binding specificity for IL-6 and have a variable heavy chain sequence comprising the sequence shown below: METGLRWLLLVAVLKGVQCQSVEESGGRLVKPDETLTLTCTASGFSLEGGYMTWVRQAPGKGLEWIGISYDSGSTYYASWAKGRFTISKTSSTTVDLKMTSLTTEDTATYFCVRSLKYPTVTSDDL (SEQ ID NO: 139)

[0187] The present disclosure further contemplates antibodies comprising one or more of the polypeptide sequences of SEQ ID NO: 140; SEQ ID NO: 141; and SEQ ID NO: 142, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 138, and / or one or more of the polypeptide sequences of SEQ ID NO: 143; SEQ ID NO: 144; and SEQ ID NO: 145, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 139, or a combination of these polypeptide sequences. In another embodiment of the present disclosure, the antibodies of the present disclosure comprise a combination of the CDRs and variable heavy and light chain sequences described above.

[0188] In another embodiment, the present disclosure contemplates other antibodies, e.g., chimeric antibodies, that comprise one or more of the polypeptide sequences of SEQ ID NO: 140; SEQ ID NO: 141; and SEQ ID NO: 142, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 138, and / or one or more of the polypeptide sequences of SEQ ID NO: 143; SEQ ID NO: 144; and SEQ ID NO: 145, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 139, or a combination of these polypeptide sequences. In another embodiment of the present disclosure, the antibodies of the present disclosure comprise a combination of the CDRs and variable heavy and light chain sequences described above.

[0189] The present disclosure also contemplates antibody fragments that have binding specificity for IL-6. In one embodiment of the present disclosure, the antibody fragment of the present disclosure comprises, or alternatively consists of, the polypeptide sequence of SEQ ID NO: 138. In another embodiment of the present disclosure, the antibody fragment of the present disclosure comprises, or alternatively consists of, the polypeptide sequence of SEQ ID NO: 139.

[0190] In further embodiments of the present disclosure, the antibody fragment having binding specificity for IL-6 comprises, or alternatively consists of, one or more of the polypeptide sequences of SEQ ID NO: 140; SEQ ID NO: 141; and SEQ ID NO: 142, which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 138.

[0191] In further embodiments of the present disclosure, the antibody fragment having binding specificity for IL-6 comprises, or alternatively consists of, one or more of the polypeptide sequences of SEQ ID NO: 143; SEQ ID NO: 144; and SEQ ID NO: 145, which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 139.

[0192] The present disclosure also contemplates antibody fragments comprising one or more of the antibody fragments described herein. In one embodiment of the present disclosure, the antibody fragment having binding specificity to IL-6 comprises, or alternatively consists of, one, two, three, or more, including all, of the following antibody fragments: the variable light chain region of SEQ ID NO: 138; the variable heavy chain region of SEQ ID NO: 139; the complementarity determining regions of the variable light chain region of SEQ ID NO: 138 (SEQ ID NO: 140; SEQ ID NO: 141; and SEQ ID NO: 142); and the complementarity determining regions of the variable heavy chain region of SEQ ID NO: 139 (SEQ ID NO: 143; SEQ ID NO: 144; and SEQ ID NO: 145).

[0193] In one embodiment of the present disclosure, the anti-IL-6 antibody is Ab9 comprising SEQ ID NO: 138 and SEQ ID NO: 139 and having at least one of the biological activities described herein.

[0194] In another embodiment, the present disclosure includes an antibody that has binding specificity for IL-6 and has a variable light chain sequence comprising the sequence shown below: MDTRAPTQLLGLLLLWLPGATFAAVLTQTPSPVSAAVGGTVTISCQSSQSVYNNNDLAWYQQKPGQPPKLLIYYASTLASGVPSRFKGSGSGTQFTLTISGVQCDDAAAYYCLGGYDDDADNA (SEQ ID NO: 154)

[0195] The present disclosure also includes antibodies that have binding specificity for IL-6 and have a variable heavy chain sequence comprising the sequence shown below: METGLRWLLLVAVLKGVQCQSVEESGGRLVTPGTPLTLTCTVSGLSLSSNTINWVRQAPGKGLEWIGYIWSGGSTYYASWVNGRFTISKTSTTVDLKITSPTTEDTATYFCARGGYASGGYPYATRLDL (SEQ ID NO: 155)

[0196] The present disclosure further contemplates antibodies comprising one or more of the polypeptide sequences of SEQ ID NO: 156; SEQ ID NO: 157; and SEQ ID NO: 158, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 154, and / or one or more of the polypeptide sequences of SEQ ID NO: 159; SEQ ID NO: 160; and SEQ ID NO: 161, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 155, or a combination of these polypeptide sequences. In another embodiment of the present disclosure, the antibodies of the present disclosure comprise a combination of the CDRs and variable heavy and light chain sequences described above.

[0197] In another embodiment, the present disclosure contemplates other antibodies, e.g., chimeric antibodies, that comprise one or more of the polypeptide sequences of SEQ ID NO: 156; SEQ ID NO: 157; and SEQ ID NO: 158, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 154, and / or one or more of the polypeptide sequences of SEQ ID NO: 159; SEQ ID NO: 160; and SEQ ID NO: 161, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 155, or a combination of these polypeptide sequences. In another embodiment of the present disclosure, the antibodies of the present disclosure comprise a combination of the CDRs and variable heavy and light chain sequences described above.

[0198] The present disclosure also contemplates antibody fragments that have binding specificity for IL-6. In one embodiment of the present disclosure, the antibody fragment of the present disclosure comprises, or alternatively consists of, the polypeptide sequence of SEQ ID NO: 154. In another embodiment of the present disclosure, the antibody fragment of the present disclosure comprises, or alternatively consists of, the polypeptide sequence of SEQ ID NO: 155.

[0199] In further embodiments of the present disclosure, antibody fragments having binding specificity for IL-6 comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO: 156; SEQ ID NO: 157; and SEQ ID NO: 158, which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 154.

[0200] In further embodiments of the present disclosure, the antibody fragment having binding specificity for IL-6 comprises, or alternatively consists of, one or more of the polypeptide sequences of SEQ ID NO: 159; SEQ ID NO: 160; and SEQ ID NO: 161, which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 155.

[0201] The present disclosure also contemplates antibody fragments comprising one or more of the antibody fragments described herein. In one embodiment of the present disclosure, the antibody fragment having binding specificity to IL-6 comprises, or alternatively consists of, one, two, three, or more, including all, of the following antibody fragments: the variable light chain region of SEQ ID NO: 154; the variable heavy chain region of SEQ ID NO: 155; the complementarity determining regions of the variable light chain region of SEQ ID NO: 154 (SEQ ID NO: 156; SEQ ID NO: 157; and SEQ ID NO: 158); and the complementarity determining regions of the variable heavy chain region of SEQ ID NO: 155 (SEQ ID NO: 159; SEQ ID NO: 160; and SEQ ID NO: 161).

[0202] In one embodiment of the present disclosure, the anti-IL-6 antibody is Ab10 comprising SEQ ID NO: 154 and SEQ ID NO: 155 and having at least one of the biological activities described herein.

[0203] In another embodiment, the present disclosure includes an antibody that has binding specificity for IL-6 and has a variable light chain sequence comprising the sequence shown below: MDTRAPTQLLGLLLLWLPGATFAAVLTQTPSSVSAAVGGTVTINCQSSQSVYNNDYLSWYQQRPGQRPKLLIYGASKLASGVPSRFKGSGSGKQFTLTISGVQCDDAATYYCLGDYDDDADNT (SEQ ID NO: 170)

[0204] The present disclosure also includes antibodies that have binding specificity for IL-6 and have a variable heavy chain sequence comprising the sequence shown below: METGLRWLLLVAVLKGVQCQSLEESGGRLVTPGTPLTLTCTVSGFTLSTNYYLSWVRQAPGKGLEWIGIIYPSGNTYCAKWAKGRFTISKTSSTTVDLKMTSPTTEDTATYFCARNYGGDESL (SEQ ID NO: 171)

[0205] The present disclosure further contemplates antibodies comprising one or more of the polypeptide sequences of SEQ ID NO: 172; SEQ ID NO: 173; and SEQ ID NO: 174, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 170, and / or one or more of the polypeptide sequences of SEQ ID NO: 175; SEQ ID NO: 176; and SEQ ID NO: 177, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 171, or a combination of these polypeptide sequences. In another embodiment of the present disclosure, an antibody of the present disclosure comprises a combination of the CDRs and variable heavy and light chain sequences described above.

[0206] In another embodiment, the present disclosure contemplates other antibodies, e.g., chimeric antibodies, that comprise one or more of the polypeptide sequences of SEQ ID NO: 172; SEQ ID NO: 173; and SEQ ID NO: 174, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 170, and / or one or more of the polypeptide sequences of SEQ ID NO: 175; SEQ ID NO: 176; and SEQ ID NO: 177, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 171, or a combination of these polypeptide sequences. In another embodiment of the present disclosure, the antibodies of the present disclosure comprise a combination of the CDRs and variable heavy and light chain sequences described above.

[0207] The present disclosure also contemplates antibody fragments that have binding specificity for IL-6. In one embodiment of the present disclosure, the antibody fragment of the present disclosure comprises, or alternatively consists of, the polypeptide sequence of SEQ ID NO: 170. In another embodiment of the present disclosure, the antibody fragment of the present disclosure comprises, or alternatively consists of, the polypeptide sequence of SEQ ID NO: 171.

[0208] In further embodiments of the present disclosure, the antibody fragment having binding specificity for IL-6 comprises, or alternatively consists of, one or more of the polypeptide sequences of SEQ ID NO: 172; SEQ ID NO: 173; and SEQ ID NO: 174, which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 170.

[0209] In further embodiments of the present disclosure, antibody fragments having binding specificity for IL-6 comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO: 175; SEQ ID NO: 176; and SEQ ID NO: 177, which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 171.

[0210] The present disclosure also contemplates antibody fragments comprising one or more of the antibody fragments described herein. In one embodiment of the present disclosure, the antibody fragment having binding specificity to IL-6 comprises, or alternatively consists of, one, two, three, or more, including all, of the following antibody fragments: the variable light chain region of SEQ ID NO: 170; the variable heavy chain region of SEQ ID NO: 171; the complementarity determining regions of the variable light chain region of SEQ ID NO: 170 (SEQ ID NO: 172; SEQ ID NO: 173; and SEQ ID NO: 174); and the complementarity determining regions of the variable heavy chain region of SEQ ID NO: 171 (SEQ ID NO: 175; SEQ ID NO: 176; and SEQ ID NO: 177).

[0211] In one embodiment of the present disclosure, the anti-IL-6 antibody is Ab11, which comprises SEQ ID NO: 170 and SEQ ID NO: 171 and has at least one of the biological activities described herein.

[0212] In another embodiment, the present disclosure includes an antibody that has binding specificity for IL-6 and has a variable light chain sequence comprising the sequence shown below: MDTRAPTQLLGLLLLWLPGARCDVVMTQTPASVEAAVGGTVTIKCQASETIGNALAWYQQKSGQPPKLLIYKASKLASGVPSRFKGSGSGTEYTLTISDLECADAATYYCQWCYFGDSV (SEQ ID NO: 186)

[0213] The present disclosure also includes antibodies that have binding specificity for IL-6 and have a variable heavy chain sequence comprising the sequence shown below: METGLRWLLLVTVLKGVQCQEQLVESGGGLVQPEGSLTLTCTASGFDFSSGYYMCWVRQAPGKGLEWIACIFTITTNTYYASWAKGRFTISKTSSTTVTLQMTSLTAADTATYLCARGIYSDNNYYAL (SEQ ID NO: 187)

[0214] The present disclosure further contemplates antibodies comprising one or more of the polypeptide sequences of SEQ ID NO: 188; SEQ ID NO: 189; and SEQ ID NO: 190, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 186, and / or one or more of the polypeptide sequences of SEQ ID NO: 191; SEQ ID NO: 192; and SEQ ID NO: 193, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 187, or a combination of these polypeptide sequences. In another embodiment of the present disclosure, the antibodies of the present disclosure comprise a combination of the CDRs and variable heavy and light chain sequences described above.

[0215] In another embodiment, the present disclosure contemplates other antibodies, e.g., chimeric antibodies, that comprise one or more of the polypeptide sequences of SEQ ID NO: 188; SEQ ID NO: 189; and SEQ ID NO: 190, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 186, and / or one or more of the polypeptide sequences of SEQ ID NO: 191; SEQ ID NO: 192; and SEQ ID NO: 193, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 187, or a combination of these polypeptide sequences. In another embodiment of the present disclosure, the antibodies of the present disclosure comprise a combination of the CDRs and variable heavy and light chain sequences described above.

[0216] The present disclosure also contemplates antibody fragments that have binding specificity for IL-6. In one embodiment of the present disclosure, the antibody fragment of the present disclosure comprises, or alternatively consists of, the polypeptide sequence of SEQ ID NO: 186. In another embodiment of the present disclosure, the antibody fragment of the present disclosure comprises, or alternatively consists of, the polypeptide sequence of SEQ ID NO: 187.

[0217] In further embodiments of the present disclosure, antibody fragments having binding specificity for IL-6 comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO: 188; SEQ ID NO: 189; and SEQ ID NO: 190, which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 186.

[0218] In further embodiments of the present disclosure, antibody fragments having binding specificity for IL-6 comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO:191; SEQ ID NO:192; and SEQ ID NO:193, which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO:187.

[0219] The present disclosure also contemplates antibody fragments comprising one or more of the antibody fragments described herein. In one embodiment of the present disclosure, the antibody fragment having binding specificity to IL-6 comprises, or alternatively consists of, one, two, three, or more, including all, of the following antibody fragments: the variable light chain region of SEQ ID NO: 186; the variable heavy chain region of SEQ ID NO: 187; the complementarity determining regions of the variable light chain region of SEQ ID NO: 186 (SEQ ID NO: 188; SEQ ID NO: 189; and SEQ ID NO: 190); and the complementarity determining regions of the variable heavy chain region of SEQ ID NO: 187 (SEQ ID NO: 191; SEQ ID NO: 192; and SEQ ID NO: 193).

[0220] In one embodiment of the present disclosure, the anti-IL-6 antibody is Ab12 comprising SEQ ID NO: 186 and SEQ ID NO: 187 and having at least one of the biological activities described herein.

[0221] In another embodiment, the present disclosure includes an antibody that has binding specificity for IL-6 and has a variable light chain sequence comprising the sequence shown below: MDTRAPTQLLGLLLLWLPGARCDVVMTQTPASVEAAVGGTVTIKCQASESIGNALAWYQQKPGQPPKLLIYKASTLASGVPSRFSGSGSGTEFTLTISGVQCADAAAYYCQWCYFGDSV (SEQ ID NO: 202)

[0222] The present disclosure also includes antibodies that have binding specificity for IL-6 and have a variable heavy chain sequence comprising the sequence shown below: METGLRWLLLVAVLKGVQCQQQLVESGGGLVKPGASLTLTCKASGFSFSSGYYMCWVRQAPGKGLESIACIFTITDNTYYANWAKGRFTISKPSSPTVTLQMTSLTAADTATYFCARGIYSTDNYYAL (SEQ ID NO: 203)

[0223] The present disclosure further contemplates antibodies comprising one or more of the polypeptide sequences of SEQ ID NO:204; SEQ ID NO:205; and SEQ ID NO:206, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO:202, and / or one or more of the polypeptide sequences of SEQ ID NO:207; SEQ ID NO:208; and SEQ ID NO:209, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO:203, or a combination of these polypeptide sequences. In another embodiment of the present disclosure, the antibodies of the present disclosure comprise a combination of the CDRs and variable heavy and light chain sequences described above.

[0224] In another embodiment, the present disclosure contemplates other antibodies, e.g., chimeric antibodies, that comprise one or more of the polypeptide sequences of SEQ ID NO:204; SEQ ID NO:205; and SEQ ID NO:206, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO:202, and / or one or more of the polypeptide sequences of SEQ ID NO:207; SEQ ID NO:208; and SEQ ID NO:209, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO:203, or a combination of these polypeptide sequences. In another embodiment of the present disclosure, the antibodies of the present disclosure comprise a combination of the CDRs and variable heavy and light chain sequences described above.

[0225] The present disclosure also contemplates antibody fragments that have binding specificity for IL-6. In one embodiment of the present disclosure, the antibody fragment of the present disclosure comprises, or alternatively consists of, the polypeptide sequence of SEQ ID NO: 202. In another embodiment of the present disclosure, the antibody fragment of the present disclosure comprises, or alternatively consists of, the polypeptide sequence of SEQ ID NO: 203.

[0226] In further embodiments of the present disclosure, antibody fragments having binding specificity for IL-6 comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO:204; SEQ ID NO:205; and SEQ ID NO:206, which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO:202.

[0227] In further embodiments of the present disclosure, antibody fragments having binding specificity for IL-6 comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO:207; SEQ ID NO:208; and SEQ ID NO:209, which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO:203.

[0228] The present disclosure also contemplates antibody fragments comprising one or more of the antibody fragments described herein. In one embodiment of the present disclosure, the antibody fragment having binding specificity to IL-6 comprises, or alternatively consists of, one, two, three, or more, including all, of the following antibody fragments: the variable light chain region of SEQ ID NO: 202; the variable heavy chain region of SEQ ID NO: 203; the complementarity determining regions of the variable light chain region of SEQ ID NO: 202 (SEQ ID NO: 204; SEQ ID NO: 205; and SEQ ID NO: 206); and the complementarity determining regions of the variable heavy chain region of SEQ ID NO: 203 (SEQ ID NO: 207; SEQ ID NO: 208; and SEQ ID NO: 209).

[0229] In one embodiment of the present disclosure, the anti-IL-6 antibody is Ab13, which comprises SEQ ID NO: 202 and SEQ ID NO: 203 and has at least one of the biological activities described herein.

[0230] In another embodiment, the present disclosure includes an antibody that has binding specificity for IL-6 and has a variable light chain sequence comprising the sequence shown below: MDTRAPTQLLGLLLLWLPGARCDVVMTQTPASVEAAVGGTVTIKCQASQSVSSYLNWYQQKPGQPPKLLIYRASTLESGVPSRFKGSGSGTEFTLTISDLECADAATYYCQCTYGTSSSYGAA (SEQ ID NO: 218)

[0231] The present disclosure also includes antibodies that have binding specificity for IL-6 and have a variable heavy chain sequence comprising the sequence shown below: METGLRWLLLVAVLKGVQCQSVEESGGRLVTPGTPLTLTCTVSGISLSSNAISWVRQAPGKGLEWIGIISYSGTTYYASWAKGRFTISKTSSTTVDLKITSPTTEDTATYFCARDDPTTVMVMLIPFGAGMDL (SEQ ID NO: 219)

[0232] The present disclosure further contemplates antibodies comprising one or more of the polypeptide sequences of SEQ ID NO:220; SEQ ID NO:221; and SEQ ID NO:222, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO:218, and / or one or more of the polypeptide sequences of SEQ ID NO:223; SEQ ID NO:224; and SEQ ID NO:225, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO:219, or a combination of these polypeptide sequences. In another embodiment of the present disclosure, the antibodies of the present disclosure comprise a combination of the CDRs and variable heavy and light chain sequences described above.

[0233] In another embodiment, the present disclosure contemplates other antibodies, e.g., chimeric antibodies, that comprise one or more of the polypeptide sequences of SEQ ID NO:220; SEQ ID NO:221; and SEQ ID NO:222, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO:218, and / or one or more of the polypeptide sequences of SEQ ID NO:223; SEQ ID NO:224; and SEQ ID NO:225, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO:219, or a combination of these polypeptide sequences. In another embodiment of the present disclosure, the antibodies of the present disclosure comprise a combination of the CDRs and variable heavy and light chain sequences described above.

[0234] The present disclosure also contemplates antibody fragments that have binding specificity for IL-6. In one embodiment of the present disclosure, the antibody fragment of the present disclosure comprises, or alternatively consists of, the polypeptide sequence of SEQ ID NO: 218. In another embodiment of the present disclosure, the antibody fragment of the present disclosure comprises, or alternatively consists of, the polypeptide sequence of SEQ ID NO: 219.

[0235] In further embodiments of the present disclosure, antibody fragments having binding specificity for IL-6 comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO:220; SEQ ID NO:221; and SEQ ID NO:222, which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO:218.

[0236] In further embodiments of the present disclosure, the antibody fragment having binding specificity for IL-6 comprises, or alternatively consists of, one or more of the polypeptide sequences of SEQ ID NO:223; SEQ ID NO:224; and SEQ ID NO:225, which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO:219.

[0237] The present disclosure also contemplates antibody fragments comprising one or more of the antibody fragments described herein. In one embodiment of the present disclosure, the antibody fragment having binding specificity to IL-6 comprises, or alternatively consists of, one, two, three, or more, including all, of the following antibody fragments: the variable light chain region of SEQ ID NO:218; the variable heavy chain region of SEQ ID NO:219; the complementarity determining regions of the variable light chain region of SEQ ID NO:218 (SEQ ID NO:220; SEQ ID NO:221; and SEQ ID NO:222); and the complementarity determining regions of the variable heavy chain region of SEQ ID NO:219 (SEQ ID NO:223; SEQ ID NO:224; and SEQ ID NO:225).

[0238] In one embodiment of the present disclosure, the anti-IL-6 antibody is Ab14 comprising SEQ ID NO:218 and SEQ ID NO:219 and having at least one of the biological activities described herein.

[0239] In another embodiment, the present disclosure includes an antibody that has binding specificity for IL-6 and has a variable light chain sequence comprising the sequence shown below: MDTRAPTQLLGLLLLWLPGATFAQVLTQTASPVSAAVGGTVTINCQASQSVYKNNYLSWYQQKPGQPPKGLIYSASTLDSGVPLRFSGSGSGTQFTLTISDVQCDDAATYYCLGSYDCSSGDCYA (SEQ ID NO: 234)

[0240] The present disclosure also includes antibodies that have binding specificity for IL-6 and have a variable heavy chain sequence comprising the sequence shown below: METGLRWLLLVAVLKGVQCQSLEESGGDLVKPEGSLTLTCTASGFSFSSYWMCWVRQAPGKGLEWIACIVTGNGNTYYANWAKGRFTISKTSSTTVTLQMTSLTAADTATYFCAKAYDL (SEQ ID NO: 235)

[0241] The present disclosure further contemplates antibodies comprising one or more of the polypeptide sequences of SEQ ID NO:236; SEQ ID NO:237; and SEQ ID NO:238, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO:234, and / or one or more of the polypeptide sequences of SEQ ID NO:239; SEQ ID NO:240; and SEQ ID NO:241, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO:235, or a combination of these polypeptide sequences. In another embodiment of the present disclosure, the antibodies of the present disclosure comprise a combination of the CDRs and variable heavy and light chain sequences described above.

[0242] In another embodiment, the present disclosure contemplates other antibodies, e.g., chimeric antibodies, that comprise one or more of the polypeptide sequences of SEQ ID NO:236; SEQ ID NO:237; and SEQ ID NO:238, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO:234, and / or one or more of the polypeptide sequences of SEQ ID NO:239; SEQ ID NO:240; and SEQ ID NO:241, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO:235, or a combination of these polypeptide sequences. In another embodiment of the present disclosure, the antibodies of the present disclosure comprise a combination of the CDRs and variable heavy and light chain sequences described above.

[0243] The present disclosure also contemplates antibody fragments that have binding specificity for IL-6. In one embodiment of the present disclosure, the antibody fragment of the present disclosure comprises, or alternatively consists of, the polypeptide sequence of SEQ ID NO: 234. In another embodiment of the present disclosure, the antibody fragment of the present disclosure comprises, or alternatively consists of, the polypeptide sequence of SEQ ID NO: 235.

[0244] In further embodiments of the present disclosure, the antibody fragment having binding specificity for IL-6 comprises, or alternatively consists of, one or more of the polypeptide sequences of SEQ ID NO:236; SEQ ID NO:237; and SEQ ID NO:238, which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO:234.

[0245] In further embodiments of the present disclosure, antibody fragments having binding specificity for IL-6 comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO:239; SEQ ID NO:240; and SEQ ID NO:241, which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO:235.

[0246] The present disclosure also contemplates antibody fragments comprising one or more of the antibody fragments described herein. In one embodiment of the present disclosure, the antibody fragment having binding specificity to IL-6 comprises, or alternatively consists of, one, two, three, or more, including all, of the following antibody fragments: the variable light chain region of SEQ ID NO: 234; the variable heavy chain region of SEQ ID NO: 235; the complementarity determining regions of the variable light chain region of SEQ ID NO: 234 (SEQ ID NO: 236; SEQ ID NO: 237; and SEQ ID NO: 238); and the complementarity determining regions of the variable heavy chain region of SEQ ID NO: 235 (SEQ ID NO: 239; SEQ ID NO: 240; and SEQ ID NO: 241).

[0247] In one embodiment of the present disclosure, the anti-IL-6 antibody is Ab15, which comprises SEQ ID NO: 234 and SEQ ID NO: 235 and has at least one of the biological activities described herein.

[0248] In another embodiment, the present disclosure includes an antibody that has binding specificity for IL-6 and has a variable light chain sequence comprising the sequence shown below: MDTRAPTQLLGLLLLWLPGSTFAAVLTQTPSPVSAAVGGTVSISCQASQSVYDNNYLSWYQQKPGQPPKLLIYGASTLASGVPSRFKGTGSGTQFTLTITDVQCDDAATYYCAGVFNDDSDDA (SEQ ID NO: 250)

[0249] The present disclosure also includes antibodies that have binding specificity for IL-6 and have a variable heavy chain sequence comprising the sequence shown below: METGLRWLLLVAVPKGVQCQSLEESGGRLVTPGTPLTLTCTLSGFSLSAYYMSWVRQAPGKGLEWIGFITLSDHISYARWAKGRFTISKTSTTVDLKMTSPTTEDTATYFCARSRGWGAMGRLDL (SEQ ID NO: 251)

[0250] The present disclosure further contemplates antibodies comprising one or more of the polypeptide sequences of SEQ ID NO:252; SEQ ID NO:253; and SEQ ID NO:254, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO:250, and / or one or more of the polypeptide sequences of SEQ ID NO:255; SEQ ID NO:256; and SEQ ID NO:257, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO:251, or a combination of these polypeptide sequences. In another embodiment of the present disclosure, the antibodies of the present disclosure comprise a combination of the CDRs and variable heavy and light chain sequences described above.

[0251] In another embodiment, the present disclosure contemplates other antibodies, e.g., chimeric antibodies, that comprise one or more of the polypeptide sequences of SEQ ID NO:252; SEQ ID NO:253; and SEQ ID NO:254, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO:250, and / or one or more of the polypeptide sequences of SEQ ID NO:255; SEQ ID NO:256; and SEQ ID NO:257, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO:251, or a combination of these polypeptide sequences. In another embodiment of the present disclosure, the antibodies of the present disclosure comprise a combination of the CDRs and variable heavy and light chain sequences described above.

[0252] The present disclosure also contemplates antibody fragments that have binding specificity for IL-6. In one embodiment of the present disclosure, the antibody fragment of the present disclosure comprises, or alternatively consists of, the polypeptide sequence of SEQ ID NO: 250. In another embodiment of the present disclosure, the antibody fragment of the present disclosure comprises, or alternatively consists of, the polypeptide sequence of SEQ ID NO: 251.

[0253] In further embodiments of the present disclosure, antibody fragments having binding specificity for IL-6 comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO:252; SEQ ID NO:253; and SEQ ID NO:254, which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO:250.

[0254] In further embodiments of the present disclosure, antibody fragments having binding specificity for IL-6 comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO:255; SEQ ID NO:256; and SEQ ID NO:257, which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO:251.

[0255] The present disclosure also contemplates antibody fragments comprising one or more of the antibody fragments described herein. In one embodiment of the present disclosure, the antibody fragment having binding specificity to IL-6 comprises, or alternatively consists of, one, two, three, or more, including all, of the following antibody fragments: the variable light chain region of SEQ ID NO: 250; the variable heavy chain region of SEQ ID NO: 251; the complementarity determining regions of the variable light chain region of SEQ ID NO: 250 (SEQ ID NO: 252; SEQ ID NO: 253; and SEQ ID NO: 254); and the complementarity determining regions of the variable heavy chain region of SEQ ID NO: 251 (SEQ ID NO: 255; SEQ ID NO: 256; and SEQ ID NO: 257).

[0256] In one embodiment of the present disclosure, the anti-IL-6 antibody is Ab16, which comprises SEQ ID NO: 250 and SEQ ID NO: 251 and has at least one of the biological activities described herein.

[0257] In another embodiment, the present disclosure includes an antibody that has binding specificity for IL-6 and has a variable light chain sequence comprising the sequence shown below: MDTRAPTQLLGLLLLWLPGATFAAVLTQTPSPVSAAVGGTVTISCQASQSVYNNKNLAWYQQKSGQPPKLLIYWASTLASGVSSRFSGSGSGTQFTLTVSGVQCDDAATYYCLGVFDDDADNA (SEQ ID NO: 266)

[0258] The present disclosure also includes antibodies that have binding specificity for IL-6 and have a variable heavy chain sequence comprising the sequence shown below: METGLRWLLLVAVLKGVQCQSVEESGGRLVTPGTPLTLTCTASGFSLSSYSMTWVRQAPGKGLEYIGVIGTSGSTYYATWAKGRFTISRTSTTVALKITSPTTEDTATYFCVRSLSSITFL (SEQ ID NO: 267)

[0259] The present disclosure further contemplates antibodies comprising one or more of the polypeptide sequences of SEQ ID NO:268; SEQ ID NO:269; and SEQ ID NO:270, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO:266, and / or one or more of the polypeptide sequences of SEQ ID NO:271; SEQ ID NO:272; and SEQ ID NO:273, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO:267, or a combination of these polypeptide sequences. In another embodiment of the present disclosure, the antibodies of the present disclosure comprise a combination of the CDRs and variable heavy and light chain sequences described above.

[0260] In another embodiment, the present disclosure contemplates other antibodies, e.g., chimeric antibodies, that comprise one or more of the polypeptide sequences of SEQ ID NO:268; SEQ ID NO:269; and SEQ ID NO:270, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO:266, and / or one or more of the polypeptide sequences of SEQ ID NO:271; SEQ ID NO:272; and SEQ ID NO:273, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO:267, or a combination of these polypeptide sequences. In another embodiment of the present disclosure, the antibodies of the present disclosure comprise a combination of the CDRs and variable heavy and light chain sequences described above.

[0261] The present disclosure also contemplates antibody fragments that have binding specificity for IL-6. In one embodiment of the present disclosure, the antibody fragment of the present disclosure comprises, or alternatively consists of, the polypeptide sequence of SEQ ID NO: 266. In another embodiment of the present disclosure, the antibody fragment of the present disclosure comprises, or alternatively consists of, the polypeptide sequence of SEQ ID NO: 267.

[0262] In further embodiments of the present disclosure, antibody fragments having binding specificity for IL-6 comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO:268; SEQ ID NO:269; and SEQ ID NO:270, which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO:266.

[0263] In further embodiments of the present disclosure, antibody fragments having binding specificity for IL-6 comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO:271; SEQ ID NO:272; and SEQ ID NO:273, which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO:267.

[0264] The present disclosure also contemplates antibody fragments comprising one or more of the antibody fragments described herein. In one embodiment of the present disclosure, the antibody fragment having binding specificity to IL-6 comprises, or alternatively consists of, one, two, three, or more, including all, of the following antibody fragments: the variable light chain region of SEQ ID NO:266; the variable heavy chain region of SEQ ID NO:267; the complementarity determining regions of the variable light chain region of SEQ ID NO:266 (SEQ ID NO:268; SEQ ID NO:269; and SEQ ID NO:270); and the complementarity determining regions of the variable heavy chain region of SEQ ID NO:267 (SEQ ID NO:271; SEQ ID NO:272; and SEQ ID NO:273).

[0265] In one embodiment of the present disclosure, the anti-IL-6 antibody is Ab17, which comprises SEQ ID NO: 266 and SEQ ID NO: 267 and has at least one of the biological activities described herein.

[0266] In another embodiment, the present disclosure includes an antibody that has binding specificity for IL-6 and has a variable light chain sequence comprising the sequence shown below: MDTRAPTQLLGLLLLWLPGARCAFELTQTPASVEAAVGGTVTINCQASQNIYRYLAWYQQKPGQPPKFLIYLASTLASGVPSRFKGSGSGTEFTLTISDLECADAATYYCQSYYSSNSVA (SEQ ID NO: 282)

[0267] The present disclosure also includes antibodies that have binding specificity for IL-6 and have a variable heavy chain sequence comprising the sequence shown below: METGLRWLLLVAVLKGVQCQEQLVESGGDLVQPEGSLTLTCTASELDFSSGYWICWVRQVPGKGLEWIGCIYTGSSGSTFYASWAKGRFTISKTSSTTVTLQMTSLTAADTATYFCARGYSGFGYFKL (SEQ ID NO: 283)

[0268] The present disclosure further contemplates antibodies comprising one or more of the polypeptide sequences of SEQ ID NO:284; SEQ ID NO:285; and SEQ ID NO:286, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO:282, and / or one or more of the polypeptide sequences of SEQ ID NO:287; SEQ ID NO:288; and SEQ ID NO:289, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO:283, or a combination of these polypeptide sequences. In another embodiment of the present disclosure, the antibodies of the present disclosure comprise a combination of the CDRs and variable heavy and light chain sequences described above.

[0269] In another embodiment, the present disclosure contemplates other antibodies, e.g., chimeric antibodies, that comprise one or more of the polypeptide sequences of SEQ ID NO:284; SEQ ID NO:285; and SEQ ID NO:286, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO:282, and / or one or more of the polypeptide sequences of SEQ ID NO:287; SEQ ID NO:288; and SEQ ID NO:289, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO:283, or a combination of these polypeptide sequences. In another embodiment of the present disclosure, the antibodies of the present disclosure comprise a combination of the CDRs and variable heavy and light chain sequences described above.

[0270] The present disclosure also contemplates antibody fragments that have binding specificity for IL-6. In one embodiment of the present disclosure, the antibody fragment of the present disclosure comprises, or alternatively consists of, the polypeptide sequence of SEQ ID NO: 282. In another embodiment of the present disclosure, the antibody fragment of the present disclosure comprises, or alternatively consists of, the polypeptide sequence of SEQ ID NO: 283.

[0271] In further embodiments of the present disclosure, antibody fragments having binding specificity for IL-6 comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO:284; SEQ ID NO:285; and SEQ ID NO:286, which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO:282.

[0272] In further embodiments of the present disclosure, antibody fragments having binding specificity for IL-6 comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO:287; SEQ ID NO:288; and SEQ ID NO:289, which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO:283.

[0273] The present disclosure also contemplates antibody fragments comprising one or more of the antibody fragments described herein. In one embodiment of the present disclosure, the antibody fragment having binding specificity to IL-6 comprises, or alternatively consists of, one, two, three, or more, including all, of the following antibody fragments: the variable light chain region of SEQ ID NO: 282; the variable heavy chain region of SEQ ID NO: 283; the complementarity determining regions of the variable light chain region of SEQ ID NO: 282 (SEQ ID NO: 284; SEQ ID NO: 285; and SEQ ID NO: 286); and the complementarity determining regions of the variable heavy chain region of SEQ ID NO: 283 (SEQ ID NO: 287; SEQ ID NO: 288; and SEQ ID NO: 289).

[0274] In one embodiment of the present disclosure, the anti-IL-6 antibody is Ab18 comprising SEQ ID NO: 282 and SEQ ID NO: 283 and having at least one of the biological activities described herein.

[0275] In another embodiment, the present disclosure includes an antibody that has binding specificity for IL-6 and has a variable light chain sequence comprising the sequence shown below: MDTRAPTQLLGLLLLWLPGARCAYDMTQTPASVEVAVGGTVTIKCQASEDIYRLLAWYQQKPGQPPKLLIYDSSDLASGVPSRFKGSGSGTEFTLAISGVQCDDAATYYCQQAWSYSDIDNA (SEQ ID NO: 298)

[0276] The present disclosure also includes antibodies that have binding specificity for IL-6 and have a variable heavy chain sequence comprising the sequence shown below: METGLRWLLLVAVLKGVQCQSVEESGGRLVTPGTPLTLTCTASGFSLSSYYMSWVRQAPGKGLEWIGIITTSGNTFYASWAKGRLTISRTSTTVDLKITSPTTEDTATYFCARTSDIFYYRNL (SEQ ID NO: 299)

[0277] The present disclosure further contemplates antibodies comprising one or more of the polypeptide sequences of SEQ ID NO: 300; SEQ ID NO: 301; and SEQ ID NO: 302, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 298, and / or one or more of the polypeptide sequences of SEQ ID NO: 303; SEQ ID NO: 304; and SEQ ID NO: 305, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 299, or a combination of these polypeptide sequences. In another embodiment of the present disclosure, the antibodies of the present disclosure comprise a combination of the CDRs and variable heavy and light chain sequences described above.

[0278] In another embodiment, the present disclosure contemplates other antibodies, e.g., chimeric antibodies, that comprise one or more of the polypeptide sequences of SEQ ID NO: 300; SEQ ID NO: 301; and SEQ ID NO: 302, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 298, and / or one or more of the polypeptide sequences of SEQ ID NO: 303; SEQ ID NO: 304; and SEQ ID NO: 305, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 299, or a combination of these polypeptide sequences. In another embodiment of the present disclosure, the antibodies of the present disclosure comprise a combination of the CDRs and variable heavy and light chain sequences described above.

[0279] The present disclosure also contemplates antibody fragments that have binding specificity for IL-6. In one embodiment of the present disclosure, the antibody fragment of the present disclosure comprises, or alternatively consists of, the polypeptide sequence of SEQ ID NO: 298. In another embodiment of the present disclosure, the antibody fragment of the present disclosure comprises, or alternatively consists of, the polypeptide sequence of SEQ ID NO: 299.

[0280] In further embodiments of the present disclosure, the antibody fragment having binding specificity for IL-6 comprises, or alternatively consists of, one or more of the polypeptide sequences of SEQ ID NO:300; SEQ ID NO:301; and SEQ ID NO:302, which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO:298.

[0281] In further embodiments of the present disclosure, the antibody fragment having binding specificity for IL-6 comprises, or alternatively consists of, one or more of the polypeptide sequences of SEQ ID NO:303; SEQ ID NO:304; and SEQ ID NO:305, which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO:299.

[0282] The present disclosure also contemplates antibody fragments comprising one or more of the antibody fragments described herein. In one embodiment of the present disclosure, the antibody fragment having binding specificity to IL-6 comprises, or alternatively consists of, one, two, three, or more, including all, of the following antibody fragments: the variable light chain region of SEQ ID NO:298; the variable heavy chain region of SEQ ID NO:299; the complementarity determining regions of the variable light chain region of SEQ ID NO:298 (SEQ ID NO:300; SEQ ID NO:301; and SEQ ID NO:302); and the complementarity determining regions of the variable heavy chain region of SEQ ID NO:299 (SEQ ID NO:303; SEQ ID NO:304; and SEQ ID NO:305).

[0283] In one embodiment of the present disclosure, the anti-IL-6 antibody is Ab19 comprising SEQ ID NO:298 and SEQ ID NO:299 and having at least one of the biological activities described herein.

[0284] In another embodiment, the present disclosure includes an antibody that has binding specificity for IL-6 and has a variable light chain sequence comprising the sequence shown below: MDTRAPTQLLGLLLLWLPGATFAAVLTQTASPVSAAVGATVTINCQSSQSVYNDMDLAWFQQKPGQPPKLLIYSASTLASGVPSRFSGSGSGTEFTLTISGVQCDDAATYYCLGAFDDDADNT (SEQ ID NO: 314)

[0285] The present disclosure also includes antibodies that have binding specificity for IL-6 and have a variable heavy chain sequence comprising the sequence shown below: METGLRWLLLVAVLKGVQCQSVEESGGRLVTPGTPLTLTCTVSGFSLTRHAITWVRQAPGKGLEWIGCIWSGGSTYYATWAKGRFTISKTSTTVDLRITSPTTEDTATYFCARVIGDTAGYAYFTGLDL (SEQ ID NO: 315)

[0286] The present disclosure further contemplates antibodies comprising one or more of the polypeptide sequences of SEQ ID NO: 316; SEQ ID NO: 317; and SEQ ID NO: 318, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 314, and / or one or more of the polypeptide sequences of SEQ ID NO: 319; SEQ ID NO: 320; and SEQ ID NO: 321, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 315, or a combination of these polypeptide sequences. In another embodiment of the present disclosure, the antibodies of the present disclosure comprise a combination of the CDRs and variable heavy and light chain sequences described above.

[0287] In another embodiment, the present disclosure contemplates other antibodies, e.g., chimeric antibodies, that comprise one or more of the polypeptide sequences of SEQ ID NO: 316; SEQ ID NO: 317; and SEQ ID NO: 318, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 314, and / or one or more of the polypeptide sequences of SEQ ID NO: 319; SEQ ID NO: 320; and SEQ ID NO: 321, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 315, or a combination of these polypeptide sequences. In another embodiment of the present disclosure, the antibodies of the present disclosure comprise a combination of the CDRs and variable heavy and light chain sequences described above.

[0288] The present disclosure also contemplates antibody fragments that have binding specificity for IL-6. In one embodiment of the present disclosure, the antibody fragment of the present disclosure comprises, or alternatively consists of, the polypeptide sequence of SEQ ID NO: 314. In another embodiment of the present disclosure, the antibody fragment of the present disclosure comprises, or alternatively consists of, the polypeptide sequence of SEQ ID NO: 315.

[0289] In further embodiments of the present disclosure, the antibody fragment having binding specificity for IL-6 comprises, or alternatively consists of, one or more of the polypeptide sequences of SEQ ID NO:316; SEQ ID NO:317; and SEQ ID NO:318, which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO:314.

[0290] In further embodiments of the present disclosure, antibody fragments having binding specificity for IL-6 comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO:319; SEQ ID NO:320; and SEQ ID NO:321, which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO:315.

[0291] The present disclosure also contemplates antibody fragments comprising one or more of the antibody fragments described herein. In one embodiment of the present disclosure, the antibody fragment having binding specificity to IL-6 comprises, or alternatively consists of, one, two, three, or more, including all, of the following antibody fragments: the variable light chain region of SEQ ID NO: 314; the variable heavy chain region of SEQ ID NO: 315; the complementarity determining regions of the variable light chain region of SEQ ID NO: 314 (SEQ ID NO: 316; SEQ ID NO: 317; and SEQ ID NO: 318); and the complementarity determining regions of the variable heavy chain region of SEQ ID NO: 315 (SEQ ID NO: 319; SEQ ID NO: 320; and SEQ ID NO: 321).

[0292] In one embodiment of the present disclosure, the anti-IL-6 antibody is Ab20 comprising SEQ ID NO: 314 and SEQ ID NO: 315 and having at least one of the biological activities described herein.

[0293] In another embodiment, the present disclosure includes an antibody that has binding specificity for IL-6 and has a variable light chain sequence comprising the sequence shown below: MDTRAPTQLLGLLLLWLPGARCAYDMTQTPASVEVAVGGTVTIKCQASQSVYNWLSWYQQKPGQPPKLLIYTASSLASGVPSRFSGSGSGTEFTLTISGVECADAATYYCQQGYTSDVDNV (SEQ ID NO: 330)

[0294] The present disclosure also includes antibodies that have binding specificity for IL-6 and have a variable heavy chain sequence comprising the sequence shown below: METGLRWLLLVAVLKGVQCQSLEEAGGRLVTPGTPLTLTCTVSGIDLSSYAMGWVRQAPGKGLEYIGIISSSGSTYYATWAKGRFTISQASSTTVDLKITSPTTEDSATYFCARGGAGSGGVWLLDGFDP (SEQ ID NO: 331)

[0295] The present disclosure further contemplates antibodies comprising one or more of the polypeptide sequences of SEQ ID NO: 332; SEQ ID NO: 333; and SEQ ID NO: 334, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 330, and / or one or more of the polypeptide sequences of SEQ ID NO: 335; SEQ ID NO: 336; and SEQ ID NO: 337, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 331, or a combination of these polypeptide sequences. In another embodiment of the present disclosure, the antibodies of the present disclosure comprise a combination of the CDRs and variable heavy and light chain sequences described above.

[0296] In another embodiment, the present disclosure contemplates other antibodies, e.g., chimeric antibodies, that comprise one or more of the polypeptide sequences of SEQ ID NOs: 332; 333; and 334, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 330, and / or one or more of the polypeptide sequences of SEQ ID NOs: 335; 336; and 337, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 331, or a combination of these polypeptide sequences. In another embodiment of the present disclosure, the antibodies of the present disclosure comprise a combination of the CDRs and variable heavy and light chain sequences described above.

[0297] The present disclosure also contemplates antibody fragments that have binding specificity for IL-6. In one embodiment of the present disclosure, the antibody fragment of the present disclosure comprises, or alternatively consists of, the polypeptide sequence of SEQ ID NO: 330. In another embodiment of the present disclosure, the antibody fragment of the present disclosure comprises, or alternatively consists of, the polypeptide sequence of SEQ ID NO: 331.

[0298] In further embodiments of the present disclosure, antibody fragments having binding specificity for IL-6 comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO: 332; SEQ ID NO: 333; and SEQ ID NO: 334, which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 330.

[0299] In further embodiments of the present disclosure, the antibody fragment having binding specificity for IL-6 comprises, or alternatively consists of, one or more of the polypeptide sequences of SEQ ID NO:335; SEQ ID NO:336; and SEQ ID NO:337, which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO:331.

[0300] The present disclosure also contemplates antibody fragments comprising one or more of the antibody fragments described herein. In one embodiment of the present disclosure, the antibody fragment having binding specificity to IL-6 comprises, or alternatively consists of, one, two, three, or more, including all, of the following antibody fragments: the variable light chain region of SEQ ID NO: 330; the variable heavy chain region of SEQ ID NO: 331; the complementarity determining regions of the variable light chain region of SEQ ID NO: 330 (SEQ ID NO: 332; SEQ ID NO: 333; and SEQ ID NO: 334); and the complementarity determining regions of the variable heavy chain region of SEQ ID NO: 331 (SEQ ID NO: 335; SEQ ID NO: 336; and SEQ ID NO: 337).

[0301] In one embodiment of the present disclosure, the anti-IL-6 antibody is Ab21 comprising SEQ ID NO: 330 and SEQ ID NO: 331 and having at least one of the biological activities described herein.

[0302] In another embodiment, the present disclosure includes an antibody that has binding specificity for IL-6 and has a variable light chain sequence comprising the sequence shown below: MDTRAPTQLLGLLLLWLPGAKCADVVMTQTPASVSAAVGGTVTINCQASENIYNWLAWYQQKPGQPPKLLIYTVGDLASGVSSRFKGSGSGTEFTLTISDLECADAATYYCQQGYSSSYVDNV (SEQ ID NO: 346)

[0303] The present disclosure also includes antibodies that have binding specificity for IL-6 and have a variable heavy chain sequence comprising the sequence shown below: METGLRWLLLVAVLKGVQCQEQLKESGGRLVTPGTPLTLTCTVSGFSLNDYAVGWFRQAPGKGLEWIGYIRSSGTTAYATWAKGRFTISATSTTVDLKITSPTTEDTATYFCARGGAGSSGVWILDGFAP (SEQ ID NO: 347)

[0304] The present disclosure further contemplates antibodies comprising one or more of the polypeptide sequences of SEQ ID NO: 348; SEQ ID NO: 349; and SEQ ID NO: 350, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 346, and / or one or more of the polypeptide sequences of SEQ ID NO: 351; SEQ ID NO: 352; and SEQ ID NO: 353, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 347, or a combination of these polypeptide sequences. In another embodiment of the present disclosure, an antibody of the present disclosure comprises a combination of the CDRs and variable heavy and light chain sequences described above.

[0305] In another embodiment, the present disclosure contemplates other antibodies, e.g., chimeric antibodies, that comprise one or more of the polypeptide sequences of SEQ ID NO: 348; SEQ ID NO: 349; and SEQ ID NO: 350, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 346, and / or one or more of the polypeptide sequences of SEQ ID NO: 351; SEQ ID NO: 352; and SEQ ID NO: 353, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 347, or a combination of these polypeptide sequences. In another embodiment of the present disclosure, the antibodies of the present disclosure comprise a combination of the CDRs and variable heavy and light chain sequences described above.

[0306] The present disclosure also contemplates antibody fragments that have binding specificity for IL-6. In one embodiment of the present disclosure, the antibody fragment of the present disclosure comprises, or alternatively consists of, the polypeptide sequence of SEQ ID NO: 346. In another embodiment of the present disclosure, the antibody fragment of the present disclosure comprises, or alternatively consists of, the polypeptide sequence of SEQ ID NO: 347.

[0307] In further embodiments of the present disclosure, antibody fragments having binding specificity for IL-6 comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO:348; SEQ ID NO:349; and SEQ ID NO:350, which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO:346.

[0308] In further embodiments of the present disclosure, antibody fragments having binding specificity for IL-6 comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO:351; SEQ ID NO:352; and SEQ ID NO:353, which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO:347.

[0309] The present disclosure also contemplates antibody fragments comprising one or more of the antibody fragments described herein. In one embodiment of the present disclosure, the antibody fragment having binding specificity to IL-6 comprises, or alternatively consists of, one, two, three, or more, including all, of the following antibody fragments: the variable light chain region of SEQ ID NO: 346; the variable heavy chain region of SEQ ID NO: 347; the complementarity determining regions of the variable light chain region of SEQ ID NO: 346 (SEQ ID NO: 348; SEQ ID NO: 349; and SEQ ID NO: 350); and the complementarity determining regions of the variable heavy chain region of SEQ ID NO: 347 (SEQ ID NO: 351; SEQ ID NO: 352; and SEQ ID NO: 353).

[0310] In one embodiment of the present disclosure, the anti-IL-6 antibody is Ab22 comprising SEQ ID NO: 346 and SEQ ID NO: 347 and having at least one of the biological activities described herein.

[0311] In another embodiment, the present disclosure includes an antibody that has binding specificity for IL-6 and has a variable light chain sequence comprising the sequence shown below: MDTRAPTQLLGLLLLWLPGATFAQVLTQTPSSVSAAVGGTVTINCQASQSVYQNNYLSWFQQKPGQPPKLLIYGAATLASGVPSRFKGSGSGTQFTLTISDLECDDAATYYCAGAYRDVDS (SEQ ID NO: 362)

[0312] The present disclosure also includes antibodies that have binding specificity for IL-6 and have a variable heavy chain sequence comprising the sequence shown below: METGLRWLLLVAVLKGVQCQSLEESGGDLVKPGASLTLTCTASGFSFTSTYYIYWVRQAPGKGLEWIACIDAGSSGSTYYATWVNGRFTISKTSSTTVTLQMTSLTAADTATYFCAKWDYGGNVGWGYDL (SEQ ID NO: 363)

[0313] The present disclosure further contemplates antibodies comprising one or more of the polypeptide sequences of SEQ ID NO: 364; SEQ ID NO: 365; and SEQ ID NO: 366, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 362, and / or one or more of the polypeptide sequences of SEQ ID NO: 367; SEQ ID NO: 368; and SEQ ID NO: 369, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 363, or a combination of these polypeptide sequences. In another embodiment of the present disclosure, the antibodies of the present disclosure comprise a combination of the CDRs and variable heavy and light chain sequences described above.

[0314] In another embodiment, the present disclosure contemplates other antibodies, e.g., chimeric antibodies, that comprise one or more of the polypeptide sequences of SEQ ID NO: 364; SEQ ID NO: 365; and SEQ ID NO: 366, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 362, and / or one or more of the polypeptide sequences of SEQ ID NO: 367; SEQ ID NO: 368; and SEQ ID NO: 369, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 363, or a combination of these polypeptide sequences. In another embodiment of the present disclosure, the antibodies of the present disclosure comprise a combination of the CDRs and variable heavy and light chain sequences described above.

[0315] The present disclosure also contemplates antibody fragments that have binding specificity for IL-6. In one embodiment of the present disclosure, the antibody fragment of the present disclosure comprises, or alternatively consists of, the polypeptide sequence of SEQ ID NO: 362. In another embodiment of the present disclosure, the antibody fragment of the present disclosure comprises, or alternatively consists of, the polypeptide sequence of SEQ ID NO: 363.

[0316] In further embodiments of the present disclosure, antibody fragments having binding specificity for IL-6 comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO:364; SEQ ID NO:365; and SEQ ID NO:366, which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO:362.

[0317] In further embodiments of the present disclosure, antibody fragments having binding specificity for IL-6 comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO:367; SEQ ID NO:368; and SEQ ID NO:369, which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO:363.

[0318] The present disclosure also contemplates antibody fragments comprising one or more of the antibody fragments described herein. In one embodiment of the present disclosure, the antibody fragment having binding specificity to IL-6 comprises, or alternatively consists of, one, two, three, or more, including all, of the following antibody fragments: the variable light chain region of SEQ ID NO: 362; the variable heavy chain region of SEQ ID NO: 363; the complementarity determining regions of the variable light chain region of SEQ ID NO: 362 (SEQ ID NO: 364; SEQ ID NO: 365; and SEQ ID NO: 366); and the complementarity determining regions of the variable heavy chain region of SEQ ID NO: 363 (SEQ ID NO: 367; SEQ ID NO: 368; and SEQ ID NO: 369).

[0319] In one embodiment of the present disclosure, the anti-IL-6 antibody is Ab23 comprising SEQ ID NO: 362 and SEQ ID NO: 363 and having at least one of the biological activities described herein.

[0320] In another embodiment, the present disclosure includes an antibody that has binding specificity for IL-6 and has a variable light chain sequence comprising the sequence shown below: MDTRAPTQLLGLLLLWLPGARCAFELTQTPSSVEAAVGGTVTIKCQASQSISSYLAWYQQKPGQPPKFLIYRASTLASGVPSRFKGSGSGTEFTLTISDLECADAATYYCQSYYDSVSNP (SEQ ID NO: 378)

[0321] The present disclosure also includes antibodies that have binding specificity for IL-6 and have a variable heavy chain sequence comprising the sequence shown below: METGLRWLLLVAVLKGVQCQSLEESGGDLVKPEGSLTLTCKASGLDLGTYWFMCWVRQAPGKGLEWIACIYTGSSGSTFYASWVNGRFTISKTSSTTVTLQMTSLTAADTATYFCARGYSGYGYFKL (SEQ ID NO: 379)

[0322] The present disclosure further contemplates antibodies comprising one or more of the polypeptide sequences of SEQ ID NO: 380; SEQ ID NO: 381; and SEQ ID NO: 382, ​​which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 378, and / or one or more of the polypeptide sequences of SEQ ID NO: 383; SEQ ID NO: 384; and SEQ ID NO: 385, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 379, or a combination of these polypeptide sequences. In another embodiment of the present disclosure, the antibodies of the present disclosure comprise a combination of the CDRs and variable heavy and light chain sequences described above.

[0323] In another embodiment, the present disclosure contemplates other antibodies, e.g., chimeric antibodies, that comprise one or more of the polypeptide sequences of SEQ ID NO: 380; SEQ ID NO: 381; and SEQ ID NO: 382, ​​which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 378, and / or one or more of the polypeptide sequences of SEQ ID NO: 383; SEQ ID NO: 384; and SEQ ID NO: 385, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 379, or a combination of these polypeptide sequences. In another embodiment of the present disclosure, the antibodies of the present disclosure comprise a combination of the CDRs and variable heavy and light chain sequences described above.

[0324] The present disclosure also contemplates antibody fragments that have binding specificity for IL-6. In one embodiment of the present disclosure, the antibody fragment of the present disclosure comprises, or alternatively consists of, the polypeptide sequence of SEQ ID NO: 378. In another embodiment of the present disclosure, the antibody fragment of the present disclosure comprises, or alternatively consists of, the polypeptide sequence of SEQ ID NO: 379.

[0325] In further embodiments of the present disclosure, the antibody fragment having binding specificity for IL-6 comprises, or alternatively consists of, one or more of the polypeptide sequences of SEQ ID NO:380; SEQ ID NO:381; and SEQ ID NO:382, which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO:378.

[0326] In further embodiments of the present disclosure, antibody fragments having binding specificity for IL-6 comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO:383; SEQ ID NO:384; and SEQ ID NO:385, which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO:379.

[0327] The present disclosure also contemplates antibody fragments comprising one or more of the antibody fragments described herein. In one embodiment of the present disclosure, the antibody fragment having binding specificity to IL-6 comprises, or alternatively consists of, one, two, three, or more, including all, of the following antibody fragments: the variable light chain region of SEQ ID NO: 378; the variable heavy chain region of SEQ ID NO: 379; the complementarity determining regions of the variable light chain region of SEQ ID NO: 378 (SEQ ID NO: 380; SEQ ID NO: 381; and SEQ ID NO: 382); and the complementarity determining regions of the variable heavy chain region of SEQ ID NO: 379 (SEQ ID NO: 383; SEQ ID NO: 384; and SEQ ID NO: 385).

[0328] In one embodiment of the present disclosure, the anti-IL-6 antibody is Ab24 comprising SEQ ID NO: 378 and SEQ ID NO: 379 and having at least one of the biological activities described herein.

[0329] In another embodiment, the present disclosure includes an antibody that has binding specificity for IL-6 and has a variable light chain sequence comprising the sequence shown below: MDTRAPTQLLGLLLLWLPGVTFAIEMTQSPFSVSAAVGGTVSISCQASQSVYKNNQLSWYQQKSGQPPKLLIYGASALASGVPSRFKGSGSGTEFTLTISDVQCDDAATYYCAGAITGSIDTDG (SEQ ID NO: 394)

[0330] The present disclosure also includes antibodies that have binding specificity for IL-6 and have a variable heavy chain sequence comprising the sequence shown below: METGLRWLLLVAVLKGVQCQSLEESGGDLVKPGASLTLTCTTSGFSFSSSYFICWVRQAPGKGLEWIACIYGGDGSTYYASWAKGRFTISKTSSTTVTLQMTSLTAADTATYFCAREWAYSQGYFGAFDL (SEQ ID NO: 395)

[0331] The present disclosure further contemplates antibodies comprising one or more of the polypeptide sequences of SEQ ID NO: 396; SEQ ID NO: 397; and SEQ ID NO: 398, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 394, and / or one or more of the polypeptide sequences of SEQ ID NO: 399; SEQ ID NO: 400; and SEQ ID NO: 401, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 395, or a combination of these polypeptide sequences. In another embodiment of the present disclosure, the antibodies of the present disclosure comprise a combination of the CDRs and variable heavy and light chain sequences described above.

[0332] In another embodiment, the present disclosure contemplates other antibodies, e.g., chimeric antibodies, that comprise one or more of the polypeptide sequences of SEQ ID NO: 396; SEQ ID NO: 397; and SEQ ID NO: 398, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 394, and / or one or more of the polypeptide sequences of SEQ ID NO: 399; SEQ ID NO: 400; and SEQ ID NO: 401, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 395, or a combination of these polypeptide sequences. In another embodiment of the present disclosure, the antibodies of the present disclosure comprise a combination of the CDRs and variable heavy and light chain sequences described above.

[0333] The present disclosure also contemplates antibody fragments that have binding specificity for IL-6. In one embodiment of the present disclosure, the antibody fragment of the present disclosure comprises, or alternatively consists of, the polypeptide sequence of SEQ ID NO: 394. In another embodiment of the present disclosure, the antibody fragment of the present disclosure comprises, or alternatively consists of, the polypeptide sequence of SEQ ID NO: 395.

[0334] In further embodiments of the present disclosure, antibody fragments having binding specificity for IL-6 comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO:396; SEQ ID NO:397; and SEQ ID NO:398, which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO:394.

[0335] In further embodiments of the present disclosure, the antibody fragment having binding specificity for IL-6 comprises, or alternatively consists of, one or more of the polypeptide sequences of SEQ ID NO:399; SEQ ID NO:400; and SEQ ID NO:401, which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO:395.

[0336] The present disclosure also contemplates antibody fragments comprising one or more of the antibody fragments described herein. In one embodiment of the present disclosure, the antibody fragment having binding specificity to IL-6 comprises, or alternatively consists of, one, two, three, or more, including all, of the following antibody fragments: the variable light chain region of SEQ ID NO: 394; the variable heavy chain region of SEQ ID NO: 395; the complementarity determining regions of the variable light chain region of SEQ ID NO: 394 (SEQ ID NO: 396; SEQ ID NO: 397; and SEQ ID NO: 398); and the complementarity determining regions of the variable heavy chain region of SEQ ID NO: 395 (SEQ ID NO: 399; SEQ ID NO: 400; and SEQ ID NO: 401).

[0337] In one embodiment of the present disclosure, the anti-IL-6 antibody is Ab25 comprising SEQ ID NO: 394 and SEQ ID NO: 395 and having at least one of the biological activities described herein.

[0338] In another embodiment, the present disclosure includes an antibody that has binding specificity for IL-6 and has a variable light chain sequence comprising the sequence shown below: MDTRAPTQLLGLLLLWLPGARCDVVMTQTPASVEAAVGGTVTIKCQASEDISSYLAWYQQKPGQPPKLLIYAASNLESGVSSRFKGSGSGTEYTLTISDLECADAATYYCQCTYGTISISDGNA (SEQ ID NO: 410)

[0339] The present disclosure also includes antibodies that have binding specificity for IL-6 and have a variable heavy chain sequence comprising the sequence shown below: METGLRWLLLVAVLKGVQCQSVEESGGRLVTPGTPLTLTCTVSGFSLSSYFMTWVRQAPGEGLEYIGFINPGGSAYYASWVKGRFTISKSSTTVDLKITSPTTEDTATYFCARVLIVSYGAFTI (SEQ ID NO: 411)

[0340] The present disclosure further contemplates antibodies comprising one or more of the polypeptide sequences of SEQ ID NO: 412; SEQ ID NO: 413; and SEQ ID NO: 414, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 410, and / or one or more of the polypeptide sequences of SEQ ID NO: 415; SEQ ID NO: 416; and SEQ ID NO: 417, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 411, or a combination of these polypeptide sequences. In another embodiment of the present disclosure, the antibodies of the present disclosure comprise a combination of the CDRs and variable heavy and light chain sequences described above.

[0341] In another embodiment, the present disclosure contemplates other antibodies, e.g., chimeric antibodies, that comprise one or more of the polypeptide sequences of SEQ ID NO: 412; SEQ ID NO: 413; and SEQ ID NO: 414, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 410, and / or one or more of the polypeptide sequences of SEQ ID NO: 415; SEQ ID NO: 416; and SEQ ID NO: 417, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 411, or a combination of these polypeptide sequences. In another embodiment of the present disclosure, the antibodies of the present disclosure comprise a combination of the CDRs and variable heavy and light chain sequences described above.

[0342] The present disclosure also contemplates antibody fragments that have binding specificity for IL-6. In one embodiment of the present disclosure, the antibody fragment of the present disclosure comprises, or alternatively consists of, the polypeptide sequence of SEQ ID NO: 410. In another embodiment of the present disclosure, the antibody fragment of the present disclosure comprises, or alternatively consists of, the polypeptide sequence of SEQ ID NO: 411.

[0343] In further embodiments of the present disclosure, antibody fragments having binding specificity for IL-6 comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO:412; SEQ ID NO:413; and SEQ ID NO:414, which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO:410.

[0344] In further embodiments of the present disclosure, antibody fragments having binding specificity for IL-6 comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO:415; SEQ ID NO:416; and SEQ ID NO:417, which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO:411.

[0345] The present disclosure also contemplates antibody fragments comprising one or more of the antibody fragments described herein. In one embodiment of the present disclosure, the antibody fragment having binding specificity to IL-6 comprises, or alternatively consists of, one, two, three, or more, including all, of the following antibody fragments: the variable light chain region of SEQ ID NO: 410; the variable heavy chain region of SEQ ID NO: 411; the complementarity determining regions of the variable light chain region of SEQ ID NO: 410 (SEQ ID NO: 412; SEQ ID NO: 413; and SEQ ID NO: 414); and the complementarity determining regions of the variable heavy chain region of SEQ ID NO: 411 (SEQ ID NO: 415; SEQ ID NO: 416; and SEQ ID NO: 417).

[0346] In one embodiment of the present disclosure, the anti-IL-6 antibody is Ab26 comprising SEQ ID NO:410 and SEQ ID NO:411 and having at least one of the biological activities described herein.

[0347] In another embodiment, the present disclosure includes an antibody that has binding specificity for IL-6 and has a variable light chain sequence comprising the sequence shown below: MDTRAPTQLLGLLLLWLPGARCDVVMTQTPASVSAAVGGTVTIKCQASEDIESYLAWYQQKPGQPPKLLIYGASNLESGVSSRFKGSGSGTEFTLTISDLECADAATYYCQCTYGIISISDGNA (SEQ ID NO: 426)

[0348] The present disclosure also includes antibodies that have binding specificity for IL-6 and have a variable heavy chain sequence comprising the sequence shown below: METGLRWLLLVAVLKGVQCQSVEESGGRLVTPGTPLTLTCTVSGFSLSSYFMTWVRQAPGEGLEYIGFMNTGDNAYYASWAKGRFTISKTSTTVDLKITSPTTEDTATYFCARVLVVAYGAFNI (SEQ ID NO: 427)

[0349] The present disclosure further contemplates antibodies comprising one or more of the polypeptide sequences of SEQ ID NO: 428; SEQ ID NO: 429; and SEQ ID NO: 430, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 426, and / or one or more of the polypeptide sequences of SEQ ID NO: 431; SEQ ID NO: 432; and SEQ ID NO: 433, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 427, or a combination of these polypeptide sequences. In another embodiment of the present disclosure, an antibody of the present disclosure comprises a combination of the CDRs and variable heavy and light chain sequences described above.

[0350] In another embodiment, the present disclosure contemplates other antibodies, e.g., chimeric antibodies, that comprise one or more of the polypeptide sequences of SEQ ID NO: 428; SEQ ID NO: 429; and SEQ ID NO: 430, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 426, and / or one or more of the polypeptide sequences of SEQ ID NO: 431; SEQ ID NO: 432; and SEQ ID NO: 433, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 427, or a combination of these polypeptide sequences. In another embodiment of the present disclosure, the antibodies of the present disclosure comprise a combination of the CDRs and variable heavy and light chain sequences described above.

[0351] The present disclosure also contemplates antibody fragments that have binding specificity for IL-6. In one embodiment of the present disclosure, the antibody fragment of the present disclosure comprises, or alternatively consists of, the polypeptide sequence of SEQ ID NO: 426. In another embodiment of the present disclosure, the antibody fragment of the present disclosure comprises, or alternatively consists of, the polypeptide sequence of SEQ ID NO: 427.

[0352] In further embodiments of the present disclosure, antibody fragments having binding specificity for IL-6 comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO:428; SEQ ID NO:429; and SEQ ID NO:430, which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO:426.

[0353] In further embodiments of the present disclosure, antibody fragments having binding specificity for IL-6 comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO:431; SEQ ID NO:432; and SEQ ID NO:433, which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO:427.

[0354] The present disclosure also contemplates antibody fragments comprising one or more of the antibody fragments described herein. In one embodiment of the present disclosure, the antibody fragment having binding specificity to IL-6 comprises, or alternatively consists of, one, two, three, or more, including all, of the following antibody fragments: the variable light chain region of SEQ ID NO: 426; the variable heavy chain region of SEQ ID NO: 427; the complementarity determining regions of the variable light chain region of SEQ ID NO: 426 (SEQ ID NO: 428; SEQ ID NO: 429; and SEQ ID NO: 430); and the complementarity determining regions of the variable heavy chain region of SEQ ID NO: 427 (SEQ ID NO: 431; SEQ ID NO: 432; and SEQ ID NO: 433).

[0355] In one embodiment of the present disclosure, the anti-IL-6 antibody is Ab27, which comprises SEQ ID NO: 426 and SEQ ID NO: 427 and has at least one of the biological activities described herein.

[0356] In another embodiment, the present disclosure includes an antibody that has binding specificity for IL-6 and has a variable light chain sequence comprising the sequence shown below: MDTRAPTQLLGLLLLWLPGATFAAVLTQTPSPVSEPVGGTVSISCQSSKSVMNNNYLAWYQQKPGQPPKLLIYGASNLASGVPSRFSGSGSGTQFTLTISDVQCDDAATYYCQGGYTGYSDHGT (SEQ ID NO: 442)

[0357] The present disclosure also includes antibodies that have binding specificity for IL-6 and have a variable heavy chain sequence comprising the sequence shown below: METGLRWLLLVAVLKGVQCQSVEESGGRLVKPDETLTLTCTVSGIDLSSYPMNWVRQAPGKGLEWIGFINTGGTIVYASWAKGRFTISKTSTTVDLKMTSPTTEDTATYFCARGSYVSSGYAYYFNV (SEQ ID NO: 443)

[0358] The present disclosure further contemplates antibodies comprising one or more of the polypeptide sequences of SEQ ID NO: 444; SEQ ID NO: 445; and SEQ ID NO: 446, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 442, and / or one or more of the polypeptide sequences of SEQ ID NO: 447; SEQ ID NO: 448; and SEQ ID NO: 449, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 443, or a combination of these polypeptide sequences. In another embodiment of the present disclosure, an antibody of the present disclosure comprises a combination of the CDRs and variable heavy and light chain sequences described above.

[0359] In another embodiment, the present disclosure contemplates other antibodies, e.g., chimeric antibodies, that comprise one or more of the polypeptide sequences of SEQ ID NO: 444; SEQ ID NO: 445; and SEQ ID NO: 446, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 442, and / or one or more of the polypeptide sequences of SEQ ID NO: 447; SEQ ID NO: 448; and SEQ ID NO: 449, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 443, or a combination of these polypeptide sequences. In another embodiment of the present disclosure, the antibodies of the present disclosure comprise a combination of the CDRs and variable heavy and light chain sequences described above.

[0360] The present disclosure also contemplates antibody fragments that have binding specificity for IL-6. In one embodiment of the present disclosure, the antibody fragment of the present disclosure comprises, or alternatively consists of, the polypeptide sequence of SEQ ID NO: 442. In another embodiment of the present disclosure, the antibody fragment of the present disclosure comprises, or alternatively consists of, the polypeptide sequence of SEQ ID NO: 443.

[0361] In further embodiments of the present disclosure, antibody fragments having binding specificity for IL-6 comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO:444; SEQ ID NO:445; and SEQ ID NO:446, which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO:442.

[0362] In further embodiments of the present disclosure, antibody fragments having binding specificity for IL-6 comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO:447; SEQ ID NO:448; and SEQ ID NO:449, which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO:443.

[0363] The present disclosure also contemplates antibody fragments comprising one or more of the antibody fragments described herein. In one embodiment of the present disclosure, the antibody fragment having binding specificity to IL-6 comprises, or alternatively consists of, one, two, three, or more, including all, of the following antibody fragments: the variable light chain region of SEQ ID NO: 442; the variable heavy chain region of SEQ ID NO: 443; the complementarity determining regions of the variable light chain region of SEQ ID NO: 442 (SEQ ID NO: 444; SEQ ID NO: 445; and SEQ ID NO: 446); and the complementarity determining regions of the variable heavy chain region of SEQ ID NO: 443 (SEQ ID NO: 447; SEQ ID NO: 448; and SEQ ID NO: 449).

[0364] In one embodiment of the present disclosure, the anti-IL-6 antibody is Ab28 comprising SEQ ID NO: 442 and SEQ ID NO: 443 and having at least one of the biological activities described herein.

[0365] In another embodiment, the present disclosure includes an antibody that has binding specificity for IL-6 and has a variable light chain sequence comprising the sequence shown below: MDTRAPTQLLGLLLLWLPGATFAAVLTQTPSPVSAAVGGTVSISCQSSQSVYNNNWLSWFQQKPGQPPKLLIYKASTLASGVPSRFKGSGSGTQFTLTISDVQCDDVATYYCAGGYLDSVI (SEQ ID NO: 458)

[0366] The present disclosure also includes antibodies that have binding specificity for IL-6 and have a variable heavy chain sequence comprising the sequence shown below: METGLRWLLLVAVLKGVQCQSVEESGGRLVTPGTPLTLTCTVSGFSLSTYSINWVRQAPGKGLEWIGIIANSGTTFYANWAKGRFTVSKTSTTVDLKITSPTTEDTATYFCARESGMYNEYGKFNI (SEQ ID NO: 459)

[0367] The present disclosure further contemplates antibodies comprising one or more of the polypeptide sequences of SEQ ID NO: 460; SEQ ID NO: 461; and SEQ ID NO: 462, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 458, and / or one or more of the polypeptide sequences of SEQ ID NO: 463; SEQ ID NO: 464; and SEQ ID NO: 465, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 459, or a combination of these polypeptide sequences. In another embodiment of the present disclosure, the antibodies of the present disclosure comprise a combination of the CDRs and variable heavy and light chain sequences described above.

[0368] In another embodiment, the present disclosure contemplates other antibodies, e.g., chimeric antibodies, that comprise one or more of the polypeptide sequences of SEQ ID NO:460; SEQ ID NO:461; and SEQ ID NO:462, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO:458, and / or one or more of the polypeptide sequences of SEQ ID NO:463; SEQ ID NO:464; and SEQ ID NO:465, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO:459, or a combination of these polypeptide sequences. In another embodiment of the present disclosure, the antibodies of the present disclosure comprise a combination of the CDRs and variable heavy and light chain sequences described above.

[0369] The present disclosure also contemplates antibody fragments that have binding specificity for IL-6. In one embodiment of the present disclosure, the antibody fragment of the present disclosure comprises, or alternatively consists of, the polypeptide sequence of SEQ ID NO: 458. In another embodiment of the present disclosure, the antibody fragment of the present disclosure comprises, or alternatively consists of, the polypeptide sequence of SEQ ID NO: 459.

[0370] In further embodiments of the present disclosure, the antibody fragment having binding specificity for IL-6 comprises, or alternatively consists of, one or more of the polypeptide sequences of SEQ ID NO:460; SEQ ID NO:461; and SEQ ID NO:462, which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO:458.

[0371] In further embodiments of the present disclosure, antibody fragments having binding specificity for IL-6 comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO:463; SEQ ID NO:464; and SEQ ID NO:465, which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO:459.

[0372] The present disclosure also contemplates antibody fragments comprising one or more of the antibody fragments described herein. In one embodiment of the present disclosure, the antibody fragment having binding specificity to IL-6 comprises, or alternatively consists of, one, two, three, or more, including all, of the following antibody fragments: the variable light chain region of SEQ ID NO:458; the variable heavy chain region of SEQ ID NO:459; the complementarity determining regions of the variable light chain region of SEQ ID NO:458 (SEQ ID NO:460; SEQ ID NO:461; and SEQ ID NO:462); and the complementarity determining regions of the variable heavy chain region of SEQ ID NO:459 (SEQ ID NO:463; SEQ ID NO:464; and SEQ ID NO:465).

[0373] In one embodiment of the present disclosure, the anti-IL-6 antibody is Ab29 comprising SEQ ID NO: 458 and SEQ ID NO: 459 and having at least one of the biological activities described herein.

[0374] In another embodiment, the present disclosure includes an antibody that has binding specificity for IL-6 and has a variable light chain sequence comprising the sequence shown below: MDTRAPTQLLGLLLLWLPGARCASDMTQTPSSVSAAVGGTVTINCQASENIYSFLAWYQQKPGQPPKLLIFKASTLASGVSSRFKGSGSGTQFTLTISDLECDDAATYYCQQGATVYDIDNN (SEQ ID NO: 474)

[0375] The present disclosure also includes antibodies that have binding specificity for IL-6 and have a variable heavy chain sequence comprising the sequence shown below: METGLRWLLLVAVLKGVQCQSLEESGGRLVTPGTPLTLTCTVSGIDLSAYAMIWVRQAPGEGLEWITIIYPNGITYYANWAKGRFTVSKTSTAMDLKITSPTTEDTATYFCARDAESSKNAYWGYFNV (SEQ ID NO: 475)

[0376] The present disclosure further contemplates antibodies comprising one or more of the polypeptide sequences of SEQ ID NO: 476; SEQ ID NO: 477; and SEQ ID NO: 478, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 474, and / or one or more of the polypeptide sequences of SEQ ID NO: 479; SEQ ID NO: 480; and SEQ ID NO: 481, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 475, or a combination of these polypeptide sequences. In another embodiment of the present disclosure, the antibodies of the present disclosure comprise a combination of the CDRs and variable heavy and light chain sequences described above.

[0377] In another embodiment, the present disclosure contemplates other antibodies, e.g., chimeric antibodies, that comprise one or more of the polypeptide sequences of SEQ ID NO:476; SEQ ID NO:477; and SEQ ID NO:478, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO:474, and / or one or more of the polypeptide sequences of SEQ ID NO:479; SEQ ID NO:480; and SEQ ID NO:481, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO:475, or a combination of these polypeptide sequences. In another embodiment of the present disclosure, the antibodies of the present disclosure comprise a combination of the CDRs and variable heavy and light chain sequences described above.

[0378] The present disclosure also contemplates antibody fragments that have binding specificity for IL-6. In one embodiment of the present disclosure, the antibody fragment of the present disclosure comprises, or alternatively consists of, the polypeptide sequence of SEQ ID NO: 474. In another embodiment of the present disclosure, the antibody fragment of the present disclosure comprises, or alternatively consists of, the polypeptide sequence of SEQ ID NO: 475.

[0379] In further embodiments of the present disclosure, antibody fragments having binding specificity for IL-6 comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO:476; SEQ ID NO:477; and SEQ ID NO:478, which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO:474.

[0380] In further embodiments of the present disclosure, antibody fragments having binding specificity for IL-6 comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO:479; SEQ ID NO:480; and SEQ ID NO:481, which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO:475.

[0381] The present disclosure also contemplates antibody fragments comprising one or more of the antibody fragments described herein. In one embodiment of the present disclosure, the antibody fragment having binding specificity to IL-6 comprises, or alternatively consists of, one, two, three, or more, including all, of the following antibody fragments: the variable light chain region of SEQ ID NO: 474; the variable heavy chain region of SEQ ID NO: 475; the complementarity determining regions of the variable light chain region of SEQ ID NO: 474 (SEQ ID NO: 476; SEQ ID NO: 477; and SEQ ID NO: 478); and the complementarity determining regions of the variable heavy chain region of SEQ ID NO: 475 (SEQ ID NO: 479; SEQ ID NO: 480; and SEQ ID NO: 481).

[0382] In one embodiment of the present disclosure, the anti-IL-6 antibody is Ab30 comprising SEQ ID NO:474 and SEQ ID NO:475 and having at least one of the biological activities described herein.

[0383] In another embodiment, the present disclosure includes an antibody that has binding specificity for IL-6 and has a variable light chain sequence comprising the sequence shown below: MDTRAPTQLLGLLLLWLPGARCASDMTQTPSSVSAAVGGTVTINCQASENIYSFLAWYQQKPGQPPKLLIFRASTLASGVSSRFKGSGSGTQFTLTISDLECDDAATYYCQQGATVYDIDNN (SEQ ID NO: 490)

[0384] The present disclosure also includes antibodies that have binding specificity for IL-6 and have a variable heavy chain sequence comprising the sequence shown below: METGLRWLLLVAVLKGVQCQSLEESGGRLVTPGTPLTLTCTVSGIDLSAYAMIWVRQAPGEGLEWITIIYPNGITYYANWAKGRFTVSKTSTAMDLKITSPTTEDTATYFCARDAESSKNAYWGYFNV (SEQ ID NO: 491)

[0385] The present disclosure further contemplates antibodies comprising one or more of the polypeptide sequences of SEQ ID NO: 492; SEQ ID NO: 493; and SEQ ID NO: 494, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 490, and / or one or more of the polypeptide sequences of SEQ ID NO: 495; SEQ ID NO: 496; and SEQ ID NO: 497, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 491, or a combination of these polypeptide sequences. In another embodiment of the present disclosure, the antibodies of the present disclosure comprise a combination of the CDRs and variable heavy and light chain sequences described above.

[0386] In another embodiment, the present disclosure contemplates other antibodies, e.g., chimeric antibodies, that comprise one or more of the polypeptide sequences of SEQ ID NO:492; SEQ ID NO:493; and SEQ ID NO:494, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO:490, and / or one or more of the polypeptide sequences of SEQ ID NO:495; SEQ ID NO:496; and SEQ ID NO:497, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO:491, or a combination of these polypeptide sequences. In another embodiment of the present disclosure, the antibodies of the present disclosure comprise a combination of the CDRs and variable heavy and light chain sequences described above.

[0387] The present disclosure also contemplates antibody fragments that have binding specificity for IL-6. In one embodiment of the present disclosure, the antibody fragment of the present disclosure comprises, or alternatively consists of, the polypeptide sequence of SEQ ID NO: 490. In another embodiment of the present disclosure, the antibody fragment of the present disclosure comprises, or alternatively consists of, the polypeptide sequence of SEQ ID NO: 491.

[0388] In further embodiments of the present disclosure, antibody fragments having binding specificity for IL-6 comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO:492; SEQ ID NO:493; and SEQ ID NO:494, which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO:490.

[0389] In further embodiments of the present disclosure, antibody fragments having binding specificity for IL-6 comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO:495; SEQ ID NO:496; and SEQ ID NO:497, which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO:491.

[0390] The present disclosure also contemplates antibody fragments comprising one or more of the antibody fragments described herein. In one embodiment of the present disclosure, the antibody fragment having binding specificity to IL-6 comprises, or alternatively consists of, one, two, three, or more, including all, of the following antibody fragments: the variable light chain region of SEQ ID NO:490; the variable heavy chain region of SEQ ID NO:491; the complementarity determining regions of the variable light chain region of SEQ ID NO:490 (SEQ ID NO:492; SEQ ID NO:493; and SEQ ID NO:494); and the complementarity determining regions of the variable heavy chain region of SEQ ID NO:491 (SEQ ID NO:495; SEQ ID NO:496; and SEQ ID NO:497).

[0391] In one embodiment of the present disclosure, the anti-IL-6 antibody is Ab31 comprising SEQ ID NO: 490 and SEQ ID NO: 491 and having at least one of the biological activities described herein.

[0392] In another embodiment, the present disclosure includes an antibody that has binding specificity for IL-6 and has a variable light chain sequence comprising the sequence shown below: MDTRAPTQLLGLLLLWLPGATFAIEMTQTPSPVSAAVGGTVTINCQASESVFNNMLSWYQQKPGHSPKLLIYDASDLASGVPSRFKGSGSGTQFTLTISGVECDDAATYYCAGYKSDSNDGDNV (SEQ ID NO: 506)

[0393] The present disclosure also includes antibodies that have binding specificity for IL-6 and have a variable heavy chain sequence comprising the sequence shown below: METGLRWLLLVAVLKGVQCQSLEESGGRLVTPGTPLTLTCTVSGFSLNRNSITWVRQAPGEGLEWIGIITGSGRTYYANWAKGRFTISKTSTTVDLKMTSPTTEDTATYFCARGHPGLGSGNI (SEQ ID NO: 507)

[0394] The present disclosure further contemplates antibodies comprising one or more of the polypeptide sequences of SEQ ID NO:508; SEQ ID NO:509; and SEQ ID NO:510, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO:506, and / or one or more of the polypeptide sequences of SEQ ID NO:511; SEQ ID NO:512; and SEQ ID NO:513, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO:507, or a combination of these polypeptide sequences. In another embodiment of the present disclosure, the antibodies of the present disclosure comprise a combination of the CDRs and variable heavy and light chain sequences described above.

[0395] In another embodiment, the present disclosure contemplates other antibodies, e.g., chimeric antibodies, that comprise one or more of the polypeptide sequences of SEQ ID NO:508; SEQ ID NO:509; and SEQ ID NO:510, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO:506, and / or one or more of the polypeptide sequences of SEQ ID NO:511; SEQ ID NO:512; and SEQ ID NO:513, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO:507, or a combination of these polypeptide sequences. In another embodiment of the present disclosure, the antibodies of the present disclosure comprise a combination of the CDRs and variable heavy and light chain sequences described above.

[0396] The present disclosure also contemplates antibody fragments that have binding specificity for IL-6. In one embodiment of the present disclosure, the antibody fragment of the present disclosure comprises, or alternatively consists of, the polypeptide sequence of SEQ ID NO: 506. In another embodiment of the present disclosure, the antibody fragment of the present disclosure comprises, or alternatively consists of, the polypeptide sequence of SEQ ID NO: 507.

[0397] In further embodiments of the present disclosure, antibody fragments having binding specificity for IL-6 comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO:508; SEQ ID NO:509; and SEQ ID NO:510, which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO:506.

[0398] In further embodiments of the present disclosure, the antibody fragment having binding specificity for IL-6 comprises, or alternatively consists of, one or more of the polypeptide sequences of SEQ ID NO:511; SEQ ID NO:512; and SEQ ID NO:513, which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO:507.

[0399] The present disclosure also contemplates antibody fragments comprising one or more of the antibody fragments described herein. In one embodiment of the present disclosure, the antibody fragment having binding specificity to IL-6 comprises, or alternatively consists of, one, two, three, or more, including all, of the following antibody fragments: the variable light chain region of SEQ ID NO:506; the variable heavy chain region of SEQ ID NO:507; the complementarity determining regions of the variable light chain region of SEQ ID NO:506 (SEQ ID NO:508; SEQ ID NO:509; and SEQ ID NO:510); and the complementarity determining regions of the variable heavy chain region of SEQ ID NO:507 (SEQ ID NO:511; SEQ ID NO:512; and SEQ ID NO:513).

[0400] In one embodiment of the present disclosure, the anti-IL-6 antibody is Ab32 comprising SEQ ID NO: 506 and SEQ ID NO: 507 and having at least one of the biological activities described herein.

[0401] In another embodiment, the present disclosure includes an antibody that has binding specificity for IL-6 and has a variable light chain sequence comprising the sequence shown below: MDTRAPTQLLGLLLLWLPGATFAQVLTQTASSVSAAVGGTVTINCQSSQSVYNNYLSWYQQKPGQPPKLLIYTASSLASGVPSRFKGSGSGTQFTLTISEVQCDDAATYYCQGYYSGPIIT (SEQ ID NO: 522)

[0402] The present disclosure also includes antibodies that have binding specificity for IL-6 and have a variable heavy chain sequence comprising the sequence shown below: METGLRWLLLVAVLKGVQCQSLEESGGRLVTPGTPLTLTCTASGFSLNNYYIQWVRQAPGEGLEWIGIIYAGGSAYYATWANGRFTIAKTSSTTVDLKMTSLTTEDTATYFCARGTFDGYEL (SEQ ID NO: 523)

[0403] The present disclosure further contemplates antibodies comprising one or more of the polypeptide sequences of SEQ ID NO: 524; SEQ ID NO: 525; and SEQ ID NO: 526, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 522, and / or one or more of the polypeptide sequences of SEQ ID NO: 527; SEQ ID NO: 528; and SEQ ID NO: 529, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 523, or a combination of these polypeptide sequences. In another embodiment of the present disclosure, the antibodies of the present disclosure comprise a combination of the CDRs and variable heavy and light chain sequences described above.

[0404] In another embodiment, the present disclosure contemplates other antibodies, e.g., chimeric antibodies, that comprise one or more of the polypeptide sequences of SEQ ID NO:524; SEQ ID NO:525; and SEQ ID NO:526, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO:522, and / or one or more of the polypeptide sequences of SEQ ID NO:527; SEQ ID NO:528; and SEQ ID NO:529, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO:523, or a combination of these polypeptide sequences. In another embodiment of the present disclosure, the antibodies of the present disclosure comprise a combination of the CDRs and variable heavy and light chain sequences described above.

[0405] The present disclosure also contemplates antibody fragments that have binding specificity for IL-6. In one embodiment of the present disclosure, the antibody fragment of the present disclosure comprises, or alternatively consists of, the polypeptide sequence of SEQ ID NO: 522. In another embodiment of the present disclosure, the antibody fragment of the present disclosure comprises, or alternatively consists of, the polypeptide sequence of SEQ ID NO: 523.

[0406] In further embodiments of the present disclosure, antibody fragments having binding specificity for IL-6 comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO:524; SEQ ID NO:525; and SEQ ID NO:526, which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO:522.

[0407] In further embodiments of the present disclosure, antibody fragments having binding specificity for IL-6 comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO:527; SEQ ID NO:528; and SEQ ID NO:529, which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO:523.

[0408] The present disclosure also contemplates antibody fragments comprising one or more of the antibody fragments described herein. In one embodiment of the present disclosure, the antibody fragment having binding specificity to IL-6 comprises, or alternatively consists of, one, two, three, or more, including all, of the following antibody fragments: the variable light chain region of SEQ ID NO: 522; the variable heavy chain region of SEQ ID NO: 523; the complementarity determining regions of the variable light chain region of SEQ ID NO: 522 (SEQ ID NO: 524; SEQ ID NO: 525; and SEQ ID NO: 526); and the complementarity determining regions of the variable heavy chain region of SEQ ID NO: 523 (SEQ ID NO: 527; SEQ ID NO: 528; and SEQ ID NO: 529).

[0409] In one embodiment of the present disclosure, the anti-IL-6 antibody is Ab33 comprising SEQ ID NO: 522 and SEQ ID NO: 523 and having at least one of the biological activities described herein.

[0410] In another embodiment, the present disclosure includes an antibody that has binding specificity for IL-6 and has a variable light chain sequence comprising the sequence shown below: MDTRAPTQLLGLLLLWLPGATFAQVLTQTPSPVSVPVGDTVTISCQSSESVYSNNLLSWYQQKPGQPPKLLIYRASNLASGVPSRFKGSGSGTQFTLTISGAQCDDAATYYCQGYYSGVINS (SEQ ID NO: 538)

[0411] The present disclosure also includes antibodies that have binding specificity for IL-6 and have a variable heavy chain sequence comprising the sequence shown below: METGLRWLLLVAVLKGVQCQSVEESGGRLVTPGTPLTLTCTVSGFSLSSYFMSWVRQAPGEGLEYIGFINPGGSAYYASWASGRLTISKTSTTVDLKITSPTTEDTATYFCARILIVSYGAFTI (SEQ ID NO: 539)

[0412] The present disclosure further contemplates antibodies comprising one or more of the polypeptide sequences of SEQ ID NO: 540; SEQ ID NO: 541; and SEQ ID NO: 542, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 538, and / or one or more of the polypeptide sequences of SEQ ID NO: 543; SEQ ID NO: 544; and SEQ ID NO: 545, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 539, or a combination of these polypeptide sequences. In another embodiment of the present disclosure, the antibodies of the present disclosure comprise a combination of the CDRs and variable heavy and light chain sequences described above.

[0413] In another embodiment, the present disclosure contemplates other antibodies, e.g., chimeric antibodies, that comprise one or more of the polypeptide sequences of SEQ ID NO:540; SEQ ID NO:541; and SEQ ID NO:542, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO:538, and / or one or more of the polypeptide sequences of SEQ ID NO:543; SEQ ID NO:544; and SEQ ID NO:545, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO:539, or a combination of these polypeptide sequences. In another embodiment of the present disclosure, the antibodies of the present disclosure comprise a combination of the CDRs and variable heavy and light chain sequences described above.

[0414] The present disclosure also contemplates antibody fragments that have binding specificity for IL-6. In one embodiment of the present disclosure, the antibody fragment of the present disclosure comprises, or alternatively consists of, the polypeptide sequence of SEQ ID NO: 538. In another embodiment of the present disclosure, the antibody fragment of the present disclosure comprises, or alternatively consists of, the polypeptide sequence of SEQ ID NO: 539.

[0415] In further embodiments of the present disclosure, the antibody fragment having binding specificity for IL-6 comprises, or alternatively consists of, one or more of the polypeptide sequences of SEQ ID NO:540; SEQ ID NO:541; and SEQ ID NO:542, which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO:538.

[0416] In further embodiments of the present disclosure, the antibody fragment having binding specificity for IL-6 comprises, or alternatively consists of, one or more of the polypeptide sequences of SEQ ID NO:543; SEQ ID NO:544; and SEQ ID NO:545, which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO:539.

[0417] The present disclosure also contemplates antibody fragments comprising one or more of the antibody fragments described herein. In one embodiment of the present disclosure, the antibody fragment having binding specificity to IL-6 comprises, or alternatively consists of, one, two, three, or more, including all, of the following antibody fragments: the variable light chain region of SEQ ID NO:538; the variable heavy chain region of SEQ ID NO:539; the complementarity determining regions of the variable light chain region of SEQ ID NO:538 (SEQ ID NO:540; SEQ ID NO:541; and SEQ ID NO:542); and the complementarity determining regions of the variable heavy chain region of SEQ ID NO:539 (SEQ ID NO:543; SEQ ID NO:544; and SEQ ID NO:545).

[0418] In one embodiment of the present disclosure, the anti-IL-6 antibody is Ab34 comprising SEQ ID NO: 538 and SEQ ID NO: 539 and having at least one of the biological activities described herein.

[0419] In another embodiment, the present disclosure includes an antibody that has binding specificity for IL-6 and has a variable light chain sequence comprising the sequence shown below: MDTRAPTQLLGLLLLWLPGARCAYDMTQTPASVEVAVGGTVTIKCQATESIGNELSWYQQKPGQAPKLLIYSASTLASGVPSRFKGSGSGTQFTLTITGVECDDAATYYCQQGYSSANIDNA (SEQ ID NO: 554)

[0420] The present disclosure also includes antibodies that have binding specificity for IL-6 and have a variable heavy chain sequence comprising the sequence shown below: METGLRWLLLVAVLKGVQCQSLEESGGRLVTPGTPLTLTCTVSGFSLSKYYMSWVRQAPEKGLKYIGYIDSTTVNTYYATWARGRFTISKTSTTVDLKITSPTSEDTATYFCARGSTYFTDGGHRLDL (SEQ ID NO: 555)

[0421] The present disclosure further contemplates antibodies comprising one or more of the polypeptide sequences of SEQ ID NO: 556; SEQ ID NO: 557; and SEQ ID NO: 558, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 554, and / or one or more of the polypeptide sequences of SEQ ID NO: 559; SEQ ID NO: 560; and SEQ ID NO: 561, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 555, or a combination of these polypeptide sequences. In another embodiment of the present disclosure, the antibodies of the present disclosure comprise a combination of the CDRs and variable heavy and light chain sequences described above.

[0422] In another embodiment, the present disclosure contemplates other antibodies, e.g., chimeric antibodies, that comprise one or more of the polypeptide sequences of SEQ ID NO:556; SEQ ID NO:557; and SEQ ID NO:558, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO:554, and / or one or more of the polypeptide sequences of SEQ ID NO:559; SEQ ID NO:560; and SEQ ID NO:561, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO:555, or a combination of these polypeptide sequences. In another embodiment of the present disclosure, the antibodies of the present disclosure comprise a combination of the CDRs and variable heavy and light chain sequences described above.

[0423] The present disclosure also contemplates antibody fragments that have binding specificity for IL-6. In one embodiment of the present disclosure, the antibody fragment of the present disclosure comprises, or alternatively consists of, the polypeptide sequence of SEQ ID NO: 554. In another embodiment of the present disclosure, the antibody fragment of the present disclosure comprises, or alternatively consists of, the polypeptide sequence of SEQ ID NO: 555.

[0424] In further embodiments of the present disclosure, antibody fragments having binding specificity for IL-6 comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO:556; SEQ ID NO:557; and SEQ ID NO:558, which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO:554.

[0425] In further embodiments of the present disclosure, antibody fragments having binding specificity for IL-6 comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO:559; SEQ ID NO:560; and SEQ ID NO:561, which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO:555.

[0426] The present disclosure also contemplates antibody fragments comprising one or more of the antibody fragments described herein. In one embodiment of the present disclosure, the antibody fragment having binding specificity to IL-6 comprises, or alternatively consists of, one, two, three, or more, including all, of the following antibody fragments: the variable light chain region of SEQ ID NO:554; the variable heavy chain region of SEQ ID NO:555; the complementarity determining regions of the variable light chain region of SEQ ID NO:554 (SEQ ID NO:556; SEQ ID NO:557; and SEQ ID NO:558); and the complementarity determining regions of the variable heavy chain region of SEQ ID NO:555 (SEQ ID NO:559; SEQ ID NO:560; and SEQ ID NO:561).

[0427] In one embodiment of the present disclosure, the anti-IL-6 antibody is Ab35 comprising SEQ ID NO:554 and SEQ ID NO:555 and having at least one of the biological activities described herein.

[0428] In another embodiment, the present disclosure includes an antibody that has binding specificity for IL-6 and has a variable light chain sequence comprising the sequence shown below: MDTRAPTQLLGLLLLWLPGARCAYDMTQTPASVEVAVGGTVTIKCQATESIGNELSWYQQKPGQAPKLLIYSASTLASGVPSRFKGSGSGTQFTLTITGVECDDAATYYCQQGYSSANIDNA (SEQ ID NO: 570)

[0429] The present disclosure also includes antibodies that have binding specificity for IL-6 and have a variable heavy chain sequence comprising the sequence shown below: METGLRWLLLVAVLKGVQCQSLEESGGRLVTPGTPLTLTCTVSGFSLSTYNMGWVRQAPGKGLEWIGSITIDGRTYYASWAKGRFTVSKSSTTVDLKMTSLTTGDTATYFCARILIVSYGAFTI (SEQ ID NO: 571)

[0430] The present disclosure further contemplates antibodies comprising one or more of the polypeptide sequences of SEQ ID NO: 572; SEQ ID NO: 573; and SEQ ID NO: 574, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 570, and / or one or more of the polypeptide sequences of SEQ ID NO: 575; SEQ ID NO: 576; and SEQ ID NO: 577, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 571, or a combination of these polypeptide sequences. In another embodiment of the present disclosure, an antibody of the present disclosure comprises a combination of the CDRs and variable heavy and light chain sequences described above.

[0431] In another embodiment, the present disclosure contemplates other antibodies, e.g., chimeric antibodies, that comprise one or more of the polypeptide sequences of SEQ ID NO:572; SEQ ID NO:573; and SEQ ID NO:574, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO:570, and / or one or more of the polypeptide sequences of SEQ ID NO:575; SEQ ID NO:576; and SEQ ID NO:577, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO:571, or a combination of these polypeptide sequences. In another embodiment of the present disclosure, the antibodies of the present disclosure comprise a combination of the CDRs and variable heavy and light chain sequences described above.

[0432] The present disclosure also contemplates antibody fragments that have binding specificity for IL-6. In one embodiment of the present disclosure, the antibody fragment of the present disclosure comprises, or alternatively consists of, the polypeptide sequence of SEQ ID NO: 570. In another embodiment of the present disclosure, the antibody fragment of the present disclosure comprises, or alternatively consists of, the polypeptide sequence of SEQ ID NO: 571.

[0433] In further embodiments of the present disclosure, the antibody fragment having binding specificity for IL-6 comprises, or alternatively consists of, one or more of the polypeptide sequences of SEQ ID NO:572; SEQ ID NO:573; and SEQ ID NO:574, which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO:570.

[0434] In further embodiments of the present disclosure, the antibody fragment having binding specificity for IL-6 comprises, or alternatively consists of, one or more of the polypeptide sequences of SEQ ID NO:575; SEQ ID NO:576; and SEQ ID NO:577, which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO:571.

[0435] The present disclosure also contemplates antibody fragments comprising one or more of the antibody fragments described herein. In one embodiment of the present disclosure, the antibody fragment having binding specificity to IL-6 comprises, or alternatively consists of, one, two, three or more, including all, of the following antibody fragments: the variable light chain region of SEQ ID NO: 570; the variable heavy chain region of SEQ ID NO: 571; the complementarity determining regions of the variable light chain region of SEQ ID NO: 570 (SEQ ID NO: 572, SEQ ID NO: 573, and SEQ ID NO: 574); and the complementarity determining regions of the variable heavy chain region of SEQ ID NO: 571 (SEQ ID NO: 575, SEQ ID NO: 576, and SEQ ID NO: 577).

[0436] In one embodiment of the present disclosure, the anti-IL-6 antibody is Ab36 comprising SEQ ID NO:570 and SEQ ID NO:571 and having at least one of the biological activities described herein.

[0437] Such antibody fragments may exist in one or more of the following non-limiting forms: ab , F ab’ , F (ab’)2 , Fv and single chain Fv antibody forms. In one embodiment, the anti-IL-6 antibodies described herein further comprise a kappa constant light chain sequence comprising the sequence shown below: VAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 586)

[0438] In another embodiment, the anti-IL-6 antibodies described herein further comprise a gamma-1 constant heavy chain polypeptide sequence comprising the sequence set forth below: ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 588)

[0439] In another embodiment, the disclosure provides a VH polypeptide sequence selected from the group consisting of SEQ ID NOs: 3, 18, 19, 22, 38, 54, 70, 86, 102, 117, 118, 123, 139, 155, 171, 187, 203, 219, 235, 251, 267, 283, 299, 315, 331, 347, 363, 379, 395, 411, 427, 443, 459, 475, 491, 507, 523, 539, 555, and SEQ ID NO: 571; and SEQ ID NOs: 2, 20, 21, 37, 53, 69, 85, 101, 119, 122, 138, 154, 170, 186, 20 and SEQ ID NO: 570, or variants thereof in which one or more framework residues (FR residues) in said VH or VL polypeptides are substituted with another amino acid residue to generate an anti-IL-6 antibody that specifically binds to IL-6. The present disclosure contemplates humanized and chimeric forms of these antibodies. Chimeric antibodies include an Fc derived from an IgG1, IgG2, IgG3, IgG4, IgG5, IgG6, IgG7, IgG8, IgG9, IgG10, IgG11, IgG12, IgG13, IgG14, IgG15, IgG16, IgG17, IgG18, or IgG19 constant region.

[0440] In one embodiment of the present disclosure, the antibody or VH or VL polypeptide originates from or is selected from one or more rabbit B cell populations prior to initiation of the humanization process referred to herein.

[0441] In another embodiment of the present disclosure, the anti-IL-6 antibody has binding specificity for a primate homolog of the human IL-6 protein. Non-limiting examples of primate homologs of the human IL-6 protein are IL-6 obtained from Macaca fascicularis (also known as cynomolgus monkey) and Rhesus monkey. In another embodiment of the present disclosure, the anti-IL-6 antibody inhibits the association of IL-6 with IL-6R, and / or the formation of the IL-6 / IL-6R / gp130 complex, and / or the formation of IL-6 / IL-6R / gp130 multimers, and / or antagonizes one or more of the biological effects thereof.

[0442] These antibodies can be post-translationally modified to attach effector moieties such as chemical linkers, detectable moieties such as fluorochromes, enzymes, substrates, bioluminescent, radioactive and chemiluminescent moieties, or functional moieties such as streptavidin, avidin, biotin, cytotoxins, cytotoxic agents and radioactive materials.

[0443] Regarding detectable moieties, further exemplary enzymes include, but are not limited to, horseradish peroxidase, acetylcholinesterase, alkaline phosphatase, beta-galactosidase, and luciferase. Further exemplary fluorescent materials include, but are not limited to, rhodamine, fluorescein, fluorescein isothiocyanate, umbelliferone, dichlorotriazinylamine, phycoerythrin, and dansyl chloride. Further exemplary chemiluminescent moieties include, but are not limited to, luminol. Further exemplary bioluminescent materials include, but are not limited to, luciferin and aequorin. Further exemplary radioactive materials include, but are not limited to, iodine-125 (125I), carbon-14 (14C), sulfur-35 (35S), tritium (3H), and phosphorus-32 (32P).

[0444] With respect to functional moieties, exemplary cytotoxic agents include methotrexate, aminoptyline, 6-mercaptopurine, 6-thioguanine, cytarabine, 5-fluorouracil, decylcarbazine; alkylating agents, such as mechlorethamine, thiotepa, chlorambucil, melphalan, carmustine (BSNU), mitomycin C, lomustine (CCNU), 1-methylnitrosourea, cyclophosphamide, mechlorethamine, busulfan, dibromomannitol, streptozotocin, mitomycin C, cis-dichlorodiamineplatinum(II) (DDP), cisplatin, and camphor. anthracyclines include daunorubicin (formerly daunomycin), doxorubicin (adriamycin), detrubicin, carminomycin, idarubicin, epirubicin, mitoxantrone, and bisantrene; antibiotics include dactinomycin (actinomycin D), bleomycin, calicheamicin, mithramycin, and anthramycin (AMC); and antimitotic agents, such as, but not limited to, the vinca alkaloids, vincristine, and vinblastine. Other cytotoxic agents include paclitaxel (taxol), ricin, pseudomonas exotoxin, gemcitabine, cytochalasin B, gramicidin D, ethidium bromide, emetine, etoposide, tenoposide, colchicine, dihydroxyanthracinedione, 1-dehydrotestosterone, glucocorticoids, procaine, tetracaine, lidocaine, propranolol, puromycin, procarbazine, hydroxyurea, asparaginase, corticosteroids, mitotane (O,P'-(DDD)), interferon, and mixtures of these cytotoxic agents.

[0445] Additional cytotoxic agents include, but are not limited to, chemotherapeutic agents such as carboplatin, cisplatin, paclitaxel, gemcitabine, calicheamicin, doxorubicin, 5-fluorouracil, mitomycin C, actinomycin D, cyclophosphamide, vincristine, and bleomycin.Toxic enzymes derived from plants and bacteria, such as ricin, diphtheria toxin, and pseudomonas toxin, can be conjugated to humanized antibodies or their binding fragments to create cell type-specific killing reagents.See Youle et al., Proc. Nat'l Acad. Sci. USA 77:5483 (1980); Gilliland et al., Proc. Nat'l Acad. Sci. USA 77:4539 (1980); Krolick et al., Proc. Nat'l Acad. Sci. USA 77:5419 (1980).

[0446] Other cytotoxic agents include cytotoxic ribonucleases, such as those described by Goldenberg in U.S. Pat. No. 6,653,104. Embodiments of the present disclosure also relate to radioimmunoconjugates in which alpha- or beta-particle-emitting radionuclides are stably coupled to antibodies or binding fragments thereof, with or without the use of complexing agents. Such radionuclides include phosphorus-32 ( 32 P), Scandium-47( 47 Sc), Copper-67( 67 Cu), Gallium-67( 67 Ga), Yttrium-88( 88 Y), Yttrium-90( 90 Y), iodine-125( 125 I), iodine-131( 131 I), samarium-153( 153 Sm), lutetium-177( 177 Lu), rhenium-186( 186 Re) or rhenium-188( 188 Beta emitters such as Re), and astatine-211 ( 211 At), lead-212( 212Pb), Bismuth-212( 212 Bi) or -213(213Bi) or Actinium-225( 225 Alpha emitters such as Ac are also included.

[0447] Methods for conjugating antibodies or binding fragments thereof to detectable moieties, etc., are known in the art, such as those described by Hunter et al., Nature 144:945 (1962); David et al., Biochemistry 13:1014 (1974); Pain et al., J. Immunol. Meth. 40:219 (1981); and Nygren, J., Histochem. and Cytochem. 30:407 (1982).

[0448] The embodiments described herein further include variants and equivalents that are substantially homologous to the antibodies, antibody fragments, diabodies, SMIPs, camelbodies, nanobodies, IgNARs, polypeptides, variable regions, and CDRs described herein. These may include, for example, conservative substitution mutations (i.e., the replacement of one or more amino acids with similar amino acids). For example, a conservative substitution refers to the substitution of an amino acid with another amino acid within the same general class, such as the substitution of one acidic amino acid with another acidic amino acid, one basic amino acid with another basic amino acid, or one neutral amino acid with another neutral amino acid. What is meant by conservative amino acid substitution is well known in the art.

[0449] In another embodiment, the present disclosure contemplates polypeptide sequences having at least 90% or more sequence identity to any one or more of the polypeptide sequences of the antibody fragments, variable regions, and CDRs described herein. In some embodiments, the present disclosure contemplates polypeptide sequences having at least 95% or more sequence identity, at least 98% or more sequence identity, or at least 99% or more sequence identity to any one or more of the polypeptide sequences of the antibody fragments, variable regions, and CDRs described herein. Methods for determining homology between nucleic acid and amino acid sequences are well known to those of skill in the art.

[0450] In another embodiment, the present disclosure further contemplates the above-listed polypeptide homologs of the antibody fragments, variable regions, and CDRs described herein, which further have anti-IL-6 activity, non-limiting examples of which are described herein.

[0451] The present disclosure also contemplates anti-IL-6 antibodies comprising any of the polypeptide or polynucleotide sequences described herein substituted with any of the other polynucleotide sequences described herein. For example, without limitation, the present disclosure contemplates antibodies comprising any combination of the variable light and variable heavy chain sequences described herein, and further contemplates antibodies resulting from the substitution of any of the CDR sequences described herein with any of the other CDR sequences described herein.

[0452] In another embodiment, the present disclosure also provides a method for the preparation of a VH polypeptide comprising the steps of: 1) a CDR comprised in a VH polypeptide sequence selected from the group consisting of SEQ ID NOs: 3, 18, 19, 22, 38, 54, 70, 86, 102, 117, 118, 123, 139, 155, 171, 187, 203, 219, 235, 251, 267, 283, 299, 315, 331, 347, 363, 379, 395, 411, 427, 443, 459, 475, 491, 507, 523, 539, 555, and SEQ ID NO: 571; and / or 2, 20, 21, 37, 53, 69, 86, 102, 117, 118, 123, 139, 155, 171, 187, 203, 219, 235, 251, 267, 283, 299, 315, 331, 347, 363, 379, 395, 411, 427, 443, 459, 475, 491, 507, 523, 539, 555, and SEQ ID NO: 571. Also contemplated is an isolated anti-IL-6 antibody comprising one or more CDRs contained in a VL polypeptide sequence consisting of SEQ ID NO: 5, 101, 119, 122, 138, 154, 170, 186, 202, 218, 234, 250, 266, 282, 298, 314, 330, 346, 362, 378, 394, 410, 426, 442, 458, 474, 490, 506, 522, 538, 554 and SEQ ID NO: 570, e.g., those of an antibody comprising the VL and VH polypeptides of SEQ ID NO: 20 and SEQ ID NO: 19.

[0453] The present disclosure further contemplates that one or more of the human anti-IL-6 antibodies discussed above are aglycosylated; contain an Fc region modified to alter effector function, half-life, proteolysis and / or glycosylation; are humanized, single chain, or chimeric; and are humanized antibodies derived from a rabbit (parent) human anti-IL-6 antibody.

[0454] The anti-IL-6 activity of anti-IL-6 antibodies herein is sometimes described by their binding strength or affinity to IL-6, which may also affect their therapeutic properties. In some cases, anti-IL-6 antibodies may be used in combination with antibodies to IL-6 in a concentration of 5×10 -7 , 10 -7 , 5×10 -8 , 10 -8 , 5×10 -9 , 10 -9 , 5×10 -10 , 10 -10 , 5×10 -11 , 10 -11 , 5×10-12 , 10 -12 , 5×10 -13 , 10 -13 , 5×10 -14 , 10 -14 , 5×10 -15 or 10 -15 In some embodiments, the anti-IL-6 antibody binds to IL-6 with a dissociation constant (KD) of less than or equal to 5×10 -10 The anti-IL-6 antibodies herein bind to IL-6 with a dissociation constant less than or equal to 10. Another way to assess affinity for IL-6 is to consider the dissociation rate, or "off-rate," between IL-6 and the antibody. In some cases, the anti-IL-6 antibodies herein bind to IL-6 with a dissociation constant less than or equal to 10. -4 S -1 , 5×10 -5 S -1 , 10 -5 S -1 , 5×10 -6 S -1 , 10 -6 S -1 , 5×10 -7 S -1 or 10 -7 S -1 has an off-rate less than or equal to

[0455] The present disclosure also contemplates one or more nucleic acid sequences that result in expression of the above-described anti-IL-6 antibodies, including those that comprise, or alternatively consist of, yeast or human preferred codons. The present disclosure also contemplates vectors (including plasmids or recombinant viral vectors) containing the nucleic acid sequences. The present disclosure also contemplates host cells or recombinant host cells that express at least one of the above-described antibodies, including mammalian cells, yeast cells, bacterial cells, and insect cells. In one embodiment, the host cell is a yeast cell. In another embodiment, the yeast cell is a diploid yeast cell. In one embodiment, the yeast cell is a Pichia yeast.

[0456] Polynucleotides encoding anti-IL-6 antibody polypeptides Also described herein are polynucleotides encoding antibody polypeptides having binding specificity for IL-6. In one embodiment of the disclosure, the polynucleotide of the disclosure comprises, or alternatively consists of, the following polynucleotide sequence, which encodes the variable light chain polypeptide sequence of SEQ ID NO:2: ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGTGCCAGATGTGCCTATGATATGACCCAGACTCCAGCCTCGGTGTCTGCAGCTGTGGGAGGCACAGTCA CCATCAAGTGCCAGGCCAGTCAGAGCATTAACAATGAATTATCCTGGTATCAGCAGAACCAGGGCAGCGTCCCAAGCTCCTGATCTATAGGGCATCCACTCTGGCATCTGGGGTCTCATCCGGG TTCAAAGGCAGTGGATCTGGGACAGAGTTCACTCTCACCATCAGCGACCTGGAGTGTGCCGATGCTGCCACTTACTACTGTCAACAGGGTTATAGTCTGAGGAATATTGATAATGCTTTCGGCGG AGGGACCGAGGTGGTGGTCAAACGTACGGTAGCGGCCCCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTT (SEQ ID NO: 10)

[0457] In another embodiment of the present disclosure, the polynucleotide of the present disclosure comprises, or alternatively consists of, the following polynucleotide sequence that encodes the variable heavy chain polypeptide sequence of SEQ ID NO:3: ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTCGCTGTGCTCAAAGGTGTCCAGTGTCAGTCGCTGGAGGAGTCCGGGGGTCGCCTGGTCACGCCTGGGACACCCCTGACACTCACCTGCACAGCC TCTGGATTCTCCCTCAGTAACTACTACGTGACCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAATGGATCGGAATCATTTATGGTAGTGATGAAACGGCCTACCGCGACCTGGGCGATAGGCCGAT TCACCATCTCCAAAACCTCGACCACGGTGGATCTGAAAATGACCAGTCTGACAGCCGCGGACACGGCCACCTATTTCTGTGCCAGAGATGATAGTAGTGACTGGGATGCAAAATTTAACTTGTGGGG CCAAGGCACCCTGGTCACCGTCTCGAGCGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGG (SEQ ID NO: 11)

[0458] In further embodiments of the present disclosure, the polynucleotide encoding the antibody fragment having binding specificity for IL-6 comprises, or alternatively consists of, one or more of the polynucleotide sequences of SEQ ID NO: 12; SEQ ID NO: 13; and SEQ ID NO: 14, which correspond to the polynucleotides encoding the complementarity determining regions (CDRs, or hypervariable regions) of the light chain variable sequence of SEQ ID NO: 2.

[0459] In further embodiments of the present disclosure, the polynucleotide encoding the antibody fragment having binding specificity for IL-6 comprises, or alternatively consists of, one or more of the polynucleotide sequences of SEQ ID NO: 15; SEQ ID NO: 16; and SEQ ID NO: 17, which correspond to polynucleotides encoding the complementarity determining regions (CDRs, or hypervariable regions) of the heavy chain variable sequence of SEQ ID NO: 3.

[0460] The present disclosure also contemplates polynucleotide sequences comprising one or more of the polynucleotide sequences encoding the antibody fragments described herein. In one embodiment of the present disclosure, the polynucleotide encoding the antibody fragment with binding specificity to IL-6 comprises, or alternatively consists of, one, two, three, or more, including all, of the following polynucleotides encoding the antibody fragment: polynucleotide SEQ ID NO:10 encoding the light chain variable region of SEQ ID NO:2; polynucleotide SEQ ID NO:11 encoding the heavy chain variable region of SEQ ID NO:3; polynucleotides (SEQ ID NO:12; SEQ ID NO:13; and SEQ ID NO:14) encoding the complementarity determining regions of the light chain variable region of SEQ ID NO:10; and polynucleotides (SEQ ID NO:15; SEQ ID NO:16; and SEQ ID NO:17) encoding the complementarity determining regions of the heavy chain variable region of SEQ ID NO:11.

[0461] The present disclosure is further directed to polynucleotides encoding polypeptides of antibodies having binding specificity for IL-6. In one embodiment of the disclosure, the polynucleotide of the disclosure comprises, or alternatively consists of, the following polynucleotide sequence that encodes the variable light chain polypeptide sequence of SEQ ID NO:21: ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGTGCCAGATGTGCCTATGATATGACCCAGACTCCAGCCTCTGTGGAGGTAGCTGTGGGAGGCACAGTCACCATC AATTGCCAGGCCAGTGAGACCATTTACAGTTGGTTATCCTGGTATCAGCAGAAGCCAGGGCAGCCTCCCAAGCTCCTGATCTACCAGGCATCCGATCTGGCATCTGGGGTCCCATCGCGATTCAGCGGCA GTGGGGCTGGGACAGAGTACACTCTCACCATCAGCGGCGTGCAGTGTGACGATGCTGCCACTTACTACTGTCAACAGGGTTATAGTGGTAGTAATGTTGATAATGTTTTCGGCGGAGGGACCGAGGTGGT GGTCAAACGTACGGTAGCGGCCCCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAG (SEQ ID NO: 29)

[0462] In another embodiment of the disclosure, the polynucleotide of the disclosure comprises, or alternatively consists of, the following polynucleotide sequence that encodes the variable heavy chain polypeptide sequence of SEQ ID NO:22: ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTCGCTGTGCTCAAAGGTGTCCAGTGTCAGGAGCAGCTGAAGGAGTCCGGGGGTCGCCTGGTCACGCCTGGGACACCCCTGACACTTACCTGCACAG CCTCTGGATTCTCCCTCAATGACCATGCAATGGGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAATACATCGGATTCATTAATAGTGGTGGTAGCGCACGCTACGCGAGCTGGGCAGAAGGCCG ATTCACCATCTCCAGAACCTCGACCACGGTGGATCTGAAAATGACCAGTCTGACAACCGAGGACACGGCCACCTATTTCTGTGTCAGAGGGGGTGCTGTTTGGAGTATTCATAGTTTTGATCCCTGG GGCCCAGGGACCCTGGTCACCGTCTCGAGCGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAG (SEQ ID NO: 30)

[0463] In further embodiments of the present disclosure, the polynucleotide encoding the antibody fragment having binding specificity for IL-6 comprises, or alternatively consists of, one or more of the polynucleotide sequences of SEQ ID NO:31; SEQ ID NO:32; and SEQ ID NO:33, which correspond to polynucleotides encoding the complementarity-determining regions (CDRs, or hypervariable regions) of the light chain variable sequence of SEQ ID NO:21.

[0464] In further embodiments of the present disclosure, the polynucleotide encoding the antibody fragment having binding specificity for IL-6 comprises, or alternatively consists of, one or more of the polynucleotide sequences of SEQ ID NO:34; SEQ ID NO:35; and SEQ ID NO:36, which correspond to polynucleotides encoding the complementarity determining regions (CDRs, or hypervariable regions) of the heavy chain variable sequence of SEQ ID NO:22.

[0465] The present disclosure also contemplates polynucleotide sequences comprising one or more of the polynucleotide sequences encoding the antibody fragments described herein. In one embodiment of the present disclosure, the polynucleotide encoding the antibody fragment with binding specificity to IL-6 comprises, or alternatively consists of, one, two, three, or more, including all, of the following polynucleotides encoding the antibody fragment: polynucleotide SEQ ID NO:29 encoding the light chain variable region of SEQ ID NO:21; polynucleotide SEQ ID NO:30 encoding the heavy chain variable region of SEQ ID NO:22; polynucleotides encoding the complementarity determining regions of the light chain variable region of SEQ ID NO:29 (SEQ ID NO:31; SEQ ID NO:32; and SEQ ID NO:33); and polynucleotides encoding the complementarity determining regions of the heavy chain variable region of SEQ ID NO:30 (SEQ ID NO:34; SEQ ID NO:35; and SEQ ID NO:36).

[0466] The present disclosure is further directed to polynucleotides encoding polypeptides of antibodies having binding specificity for IL-6. In one embodiment of the disclosure, the polynucleotide of the disclosure comprises, or alternatively consists of, the following polynucleotide sequence that encodes the variable light chain polypeptide sequence of SEQ ID NO: 37: ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGTGCCACATTTGCCGCCGTGCTGACCCAGACTCCATCTCCCGTGTCTGCAGCTGTGGGAGGCACAGTCAGC ATCAGTTGCCAGGCCAGTCAGAGTGTTTATGACAACAACTACTTATCCTGGTTTCAGCAGAAACCAGGGCAGCCTCCCAAGCTCCTGATCTATGGTGCATCCACTCTGGCATCTGGGGTCCCATCG CGGTTCGTGGGCAGTGGATCTGGGACACAGTTCACTCTCACCATCACAGACGTGCAGTGTGACGATGCTGCCACTTACTATTGTGCAGGCGTTTATGATGATGATAGTGATAATGCCTTCGGCGGA GGGACCGAGGTGGTGGTCAAACGTACGGTAGCGGCCCCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCT (SEQ ID NO: 45)

[0467] In another embodiment of the disclosure, the polynucleotide of the disclosure comprises, or alternatively consists of, the following polynucleotide sequence that encodes the variable heavy chain polypeptide sequence of SEQ ID NO: 38: ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTGGCTGTGCTCAAAGGTGTCCAGTGTCAGTCGCTGGAGGAGTCCGGGGGTCGCCTGGTCACCCCTGGGACACCCCTGACACTCACCTGCACAGCC TCTGGATTCTCCCTCAGTGTCTACTACATGAACTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAATGGATCGGATTCATTACAATGAGTGATAATATAAATTACGCGAGCTGGGCGAAAGGCCGAT TCACCATCTCCAAAACCTCGACCACGGTGGATCTGAAAATGACCAGTCCGACAACCGAGGACACGGCCACCTATTTCTGTGCCAGGAGTCGTGGCTGGGGTACAATGGGTCGGTTGGATCTCTGGGG CCCAGGCACCCTCGTCACCGTCTCGAGCGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGG (SEQ ID NO: 46)

[0468] In further embodiments of the present disclosure, the polynucleotide encoding the antibody fragment having binding specificity for IL-6 comprises, or alternatively consists of, one or more of the polynucleotide sequences of SEQ ID NO:47; SEQ ID NO:48; and SEQ ID NO:49, which correspond to the polynucleotide encoding the complementarity determining regions (CDRs, or hypervariable regions) of the light chain variable sequence of SEQ ID NO:37.

[0469] In further embodiments of the present disclosure, the polynucleotide encoding the antibody fragment having binding specificity for IL-6 comprises, or alternatively consists of, one or more of the polynucleotide sequences of SEQ ID NO:50; SEQ ID NO:51; and SEQ ID NO:52, which correspond to polynucleotides encoding the complementarity determining regions (CDRs, or hypervariable regions) of the heavy chain variable sequence of SEQ ID NO:38.

[0470] The present disclosure also contemplates polynucleotide sequences comprising one or more of the polynucleotide sequences encoding the antibody fragments described herein. In one embodiment of the present disclosure, the polynucleotide encoding the antibody fragment with binding specificity to IL-6 comprises, or alternatively consists of, one, two, three, or more, including all, of the following polynucleotides encoding the antibody fragment: polynucleotide SEQ ID NO:45 encoding the light chain variable region of SEQ ID NO:37; polynucleotide SEQ ID NO:46 encoding the heavy chain variable region of SEQ ID NO:38; polynucleotides encoding the complementarity determining regions of the light chain variable region of SEQ ID NO:37 (SEQ ID NO:47; SEQ ID NO:48; and SEQ ID NO:49); and polynucleotides encoding the complementarity determining regions of the heavy chain variable region of SEQ ID NO:38 (SEQ ID NO:50; SEQ ID NO:51; and SEQ ID NO:52).

[0471] The present disclosure is further directed to polynucleotides encoding polypeptides of antibodies having binding specificity for IL-6. In one embodiment of the disclosure, the polynucleotide of the disclosure comprises, or alternatively consists of, the following polynucleotide sequence that encodes the variable light chain polypeptide sequence of SEQ ID NO: 53: ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGTGCCATATGTGACCCTGTGCTGACCCAGACTCCATCTCCCGTATCTGCACCTGTGGGAGGCACAGTCAG CATCAGTTGCCAGGCCAGTCAGAGTGTTTATGAGAACAACTATTTATCCTGGTTTCAGCAGAAACCAGGGCAGCCTCCCAAGCTCCTGATCTATGGTGCATCCACTCTGGATTCTGGGGTCCCATC GCGGTTCAAAGGCAGTGGATCTGGGACACAGTTCACTCTCACCATTACAGACGTGCAGTGTGACGATGCTGCCACTTACTATTGTGCAGGCGTTTATGATGATGATAGTGATGATGCCTTCGGCG GAGGGACCGAGGTGGTGGTCAAACGTACGGTAGCGGCCCCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTT (SEQ ID NO: 61)

[0472] In another embodiment of the disclosure, the polynucleotide of the disclosure comprises, or alternatively consists of, the following polynucleotide sequence that encodes the variable heavy chain polypeptide sequence of SEQ ID NO: 54: ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTGGCTGTGCTCAAAGGTGTCCAGTGTCAGGAGCAGCTGAAGGAGTCCGGAGGAGGCCTGGTAACGCCTGGAGGAACCCTGACACTCACCTGCACAG CCTCTGGATTCTCCCTCAATGCCTACTACATGAACTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAATGGATCGGATTCATTACTCTGAATAATAATGTAGCTTACGCGAACTGGGCGAAAGGCCGA TTCACCTTCTCCAAAACCTCGACCACGGTGGATCTGAAAATGACCAGTCCGACACCCGAGGACACGGCCACCTATTTCTGTGCCAGGAGTCGTGGCTGGGGTGCAATGGGTCGGTTGGATCTCTGGG GCCATGGCACCCTGGTCACCGTCTCGAGCGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGG (SEQ ID NO: 62)

[0473] In further embodiments of the present disclosure, the polynucleotide encoding the antibody fragment having binding specificity for IL-6 comprises, or alternatively consists of, one or more of the polynucleotide sequences of SEQ ID NO:63; SEQ ID NO:64; and SEQ ID NO:65, which correspond to polynucleotides encoding the complementarity determining regions (CDRs, or hypervariable regions) of the light chain variable sequence of SEQ ID NO:53.

[0474] In further embodiments of the present disclosure, the polynucleotide encoding the antibody fragment having binding specificity for IL-6 comprises, or alternatively consists of, one or more of the polynucleotide sequences of SEQ ID NO:66; SEQ ID NO:67; and SEQ ID NO:68, which correspond to polynucleotides encoding the complementarity determining regions (CDRs, or hypervariable regions) of the heavy chain variable sequence of SEQ ID NO:54.

[0475] The present disclosure also contemplates polynucleotide sequences comprising one or more of the polynucleotide sequences encoding the antibody fragments described herein. In one embodiment of the present disclosure, the polynucleotide encoding the antibody fragment with binding specificity to IL-6 comprises, or alternatively consists of, one, two, three, or more, including all, of the following polynucleotides encoding the antibody fragment: polynucleotide SEQ ID NO:61 encoding the light chain variable region of SEQ ID NO:53; polynucleotide SEQ ID NO:62 encoding the heavy chain variable region of SEQ ID NO:54; polynucleotides encoding the complementarity determining regions of the light chain variable region of SEQ ID NO:53 (SEQ ID NO:63; SEQ ID NO:64; and SEQ ID NO:65); and polynucleotides encoding the complementarity determining regions of the heavy chain variable region of SEQ ID NO:54 (SEQ ID NO:66; SEQ ID NO:67; and SEQ ID NO:68).

[0476] The present disclosure is further directed to polynucleotides encoding polypeptides of antibodies having binding specificity for IL-6. In one embodiment of the disclosure, the polynucleotide of the disclosure comprises, or alternatively consists of, the following polynucleotide sequence that encodes the variable light chain polypeptide sequence of SEQ ID NO:69: ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGTGCCACATTTGCCCAAGTGCTGACCCAGACTCCATCGCCTGTGTCTGCAGCTGTGGGAGGCACAGTCAC CATCAACTGCCAGGCCAGTCAGAGTGTTGATGATAACAACTGGTTAGGCTGGTATCAGCAGAAACGAGGGCAGCCTCCCAAGTACCTGATCTATTCTGCATCCACTCTGGCATCTGGGGTCCCAT CGCGGTTCAAAGGCAGTGGATCTGGGACACAGTTCACTCTCACCATCAGCGACCTGGAGTGTGACGATGCTGCCACTTACTACTGTGCAGGCGGTTTTAGTGGTAATATCTTTGCTTTCGGCGGA GGGACCGAGGTGGTGGTCAAACGTACGGTAGCGGCCCCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCT (SEQ ID NO: 77)

[0477] In another embodiment of the disclosure, the polynucleotide of the disclosure comprises, or alternatively consists of, the following polynucleotide sequence that encodes the variable heavy chain polypeptide sequence of SEQ ID NO: 70: ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTCGCTGTGCTCAAAGGTGTCCAGTGTCAGTCGGTGGAGGAGTCCGGGGGTCGCCTGGTCACGCCTGGGACACCCCTGACACTCACCTGCACAGT CTCTGGCTTCTCCCTCAGTAGCTATGCAATGAGCTGGGTCCGCCAGGCTCCAGGAAAGGGGCTGGAGTGGATCGGAATCATTGGTGGTTTTGGTACCACATACTACGCGACCTGGGCGAAAGGCC GATTCACCATCTCCAAAACCTCGACCACGGTGGATCTGAGAATCACCAGTCCGACAACCGAGGACACGGCCACCTATTTCTGTGCCAGAGGTGGTCCTGGTAATGGTGGTGACATCTGGGGCCAA GGGACCCTGGTCACCGTCTCGAGCGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACT (SEQ ID NO: 78)

[0478] In further embodiments of the present disclosure, the polynucleotide encoding the antibody fragment having binding specificity for IL-6 comprises, or alternatively consists of, one or more of the polynucleotide sequences of SEQ ID NO:79; SEQ ID NO:80; and SEQ ID NO:81, which correspond to polynucleotides encoding the complementarity determining regions (CDRs, or hypervariable regions) of the light chain variable sequence of SEQ ID NO:69.

[0479] In further embodiments of the present disclosure, the polynucleotide encoding the antibody fragment having binding specificity for IL-6 comprises, or alternatively consists of, one or more of the polynucleotide sequences of SEQ ID NO:82; SEQ ID NO:83; and SEQ ID NO:84, which correspond to polynucleotides encoding the complementarity determining regions (CDRs, or hypervariable regions) of the heavy chain variable sequence of SEQ ID NO:70.

[0480] The present disclosure also contemplates polynucleotide sequences comprising one or more of the polynucleotide sequences encoding the antibody fragments described herein. In one embodiment of the present disclosure, the polynucleotide encoding the antibody fragment with binding specificity to IL-6 comprises, or alternatively consists of, one, two, three, or more, including all, of the following polynucleotides encoding the antibody fragment: polynucleotide SEQ ID NO:77 encoding the light chain variable region of SEQ ID NO:69; polynucleotide SEQ ID NO:78 encoding the heavy chain variable region of SEQ ID NO:70; polynucleotides (SEQ ID NO:79, SEQ ID NO:80, and SEQ ID NO:81) encoding the complementarity determining regions of the light chain variable region of SEQ ID NO:69; and polynucleotides (SEQ ID NO:82, SEQ ID NO:83, and SEQ ID NO:84) encoding the complementarity determining regions of the heavy chain variable region of SEQ ID NO:70.

[0481] The present disclosure is further directed to polynucleotides encoding polypeptides of antibodies having binding specificity for IL-6. In one embodiment of the disclosure, the polynucleotides of the disclosure comprise, or alternatively consist of, the following polynucleotide sequence that encodes the variable light chain polypeptide sequence of SEQ ID NO: 85: ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGTGCCACATTTGCAGCCGTGCTGACCCAGACACCATCGCCCGTGTCTGTACCTGTGGGAGGCACAGTCAC CATCAAGTGCCAGTCCAGTCAGAGTGTTTATAATAATTTCTTATCGTGGTATCAGCAGAAACCAGGGCAGCCTCCCAAGCTCCTGATCTACCAGGCATCCAAACTGGCATCTGGGGTCCCAGATA GGTTCAGCGGCAGTGGATCTGGGACACAGTTCACTCTCACCATCAGCGGCGTGCAGTGTGACGATGCTGCCACTTACTACTGTCTAGGCGGTTATGATGATGATGCTGATAATGCTTTCGGCGGA GGGACCGAGGTGGTGGTCAAACGTACGGTAGCGGCCCCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTC (SEQ ID NO: 93)

[0482] In another embodiment of the disclosure, the polynucleotide of the disclosure comprises, or alternatively consists of, the following polynucleotide sequence that encodes the variable heavy chain polypeptide sequence of SEQ ID NO: 86: ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTCGCTGTGCTCAAAGGTGTCCAGTGTCAGTCGGTGGAGGAGTCCGGGGGTCGCCTGGTCACGCCTGGGACACCCCTGACGCTCACCTGCACAGTCTCT GGAATCGACCTCAGTGACTATGCAATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAATGGATCGGAATCATTTATGCTGGTAGTGGTAGCACATGGTACGCGAGCTGGGCGAAAGGCCGATTCA CCATCTCCAAAACCTCGACCACGGTGGATCTGAAAATCACCAGTCCGACAACCGAGGACACGGCCACCTATTTCTGTGCCAGAGATGGATACGATGACTATGGTGATTTCGATCGATTGGATCTCTGGGG CCCAGGCACCCTCGTCACCGTCTCGAGCGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACT (SEQ ID NO: 94)

[0483] In further embodiments of the present disclosure, the polynucleotide encoding the antibody fragment having binding specificity for IL-6 comprises, or alternatively consists of, one or more of the polynucleotide sequences of SEQ ID NO:95; SEQ ID NO:96; and SEQ ID NO:97, which correspond to the polynucleotide encoding the complementarity determining regions (CDRs, or hypervariable regions) of the light chain variable sequence of SEQ ID NO:85.

[0484] In further embodiments of the present disclosure, the polynucleotide encoding the antibody fragment having binding specificity for IL-6 comprises, or alternatively consists of, one or more of the polynucleotide sequences of SEQ ID NO:98; SEQ ID NO:99; and SEQ ID NO:100, which correspond to polynucleotides encoding the complementarity determining regions (CDRs, or hypervariable regions) of the heavy chain variable sequence of SEQ ID NO:86.

[0485] The present disclosure also contemplates polynucleotide sequences comprising one or more of the polynucleotide sequences encoding the antibody fragments described herein. In one embodiment of the present disclosure, the polynucleotide encoding the antibody fragment with binding specificity to IL-6 comprises, or alternatively consists of, one, two, three, or more, including all, of the following polynucleotides encoding the antibody fragment: polynucleotide SEQ ID NO:93 encoding the light chain variable region of SEQ ID NO:85; polynucleotide SEQ ID NO:94 encoding the heavy chain variable region of SEQ ID NO:86; polynucleotides encoding the complementarity determining regions of the light chain variable region of SEQ ID NO:85 (SEQ ID NO:95; SEQ ID NO:96; and SEQ ID NO:97); and polynucleotides encoding the complementarity determining regions of the heavy chain variable region of SEQ ID NO:86 (SEQ ID NO:98; SEQ ID NO:99; and SEQ ID NO:100).

[0486] The present disclosure is further directed to polynucleotides encoding polypeptides of antibodies having binding specificity for IL-6. In one embodiment of the disclosure, the polynucleotides of the disclosure comprise, or alternatively consist of, the following polynucleotide sequence that encodes the variable light chain polypeptide sequence of SEQ ID NO: 101: ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGTGCCAGATGTGCCTATGATATGACCCAGACTCCAGCCTCGGTGTCTGCAGCTGTGGGAGGCACAGTCAC CATCAAATGCCAGGCCAGTCAGAGCATTAACAATGAATTATCCTGGTATCAGCAGAAATCAGGGCAGCGTCCCAAGCTCCTGATCTATAGGGCATCCACTCTGGCATCTGGGGTCTCATCGCGGT TCAAAGGCAGTGGATCTGGGACAGAGTTCACTCTCACCATCAGCGACCTGGAGTGTGCCGATGCTGCCACTTACTACTGTCAACAGGGTTATAGTCTGAGGAATATTGATAATGCTTTCGGCGGA GGGACCGAGGTGGTGGTCAAACGTACGGTAGCGGCCCCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTC (SEQ ID NO: 109)

[0487] In another embodiment of the disclosure, the polynucleotide of the disclosure comprises, or alternatively consists of, the following polynucleotide sequence that encodes the variable heavy chain polypeptide sequence of SEQ ID NO: 102: ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTCGCTGTGCTCTCAGGTGTCCAGTGTCAGTCGCTGGAGGAGTCCGGGGGTCGCCTGGTCACGCCTGGGACACCCCTGACACTCACCTGCACAGCCT CTGGATTCTCCTCAGTAACTACTACATGACCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAATGGATCGGAATGATTTATGGTAGTGATGAAACAGCCTACGCGAACTGGGCGATAGGCCGATT CACCATCTCCAAAACCTCGACCACGGTGGATCTGAAAATGACCAGTCTGACAGCCGCGGACACGGCCACCTATTTCTGTGCCAGAGATGATAGTAGTGACTGGGATGCAAAATTTAACTTGTGGGGC CAAGGGACCCTCGTCACCGTCTCGAGCGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGG (SEQ ID NO: 110)

[0488] In further embodiments of the present disclosure, the polynucleotide encoding the antibody fragment having binding specificity for IL-6 comprises, or alternatively consists of, one or more of the polynucleotide sequences of SEQ ID NO:111; SEQ ID NO:112; and SEQ ID NO:113, which correspond to the polynucleotide encoding the complementarity determining regions (CDRs, or hypervariable regions) of the light chain variable sequence of SEQ ID NO:101.

[0489] In further embodiments of the present disclosure, the polynucleotide encoding the antibody fragment having binding specificity for IL-6 comprises, or alternatively consists of, one or more of the polynucleotide sequences of SEQ ID NO:114; SEQ ID NO:115; and SEQ ID NO:116, which correspond to polynucleotides encoding the complementarity determining regions (CDRs, or hypervariable regions) of the heavy chain variable sequence of SEQ ID NO:102.

[0490] The present disclosure also contemplates polynucleotide sequences comprising one or more of the polynucleotide sequences encoding the antibody fragments described herein. In one embodiment of the present disclosure, the polynucleotide encoding the antibody fragment having binding specificity to IL-6 comprises, or alternatively consists of, one, two, three, or more, including all, of the following polynucleotides encoding the antibody fragment: polynucleotide SEQ ID NO: 109 encoding the light chain variable region of SEQ ID NO: 101; polynucleotide SEQ ID NO: 110 encoding the heavy chain variable region of SEQ ID NO: 102; polynucleotides encoding the complementarity determining regions of the light chain variable region of SEQ ID NO: 101 (SEQ ID NO: 111; SEQ ID NO: 112; and SEQ ID NO: 113); and polynucleotides encoding the complementarity determining regions of the heavy chain variable region of SEQ ID NO: 102 (SEQ ID NO: 114; SEQ ID NO: 115; and SEQ ID NO: 116).

[0491] The present disclosure is further directed to polynucleotides encoding polypeptides of antibodies having binding specificity for IL-6. In one embodiment of the disclosure, the polynucleotide of the disclosure comprises, or alternatively consists of, the following polynucleotide sequence that encodes the variable light chain polypeptide sequence of SEQ ID NO: 122: ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGTGCCACATTTGCAGCCGTGCTGACCCAGACACCATCACCCGTGTCTGCAGCTGTGGGAGGCACAGTCACCATCAGTTGCCAGTCCAGTCAGAGTGTTGGTAATAACCAGGACTTATCCTGGTTTCAGCAGAGA CCAGGGCAGCCTCCCAAGCTCCTGATCTACGAAATATCCAAACTGGAATCTGGGGTCCCATCGCGGTTCAGCGGCAGTGGATCTGGGACACACTTCACTCTCACCATCAGCGGCGTACAGTGTGACGATGCTGCCACTTACTACTGTCTAGGCGGTTATGATGATGATGCTGATAATGCT (SEQ ID NO: 130)

[0492] In another embodiment of the disclosure, the polynucleotide of the disclosure comprises, or alternatively consists of, the following polynucleotide sequence that encodes the variable heavy chain polypeptide sequence of SEQ ID NO: 123: ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTCGCTGTGCTCAAAGGTGTCCAGTGTCACTCGGTGGAGGAGTCCGGGGGTCGCCTGGTCACGCCTGGGACACCCCTGACACTCACCTGCACAGTCTCTGGATTCTCCCTCAGTAGTCGTACAATGTCCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGA TCGGATACATTTGGAGTGGTGGTAGCACATACTACGCGACCTGGGCGAAAGGCCGATTCACCATCTCCAAAACCTCGACCACGGTGGATCTGAAAATCACCAGTCCGACAACCGAGGACACGGCCACCTATTTCTGTGCCAGATTGGGCGATACTGGTGGTCACGCTTATGCTACTCGCTTAAATCTC (SEQ ID NO: 131)

[0493] In further embodiments of the present disclosure, the polynucleotide encoding the antibody fragment having binding specificity for IL-6 comprises, or alternatively consists of, one or more of the polynucleotide sequences of SEQ ID NO: 132; SEQ ID NO: 133; and SEQ ID NO: 134, which correspond to polynucleotides encoding the complementarity determining regions (CDRs, or hypervariable regions) of the light chain variable sequence of SEQ ID NO: 122.

[0494] In further embodiments of the present disclosure, the polynucleotide encoding the antibody fragment having binding specificity for IL-6 comprises, or alternatively consists of, one or more of the polynucleotide sequences of SEQ ID NO: 135; SEQ ID NO: 136; and SEQ ID NO: 137, which correspond to polynucleotides encoding the complementarity determining regions (CDRs, or hypervariable regions) of the heavy chain variable sequence of SEQ ID NO: 123.

[0495] The present disclosure also contemplates polynucleotide sequences comprising one or more of the polynucleotide sequences encoding the antibody fragments described herein. In one embodiment of the present disclosure, the polynucleotide encoding the antibody fragment with binding specificity to IL-6 comprises, or alternatively consists of, one, two, three, or more, including all, of the following polynucleotides encoding the antibody fragment: polynucleotide SEQ ID NO: 130 encoding the light chain variable region of SEQ ID NO: 122; polynucleotide SEQ ID NO: 131 encoding the heavy chain variable region of SEQ ID NO: 123; polynucleotides encoding the complementarity determining regions of the light chain variable region of SEQ ID NO: 122 (SEQ ID NO: 132; SEQ ID NO: 133; and SEQ ID NO: 134); and polynucleotides encoding the complementarity determining regions of the heavy chain variable region of SEQ ID NO: 123 (SEQ ID NO: 135; SEQ ID NO: 136; and SEQ ID NO: 137).

[0496] The present disclosure is further directed to polynucleotides encoding polypeptides of antibodies having binding specificity for IL-6. In one embodiment of the disclosure, the polynucleotide of the disclosure comprises, or alternatively consists of, the following polynucleotide sequence that encodes the variable light chain polypeptide sequence of SEQ ID NO: 138: ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGTGCCACATTTGCAGCCGTGCTGACCCAGACACCATCGTCCGTGTCTGCAGCTGTGGGAGGCACAGTCAGCATCAGTTGCCAGTCCAGTCAGAGTGTTTATAGTAATAAGTACCTAGCCTGGTATCAGCAGAAA CCAGGGCAGCCTCCCAAGCTCTGATCTACTGGACATCCAAACTGGCATCTGGGGCCCCATCACGGTTCAGCGGCAGTGGATCTGGGACACAATTCACTCTCACCATCAGCGGCGTGCAGTGTGACGATGCTGCCACTTACTACTGTCTAGGCGCTTATGATGATGATGCTGATAATGCT (SEQ ID NO: 146)

[0497] In another embodiment of the disclosure, the polynucleotide of the disclosure comprises, or alternatively consists of, the following polynucleotide sequence that encodes the variable heavy chain polypeptide sequence of SEQ ID NO: 139: ATGGAGACTGGGCTGCGCTGGCTTCCTGGTCGCTGTGCTCAAAGGTGTCCAGTGTCAGTCGGTGGAAGAGTCCGGGGGTCGCCTGGTCAAGCCTGACGAAACCCTGACACTCACCTGCACAGCCTCTGGATTCTCCCTGGAGGGCGGCTACATGACCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAAT GGATCGGAATCAGTTATGATAGTGGTAGCACATACTACGCGAGCTGGGCGAAAGGCCGATTCACCATCTCCAAGACCTCGTCGACCACGGTGGATCTGAAAATGACCAGTCTGACAACCGAGGACACGGCCACCTATTTCTGCGTCAGATCACTAAAATATCCTACTGTTACTTCTGATGACTTG (SEQ ID NO: 147)

[0498] In further embodiments of the present disclosure, the polynucleotide encoding the antibody fragment having binding specificity for IL-6 comprises, or alternatively consists of, one or more of the polynucleotide sequences of SEQ ID NO: 148; SEQ ID NO: 149; and SEQ ID NO: 150, which correspond to the polynucleotide encoding the complementarity determining regions (CDRs, or hypervariable regions) of the light chain variable sequence of SEQ ID NO: 138.

[0499] In further embodiments of the present disclosure, the polynucleotide encoding the antibody fragment having binding specificity for IL-6 comprises, or alternatively consists of, one or more of the polynucleotide sequences of SEQ ID NO: 151; SEQ ID NO: 152; and SEQ ID NO: 153, which correspond to polynucleotides encoding the complementarity determining regions (CDRs, or hypervariable regions) of the heavy chain variable sequence of SEQ ID NO: 139.

[0500] The present disclosure also contemplates polynucleotide sequences comprising one or more of the polynucleotide sequences encoding the antibody fragments described herein. In one embodiment of the present disclosure, the polynucleotide encoding the antibody fragment having binding specificity to IL-6 comprises, or alternatively consists of, one, two, three, or more, including all, of the following polynucleotides encoding the antibody fragment: polynucleotide SEQ ID NO: 146 encoding the light chain variable region of SEQ ID NO: 138; polynucleotide SEQ ID NO: 147 encoding the heavy chain variable region of SEQ ID NO: 139; polynucleotides encoding the complementarity determining regions of the light chain variable region of SEQ ID NO: 138 (SEQ ID NO: 148; SEQ ID NO: 149; and SEQ ID NO: 150); and polynucleotides encoding the complementarity determining regions of the heavy chain variable region of SEQ ID NO: 139 (SEQ ID NO: 151; SEQ ID NO: 152; and SEQ ID NO: 153).

[0501] The present disclosure is further directed to polynucleotides encoding polypeptides of antibodies having binding specificity for IL-6. In one embodiment of the disclosure, the polynucleotides of the disclosure comprise, or alternatively consist of, the following polynucleotide sequence that encodes the variable light chain polypeptide sequence of SEQ ID NO: 154: ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGTGCCACATTTGCAGCCGTGCTGACCCAGACACCATCACCCGTGTCTGCAGCTGTGGGAGGCACAGTCACCATCAGTTGCCAGTCCAGTCAGAGTGTTTATAATAATAACGACTTAGCCTGGTATCAGCAGAAA CCAGGGCAGCCTCCTAAACTCCTGATCTATTATGCATCCACTCTGGCATCTGGGGTCCCATCGCGGTTCAAAGGCAGTGGATCTGGGACACAGTTCACTCTCACCATCAGCGGCGTGCAGTGTGACGATGCTGCCGCTTACTACTGTCTAGGCGGTTATGATGATGATGCTGATAATGCT (SEQ ID NO: 162)

[0502] In another embodiment of the disclosure, the polynucleotide of the disclosure comprises, or alternatively consists of, the following polynucleotide sequence that encodes the variable heavy chain polypeptide sequence of SEQ ID NO: 155: ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTCGCTGTGCTCAAAGGTGTCCAGTGTCAGTCGGTGGAGGAGTCCGGGGGTCGCCTGGTCACGCCTGGGACACCCCTGACACTCACCTGCACAGTATCTGGATTATCCCTCAGTAGCAATACAATAAACTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATC GGATACATTTGGAGTGGTGGTAGTACATACTACGCGAGCTGGGTGAATGGTCGATTCACCATCTCCAAAACCTCGACCACGGTGGATCTGAAAATCACCAGTCCGACAACCGAGGACACGGCCACCTATTTCTGTGCCAGAGGGGGTTACGCTAGTGGTGGTTATCCTTATGCCACTCGGTTGGATCTC (SEQ ID NO: 163)

[0503] In further embodiments of the present disclosure, the polynucleotide encoding the antibody fragment having binding specificity for IL-6 comprises, or alternatively consists of, one or more of the polynucleotide sequences of SEQ ID NO: 164; SEQ ID NO: 165; and SEQ ID NO: 166, which correspond to polynucleotides encoding the complementarity determining regions (CDRs, or hypervariable regions) of the light chain variable sequence of SEQ ID NO: 154.

[0504] In further embodiments of the present disclosure, the polynucleotide encoding the antibody fragment having binding specificity for IL-6 comprises, or alternatively consists of, one or more of the polynucleotide sequences of SEQ ID NO: 167; SEQ ID NO: 168; and SEQ ID NO: 169, which correspond to polynucleotides encoding the complementarity determining regions (CDRs, or hypervariable regions) of the heavy chain variable sequence of SEQ ID NO: 155.

[0505] The present disclosure also contemplates polynucleotide sequences comprising one or more of the polynucleotide sequences encoding the antibody fragments described herein. In one embodiment of the present disclosure, the polynucleotide encoding the antibody fragment with binding specificity to IL-6 comprises, or alternatively consists of, one, two, three, or more, including all, of the following polynucleotides encoding the antibody fragment: polynucleotide SEQ ID NO: 162 encoding the light chain variable region of SEQ ID NO: 154; polynucleotide SEQ ID NO: 163 encoding the heavy chain variable region of SEQ ID NO: 155; polynucleotides encoding the complementarity determining regions of the light chain variable region of SEQ ID NO: 154 (SEQ ID NO: 164; SEQ ID NO: 165; and SEQ ID NO: 166); and polynucleotides encoding the complementarity determining regions of the heavy chain variable region of SEQ ID NO: 155 (SEQ ID NO: 167; SEQ ID NO: 168; and SEQ ID NO: 169).

[0506] The present disclosure is further directed to polynucleotides encoding polypeptides of antibodies having binding specificity for IL-6. In one embodiment of the disclosure, the polynucleotides of the disclosure comprise, or alternatively consist of, the following polynucleotide sequence that encodes the variable light chain polypeptide sequence of SEQ ID NO: 170: ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGTGCCACATTTGCAGCCGTGCTGACCCAGACACCATCCTCCGTGTCTGCAGCTGTGGGAGGCACAGTCACCATCAATTGCCAGTCCAGTCAGAGTGTTTATAATAACGACTACTTATCCTGGTATCAACAGAGG CCAGGGCAACGTCCCAAGCTCCTAATCTATGGTGCTTCCAAACTGGCATCTGGGGTCCCGTCACGGTTCAAAGGCAGTGGATCTGGGAAACAGTTTACTCTCACCATCAGCGGCGTGCAGTGTGACGATGCTGCCACTTACTACTGTCTGGGCGATTATGATGATGATGCTGATAATACT (SEQ ID NO: 178)

[0507] In another embodiment of the disclosure, the polynucleotide of the disclosure comprises, or alternatively consists of, the following polynucleotide sequence that encodes the variable heavy chain polypeptide sequence of SEQ ID NO: 171: ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTCGCTGTGCTCAAAGGTGTCCAGTGTCAGTCGCTGGAGGAGTCCGGGGGTCGCCTGGTCACGCCTGGGACACCCCTGACACTCACTTGCACAGTCTCTGGATTCACCCTCAGTACCAACTACTACCTGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGG CTAGAATGGATCGGAATCATTTATCCTAGTGGTAACACATATTGCGCGAAGTGGGCGAAAGGCCGATTCACCATCTCCAAAACCTCGTCGACCACGGTGGATCTGAAAATGACCAGTCCGACAACCGAGGACACAGCCACGTATTTCTGTGCCAGAAATTATGGTGGTGATGAAAGTTTG (SEQ ID NO: 179)

[0508] In further embodiments of the present disclosure, the polynucleotide encoding the antibody fragment having binding specificity for IL-6 comprises, or alternatively consists of, one or more of the polynucleotide sequences of SEQ ID NO: 180; SEQ ID NO: 181; and SEQ ID NO: 182, which correspond to polynucleotides encoding the complementarity determining regions (CDRs, or hypervariable regions) of the light chain variable sequence of SEQ ID NO: 170.

[0509] In further embodiments of the present disclosure, the polynucleotide encoding the antibody fragment having binding specificity for IL-6 comprises, or alternatively consists of, one or more of the polynucleotide sequences of SEQ ID NO: 183; SEQ ID NO: 184; and SEQ ID NO: 185, which correspond to polynucleotides encoding the complementarity determining regions (CDRs, or hypervariable regions) of the heavy chain variable sequence of SEQ ID NO: 171.

[0510] The present disclosure also contemplates polynucleotide sequences comprising one or more of the polynucleotide sequences encoding the antibody fragments described herein. In one embodiment of the present disclosure, the polynucleotide encoding the antibody fragment with binding specificity to IL-6 comprises, or alternatively consists of, one, two, three, or more, including all, of the following polynucleotides encoding the antibody fragment: polynucleotide SEQ ID NO: 178 encoding the light chain variable region of SEQ ID NO: 170; polynucleotide SEQ ID NO: 179 encoding the heavy chain variable region of SEQ ID NO: 171; polynucleotides encoding the complementarity determining regions of the light chain variable region of SEQ ID NO: 170 (SEQ ID NO: 180; SEQ ID NO: 181; and SEQ ID NO: 182); and polynucleotides encoding the complementarity determining regions of the heavy chain variable region of SEQ ID NO: 171 (SEQ ID NO: 183; SEQ ID NO: 184; and SEQ ID NO: 185).

[0511] The present disclosure is further directed to polynucleotides encoding polypeptides of antibodies having binding specificity for IL-6. In one embodiment of the disclosure, the polynucleotide of the disclosure comprises, or alternatively consists of, the following polynucleotide sequence that encodes the variable light chain polypeptide sequence of SEQ ID NO: 186: ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGTGCCAGATGTGATGTTGTGATGACCCAGACTCCAGCCTCCGTGGAGGCAGCTGTGGGAGGCACAGTCACCATCAAGTGCCAGGCCAGTGAGACCATTGGCAATGCATTAGCCTGGTATCAGCAGAAA TCAGGGCAGCCTCCCAAGCTCCTGATCTACAAGGCATCCAAACTGGCATCTGGGGTCCCATCGCGGTTCAAAGGCAGTGGATCTGGGACAGAGTACACTCTCACCATCAGCGACCTGGAGTGTGCCGATGCTGCCACTTACTACTGTCAATGGTGTTATTTTGGTGATAGTGTT (SEQ ID NO: 194)

[0512] In another embodiment of the disclosure, the polynucleotide of the disclosure comprises, or alternatively consists of, the following polynucleotide sequence that encodes the variable heavy chain polypeptide sequence of SEQ ID NO: 187: ATGGAGACTGGGCTGCGCTGGCTTCCTGGTCACTGTGCTCAAAGGTGTCCAGTGTCAGGAGCAGCTGGTGGAGTCCGGGGGAGGCCTGGTCCAGCCTGAGGGATCCCTGACACTCACCTGCACAGCCTCTGGATTCGACTTCAGTAGCGGCTACTACATGTGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGG AGTGGATCGCGTGTATTTTCACTATTACTACTAACACTTACTACGCGAGCTGGGCGAAAGGCCGATTCACCATCTCCAAGACCTCGTCGACCACGGTGACTCTGCAAATGACCAGTCTGACAGCCGCGGACACGGCCACCTATCTCTGTGCGAGAGGGATTTATTCTGATAATAATTATTATGCCTTG (SEQ ID NO: 195)

[0513] In further embodiments of the present disclosure, the polynucleotide encoding the antibody fragment having binding specificity for IL-6 comprises, or alternatively consists of, one or more of the polynucleotide sequences of SEQ ID NO: 196; SEQ ID NO: 197; and SEQ ID NO: 198, which correspond to polynucleotides encoding the complementarity determining regions (CDRs, or hypervariable regions) of the light chain variable sequence of SEQ ID NO: 186.

[0514] In further embodiments of the present disclosure, the polynucleotide encoding the antibody fragment having binding specificity for IL-6 comprises, or alternatively consists of, one or more of the polynucleotide sequences of SEQ ID NO: 199; SEQ ID NO: 200; and SEQ ID NO: 201, which correspond to polynucleotides encoding the complementarity determining regions (CDRs, or hypervariable regions) of the heavy chain variable sequence of SEQ ID NO: 187.

[0515] The present disclosure also contemplates polynucleotide sequences comprising one or more of the polynucleotide sequences encoding the antibody fragments described herein. In one embodiment of the present disclosure, the polynucleotide encoding the antibody fragment having binding specificity to IL-6 comprises, or alternatively consists of, one, two, three, or more, including all, of the following polynucleotides encoding the antibody fragment: polynucleotide SEQ ID NO: 194 encoding the light chain variable region of SEQ ID NO: 186; polynucleotide SEQ ID NO: 195 encoding the heavy chain variable region of SEQ ID NO: 187; polynucleotides encoding the complementarity determining regions of the light chain variable region of SEQ ID NO: 186 (SEQ ID NO: 196; SEQ ID NO: 197; and SEQ ID NO: 198); and polynucleotides encoding the complementarity determining regions of the heavy chain variable region of SEQ ID NO: 187 (SEQ ID NO: 199; SEQ ID NO: 200; and SEQ ID NO: 201).

[0516] The present disclosure is further directed to polynucleotides encoding polypeptides of antibodies having binding specificity for IL-6. In one embodiment of the disclosure, the polynucleotide of the disclosure comprises, or alternatively consists of, the following polynucleotide sequence that encodes the variable light chain polypeptide sequence of SEQ ID NO: 202: ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGTGCCAGATGTGATGTTGTGATGACCCAGACTCCAGCCTCCGTGGAGGCAGCTGTGGGAGGCACAGTCACCATCAAGTGCCAGGCCAGTGAGAGCATTGGCAATGCATTAGCCTGGTATCAGCAGAAA CCAGGGCAGCCTCCCAAGCTCCTGATCTACAAGGCATCCACTCTGGCATCTGGGGTCCCATCGCGGTTCAGCGGCAGTGGATCTGGGACAGAGTTCACTCTCACCATCAGCGGCGTGCAGTGTGCCGATGCTGCCGCTTACTACTGTCAATGGTGTTATTTTGGTGATAGTGTT (SEQ ID NO: 210)

[0517] In another embodiment of the disclosure, the polynucleotide of the disclosure comprises, or alternatively consists of, the following polynucleotide sequence that encodes the variable heavy chain polypeptide sequence of SEQ ID NO:203: ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTCGCTGTGCTCAAAGGTGTCCAGTGTCAGCAGCAGCTGGTGGAGTCCGGGGGAGGCCTGGTCAAGCCGGGGGCATCCCTGACACTCACCTGCAAAGCCTCTGGATTCTCCTTCAGTAGCGGCTACTACATGTGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGG AGTCGATCGCATGCATTTTTACTATTACTGATAACACTTACTACGCGAACTGGGCGAAAGGCCGATTCACCATCTCCAAGCCCTCGTCGCCCACGGTGACTCTGCAAATGACCAGTCTGACAGCCGCGGACACGGCCACCTATTTCTGTGCGAGGGGGATTTATTCTACTGATAATTATTATGCCTTG (SEQ ID NO: 211)

[0518] In further embodiments of the present disclosure, the polynucleotide encoding the antibody fragment having binding specificity for IL-6 comprises, or alternatively consists of, one or more of the polynucleotide sequences of SEQ ID NO:212; SEQ ID NO:213; and SEQ ID NO:214, which correspond to polynucleotides encoding the complementarity determining regions (CDRs, or hypervariable regions) of the light chain variable sequence of SEQ ID NO:202.

[0519] In further embodiments of the present disclosure, the polynucleotide encoding the antibody fragment having binding specificity for IL-6 comprises, or alternatively consists of, one or more of the polynucleotide sequences of SEQ ID NO:215; SEQ ID NO:216; and SEQ ID NO:217, which correspond to polynucleotides encoding the complementarity determining regions (CDRs, or hypervariable regions) of the heavy chain variable sequence of SEQ ID NO:203.

[0520] The present disclosure also contemplates polynucleotide sequences comprising one or more of the polynucleotide sequences encoding the antibody fragments described herein. In one embodiment of the present disclosure, the polynucleotide encoding the antibody fragment with binding specificity to IL-6 comprises, or alternatively consists of, one, two, three, or more, including all, of the following polynucleotides encoding the antibody fragment: polynucleotide SEQ ID NO:210 encoding the light chain variable region of SEQ ID NO:202; polynucleotide SEQ ID NO:211 encoding the heavy chain variable region of SEQ ID NO:203; polynucleotides encoding the complementarity determining regions of the light chain variable region of SEQ ID NO:202 (SEQ ID NO:212; SEQ ID NO:213; and SEQ ID NO:214); and polynucleotides encoding the complementarity determining regions of the heavy chain variable region of SEQ ID NO:203 (SEQ ID NO:215; SEQ ID NO:216; and SEQ ID NO:217).

[0521] The present disclosure is further directed to polynucleotides encoding polypeptides of antibodies having binding specificity for IL-6. In one embodiment of the disclosure, the polynucleotide of the disclosure comprises, or alternatively consists of, the following polynucleotide sequence that encodes the variable light chain polypeptide sequence of SEQ ID NO:218: ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGTGCCAGATGTGATGTTGTGATGACCCAGACTCCAGCCTCCGTGGAGGCAGCTGTGGGAGGCACAGTCACCATCAAGTGCCAGGCCAGTCAGAGCGTTAGTAGCTACTTAAACTGGTATCAGCAGAAACCAGGG CAGCCTCCCAAGCTCCTGATCTACAGGGCATCCACTCTGGAATCTGGGGTCCCATCGCGGTTCAAAGGCAGTGGATCTGGGACAGAGTTCACTCTCACCATCAGCGACCTGGAGTGTGCCGATGCTGCCACTTACTACTGTCAATGTACTTATGGTACTAGTAGTAGTTATGGTGCTGCT (SEQ ID NO: 226)

[0522] In another embodiment of the disclosure, the polynucleotide of the disclosure comprises, or alternatively consists of, the following polynucleotide sequence that encodes the variable heavy chain polypeptide sequence of SEQ ID NO:219: ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTCGCTGTGCTCAAAGGTGTCCAGTGTCAGTCGGTGGAGGAGTCCGGGGGTCGCCTGGTCACGCCTGGGACACCCCTGACACTCACCTGCACCGTCTCTGGTATCTCCCTCAGTAGCAATGCAATAAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAATGGATCGGAATC ATTAGTTATAGTGGTACCACATACTACGCGAGCTGGGCGAAAGGCCGATTCACCATCTCCAAAACCTCGTCGACCACGGTGGATCTGAAAATCACTAGTCCGACAACCGAGGACACGGCCACCTACTTCTGTGCCAGAGATGACCCTACGACAGTTATGGTTATGTTGATACCTTTTGGAGCCGGCATGGACCTC (SEQ ID NO: 227)

[0523] In further embodiments of the present disclosure, the polynucleotide encoding the antibody fragment with binding specificity to IL-6 comprises, or alternatively consists of, one or more of the polynucleotide sequences of SEQ ID NO:228; SEQ ID NO:229; and SEQ ID NO:230, which correspond to polynucleotides encoding the complementarity determining regions (CDRs, or hypervariable regions) of the light chain variable sequence of SEQ ID NO:218.

[0524] In further embodiments of the present disclosure, the polynucleotide encoding the antibody fragment having binding specificity for IL-6 comprises, or alternatively consists of, one or more of the polynucleotide sequences of SEQ ID NO:231; SEQ ID NO:232; and SEQ ID NO:233, which correspond to polynucleotides encoding the complementarity determining regions (CDRs, or hypervariable regions) of the heavy chain variable sequence of SEQ ID NO:219.

[0525] The present disclosure also contemplates polynucleotide sequences comprising one or more of the polynucleotide sequences encoding the antibody fragments described herein. In one embodiment of the present disclosure, the polynucleotide encoding the antibody fragment with binding specificity to IL-6 comprises, or alternatively consists of, one, two, three, or more, including all, of the following polynucleotides encoding the antibody fragment: polynucleotide SEQ ID NO:226 encoding the light chain variable region of SEQ ID NO:218; polynucleotide SEQ ID NO:227 encoding the heavy chain variable region of SEQ ID NO:219; polynucleotides encoding the complementarity determining regions of the light chain variable region of SEQ ID NO:218 (SEQ ID NO:228; SEQ ID NO:229; and SEQ ID NO:230); and polynucleotides encoding the complementarity determining regions of the heavy chain variable region of SEQ ID NO:219 (SEQ ID NO:231; SEQ ID NO:232; and SEQ ID NO:233).

[0526] The present disclosure is further directed to polynucleotides encoding polypeptides of antibodies having binding specificity for IL-6. In one embodiment of the disclosure, the polynucleotide of the disclosure comprises, or alternatively consists of, the following polynucleotide sequence that encodes the variable light chain polypeptide sequence of SEQ ID NO: 234: ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGTGCCACATTTGCCCAAGTGCTGACCCAGACTGCATCGCCCGTGTCTGCAGCTGTGGGAGGCACAGTCACCATCAACTGCCAGGCCAGTCAGAGTGTTTATAAGAACAACTACTTATCCTGGTATCAGCAGAAACCA GGGCAGCCTCCCAAAGGCCTGATCTATTCTGCATCGACTCTAGATTCTGGGGTCCCATTGCGGTTCAGCGGCAGTGGATCTGGGACACAGTTCACTCTCACCATCAGCGACGTGCAGTGTGACGATGCTGCCACTTACTACTGTCTAGGCAGTTATGATTGTAGTAGTGGTGATTGTTATGCT (SEQ ID NO: 242)

[0527] In another embodiment of the disclosure, the polynucleotide of the disclosure comprises, or alternatively consists of, the following polynucleotide sequence that encodes the variable heavy chain polypeptide sequence of SEQ ID NO: 235: ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTCGCTGTGCTCAAAGGTGTCCAGTGTCAGTCGTTGGAGGAGTCCGGGGGAGACCTGGTCAAGCCTGAGGGATCCCTGACACTCACCTGCACAGCCTCTGGATTCTCCTTCAGTAGCTACTGGATGTGCTGGGTCCGCCAGGCTCCAGGGAAG GGGCTGGAGTGGATCGCATGCATTGTTACTGGTAATGGTAACACTTACTACGCGAACTGGGCGAAAGGCCGATTCACCATCTCCAAAACCTCGTCGACCACGGTGACTCTGCAAATGACCAGTCTGACAGCCGCGGACACGGCCACCTATTTTTGTGCGAAAGCCTATGACTTG (SEQ ID NO: 243)

[0528] In further embodiments of the present disclosure, the polynucleotide encoding the antibody fragment having binding specificity for IL-6 comprises, or alternatively consists of, one or more of the polynucleotide sequences of SEQ ID NO:244; SEQ ID NO:245; and SEQ ID NO:246, which correspond to polynucleotides encoding the complementarity determining regions (CDRs, or hypervariable regions) of the light chain variable sequence of SEQ ID NO:234.

[0529] In further embodiments of the present disclosure, the polynucleotide encoding the antibody fragment having binding specificity for IL-6 comprises, or alternatively consists of, one or more of the polynucleotide sequences of SEQ ID NO:247; SEQ ID NO:248; and SEQ ID NO:249, which correspond to polynucleotides encoding the complementarity determining regions (CDRs, or hypervariable regions) of the heavy chain variable sequence of SEQ ID NO:235.

[0530] The present disclosure also contemplates polynucleotide sequences comprising one or more of the polynucleotide sequences encoding the antibody fragments described herein. In one embodiment of the present disclosure, the polynucleotide encoding the antibody fragment with binding specificity to IL-6 comprises, or alternatively consists of, one, two, three, or more, including all, of the following polynucleotides encoding the antibody fragment: polynucleotide SEQ ID NO:242 encoding the light chain variable region of SEQ ID NO:234; polynucleotide SEQ ID NO:243 encoding the heavy chain variable region of SEQ ID NO:235; polynucleotides encoding the complementarity determining regions of the light chain variable region of SEQ ID NO:234 ​​(SEQ ID NO:244; SEQ ID NO:245; and SEQ ID NO:246); and polynucleotides encoding the complementarity determining regions of the heavy chain variable region of SEQ ID NO:235 (SEQ ID NO:247; SEQ ID NO:248; and SEQ ID NO:249).

[0531] The present disclosure is further directed to polynucleotides encoding polypeptides of antibodies having binding specificity for IL-6. In one embodiment of the disclosure, the polynucleotide of the disclosure comprises, or alternatively consists of, the following polynucleotide sequence that encodes the variable light chain polypeptide sequence of SEQ ID NO: 250: ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGTTCCACATTTGCCGCCGTGCTGACCCAGACTCCATCTCCCGTGTCTGCAGCTGTGGGAGGCACAGTCAGCATCAGTTGCCAGGCCAGTCAGAGTGTTTATGACAACAACTATTTATCCTGGTATCAGCAGAAA CCAGGACAGCCTCCCAAGCTCCTGATCTATGGTGCATCCACTCTGGCATCTGGGGTCCCATCGCGGTTCAAAGGCACGGGATCTGGGACACAGTTCACTCTCACCATCACAGACGTGCAGTGTGACGATGCTGCCACTTACTATTGTGCAGGCGTTTTTAATGATGATAGTGATGATGCC (SEQ ID NO: 258)

[0532] In another embodiment of the disclosure, the polynucleotide of the disclosure comprises, or alternatively consists of, the following polynucleotide sequence that encodes the variable heavy chain polypeptide sequence of SEQ ID NO: 251: ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTCGCTGTGCCCAAAGGTGTCCAGTGTCAGTCGCTGGAGGAGTCCGGGGGTCGCCTGGTCACGCCTGGGACACCCCTGACACTCACCTGCACACTCTCTGGATTCTCCCTCAGTGCATACTATATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAA TGGATCGGATTCATTACTCTGAGTGATCATATATCTTACGCGAGGTGGGCGAAAGGCCGATTCACCATCTCCAAAACCTCGACCACGGTGGATCTGAAATGACCAGTCCGACAACCGAGGACACGGCCACCTATTTCTGTGCCAGGAGTCGTGGCTGGGGTGCAATGGGTCGGTTGGATCTC (SEQ ID NO: 259)

[0533] In further embodiments of the present disclosure, the polynucleotide encoding the antibody fragment having binding specificity for IL-6 comprises, or alternatively consists of, one or more of the polynucleotide sequences of SEQ ID NO:260; SEQ ID NO:261; and SEQ ID NO:262, which correspond to polynucleotides encoding the complementarity determining regions (CDRs, or hypervariable regions) of the light chain variable sequence of SEQ ID NO:250.

[0534] In further embodiments of the present disclosure, the polynucleotide encoding the antibody fragment having binding specificity for IL-6 comprises, or alternatively consists of, one or more of the polynucleotide sequences of SEQ ID NO:263; SEQ ID NO:264; and SEQ ID NO:265, which correspond to polynucleotides encoding the complementarity determining regions (CDRs, or hypervariable regions) of the heavy chain variable sequence of SEQ ID NO:251.

[0535] The present disclosure also contemplates polynucleotide sequences comprising one or more of the polynucleotide sequences encoding the antibody fragments described herein. In one embodiment of the present disclosure, the polynucleotide encoding the antibody fragment with binding specificity to IL-6 comprises, or alternatively consists of, one, two, three, or more, including all, of the following polynucleotides encoding the antibody fragment: polynucleotide SEQ ID NO:258 encoding the light chain variable region of SEQ ID NO:250; polynucleotide SEQ ID NO:259 encoding the heavy chain variable region of SEQ ID NO:251; polynucleotides encoding the complementarity determining regions of the light chain variable region of SEQ ID NO:250 (SEQ ID NO:260; SEQ ID NO:261; and SEQ ID NO:262); and polynucleotides encoding the complementarity determining regions of the heavy chain variable region of SEQ ID NO:251 (SEQ ID NO:263; SEQ ID NO:264; and SEQ ID NO:265).

[0536] The present disclosure is further directed to polynucleotides encoding polypeptides of antibodies having binding specificity for IL-6. In one embodiment of the disclosure, the polynucleotide of the disclosure comprises, or alternatively consists of, the following polynucleotide sequence that encodes the variable light chain polypeptide sequence of SEQ ID NO: 266: ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGTGCCACATTCGCAGCCGTGCTGACCCAGACACCATCGCCCGTGTCTGCGGCTGTGGGAGGCACAGTCACCATCAGTTGCCAGGCCAGTCAGAGTGTTTATAACAACAAAAATTTAGCCTGGTATCAGCAGAAA TCAGGGCAGCCTCCCAAGCTCCTGATCTACTGGGCATCCACTCTGGCATCTGGGGTCTCATCGCGGTTCAGCGGCAGTGGATCTGGGACACAGTTCACTCTCACCGTCAGCGGCGTGCAGTGTGACGATGCTGCCACTTACTACTGTCTAGGCGTTTTTGATGATGATGCTGATAATGCT (SEQ ID NO: 274)

[0537] In another embodiment of the disclosure, the polynucleotide of the disclosure comprises, or alternatively consists of, the following polynucleotide sequence that encodes the variable heavy chain polypeptide sequence of SEQ ID NO:267: ATGGAGACTGGGCTGCGCTGGCTTCCTGGTCGCTGTGCTCAAAGGTGTCCAATGTCAGTCGGTGGAGGAGTCCGGGGGTCGCCTGGTCACGCCTGGGACCCCCTGACACTCACCTGCACAGCCTCTGGATTCTCCCTCAGTAGCTACTCCATGACCTGGGTCCGCCAGGCTCCAGGGAAGGGG CTGGAATATATCGGAGTCATTGGTACTAGTGGTAGCACATACTACGCGACCTGGGCGAAAGGCCGATTCACCATCTCCAGAACCTCGACCACGGTGGCTCTGAAAATCACCAGTCCGACAACCGAGGACACGGCCACCTATTTCTGTGTCAGGAGTCTTTCTTCTATTACTTTCTTG (SEQ ID NO: 275)

[0538] In further embodiments of the present disclosure, the polynucleotide encoding the antibody fragment having binding specificity for IL-6 comprises, or alternatively consists of, one or more of the polynucleotide sequences of SEQ ID NO:276; SEQ ID NO:277; and SEQ ID NO:278, which correspond to polynucleotides encoding the complementarity determining regions (CDRs, or hypervariable regions) of the light chain variable sequence of SEQ ID NO:266.

[0539] In further embodiments of the present disclosure, the polynucleotide encoding the antibody fragment having binding specificity for IL-6 comprises, or alternatively consists of, one or more of the polynucleotide sequences of SEQ ID NO:279; SEQ ID NO:280; and SEQ ID NO:281, which correspond to polynucleotides encoding the complementarity determining regions (CDRs, or hypervariable regions) of the heavy chain variable sequence of SEQ ID NO:267.

[0540] The present disclosure also contemplates polynucleotide sequences comprising one or more of the polynucleotide sequences encoding the antibody fragments described herein. In one embodiment of the present disclosure, the polynucleotide ...

Claims

1. A method for treating myocarditis in a human subject in need thereof, comprising subcutaneously or intravenously administering a therapeutically effective amount of an anti-IL-6 antibody to the human subject once every four weeks or once a month.

2. 1. Use of an anti-IL-6 antibody for treating myocarditis in a human subject in need thereof, wherein a therapeutically effective amount of the antibody is administered subcutaneously or intravenously to the human subject once every four weeks or once a month.

3. The method of claim 1 or the use of claim 2, wherein the antibody comprises a variable light chain (VL) polypeptide comprising the complementarity determining regions (CDRs) of SEQ ID NOs: 4, 5 and 6, and a variable heavy chain (VH) polypeptide comprising the CDRs of SEQ ID NOs: 7, 8 or 120, and 9.

4. The method or use of any one of claims 1 to 3, wherein the antibody comprises a heavy chain polypeptide of SEQ ID NO: 704 and a light chain polypeptide of SEQ ID NO:

702.

5. The method or use of any one of claims 1 to 4, wherein the antibody comprises a human IgG1 constant region.

6. The method or use according to any one of claims 1 to 5, wherein the antibody is clazakizumab.

7. The method or use of any one of claims 1 to 6, wherein the antibody is administered subcutaneously.

8. The method or use of any one of claims 1 to 7, wherein the antibody is administered intravenously.

9. 9. The method or use of any one of claims 1 to 8, wherein the antibody is administered at a dose of 0.3 to 100 mg, 1 to 60 mg, 2 to 25 mg, 3 to 15 mg, or 5 to 10 mg.

10. 10. The method or use of claim 9, wherein the antibody is administered at a dose of 3, 4, 5, 6, 7, 8, 9, 10, 12, 12.5, 15, 20, 24, 25, 36, 40, 60 or 100 mg.

11. 11. The method or use of claim 10, wherein the antibody is administered at a dose of 5 mg, 10 mg, 12.5 mg or 25 mg.

12. 12. The method or use of any one of claims 1 to 11, wherein the antibody is administered for at least 4, 6, 9, 10, 12, 14, 16, 18, 20, 22, 24 or 36 months.

13. 13. The method or use of any one of claims 1 to 12, wherein the antibody is clazakizumab and is administered subcutaneously or intravenously at a dose of 5 to 12.5 mg every four weeks or monthly, and optionally the antibody is administered for a period of at least 3 months, at least 6 months, at least 9 months, at least 1 year, or at least 2 years.

14. 14. The method or use of any one of claims 1 to 13, wherein the human subject has elevated serum C-reactive protein (CRP) levels before treatment, optionally wherein the CRP levels are determined by an hs-CRP test.

15. 15. The method or use of claim 14, wherein the human subject has a pre-treatment CRP level of at least 2, 4, 6 or 10 mg / L.

16. 16. The method or use of any one of claims 1 to 15, wherein the human subject has elevated serum IL-6 levels before treatment.

17. 17. The method or use of claim 16, wherein the serum IL-6 level before treatment is at least 2, 4, 5 or 10 ng / L.

18. 18. The method or use of any one of claims 1 to 17, wherein the CRP level after treatment is reduced by at least 50%, 70%, 80% or 90% compared to the CRP level before treatment.

19. The method or use of any one of claims 1 to 18, further comprising determining the level of serum IL-6 or serum CRP at least once after treatment.

20. 20. The method or use of any one of claims 1 to 19, wherein the human subject prior to treatment has been diagnosed with reduced ejection fraction (less than or equal to 45%), ventricular arrhythmias such as sustained ventricular arrhythmias, heart failure, chest pain, and / or cardiogenic shock.

21. The method or use of any one of claims 1 to 20, further comprising the administration of at least one other therapeutic agent.

22. 22. The method or use of claim 21, wherein the at least one other therapeutic agent comprises a corticosteroid, an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin II receptor blocker (ARB), a beta-blocker, intravenous IgG (IVIG), subcutaneous IgG (SCIG), and / or a diuretic.

23. 23. The method or use of any one of claims 1 to 22, wherein the myocarditis is caused by one or more of a viral infection, a bacterial infection, a fungal infection, a parasite, one or more medicines, drugs, toxins or chemicals, radiation, an autoimmune disease or other inflammatory disease, or an insect or other animal bite or sting.

24. 24. The method or use of claim 23, wherein the myocarditis is caused by a viral infection.

25. 24. The method or use of claim 23, wherein the myocarditis is caused by an autoimmune disease.

26. The method or use according to any one of claims 1 to 25, wherein the myocarditis is (sub)acute myocarditis and / or early myocarditis, in particular early sub(acute) myocarditis.

27. 27. The method or use of claim 26, wherein the myocarditis is acute myocarditis.

28. 27. The method or use of claim 26, wherein the myocarditis is subacute myocarditis.

29. The method of any one of claims 1 to 28, wherein the human subject does not have an active viral infection.

30. A method for treating acute or subacute myocarditis caused by a viral infection or an autoimmune disease in a human subject in need thereof, comprising subcutaneously or intravenously administering clazakizumab at a dose of less than 30 mg to the human subject every four weeks or monthly.

31. 31. The method of claim 30, wherein the dose of clazakizumab is less than or equal to 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 12.5, 15, 20, or 25 mg.

32. 31. The method of claim 30, wherein the dose of clazakizumab is 5 to 25 mg or 5 to 12.5 mg.

33. 33. The method of any one of claims 30-32, wherein clazakizumab is administered for a period of at least 3 months, at least 6 months, at least 9 months, or at least 1 year.

34. 34. The method of any one of claims 30-33, wherein the human subject prior to treatment has been diagnosed with reduced ejection fraction (less than or equal to 45%), ventricular arrhythmias such as sustained ventricular arrhythmias, heart failure, the presence of anti-cardiac antibodies (e.g., anti-myosin antibodies), elevated troponin (troponin I and T) levels, chest pain, and / or cardiogenic shock.

35. The method of any one of claims 30 to 34, wherein the treatment comprises long-term care.

36. 36. The method of any one of claims 30 to 35, wherein the human subject does not have an active viral infection.

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