EP4638499A1 - Treatment of myocarditis by administration of anti-interleukin-6 antibodies - Google Patents

Abstract

This disclosure pertains to the use of an anti-IL-6 antibody for the treatment of myocarditis and for managing the symptoms of myocarditis, in particular for (sub)acute myocarditis. This disclosure also pertains to the use of an anti-interleukin-6 (IL-6) antibody for the prevention of chronic myocarditis. In some embodiments, the myocarditis is caused by viral infection or autoimmune disease.

Description

TREATMENT OF MYOCARDITIS BY ADMINISTRATION OF ANTI-INTERLEUKIN-6 ANTIBODIES

RELATED APPLICATION DATA

This application claims priority from US patent application No 63/435149 filed on 23 December 2022 and US patent application No 63/513463 filed on 13 July 2023, the entire contents of these applications are hereby incorporated by reference.

SEQUENCE LISTING

The present application is filed together with a Sequence Listing in electronic form. The entire contents of the Sequence Listing are hereby incorporated by reference.

FIELD

This disclosure pertains to the use of an anti-interleukin-6 (IL-6) antibody, such as clazakizumab, forthe treatment of myocarditis and for managing the symptoms of myocarditis, in particular for (sub)acute myocarditis. This disclosure also pertains to the use of an anti- interleukin-6 (IL-6) antibody for the prevention of chronic myocarditis. In some embodiments, the myocarditis is caused by viral infection or autoimmune disease.

BACKGROUND lnterleukin-6 (hereinafter “IL-6”) (also known as interferon-beta2; B-cell differentiation factor; B-cell stimulatory factor-2; hepatocyte stimulatory factor; hybridoma growth factor; and plasmacytoma growth factor) is a multifunctional cytokine involved in numerous biological processes such as the regulation of the acute inflammatory response, the modulation of specific immune responses including B- and T-cell differentiation, bone metabolism, thrombopoiesis, epidermal proliferation, menses, neuronal cell differentiation, neuroprotection, aging, cancer, and the inflammatory reaction occurring in Alzheimer’s disease. See Papassotiropoulos et al., Neurobiology of Aging, 22:863-871 (2001). lnterleukin-6 (IL-6) is a member of a family of cytokines that promote cellular responses through a receptor complex consisting of at least one subunit of the signal-transducing glycoprotein gp130 and the IL-6 receptor (“IL-6R”) (also known as gp80). The IL-6R may also be present in a soluble form (“slL-6R”). IL-6 binds to IL-6R, which then dimerizes the signaltransducing receptor gp130. See Jones, SA, J. Immunology, 175:3463-3468 (2005). In humans, the gene encoding for IL-6 is organized in five exons and four introns, and maps to the short arm of chromosome 7 at 7p21. Translation of IL-6 RNA and post-translational processing result in the formation of a 21 to 28 kDa protein with 184 amino acids in its mature form. See Papassotiropoulos et al, Neurobiology of Aging, 22:863-871 (2001).

IL-6 inhibitors have been developed to treat certain inflammatory disorders in which IL-6 has been shown to contribute significantly to disease etiology. For example, anti-IL-6 receptor (anti-IL-6R) antibody, tocilizumab (ACTEMRA®), has been approved for 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 to treat adult patients with moderately to severely active rheumatoid arthritis. Other exemplary anti-IL6R antibodies include isvobarilizumab and levilimab (BCD-089). The IL-6 antibody clazakizumab (BMS-945429, ALD518), for example, is a humanized rabbit anti-IL-6 antibody and also acts as an IL-6 inhibitor. Other exemplary anti-IL-6 antibodies include ziltivekimab, siltuximab (SYLVANT™), olokizumab (CDP6038), elsilimomab, and sirukumab (CNTO 136).

Myocarditis is an inflammation of the heart muscle (myocardium). Histopathologically, myocarditis is characterized by an inflammatory cellular infiltrate (which may be focal or diffuse) in the presence or absence of cardiac myocyte injury. See, e.g., Aretz ef al., Myocarditis. A histopathologic definition and classification, Am J Cardiovasc Pathol, 1 :3-14 (1987); Ammirati et al., Management of acute myocarditis and chronic inflammatory cardiomyopathy: an expert consensus document. Circ Heart Fail 663-87 (2020). Myocarditis can have a variety of causes, such as viral infections or autoimmune conditions, as well as certain drugs or vaccine regimens. After exposure to a causative agent or condition, (sub)acute myocarditis may result, in some cases in the first few weeks or months. Acute or subacute myocarditis may in some cases progress to chronic myocarditis.

To the best of Applicant’s knowledge, there has not been any reported clinical trial using an anti-IL-6 antibody for treating myocarditis, particularly acute or subacute myocarditis, or for prevention of chronic myocarditis.

SUMMARY

There is a need in the art for improved methods for treatment of myocarditis, particularly acute and subacute myocarditis. Interleukin-6 (IL-6) is a cytokine with powerful stimulatory effects on B cells and plasma cells and is responsible, in conjunction with other cytokines, for normal antibody production. IL-6 also has powerful stimulatory effects on T-cell mediated inflammatory processes. This disclosure relates to the use of anti-IL-6 monoclonal antibodies (mAbs), such as clazakizumab or ziltivekimab, or to the use of anti-IL6R antibodies, for the treatment of myocarditis. This disclosure provides, inter alia, a method of treating myocarditis in a human subject in need thereof, comprising subcutaneously or intravenously administering to the human subject a therapeutically effective amount of an anti-IL-6 antibody once every 4 weeks or monthly.

This disclosure also provides for 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 4 weeks or monthly.

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 variably heavy chain (VH) polypeptide comprising the CDRs of SEQ ID NOs: 7, 8 or 120, and 9.

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

In some embodiments, the antibody comprises human lgG1 constant regions.

In some embodiments, the antibody is clazakizumab.

In some embodiments, the antibody is administered subcutaneously.

In some embodiments, the antibody is administered intravenously.

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.

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.

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

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

In some embodiments, the antibody is clazakizumab and is administered at a dose of 5 to 12.5 mg subcutaneously or intravenously every 4 weeks or monthly, optionally wherein 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. In some embodiments, the human subject has an elevated pre-treatment serum C-reactive protein (CRP) level, optionally wherein the CRP level is determined by an hs-CRP test.

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

In some embodiments, the human subject has an elevated pre-treatment serum IL-6 level.

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

In some embodiments, the CRP level after treatment is decreased by at least 50%, 70%, 80%, or 90 % as compared to the pre-treatment CRP level.

In some embodiments, the method or use further comprises determining serum IL-6 or serum CRP level at least once post-treatment.

In some embodiments, the human subject pre-treatment has been diagnosed with reduced ejection fraction (such as < 45%), ventricular arrhythmia such as sustained ventricular arrhythmia, heart failure, chest pain, and/or cardiogenic shock.

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

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, an intravenous IgG (I VIG), a subcutaneous IgG (SCIG), and/or a diuretic.

In some embodiments, the myocarditis is caused by one or more of the following: viral infection, bacterial infection, fungal infection, parasites, one or more medications, drugs, toxins, or chemicals, radiation, autoimmune disease or other inflammatory disease, or insect or other animal bite or sting.

In some embodiments, the myocarditis is caused by viral infection.

In some embodiments, the myocarditis is caused by autoimmune disease.

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

In some embodiments, the myocarditis is acute myocarditis.

In some embodiments, the myocarditis is subacute myocarditis. In some embodiments, the human subject has no active virus infection.

The disclosure also provides for a method of treating acute or subacute myocarditis (i.e., (sub)acute myocarditis) caused by viral infection or autoimmune disease in a human subject in need thereof, comprising administering subcutaneously or intravenously to the human subject a dose of less than 30 mg clazakizumab every 4 weeks or monthly.

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.

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

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

In some embodiments, the human subject pre-treatment has been diagnosed with reduced ejection fraction (such as < 45%), ventricular arrhythmia (such as sustained ventricular arrhythmia), heart failure, chest pain, and/or cardiogenic shock.

In some embodiments, the treating comprises chronic care.

In some embodiments, the human subject has no active virus infection.

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 claims.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 shows an experimental outline in a murine model of experimental autoimmune myocarditis (EAM) in disease susceptible BALB/c mice. Mice received subcutaneous auxiliary immunizations of 100 pg of MyHCa₆i4-629 emulsified in CFA on day 0 and day 7, as previously described. See Cihakova et al., Am J Pathol. 2008 May, 172(5):1195-1208. Randomly assigned mice were treated with isotype control (25 mg/kg) or murine anti-IL-6 antibody (5 mg/kg or 25 mg/kg) on days 7, 10, 14, 21 , 28, 35, and sacrificed on day 42 post first immunization. Echocardiograms were performed at day 0, 7, 14, 21 , 28, 35, and 42 post immunization.

Figure 2 shows percent changes in weight between BALB/c mice administered 5 mg/kg or 25 mg/kg anti-IL-6, as compared to isotype control overtime (days 0 to 43). Statistical test: 2-way ANOVA with Dunnet’s multiple comparisons. Stars indicate significant differences compared to isotype control in post-hoc analysis (*** P<0.001 , ** P= 0.001 , * P=0.01). The first row of stars with an underline corresponds to the 5 mg/kg anti-IL-6 treatment group and the second row of stars corresponds to the 25 mg/kg anti-IL-6 treatment group as statistically significantly different compared to isotype in post-hoc analysis. Based on the changes in the percent of body weight compared to day 0, treatment with any dose of anti-IL-6 significantly protects against weight loss on days 10 and 14 of the EAM model (i.e., in the acute phase of the disease). Treatment with low dose anti-IL-6 (5 mg/kg) significantly protects against weight loss on day 21 of EAM.

Figures 3A to 3E show general measurements of heart weight (HW) to body weight (BW) (Fig. 3A), HW to tibia length (TL) (Fig. 3B), HW to spleen weight (SPL) (Fig. 3C), SPL to BW (Fig. 3D), and SPL to TL (Fig. 3E) of 5 or 25 mg/kg anti-IL-6 groups, as compared to isotype control (* P<0.05, ** P<0.01 , Tukey’s multiple comparison test).

Figure 4 shows semi-quantitative evaluation of cardiac fibrosis at day 42 in mice treated with 5 mg/kg or 25 mg/kg anti-IL-6 antibody, as compared to isotype control treatment.

Figures 5A and 5B show ejection fraction (EF) (Fig. 5A) and fractional shortening (FS) (Fig. 5B) measured by echocardiography, respectively. Stars indicate significant differences of the

5 mg/kg and 25 mg/kg anti-IL-6 groups compared to isotype control in post-hoc analysis (* P<0.05, **P<0.01 , ***P<0.001).

Figures 6A and 6B show multiple comparisons of left ventricular internal diameter (LVID). Figure 6A shows LVID end diastole (LVID;d) changes and Figure 6B shows LVID end systole (LVID;s) changes from day 0 to day 42 in all treatment groups. Stars indicate significant differences of the 5 mg/kg and 25 mg/kg anti-IL-6 groups compared to isotype control in post- hoc analysis (*P<0.05, **P<0.01).

Figures 7 A and 7B show multiple comparisons for interventricular septum (IVS) changes at end diastole (IVS;d) (Fig. 7A) and end systole (IVS;s) (Fig. 7B) from day 0 to day 42 in all treatment groups. Stars indicate significant differences of the 5 mg/kg anti-IL-6 groups compared to isotype control in post-hoc analysis (*P<0.05, **P<0.01 , ***P<0.001) in Fig. 7B.

Figures 8A and 8B show multiple comparisons for left ventricular posterior wall (LVPW) thickness at end diastole (LVPW;d)(Fig. 8A) and end systole (LVPW;s) (Fig. 8B) in all treatment groups. No differences were observed with LVPW following treatment with anti-IL-

6 antibody.

Figure 9 shows plasma levels of murine IL-6 following treatment with isotype control or anti- IL-6 antibodies (****P<0.0001). Figures 10A to 10D show plasma levels of C-reactive protein (CRP, an IL-6 surrogate marker) (Fig. 10A), anti-Myosin IgG (Fig. 10B), serum amyeloid A (SAA) (Fig. 10C), and anti-Troponin IgG (Fig. 10D) (**P<0.01 , ***P<0.001 , ****p<0.0001).

Figures 1 1A to 11 D show plasma levels of inflammatory cytokines granulocyte macrophage colony-stimulating factor (GM-CSF) (Fig. 1 1 A), Interleukin 1A (IL-1 A) (Fig. 11 B), IL-1 B (Fig. 11C), and TNFa (Fig. 11 D) (***P< 0.001).

Figures 12A to 12C show plasma levels of T cell cytokines IL-2 (Fig. 12A), IL-7 (Fig. 12B), and IL-10 (Fig. 12C).

Figures 13A to 13C show plasma levels of T helper cell cytokines. Figure 13A shows plasma levels of T helper-1 cell related cytokines IFNy and IL-12, Figure 13B shows plasma levels of T helper-2 cell related cytokines IL-4, IL-5 and IL-13, and Figure 13C shows plasma levels of T helper-3cell related cytokines IL-17A (*P<0.05, ***P<0.001).

Figures 14A to 14E show plasma levels of chemokines CXCL1 (KC) (Fig. 14A), CXCL2 (MIP- 2) (Fig. 14B), CXCL5 (LIX) (Fig. 14C), CCL2 (MCP-1) (Fig. 14D), and CXCL16 (Fig. 14E).

Figures 15A to 15D show plasma levels of follistatin (Fig. 15A), placenta growth factor 2 (PIGF- 2) (Fig. 15B), NT-proBNP (Fig. 15C), and fibrinogen (Fig. 15D).

DESCRIPTION OF EXEMPLARY EMBODIMENTS

As noted in the above summary, there is a need in the art for improved methods for treatment of myocarditis. Interleukin-6 (IL-6) is a cytokine with powerful stimulatory effects on B cells and plasma cells and is responsible, in conjunction with other cytokines, for normal antibody production. IL-6 also has powerful stimulatory effects on T-cell mediated inflammatory processes. This disclosure relates to the use of anti-IL-6 antibodies (mAbs), such as clazakizumab or ziltivekimab, or anti-IL-6R antibodies, for the treatment of myocarditis.

Definitions

It is to be understood that this disclosure is not limited to the particular methodology, protocols, cell lines, animal species or genera, and reagents described, as such 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 present disclosure which will be limited only by the appended claims.

As used herein, the term about refers to a numeric value, including, for example, whole numbers, fractions, and percentages, whether or not explicitly indicated. The term about generally refers to a range of numerical values (e.g., +/-5-10% 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 terms such as at least and about precede a list of numerical values or ranges, the terms modify all of the values or ranges provided in the list. In some instances, the term about may include numerical values that are rounded to the nearest significant figure.

As used herein, the singular forms “a”, “and”, and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a cell” includes a plurality of such cells and reference to “the protein” includes 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 to one of ordinary skill in the art to which this disclosure belongs unless clearly indicated otherwise.

In this disclosure, “comprises,” “comprising,” “containing,” “having,” “includes,” “including,” and linguistic variants thereof have the meaning ascribed to them in U.S. Patent law, permitting the presence of additional components beyond those explicitly recited.

In this application, the use of “or” means “and/or” unless stated otherwise. In the context of a multiple dependent claim, the use of “or” refers back to more than one preceding independent or dependent claim in the alternative only. Also, terms such as “element” or “component” encompass both elements and components comprising one unit and elements and components that comprise more than one subunit unless specifically stated otherwise.

“Myocarditis” as used herein, is an inflammation of the heart muscle (myocardium). Myocarditis can be segregated into sub-types such as acute and subacute myocarditis, as well as chronic myocarditis, for example.

“Acute myocarditis” is defined with reference to Caforio, Eur. Heart J., 34: 2636-48 (2013), as a first phase of myocarditis progression (see, e.g., Caforio at Fig. 2 referring to Phase I) following exposure to a causative agent or condition. One type of acute myocarditis is “fulminant myocarditis” (FM), which is characterized by sudden and severe diffuse cardiac inflammation with the need for hemodynamic support.

“Subacute myocarditis” is a second phase of myocarditis progression, which for example, may be characterized by ongoing inflammation, and wherein, in some cases progression may be driven by an adaptive immune response (see Caforio, at Fig. 2, referring to phase II; see also Sozzi et al., Frontiers Cardiovasc. Med. Vol. 9, Article 908663 (2022) doi: 10.3389/fcvm.2022.908663).

“(Sub)acute myocarditis” is used herein as a term for subacute myocarditis and/or acute myocarditis, i.e., a generic term encompassing both of these types of myocarditis. Furthermore, “early myocarditis” is used herein as a term for myocarditis characterized by a period of less than 6 months, in particular less than 3 months, between onset of symptoms and diagnosis (regardless of the type of myocarditis). The present disclosure in particular also relates to treatment of early myocarditis, which is (sub)acute (also “early sub(acute) myocarditis”). In some embodiments early myocarditis may be acute myocarditis. In some embodiments, treatment continues beyond the early myocarditis period, for example, for at least 6 months, at least 9 months, at least 1 year, or at least 2 years, or longer.

When myocarditis symptoms continue for a prolonged period (e.g., more than 6 months from symptom onset), the disease process may be considered to be a “chronic myocarditis” or “chronic inflammatory cardiomyopathy”.

As used herein, the terms “treat,” “treating,” “treatment,” and the like include reducing, 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 appreciated that, although not precluded, treating a disorder or condition does not require that the disorder, condition or symptoms associated therewith be completely eliminated. It will be further appreciated that treatment is often initiated after onset of myocarditis, in particular after diagnosis of subacute or acute myocarditis. In some embodiments, the treatment may also comprise “chronic care,” which is understood as medical care or treatment for more than 6 months, in particular more than a year, as described herein (different from acute care which is concerned with the short-term duration of administration of a few days or weeks, i.e., less than 6 months). Treatment of a first condition may encompass prevention of another condition, e.g., treatment of an acute phase may prevent progression into a chronic phase of myocarditis. Treatment, in some cases, may also include prevention of progression into chronic myocarditis.

The terms “prevent,” “preventing,” “prevention,” “prophylaxis,” and the like, as used herein, refer to reducing occurrence of or delaying, in particular avoiding, onset of a disorder or at least one symptom of myocarditis or a type or stage of myocarditis. In some cases in a subject who has acute or subacute myocarditis, for example, this may be prevention of chronic myocarditis, dilated cardiomyopathy, or heart failure. In other cases, such as in a subject with a viral disease, or autoimmune disease, prevention may include preventing onset of one or more symptoms or signs of myocarditis or a particular stage of myocarditis.

A “therapeutically effective amount” refers to an amount of a drug sufficient to provide a treatment effect in a human subject, such as to alleviate at least one symptom, reduce or slow the progression, or prevent the onset of at least one symptom of a condition or disease. A “prophylactically effective amount” refers to an amount of a drug sufficient to provide a prophylactic effect, such as to prevent onset of at least one symptom of a condition or disease in a subject at risk for the onset of that condition or disease. A “subject” or “patient” or “individual” to be treated herein refers to a human, such as either diagnosed with myocarditis or with a risk factor for developing myocarditis, such as a viral disease or suspected viral disease, or an autoimmune disease.

As used herein, “pre-treatment,” for example in the context of measuring a level of a marker in a patient such as C-reactive protein (CRP), high-sensitivity CRP (hs-CRP), or determining some other indication of a patient’s condition, means prior to the first administration of an IL- 6 antibody according to the methods described herein. Pre-treatment does not exclude, and often includes, the prior administration of treatments other than an IL-6 antibody.

As used herein, “post-treatment” in this context means after the 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 treatment phase of an IL-6 antibody.

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

The term “antibody” herein refers to a molecule comprising at least complementaritydetermining region (CDR) 1 , CDR2, and CDR3 of a heavy chain and at least CDR1 , CDR2, and CDR3 of a light chain, wherein the molecule is capable of binding to antigen. The term is used in the broadest sense and encompasses various 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 instance, the term “antibody” is intended to include any polypeptide chain-containing molecular structure with a specific shape that fits to and recognizes an epitope, where one or more non-covalent binding interactions stabilize the complex between the molecular structure and the epitope. The archetypal antibody molecule is the immunoglobulin, and all types of immunoglobulins, IgG, IgM, IgA, IgE, IgD, etc., from all sources, e.g., human, rodent, rabbit, cow, sheep, pig, dog, other mammals, chicken, other avians, etc., are considered to be “antibodies.” Examples include chimeric antibodies, humanized antibodies, single chain antibodies such as scFvs, camelbodies, nanobodies, IgNAR (single-chain antibodies derived from sharks), small-modular immunopharmaceuticals (SMIPs), and antibody fragments such as Fab, Fab', F_(ab)2 and the like. See Streltsov et al., Structure of a shark IgNAR antibody variable domain and modeling of an early-developmental isotype, Protein Sci. 2005 Nov;14(11):2901 -9. Epub 2005 Sep 30; Greenberg et al., A new antigen receptor gene family that undergoes rearrangement and extensive somatic diversification in sharks, Nature. 1995 Mar 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 Aug; 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, antibody constant region residue numbering is according to the EU index as in Kabat.

“Anti-interleukin-6 antibodies” (synonymously used: “anti-IL-6 antibody” and “IL-6 antibody”) as used herein are antibodies that are capable of binding and antagonizing IL-6, in particular human IL-6. Similarly, “anti-interleukin-6R antibodies” (synonymously used: “anti-IL-6R antibody” and “IL-6R antibody”) as used herein are antibodies that are capable of inhibiting the signaling of IL-6 via IL-6 receptor by binding to IL-6R, in particular human IL-6R. Both anti- IL-6 and anti-IL-6R antibodies antagonize IL-6 signaling. If this disclosure refers to an “antibody”, it is an anti-IL-6 antibody or an anti-IL-6R antibody, in particular an anti-IL-6 antibody, unless explicitly specified otherwise or by context.

For example, antibodies (which include antibody fragments or antigen binding fragments) may be produced by genetic engineering. In this technique, as with other methods, antibodyproducing cells are sensitized to the desired antigen or immunogen. The messenger RNA isolated from antibody producing cells is used as a template to make cDNA using PCR amplification. A library of vectors, each containing one heavy chain gene and one light chain gene retaining the initial antigen specificity, is produced by insertion of appropriate sections of the amplified immunoglobulin cDNA into the expression vectors. 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 which co-express a heavy and light chain (resembling the Fab fragment or antigen binding fragment of an antibody molecule). The vectors that carry these genes are co-transfected into a host cell. When antibody gene synthesis is induced in the transfected host, the heavy and light chain proteins self-assemble to produce active antibodies that can be detected by screening with the antigen or immunogen.

Antibody coding sequences of interest include those encoded by native sequences, as well as nucleic acids that, by virtue of the degeneracy of the genetic code, are not identical in sequence to the disclosed nucleic acids, and variants thereof. Variant polypeptides can include amino acid (aa) substitutions, additions or deletions. The amino acid substitutions can be conservative amino acid substitutions or substitutions to eliminate non-essential amino acids, such as to alter a glycosylation site, or to minimize misfolding by substitution or deletion of one or more cysteine residues that are not necessary for function. Variants can be designed to retain or have enhanced biological activity of a particular region of the protein (e.g., a functional domain, 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. Also included in the subject disclosure are polypeptides that have been modified using ordinary molecular biological techniques to improve their resistance to proteolytic degradation or to optimize solubility properties or to render them more suitable as a therapeutic agent.

Chimeric antibodies may be made by recombinant means by combining the variable light and heavy chain regions (VL and VH), obtained from antibody producing cells of one species with the constant light and heavy chain regions from another. Typically, chimeric antibodies utilize rodent or rabbit variable regions and human constant regions, in order to produce an antibody with predominantly human domains. The production of such chimeric antibodies is well known in the art, and may be achieved by standard means (as described, e.g., in U.S. Patent No. 5,624,659, incorporated herein by reference in its entirety). It is further contemplated that the human constant regions of chimeric antibodies of the disclosure may be selected from lgG1 , lgG2, lgG3, lgG4, lgG5, lgG6, lgG7, lgG8, lgG9, lgG10, lgG1 1 , lgG12, lgG13, lgG14, lgG15, lgG16, lgG17, lgG18, or lgG19 constant regions.

Humanized antibodies are engineered to contain even 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 hyper-variable loops of the variable regions of the monoclonal antibody, and fitting them to the structure of the human antibody chains. Although facially complex, the process is straightforward in practice. See, e.g., U.S. Patent No. 6,187,287, incorporated fully herein by reference.

In addition to entire immunoglobulins (or their recombinant counterparts), immunoglobulin fragments comprising the epitope binding site (e.g., Fab’, F(ab’)2, or other fragments) may be synthesized. “Fragment,” or minimal immunoglobulins may be designed utilizing recombinant immunoglobulin techniques. For instance, “Fv” immunoglobulins for use in the present disclosure may be produced by synthesizing a fused variable light chain region and a variable heavy chain region. Combinations of antibodies are also of interest, e.g., diabodies, which comprise two distinct Fv specificities. In another embodiment of the disclosure, SMIPs (small molecule immunopharmaceuticals), camelbodies, nanobodies, and IgNAR are encompassed by immunoglobulin fragments.

Immunoglobulins and fragments thereof may be modified post-translationally, e.g., to add effector moieties such as chemical linkers, detectable moieties, such as fluorescent dyes, enzymes, toxins, substrates, bioluminescent materials, radioactive materials, chemiluminescent moieties and the like, or specific binding moieties, such as streptavidin, avidin, or biotin, and the like may be utilized in the methods and compositions of the present disclosure. Examples of additional effector molecules are provided infra.

The general structure of antibodies in vertebrates now is well understood. See Edelman, G. M., Ann. N.Y. Acad. Sci., 190: 5 (1971). Antibodies consist of two identical light polypeptide chains of molecular weight approximately 23,000 daltons (the “light chain”), and two identical heavy chains of molecular weight 53,000-70,000 (the “heavy chain”). The four chains are joined by disulfide bonds in a “Y” configuration wherein the light chains bracket the heavy chains starting at the mouth of the “Y” configuration. The “branch” portion of the “Y” configuration is designated the Fab region; the stem portion of the “Y” configuration is designated the FC region. The amino acid sequence orientation runs from the N-terminal end at the top of the “Y” configuration to the C-terminal end at the bottom of each chain. The N- terminal end possesses the variable region having specificity for the antigen that elicited it, and is approximately 100 amino acids in length, there being slight variations between light and heavy chain and from antibody to antibody.

The variable region is linked in each chain to a constant region that extends the remaining length of the chain and that within a particular class of antibody does not vary with the specificity of the antibody (i.e., the antigen eliciting it). There are five known major classes of constant regions that determine the class of the immunoglobulin molecule (IgG, IgM, IgA, IgD, and IgE corresponding to y, p, a, 6, and s (gamma, mu, alpha, delta, or epsilon) heavy chain constant regions). The constant region or class determines subsequent effector function of the antibody, including activation of complement (Kabat, E. A., Structural Concepts in Immunology and Immunochemistry, 2nd Ed., p. 413-436, Holt, Rinehart, 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)); while the variable region determines the antigen with which it will react. Light chains are classified as either K (kappa) or A (lambda). Each heavy chain class can be paired with either kappa or lambda light chain. The light and heavy chains are covalently bonded to each other, and the “tail” portions of the two heavy chains are bonded to each other by covalent disulfide linkages when the immunoglobulins are generated either by hybridomas or by B cells.

The expression “variable region” or “VR” refers to the domains within each pair of light and heavy chains in an antibody that are involved directly in binding the antibody to the antigen. Each heavy chain has at one end a variable domain (VH) followed by a number of constant domains. Each light chain has a variable domain (VL) at one end and a constant domain at its 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.

The expressions “complementarity determining region,” “hypervariable region,” or“CDR” refer to one or more of the hyper-variable or complementarity determining regions (CDRs) found in the variable regions of light or heavy chains of an antibody. See Kabat et al., Sequences of Proteins of Immunological Interest, National Institutes of Health, Bethesda, Md., (1987). These expressions 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 3-dimensional structures of antibodies (Chothia and Lesk, J Mol. Biol. 196: 901-917 (1987)). The CDRs in each chain are held in close proximity by framework regions and, with the CDRs from the other chain, contribute to the formation of the antigen binding site. Within the CDRs there are select amino acids that have been described as the selectivity determining regions (SDRs) which represent the critical contact residues used by the CDR in the anybody-antigen interaction. See Kashmiri, S., Methods, 36:25-34 (2005).

The expressions “framework region” or “FR” refer to one or more of the framework regions within the variable regions of the light and heavy chains of an antibody. See Kabat et al., Sequences of Proteins of Immunological Interest, National Institutes of Health, Bethesda, Md., (1987). These expressions include those amino acid sequence regions interposed between the CDRs within the variable regions of the light and heavy chains of an antibody. In general, each heavy and light chain variable region comprises a series of FR and CDR elements as follows: FR1 -CDR1 -FR2-CDR2-FR3-CDR3-FR4. Antigen binding fragments such as Fv and others typically comprise all three CDRs and the intervening framework regions FR2 and FR3 and a least a portion of FR1 and/or FR4.

An “isolated” antibody is one that has been separated from a component of its natural environment. In some aspects, an antibody is purified, such as to greater than 95% or 99% purity as determined by, for example, 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 assessment of antibody purity, see, e.g., Flatman et al., J. Chromatogr. B 848:79-87 (2007).

“Interleukin-6 (IL-6)” is an indicator of systemic inflammation and metabolic dysfunction. The term refers to a naturally occurring human protein unless clearly indicated otherwise. Wildtype human interleukin-6 (IL-6) is synthesized as a precursor protein of 212 amino acids, which is then cleaved into its active form. Also any pre-pro, pro- and mature forms as well as naturally occurring mutants and variants including allelic variants of human II-6 having IL-6 biological activity are understood to be encompassed by “interleukin-6 (IL-6)”.

An exemplary human IL-6 212 amino acid precursor sequence is found at Uniprot No. P05231 (see the uniport “dot” org web site). This sequence is as follows:

MNSFSTSAFGPVAFSLGLLLVLPAAFPAPVPPGEDSKDVAAPHRQPLTSSERIDKQIRYILD GISALRKETCNKSNMCESSKEALAENNLNLPKMAEKDGCFQSGFNEETCLVKIITGLLEFEV YLEYLQNRFESSEEQARAVQMSTKVLIQFLQKKAKNLDAITTPDPTTNASLLTKLQAQNQWL QDMTTHLILRSFKEFLQSSLRALRQM (SEQ ID NO: 647)

An “interleukin 6 receptor” or (IL-6R) refers herein 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 called 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 having IL-6Ra and/or IL-6Rb activity. Exemplary IL-6Ra biological activities include binding to IL-6, binding to glycoprotein 130 (gpl30), and regulation of cell growth and differentiation. Exemplary IL-6Rb biological activities include binding to IL-6Ra, IL-6 receptor signaling activity, and regulation of cell growth, differentiation, hepcidin expression etc. An exemplary amino acid sequence of human IL-6Ra is provided at NCBI Accession No. NP_000556 or NP_852004. An exemplary IL-6Ra sequence is provided at Uniprot P08887, which is as follows below.

MLAVGCALLAALLAAPGAALAPRRCPAQEVARGVLTSLPGDSVTLTCPGVEPEDNATVHW VLRKPAAGSHPSRWAGMGRRLLLRSVQLHDSGNYSCYRAGRPAGTVHLLVDVPPEEPQL SCFRKSPLSNVVCEWGPRSTPSLTTKAVLLVRKFQNSPAEDFQEPCQYSQESQKFSCQLA VPEGDSSFYIVSMCVASSVGSKFSKTQTFQGCGILQPDPPANITVTAVARNPRWLSVTWQD PHSWNSSFYRLRFELRYRAERSKTFTTWMVKDLQHHCVIHDAWSGLRHVVQLRAQEEFG QGEWSEWSPEAMGTPWTESRSPPAENEVSTPMQALTTNKDDDNILFRDSANATSLPVQD SSSVPLPTFLVAGGSLAFGTLLCIAIVLRFKKTWKLRALKEGKTSMHPPYSLGQLVPERPRP TPVLVPLISPPVSPSSLGSDNTSSHNRPDARDPRSPYDISNTDYFFPR (SEQ ID NO: 648)

An exemplary human “glycoprotein 130 (gpl30)” or “interleukin 6 receptor subunit b (IL-6Rb) polypeptide” amino acid sequence is provided at NCBI Accession No. NP_OO2I75, NP_786943, or NP_00l 177910. An exemplary IL-6Rb amino acid sequence is provided at Uniprot P40189-1 , which is as follows below.

MKEDGKGYWSDWSEEASGITYEDRPSKAPSFWYKIDPSHTQGYRTVQLVWKTLPPFEAN GKILDYEVTLTRWKSHLQNYTVNATKLTVNLTNDRYLATLTVRNLVGKSDAAVLTIPACDFQ ATHPVMDLKAFPKDNMLWVEWTTPRESVKKYILEWCVLSDKAPCITDWQQEDGTVHRTYL RGNLAESKCYLITVTPVYADGPGSPESIKAYLKQAPPSKGPTVRTKKVGKNEAVLEWDQLP VDVQNGFIRNYTIFYRTIIGNETAVNVDSSHTEYTLSSLTSDTLYMVRMAAYTDEGGKDGPE FTFTTPKFAQGEIEAIVVPVCLAFLLTTLLGVLFCFNKRDLIKKHIWPNVPDPSKSHIAQWSPH TPPRHNFNSKDQMYSDGNFTDVSVVEIEANDKKPFPEDLKSLDLFKKEKINTEGHSSGIGG SSCMSSSRPSISSSDENESSQNTSSTVQYSTWHSGYRHQVPSVQVFSRSESTQPLLDSE ERPEDLQLVDHVDGGDGILPRQQYFKQNCSQHESSPDISHFERSKQVSSVNEEDFVRLKQ QISDHISQSCGSGQMKMFQEVSAADAFGPGTEGQVERFETVGMEAATDEGMPKSYLPQT VRQGGYMPQ (SEQ ID NO: 649)

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

The term “C-reactive protein” or “CRP” refers to human CRP. CRP levels increase in response to inflammation, and can be measured with an hsCRP (high-sensitivity C-reactive protein) test. An exemplary CRP sequence is provided at NCBI Accession No. NP_000558.

In some embodiments, the human subject has “no active virus infection.” As used herein, “no active virus infection” refers to the subject having no ongoing, detectable amount of viral activity. For example, in some embodiments, the subject has no detectable amount of infection related to adenovirus, SARS-CoV-2, hepatitis B and C, parvovirus, herpes simplex virus, or a combination thereof. In some embodiments, the subject has no detectable amount of adenovirus, parvovirus B19, coxsackie virus, rubella virus, polio virus, Epstein-Barr virus, hepatitis C virus, influenza virus and SARS-CoV-2 virus.

In some embodiments, the myocarditis is caused by a virus infection, but virus levels in the subject are declining and/or there is no active virus infection. In some embodiments, the myocarditis is caused by viral infection, but virus levels in the subject declined at least 10 fold from peak levels. In some embodiments, the subject is no longer contagious. In some embodiments, the myocarditis is not caused by viral infection.

Treatment of Myocarditis

Myocarditis is an inflammation of the heart muscle (myocardium). Myocarditis may be caused by one or more of a viral infection, bacterial infection, fungal infection, parasites, one or more medications, drugs, toxins, or chemicals, radiation, autoimmune disease or other inflammatory disease, or an insect or other animal bite or sting. Symptoms of myocarditis may include, but are not limited to, chest pain, fatigue, rapid or abnormal heart rhythm (arrhythmia), signs of infection, diarrhea, headache, fever, muscle aches, sore throat, shortness of breath, and swelling in legs. Myocarditis affects people of all ages. In some embodiments, subjects are adults between 18 and 50 years of age. The myocarditis patient may also be an adult (i.e., 18 or older) or of advanced age, e.g., 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 with pediatric myocarditis (i.e., below the age of 18). Diagnosis of myocarditis may be assisted, for example, by blood tests, chest x-rays, electrocardiogram (ECG), echocardiogram, cardiac MR!, iate gadolinium enhancement (LGE), and/or endomyocardial biopsy.

Myocarditis may present in acute, subacute, and chronic forms. For example, in some subjects, acute or subacute myocarditis may be characterized by reduced ejection fraction (e.g., < 45%), presence of sustained ventricular arrhythmias, presence of anti-cardiac antibodies (for example anti-myosin antibodies), increase in Troponin (Troponin I and T) levels, heart failure, chest pain, and/or cardiogenic shock. At the histopathologic level, myocarditis is characterized by an inflammatory cellular infiltrate (which may be focal or diffuse) in the presence or absence of cardiac myocyte injury. See Aretz ef a/. Myocarditis. A histopathologic definition and classification. Am J Cardiovasc Pathol, 1 :3—14 (1987). The type of cellular infiltrate can be used to classify myocarditis:

Lymphocytic myocarditis - associated with a range of pathogens (predominantly viruses), drugs, radiation exposure and autoimmune disorders.

Eosinophilic myocarditis - a relatively uncommon form associated with parasitic infections, hypersensitivity reactions to various agents, eosinophilic inflammatory disorders and rarely a neoplastic process.

Giant-cell myocarditis - idiopathic in most cases but can also be associated with certain autoimmune disorders including autoimmune thyroid disease and inflammatory bowel diseases.

Granulomatous myocarditis - associated with sarcoidosis.

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

In some cases, herein, the myocarditis occurs with pericarditis, which is a swelling and/or inflammation of the pericardium. In other cases, the myocarditis is without pericarditis.

Acute and subacute myocarditis have also been associated with a Th1 and Th17 immune response in patients, and with elevated serum levels of certain cytokines that may contribute to a Th17 immune response, such as IL-6, TGF-beta, IL-17, and GM-CSF compared to normal subjects. See, e.g., Myers et al., JCI Insight 1 (9):e85851 (2016); Sawatis et al. Basic Res Cardiology 109:449 (2014); Amioka et al., J Cardiology 78: 157-65 (2021). In a study of 6-7 human patients, IL-6 was also found to be expressed in acute myocarditis patients in infiltrating inflammatory cells in myocardial tissue, suggesting that IL-6 released from inflammatory cells might cause cardiac damage by inducing and maintaining acute inflammation. Moreover, serum IL-6 levels correlated with the presence of such infiltrating IL-6 expressing inflammatory cells. See Amioka et al. While these studies suggest that IL-6 could be a target for consideration in myocarditis, no trials in humans have been conducted to Applicant’s knowledge.

The present disclosure is directed, inter alia, to methods of treating myocarditis, such as acute or subacute or early myocarditis, by administering a therapeutically effective amount of an anti-IL-6 or anti-IL-6R antibody, in particular an anti-IL-6 antibody. The present disclosure is also directed, inter alia, to methods of 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 antibodies may be administered to a subject at risk of developing myocarditis with the goal of preventing myocarditis or reducing the severity of or slowing onset of its symptoms.

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 which blocks the binding of IL-6 to IL-6R (such as to IL-6Ra or IL-6Rb, aka., 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 4 weeks or monthly. Exemplary IL-6 and IL-6R antibodies are described in the below and throughout the disclosure. In some embodiments, a prophylactically effective amount of an anti-IL-6 or anti-IL-6R antibody, e.g., an anti-IL-6 antibody, may be administered to a human subject at risk of developing myocarditis, such as acute or subacute myocarditis, such as a subject diagnosed with a viral disease or autoimmune disease, for example, with the goal of preventing onset of myocarditis or preventing onset of at least one symptom or myocarditis, or reducing the severity of myocarditis should it occur in the subject. In some embodiments, a prophylactically effective amount of the antibody to prevent onset of chronic myocarditis, e.g., in a subject with acute or subacute myocarditis, may be administered.

In some cases, treated subjects have been diagnosed with acute or subacute myocarditis based on tests revealing reduced ejection fraction (e.g., < 45%), presence of sustained ventricular arrhythmias, heart failure, presence of anti-cardiac antibodies (for example antimyosin antibodies), increase in Troponin (Troponin I and T) levels, chest pain, and/or cardiogenic shock.

In some embodiments, an IL-6R antibody, such as an IL-6R antagonist antibody, is administered. Examples include tocilizumab (ACTEMRA®), sarilumab (KEVZARA®), isvobarilizumab and levilimab (BCD-089). In some embodiments, an IL-6 antibody, such as an IL-6 antagonist antibody, is administered. Exemplary IL-6 antibodies include clazakizumab (BMS-945429, ALD518), ziltivekimab, siltuximab (SYLVANT™), olokizumab (CDP6038), elsilimomab, and sirukumab (CNTO 136). In some embodiments, the antibody used in the methods is clazakizumab. In some embodiments, the antibody used in the methods is ziltivekimab.

In some embodiments, the anti-IL-6 antibody used in the claimed treatment methods will include the VL CDRs of SEQ ID NO: 4, 5 and 6 and the VH CDRs of SEQ ID NO: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 NQ: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 human lgG1 constant regions. 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.

In some embodiments, the antibody is clazakizumab. Clazakizumab comprises the heavy and light chain sequences set forth below:

(Heavy chain) SEQ ID NO: 704

EVQLVESGGGLVQPGGSLRLSCAASGFSLSNYYVTWVRQAPGKGLEWVGI IYGSDETAYATSAIGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDDS SDWDAKFNLWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVK DYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQT YICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKP KDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYA STYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQ VYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPV LDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

(Light chain) SEQ ID NO: 702

AIQMTQSPSSLSASVGDRVTITCQASQSINNELSWYQQKPGKAPKLLIYR ASTLASGVPSRFSGSGSGTDFTLTISSLQPDDFATYYCQQGYSLRNIDNA FGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQ WKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVT HQGLSSPVTK SFNRGEC

Alternatively, in any of the subject therapeutic or detection methods 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 next section). For example, an anti-IL-6 antibody may comprise at least one VH polypeptide sequence selected from the group consisting of: SEQ ID NO: 3, 18, 19, 22, 38, 54, 70, 86, 102, 117, 1 18, 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 at least one VL polypeptide sequence selected from the group consisting of: SEQ ID NO: 2, 20, 21 , 37, 53, 69, 85, 101 , 1 19, 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, or it comprises a humanized variant of any of the foregoing comprising at least one VH polypeptides and at least one VL polypeptides possessing at least 80, 90, 96, 96, 97, 98, 99 percent sequence identity to any of the foregoing VH polypeptides or VL polypeptides.

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 monthly, every 5 weeks, or every 6 weeks. In some cases, the antibody is administered every 4 weeks or monthly. In some embodiments, the anti-IL-6 antibody of the above dosing regimen is clazakizumab or ziltivekimab.

In some cases, the anti-IL-6 antibody is clazakizumab and is administered at a dose of 4 to 12.5 mg subcutaneously or intravenously every 4 weeks or monthly. In some cases, the anti- IL-6 antibody is clazakizumab and is administered at a dose of 5 to 25 mg subcutaneously or intravenously every 4 weeks or monthly. In some cases, the anti-IL-6 antibody is clazakizumab and is administered at a dose of 5 to 12.5 mg subcutaneously or intravenously every 4 weeks or monthly. In some cases, the dosing continues for at least 3 months, at least 6 months, at least 9 months, at least 1 year, or at least 2 years. In some cases, it continues for at least 1 year. In some embodiments, clazakizumab is administered at dose of 0.3 to 25 mg subcutaneously or intravenously every 4 weeks or monthly for at least 6 months, in particular for at least 1 year. In some embodiments, clazakizumab is administered at a dose of to 15 mg subcutaneously or intravenously every 4 weeks or monthly for at least 6 months, in particular for at least 1 year.

The anti-IL-6 antibody may also be ziltivekimab. In some embodiments, ziltivekimab is administered at a dose of 1 to 50 mg subcutaneously or intravenously every 4 weeks or monthly. In some embodiments, ziltivekimab is administered at a dose of 2.5 to 25 mg subcutaneously or intravenously every 4 weeks or monthly. In some embodiments, ziltivekimab is administered at a dose of 5 to 15 mg subcutaneously or intravenously every 4 weeks or monthly. In some embodiments, the dosing of ziltivekimab continues for at least 3 months, at least 6 months, at least 9 months, at least 1 year, or at least 2 years. In some embodiments, dosing of ziltivekimab continues for at least 1 year. In some embodiments, ziltivekimab is administered at a dose of 1 to 20 mg subcutaneously or intravenously every 4 weeks or monthly for at least 6 months, in particular for at least 1 year. In some embodiments, ziltivekimab is administered at a dose of 5 to 15 mg subcutaneously or intravenously every 4 weeks or monthly for at least 6 months, in particular for at least 1 year.

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

In some embodiments, the methods further comprise determining IL-6 levels and/or the levels of C-reactive protein (CRP) (e.g., as measured by a high sensitivity CRP or hs-CRP test or other available tests), leptin, IL-17, TGT-beta, GM-CSF, troponins (e.g., troponin-l and troponin-T), N-terminal pro b natriuretic peptide (NT-proBNP), certain cardiac auto-antibodies, and/or TNF-alpha, such as in a blood or serum sample from the patient. These levels may be detected in a biological sample from the subject by known methods and compared to known levels for normal subjects. In some cases, the myocarditis patient will exhibit elevated IL-6 levels such as elevated serum IL-6 levels pre-treatment. In some embodiments, the pretreatment serum IL-6 level is at least 2, at least 4, at least 5, or at least 10 ng/L. In some embodiments, the pre-treatment serum levels are at least 10%, at least 20%, at least 30% or more higher than normal levels, or even 0.5, 1 , 1.5, 2, 3, 4, 5, 10 ng/L or more higher than normal levels. In some embodiments an elevated pre-treatment serum IL-6 level indicates that a patient should receive treatment with an anti-IL-6 or anti-IL-6R antibody. In some cases, serum IL-6 levels are determined not only pre-treatment, but also post-treatment, such as once per week, once per two weeks, or once per month of four weeks after the start of treatment. In some cases, serum IL-6 levels decrease after treatment with the anti-IL-6 or anti- IL-6R antibody.

Also, the myocarditis patient may further comprise elevated C-reactive protein (CRP) (e.g., hs-CRP), leptin, IL-17, TGT-beta, GM-CSF, troponins (e.g., troponin-l and troponin-T), NT- proBNP, certain cardiac auto-antibodies, and/or increased TNF-a levels, for example, in a serum or blood sample. These proteins also may be detected by known methods in biological samples from the subject, such as by ELISA assays, and the detected levels compared to normal levels. In some cases, CRP levels are determined not only pre-treatment, but also post-treatment, such as once per week, once per two weeks, or once per month of four weeks after the start of treatment. In some cases, CRP levels decrease after treatment with the anti- IL-6 or anti-IL-6R antibody. In some cases, the CRP level after treatment is decreased by at least 50%, 70%, 80%, or 90 % as compared to the pre-treatment CRP level. Any of the methods may further include the administration of another anti-myocarditis agent such as a corticosteroid, an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin II receptor blocker (ARB), a beta blocker, an intravenous IgG (MG) or subcutaneous IgG (SCIG), and/or a diuretic. In some embodiments, a subject is further receiving additional myocarditis treatment, such as mechanical support. Mechanical support may include, but is not limited to, extracorporeal membrane oxygenation (ECMO), intra-aortic balloon pump (IABP), and/or hemodynamic stabilization (e.g., with a heart pump, such as an IMPELLA® device (ABIOMED®, Massachusetts).

In some embodiments, treatment of subacute or acute myocarditis encompasses prevention of chronic myocarditis. For example, in some cases, treatment of a (sub)acute and/or early myocarditis patient is intended to prevent onset of chronic myocarditis or its sequelae.

Exemplary Anti-IL-6 Antibodies

In addition to the anti-IL-6 and anti-IL-6R antibodies discussed above, this disclosure includes antibodies having binding specificity to IL-6 and possessing a variable light chain sequence comprising the sequence set forth below:

MDTRAPTQLLGLLLLWLPGARCAYDMTQTPASVSAAVGGTVTIKCQASQSINNELSWYQQ KPGQRPKLLIYRASTLASGVSSRFKGSGSGTEFTLTISDLECADAATYYCQQGYSLRNIDNA FGGGTEVVVKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNN (SEQ ID NO: 2).

The disclosure also includes antibodies having binding specificity to IL-6 and possessing a variable heavy chain sequence comprising the sequence set forth below:

METGLRWLLLVAVLKGVQCQSLEESGGRLVTPGTPLTLTCTASGFSLSNYYVTWVRQAPG KGLEWIGIIYGSDETAYATWAIGRFTISKTSTTVDLKMTSLTAADTATYFCARDDSSDWDAKF NLWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVK (SEQ ID NO: 3).

The 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 complementaritydetermining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 3, or combinations of these polypeptide sequences. In another embodiment of the disclosure, the antibodies of the disclosure include combinations of the CDRs and the variable heavy and light chain sequences set forth above. In another embodiment, the disclosure contemplates other antibodies, such as for example chimeric 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 combinations of these polypeptide sequences. In another embodiment of the disclosure, the antibodies of the disclosure include combinations of the CDRs and the variable heavy and light chain sequences set forth above.

The disclosure also contemplates fragments of the antibody having binding specificity to IL-6. In one embodiment of the disclosure, antibody fragments of the disclosure comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 2. In another embodiment of the disclosure, antibody fragments of the disclosure comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 3.

In a further embodiment of the disclosure, fragments of the antibody having binding specificity to 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 complementaritydetermining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 2.

In a further embodiment of the disclosure, fragments of the antibody having binding specificity to 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 complementaritydetermining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 3.

The disclosure also contemplates antibody fragments which include one or more of the antibody fragments described herein. In one embodiment of the disclosure, fragments of the antibodies having binding specificity to IL-6 comprise, or alternatively consist 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 complementaritydetermining regions (SEQ ID NO: 4; SEQ ID NO: 5; and SEQ ID NO: 6) of the variable light chain region of SEQ ID NO: 2; and the complementarity-determining regions (SEQ ID NO: 7; SEQ ID NO: 8; and SEQ ID NO: 9) of the variable heavy chain region of SEQ ID NO: 3.

The disclosure also contemplates variants wherein either of the heavy chain polypeptide sequences of SEQ ID NO: 18 or SEQ ID NO: 19 is substituted for the heavy chain polypeptide sequence of SEQ ID NO: 3; the light chain polypeptide sequence of SEQ ID NO: 20 is substituted for the light chain polypeptide sequence of SEQ ID NO: 2; and the heavy chain CDR sequence of SEQ ID NO: 120 is substituted for the heavy chain CDR sequence of SEQ ID NO: 8.

In one embodiment of the disclosure, the anti-IL-6 antibody is Ab1 , comprising SEQ ID NO: 2 and SEQ ID NO: 3, or the alternative SEQ ID NOs set forth in paragraph [0083] above, and having at least one of the biological activities set forth herein.

In another embodiment, the disclosure includes antibodies having binding specificity to IL-6 and possessing a variable light chain sequence comprising the sequence set forth below:

MDTRAPTQLLGLLLLWLPGARCAYDMTQTPASVEVAVGGTVTINCQASETIYSWLSWYQQ KPGQPPKLLIYQASDLASGVPSRFSGSGAGTEYTLTISGVQCDDAATYYCQQGYSGSNVD NVFGGGTEVVVKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFY (SEQ ID NO: 21).

The disclosure also includes antibodies having binding specificity to IL-6 and possessing a variable heavy chain sequence comprising the sequence set forth below:

METGLRWLLLVAVLKGVQCQEQLKESGGRLVTPGTPLTLTCTASGFSLNDHAMGWVRQA PGKGLEYIGFINSGGSARYASWAEGRFTISRTSTTVDLKMTSLTTEDTATYFCVRGGAVWSI HSFDPWGPGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVK (SEQ ID NO: 22).

The 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 complementaritydetermining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 22, or combinations of these polypeptide sequences. In another embodiment of the disclosure, the antibodies of the disclosure include combinations of the CDRs and the variable heavy and light chain sequences set forth above.

In another embodiment, the disclosure contemplates other antibodies, such as for example chimeric 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 combinations of these polypeptide sequences. In another embodiment of the disclosure, the antibodies of the disclosure include combinations of the CDRs and the variable heavy and light chain sequences set forth above. The disclosure also contemplates fragments of the antibody having binding specificity to IL-6. In one embodiment of the disclosure, antibody fragments of the disclosure comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 21. In another embodiment of the disclosure, antibody fragments of the disclosure comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 22.

In a further embodiment of the disclosure, fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist 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 complementaritydetermining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 21.

In a further embodiment of the disclosure, fragments of the antibody having binding specificity to 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 complementaritydetermining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 22.

The disclosure also contemplates antibody fragments which include one or more of the antibody fragments described herein. In one embodiment of the disclosure, fragments of the antibodies having binding specificity to IL-6 comprise, or alternatively consist 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 complementaritydetermining regions (SEQ ID NO: 23; SEQ ID NO: 24; and SEQ ID NO: 25) of the variable light chain region of SEQ ID NO: 21 ; and the complementarity-determining regions (SEQ ID NO: 26; SEQ ID NO: 27; and SEQ ID NO: 28) of the variable heavy chain region of SEQ ID NO: 22.

In one embodiment of the disclosure, the anti-IL-6 antibody is Ab2, comprising SEQ ID NO: 21 and SEQ ID NO: 22, and having at least one of the biological activities set forth herein.

In another embodiment, the disclosure includes antibodies having binding specificity to IL-6 and possessing a variable light chain sequence comprising the sequence set forth below:

MDTRAPTQLLGLLLLWLPGATFAAVLTQTPSPVSAAVGGTVSISCQASQSVYDNNYLSWFQ QKPGQPPKLLIYGASTLASGVPSRFVGSGSGTQFTLTITDVQCDDAATYYCAGVYDDDSDN AFGGGTEVVVKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNN (SEQ ID NO: 37).

The disclosure also includes antibodies having binding specificity to IL-6 and possessing a variable heavy chain sequence comprising the sequence set forth below: METGLRWLLLVAVLKGVQCQSLEESGGRLVTPGTPLTLTCTASGFSLSVYYMNWVRQAPG

KGLEWIGFITMSDNINYASWAKGRFTISKTSTTVDLKMTSPTTEDTATYFCARSRGWGTMG RLDLWGPGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVK (SEQ ID NO: 38).

The 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 complementaritydetermining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 38, or combinations of these polypeptide sequences. In another embodiment of the disclosure, the antibodies of the disclosure include combinations of the CDRs and the variable heavy and light chain sequences set forth above.

In another embodiment, the disclosure contemplates other antibodies, such as for example chimeric 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 combinations of these polypeptide sequences. In another embodiment of the disclosure, the antibodies of the disclosure include combinations of the CDRs and the variable heavy and light chain sequences set forth above.

The disclosure also contemplates fragments of the antibody having binding specificity to IL-6. In one embodiment of the disclosure, antibody fragments of the disclosure comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 37. In another embodiment of the disclosure, antibody fragments of the disclosure comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 38.

In a further embodiment of the disclosure, fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist 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 complementaritydetermining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 37.

In a further embodiment of the disclosure, fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist 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 complementaritydetermining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 38. The disclosure also contemplates antibody fragments which include one or more of the antibody fragments described herein. In one embodiment of the disclosure, fragments of the antibodies having binding specificity to IL-6 comprise, or alternatively consist 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 complementaritydetermining regions (SEQ ID NO: 39; SEQ ID NO: 40; and SEQ ID NO: 41) of the variable light chain region of SEQ ID NO: 37; and the complementarity-determining regions (SEQ ID NO: 42; SEQ ID NO: 43; and SEQ ID NO: 44) of the variable heavy chain region of SEQ ID NO: 38.

In one embodiment of the disclosure, the anti-IL-6 antibody is Ab3, comprising SEQ ID NO: 37 and SEQ ID NO: 38, and having at least one of the biological activities set forth herein.

In another embodiment, the disclosure includes antibodies having binding specificity to IL-6 and possessing a variable light chain sequence comprising the sequence set forth below:

MDTRAPTQLLGLLLLWLPGAICDPVLTQTPSPVSAPVGGTVSISCQASQSVYENNYLSWFQ QKPGQPPKLLIYGASTLDSGVPSRFKGSGSGTQFTLTITDVQCDDAATYYCAGVYDDDSDD AFGGGTEVVVKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNN (SEQ ID NO: 53).

The disclosure also includes antibodies having binding specificity to IL-6 and possessing a variable heavy chain sequence comprising the sequence set forth below:

METGLRWLLLVAVLKGVQCQEQLKESGGGLVTPGGTLTLTCTASGFSLNAYYMNWVRQA PGKGLEWIGFITLNNNVAYANWAKGRFTFSKTSTTVDLKMTSPTPEDTATYFCARSRGWG AMGRLDLWGHGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVK (SEQ ID NO: 54).

The 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 complementaritydetermining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 54, or combinations of these polypeptide sequences. In another embodiment of the disclosure, the antibodies of the disclosure include combinations of the CDRs and the variable heavy and light chain sequences set forth above.

In another embodiment, the disclosure contemplates other antibodies, such as for example chimeric 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 combinations of these polypeptide sequences. In another embodiment of the disclosure, the antibodies of the disclosure include combinations of the CDRs and the variable heavy and light chain sequences set forth above.

The disclosure also contemplates fragments of the antibody having binding specificity to IL-6. In one embodiment of the disclosure, antibody fragments of the disclosure comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 53. In another embodiment of the disclosure, antibody fragments of the disclosure comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 54.

In a further embodiment of the disclosure, fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist 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 complementaritydetermining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 53.

In a further embodiment of the disclosure, fragments of the antibody having binding specificity to 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 complementaritydetermining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 54.

The disclosure also contemplates antibody fragments which include one or more of the antibody fragments described herein. In one embodiment of the disclosure, fragments of the antibodies having binding specificity to IL-6 comprise, or alternatively consist 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 complementaritydetermining regions (SEQ ID NO: 55; SEQ ID NO: 56; and SEQ ID NO: 57) of the variable light chain region of SEQ ID NO: 53; and the complementarity-determining regions (SEQ ID NO: 58; SEQ ID NO: 59; and SEQ ID NO: 60) of the variable heavy chain region of SEQ ID NO: 54.

In one embodiment of the disclosure, the anti-IL-6 antibody is Ab4, comprising SEQ ID NO: 53 and SEQ ID NO: 54, and having at least one of the biological activities set forth herein.

In another embodiment, the disclosure includes antibodies having binding specificity to IL-6 and possessing a variable light chain sequence comprising the sequence set forth below: MDTRAPTQLLGLLLLWLPGATFAQVLTQTPSPVSAAVGGTVTINCQASQSVDDNNWLGWY QQKRGQPPKYLIYSASTLASGVPSRFKGSGSGTQFTLTISDLECDDAATYYCAGGFSGNIFA FGGGTEVVVKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNF (SEQ ID NO: 69).

The disclosure also includes antibodies having binding specificity to IL-6 and possessing a variable heavy chain sequence comprising the sequence set forth below:

METGLRWLLLVAVLKGVQCQSVEESGGRLVTPGTPLTLTCTVSGFSLSSYAMSWVRQAPG KGLEWIGIIGGFGTTYYATWAKGRFTISKTSTTVDLRITSPTTEDTATYFCARGGPGNGGDI WGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKD (SEQ ID NO: 70).

The 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 complementaritydetermining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 70, or combinations of these polypeptide sequences. In another embodiment of the disclosure, the antibodies of the disclosure include combinations of the CDRs and the variable heavy and light chain sequences set forth above.

In another embodiment, the disclosure contemplates other antibodies, such as for example chimeric 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 combinations of these polypeptide sequences. In another embodiment of the disclosure, the antibodies of the disclosure include combinations of the CDRs and the variable heavy and light chain sequences set forth above.

The disclosure also contemplates fragments of the antibody having binding specificity to IL-6. In one embodiment of the disclosure, antibody fragments of the disclosure comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 69. In another embodiment of the disclosure, antibody fragments of the disclosure comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 70.

In a further embodiment of the disclosure, fragments of the antibody having binding specificity to 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.

In a further embodiment of the disclosure, fragments of the antibody having binding specificity to 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 complementaritydetermining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 70.

The disclosure also contemplates antibody fragments which include one or more of the antibody fragments described herein. In one embodiment of the disclosure, fragments of the antibodies having binding specificity to IL-6 comprise, or alternatively consist 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 complementaritydetermining regions (SEQ ID NO: 71 ; SEQ ID NO: 72; and SEQ ID NO: 73) of the variable light chain region of SEQ ID NO: 69; and the complementarity-determining regions (SEQ ID NO: 74; SEQ ID NO: 75; and SEQ ID NO: 76) of the variable heavy chain region of SEQ ID NO: 70.

In one embodiment of the 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 set forth herein.

In another embodiment, the disclosure includes antibodies having binding specificity to IL-6 and possessing a variable light chain sequence comprising the sequence set forth below:

MDTRAPTQLLGLLLLWLPGATFAAVLTQTPSPVSVPVGGTVTIKCQSSQSVYNNFLSWYQQ KPGQPPKLLIYQASKLASGVPDRFSGSGSGTQFTLTISGVQCDDAATYYCLGGYDDDADNA FGGGTEVVVKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNF (SEQ ID NO: 85).

The disclosure also includes antibodies having binding specificity to IL-6 and possessing a variable heavy chain sequence comprising the sequence set forth below:

METGLRWLLLVAVLKGVQCQSVEESGGRLVTPGTPLTLTCTVSGIDLSDYAMSWVRQAPG KGLEWIGIIYAGSGSTWYASWAKGRFTISKTSTTVDLKITSPTTEDTATYFCARDGYDDYGD FDRLDLWGPGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKD (SEQ ID NO: 86).

The 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 complementaritydetermining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 86, or combinations of these polypeptide sequences. In another embodiment of the disclosure, the antibodies of the disclosure include combinations of the CDRs and the variable heavy and light chain sequences set forth above.

In another embodiment, the disclosure contemplates other antibodies, such as for example chimeric 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 combinations of these polypeptide sequences. In another embodiment of the disclosure, the antibodies of the disclosure include combinations of the CDRs and the variable heavy and light chain sequences set forth above.

The disclosure also contemplates fragments of the antibody having binding specificity to IL-6. In one embodiment of the disclosure, antibody fragments of the disclosure comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 85. In another embodiment of the disclosure, antibody fragments of the disclosure comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 86.

In a further embodiment of the disclosure, fragments of the antibody having binding specificity to 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 complementaritydetermining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 85.

In a further embodiment of the disclosure, fragments of the antibody having binding specificity to 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 complementaritydetermining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 86.

The disclosure also contemplates antibody fragments which include one or more of the antibody fragments described herein. In one embodiment of the disclosure, fragments of the antibodies having binding specificity to IL-6 comprise, or alternatively consist 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 complementaritydetermining regions (SEQ ID NO: 87; SEQ ID NO: 88; and SEQ ID NO: 89) of the variable light chain region of SEQ ID NO: 85; and the complementarity-determining regions (SEQ ID NO: 90; SEQ ID NO: 91 ; and SEQ ID NO: 92) of the variable heavy chain region of SEQ ID NO: 86. In one embodiment of the 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 set forth herein.

In another embodiment, the disclosure includes antibodies having binding specificity to IL-6 and possessing a variable light chain sequence comprising the sequence set forth below:

MDTRAPTQLLGLLLLWLPGARCAYDMTQTPASVSAAVGGTVTIKCQASQSINNELSWYQQ KSGQRPKLLIYRASTLASGVSSRFKGSGSGTEFTLTISDLECADAATYYCQQGYSLRNIDNA FGGGTEVVVKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNF (SEQ ID NO: 101).

The disclosure also includes antibodies having binding specificity to IL-6 and possessing a variable heavy chain sequence comprising the sequence set forth below:

METGLRWLLLVAVLSGVQCQSLEESGGRLVTPGTPLTLTCTASGFSLSNYYMTWVRQAPG KGLEWIGMIYGSDETAYANWAIGRFTISKTSTTVDLKMTSLTAADTATYFCARDDSSDWDA KFNLWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVK (SEQ ID NO: 102).

The 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 complementaritydetermining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 102, or combinations of these polypeptide sequences. In another embodiment of the disclosure, the antibodies of the disclosure include combinations of the CDRs and the variable heavy and light chain sequences set forth above.

In another embodiment, the disclosure contemplates other antibodies, such as for example chimeric 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 complementaritydetermining 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 combinations of these polypeptide sequences. In another embodiment of the disclosure, the antibodies of the disclosure include combinations of the CDRs and the variable heavy and light chain sequences set forth above.

The disclosure also contemplates fragments of the antibody having binding specificity to IL-6. In one embodiment of the disclosure, antibody fragments of the disclosure comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 101. In another embodiment of the disclosure, antibody fragments of the disclosure comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 102.

In a further embodiment of the disclosure, fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist 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 complementaritydetermining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 101 .

In a further embodiment of the disclosure, fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist 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 complementaritydetermining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 102.

The disclosure also contemplates antibody fragments which include one or more of the antibody fragments described herein. In one embodiment of the disclosure, fragments of the antibodies having binding specificity to IL-6 comprise, or alternatively consist 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 complementaritydetermining regions (SEQ ID NO: 103; SEQ ID NO: 104; and SEQ ID NO: 105) of the variable light chain region of SEQ ID NO: 101 ; and the complementarity-determining regions (SEQ ID NO: 106; SEQ ID NO: 107; and SEQ ID NO: 108) of the variable heavy chain region of SEQ ID NO: 102.

The disclosure also contemplates variants wherein either of the heavy chain polypeptide sequences of SEQ ID NO: 117 or SEQ ID NO: 1 18 is substituted for the heavy chain polypeptide sequence of SEQ ID NO: 102; the light chain polypeptide sequence of SEQ ID NO: 1 19 is substituted for the light chain polypeptide sequence of SEQ ID NO: 101 ; and the heavy chain CDR sequence of SEQ ID NO: 121 is substituted for the heavy chain CDR sequence of SEQ ID NO: 107.

In one embodiment of the disclosure, the anti-IL-6 antibody is Ab7, comprising SEQ ID NO: 101 and SEQ ID NO: 102, or the alternative SEQ ID NOs set forth in paragraph [0138] above, and having at least one of the biological activities set forth herein.

In another embodiment, the disclosure includes antibodies having binding specificity to IL-6 and possessing a variable light chain sequence comprising the sequence set forth below:

MDTRAPTQLLGLLLLWLPGATFAAVLTQTPSPVSAAVGGTVTISCQSSQSVGNNQDLSWF QQRPGQPPKLLIYEISKLESGVPSRFSGSGSGTHFTLTISGVQCDDAATYYCLGGYDDDAD NA (SEQ ID NO: 122). The disclosure also includes antibodies having binding specificity to IL-6 and possessing a variable heavy chain sequence comprising the sequence set forth below:

METGLRWLLLVAVLKGVQCHSVEESGGRLVTPGTPLTLTCTVSGFSLSSRTMSWVRQAPG KGLEWIGYIWSGGSTYYATWAKGRFTISKTSTTVDLKITSPTTEDTATYFCARLGDTGGHAY ATRLNL (SEQ ID NO: 123).

The 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 complementaritydetermining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 123, or combinations of these polypeptide sequences. In another embodiment of the disclosure, the antibodies of the disclosure include combinations of the CDRs and the variable heavy and light chain sequences set forth above.

In another embodiment, the disclosure contemplates other antibodies, such as for example chimeric 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 complementaritydetermining 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 combinations of these polypeptide sequences. In another embodiment of the disclosure, the antibodies of the disclosure include combinations of the CDRs and the variable heavy and light chain sequences set forth above.

The disclosure also contemplates fragments of the antibody having binding specificity to IL-6. In one embodiment of the disclosure, antibody fragments of the disclosure comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 122. In another embodiment of the disclosure, antibody fragments of the disclosure comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 123.

In a further embodiment of the disclosure, fragments of the antibody having binding specificity to 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 complementaritydetermining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 122. In a further embodiment of the disclosure, fragments of the antibody having binding specificity to 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 complementaritydetermining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 123.

The disclosure also contemplates antibody fragments which include one or more of the antibody fragments described herein. In one embodiment of the disclosure, fragments of the antibodies having binding specificity to IL-6 comprise, or alternatively consist 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 complementaritydetermining regions (SEQ ID NO: 124; SEQ ID NO: 125; and SEQ ID NO: 126) of the variable light chain region of SEQ ID NO: 122; and the complementarity-determining regions (SEQ ID NO: 127; SEQ ID NO: 128; and SEQ ID NO: 129) of the variable heavy chain region of SEQ ID NO: 123.

In one embodiment of the 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 set forth herein.

In another embodiment, the disclosure includes antibodies having binding specificity to IL-6 and possessing a variable light chain sequence comprising the sequence set forth below:

MDTRAPTQLLGLLLLWLPGATFAAVLTQTPSSVSAAVGGTVSISCQSSQSVYSNKYLAWYQ QKPGQPPKLLIYWTSKLASGAPSRFSGSGSGTQFTLTISGVQCDDAATYYCLGAYDDDADN A (SEQ ID NO: 138).

The disclosure also includes antibodies having binding specificity to IL-6 and possessing a variable heavy chain sequence comprising the sequence set forth below:

METGLRWLLLVAVLKGVQCQSVEESGGRLVKPDETLTLTCTASGFSLEGGYMTWVRQAP GKGLEWIGISYDSGSTYYASWAKGRFTISKTSSTTVDLKMTSLTTEDTATYFCVRSLKYPTV TSDDL (SEQ ID NO: 139).

The 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 complementaritydetermining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 139, or combinations of these polypeptide sequences. In another embodiment of the disclosure, the antibodies of the disclosure include combinations of the CDRs and the variable heavy and light chain sequences set forth above. In another embodiment, the disclosure contemplates other antibodies, such as for example chimeric 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 complementaritydetermining 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 combinations of these polypeptide sequences. In another embodiment of the disclosure, the antibodies of the disclosure include combinations of the CDRs and the variable heavy and light chain sequences set forth above.

The disclosure also contemplates fragments of the antibody having binding specificity to IL-6. In one embodiment of the disclosure, antibody fragments of the disclosure comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 138. In another embodiment of the disclosure, antibody fragments of the disclosure comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 139.

In a further embodiment of the disclosure, fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist 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 complementaritydetermining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 138.

In a further embodiment of the disclosure, fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist 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 complementaritydetermining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 139.

The disclosure also contemplates antibody fragments which include one or more of the antibody fragments described herein. In one embodiment of the disclosure, fragments of the antibodies having binding specificity to IL-6 comprise, or alternatively consist 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 complementaritydetermining regions (SEQ ID NO: 140; SEQ ID NO: 141 ; and SEQ ID NO: 142) of the variable light chain region of SEQ ID NO: 138; and the complementarity-determining regions (SEQ ID NO: 143; SEQ ID NO: 144; and SEQ ID NO: 145) of the variable heavy chain region of SEQ ID NO: 139.

In one embodiment of the 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 set forth herein. In another embodiment, the disclosure includes antibodies having binding specificity to IL-6 and possessing a variable light chain sequence comprising the sequence set forth below:

MDTRAPTQLLGLLLLWLPGATFAAVLTQTPSPVSAAVGGTVTISCQSSQSVYNNNDLAWYQ QKPGQPPKLLIYYASTLASGVPSRFKGSGSGTQFTLTISGVQCDDAAAYYCLGGYDDDADN A (SEQ ID NO: 154).

The disclosure also includes antibodies having binding specificity to IL-6 and possessing a variable heavy chain sequence comprising the sequence set forth below:

METGLRWLLLVAVLKGVQCQSVEESGGRLVTPGTPLTLTCTVSGLSLSSNTINWVRQAPGK GLEWIGYIWSGGSTYYASWVNGRFTISKTSTTVDLKITSPTTEDTATYFCARGGYASGGYP YATRLDL (SEQ ID NO: 155).

The 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 complementaritydetermining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 155, or combinations of these polypeptide sequences. In another embodiment of the disclosure, the antibodies of the disclosure include combinations of the CDRs and the variable heavy and light chain sequences set forth above.

In another embodiment, the disclosure contemplates other antibodies, such as for example chimeric 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 complementaritydetermining 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 combinations of these polypeptide sequences. In another embodiment of the disclosure, the antibodies of the disclosure include combinations of the CDRs and the variable heavy and light chain sequences set forth above.

The disclosure also contemplates fragments of the antibody having binding specificity to IL-6. In one embodiment of the disclosure, antibody fragments of the disclosure comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 154. In another embodiment of the disclosure, antibody fragments of the disclosure comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 155. In a further embodiment of the disclosure, fragments of the antibody having binding specificity to 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 complementaritydetermining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 154.

In a further embodiment of the disclosure, fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist 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 complementaritydetermining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 155.

The disclosure also contemplates antibody fragments which include one or more of the antibody fragments described herein. In one embodiment of the disclosure, fragments of the antibodies having binding specificity to IL-6 comprise, or alternatively consist 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 complementaritydetermining regions (SEQ ID NO: 156; SEQ ID NO: 157; and SEQ ID NO: 158) of the variable light chain region of SEQ ID NO: 154; and the complementarity-determining regions (SEQ ID NO: 159; SEQ ID NO: 160; and SEQ ID NO: 161) of the variable heavy chain region of SEQ ID NO: 155.

In one embodiment of the 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 set forth herein.

In another embodiment, the disclosure includes antibodies having binding specificity to IL-6 and possessing a variable light chain sequence comprising the sequence set forth below:

MDTRAPTQLLGLLLLWLPGATFAAVLTQTPSSVSAAVGGTVTINCQSSQSVYNNDYLSWYQ QRPGQRPKLLIYGASKLASGVPSRFKGSGSGKQFTLTISGVQCDDAATYYCLGDYDDDAD NT (SEQ ID NO: 170).

The disclosure also includes antibodies having binding specificity to IL-6 and possessing a variable heavy chain sequence comprising the sequence set forth below:

METGLRWLLLVAVLKGVQCQSLEESGGRLVTPGTPLTLTCTVSGFTLSTNYYLSWVRQAP GKGLEWIGIIYPSGNTYCAKWAKGRFTISKTSSTTVDLKMTSPTTEDTATYFCARNYGGDES L (SEQ ID NO: 171).

The 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 complementaritydetermining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 171 , or combinations of these polypeptide sequences. In another embodiment of the disclosure, the antibodies of the disclosure include combinations of the CDRs and the variable heavy and light chain sequences set forth above.

In another embodiment, the disclosure contemplates other antibodies, such as for example chimeric 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 complementaritydetermining 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 combinations of these polypeptide sequences. In another embodiment of the disclosure, the antibodies of the disclosure include combinations of the CDRs and the variable heavy and light chain sequences set forth above.

The disclosure also contemplates fragments of the antibody having binding specificity to IL-6. In one embodiment of the disclosure, antibody fragments of the disclosure comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 170. In another embodiment of the disclosure, antibody fragments of the disclosure comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 171.

In a further embodiment of the disclosure, fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist 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 complementaritydetermining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 170.

In a further embodiment of the disclosure, fragments of the antibody having binding specificity to 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 complementaritydetermining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 171.

The disclosure also contemplates antibody fragments which include one or more of the antibody fragments described herein. In one embodiment of the disclosure, fragments of the antibodies having binding specificity to IL-6 comprise, or alternatively consist 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 complementaritydetermining regions (SEQ ID NO: 172; SEQ ID NO: 173; and SEQ ID NO: 174) of the variable light chain region of SEQ ID NO: 170; and the complementarity-determining regions (SEQ ID NO: 175; SEQ ID NO: 176; and SEQ ID NO: 177) of the variable heavy chain region of SEQ ID NO: 171.

In one embodiment of the disclosure, the anti-IL-6 antibody is Ab1 1 , comprising SEQ ID NO: 170 and SEQ ID NO: 171 , and having at least one of the biological activities set forth herein.

In another embodiment, the disclosure includes antibodies having binding specificity to IL-6 and possessing a variable light chain sequence comprising the sequence set forth below:

MDTRAPTQLLGLLLLWLPGARCDVVMTQTPASVEAAVGGTVTIKCQASETIGNALAWYQQK SGQPPKLLIYKASKLASGVPSRFKGSGSGTEYTLTISDLECADAATYYCQWCYFGDSV (SEQ ID NO: 186).

The disclosure also includes antibodies having binding specificity to IL-6 and possessing a variable heavy chain sequence comprising the sequence set forth below:

METGLRWLLLVTVLKGVQCQEQLVESGGGLVQPEGSLTLTCTASGFDFSSGYYMCWVRQ APGKGLEWIACIFTITTNTYYASWAKGRFTISKTSSTTVTLQMTSLTAADTATYLCARGIYSD NNYYAL (SEQ ID NO: 187).

The 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 complementaritydetermining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 187, or combinations of these polypeptide sequences. In another embodiment of the disclosure, the antibodies of the disclosure include combinations of the CDRs and the variable heavy and light chain sequences set forth above.

In another embodiment, the disclosure contemplates other antibodies, such as for example chimeric 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 complementaritydetermining 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 combinations of these polypeptide sequences. In another embodiment of the disclosure, the antibodies of the disclosure include combinations of the CDRs and the variable heavy and light chain sequences set forth above. The disclosure also contemplates fragments of the antibody having binding specificity to IL-6. In one embodiment of the disclosure, antibody fragments of the disclosure comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 186. In another embodiment of the disclosure, antibody fragments of the disclosure comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 187.

In a further embodiment of the disclosure, fragments of the antibody having binding specificity to 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 complementaritydetermining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 186.

In a further embodiment of the disclosure, fragments of the antibody having binding specificity to 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 complementaritydetermining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 187.

The disclosure also contemplates antibody fragments which include one or more of the antibody fragments described herein. In one embodiment of the disclosure, fragments of the antibodies having binding specificity to IL-6 comprise, or alternatively consist 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 complementaritydetermining regions (SEQ ID NO: 188; SEQ ID NO: 189; and SEQ ID NO: 190) of the variable light chain region of SEQ ID NO: 186; and the complementarity-determining regions (SEQ ID NO: 191 ; SEQ ID NO: 192; and SEQ ID NO: 193) of the variable heavy chain region of SEQ ID NO: 187.

In one embodiment of the 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 set forth herein.

In another embodiment, the disclosure includes antibodies having binding specificity to IL-6 and possessing a variable light chain sequence comprising the sequence set forth below:

MDTRAPTQLLGLLLLWLPGARCDVVMTQTPASVEAAVGGTVTIKCQASESIGNALAWYQQ KPGQPPKLLIYKASTLASGVPSRFSGSGSGTEFTLTISGVQCADAAAYYCQWCYFGDSV (SEQ ID NO: 202).

The disclosure also includes antibodies having binding specificity to IL-6 and possessing a variable heavy chain sequence comprising the sequence set forth below: METGLRWLLLVAVLKGVQCQQQLVESGGGLVKPGASLTLTCKASGFSFSSGYYMCWVRQ APGKGLESIACIFTITDNTYYANWAKGRFTISKPSSPTVTLQMTSLTAADTATYFCARGIYST DNYYAL (SEQ ID NO: 203).

The 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 complementaritydetermining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 203, or combinations of these polypeptide sequences. In another embodiment of the disclosure, the antibodies of the disclosure include combinations of the CDRs and the variable heavy and light chain sequences set forth above.

In another embodiment, the disclosure contemplates other antibodies, such as for example chimeric 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 complementaritydetermining 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 combinations of these polypeptide sequences. In another embodiment of the disclosure, the antibodies of the disclosure include combinations of the CDRs and the variable heavy and light chain sequences set forth above.

The disclosure also contemplates fragments of the antibody having binding specificity to IL-6. In one embodiment of the disclosure, antibody fragments of the disclosure comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 202. In another embodiment of the disclosure, antibody fragments of the disclosure comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 203.

In a further embodiment of the disclosure, fragments of the antibody having binding specificity to 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 complementaritydetermining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 202.

In a further embodiment of the disclosure, fragments of the antibody having binding specificity to 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 complementaritydetermining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 203. The disclosure also contemplates antibody fragments which include one or more of the antibody fragments described herein. In one embodiment of the disclosure, fragments of the antibodies having binding specificity to IL-6 comprise, or alternatively consist 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 complementaritydetermining regions (SEQ ID NO: 204; SEQ ID NO: 205; and SEQ ID NO: 206) of the variable light chain region of SEQ ID NO: 202; and the complementarity-determining regions (SEQ ID NO: 207; SEQ ID NO: 208; and SEQ ID NO: 209) of the variable heavy chain region of SEQ ID NO: 203.

In one embodiment of the disclosure, the anti-IL-6 antibody is Ab13, comprising SEQ ID NO: 202 and SEQ ID NO: 203, and having at least one of the biological activities set forth herein.

In another embodiment, the disclosure includes antibodies having binding specificity to IL-6 and possessing a variable light chain sequence comprising the sequence set forth below:

MDTRAPTQLLGLLLLWLPGARCDVVMTQTPASVEAAVGGTVTIKCQASQSVSSYLNWYQQ KPGQPPKLLIYRASTLESGVPSRFKGSGSGTEFTLTISDLECADAATYYCQCTYGTSSSYGA A (SEQ ID NO: 218).

The disclosure also includes antibodies having binding specificity to IL-6 and possessing a variable heavy chain sequence comprising the sequence set forth below:

METGLRWLLLVAVLKGVQCQSVEESGGRLVTPGTPLTLTCTVSGISLSSNAISWVRQAPGK GLEWIGIISYSGTTYYASWAKGRFTISKTSSTTVDLKITSPTTEDTATYFCARDDPTTVMVMLI PFGAGMDL (SEQ ID NO: 219).

The 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 complementaritydetermining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 219, or combinations of these polypeptide sequences. In another embodiment of the disclosure, the antibodies of the disclosure include combinations of the CDRs and the variable heavy and light chain sequences set forth above.

In another embodiment, the disclosure contemplates other antibodies, such as for example chimeric 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 complementaritydetermining 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 combinations of these polypeptide sequences. In another embodiment of the disclosure, the antibodies of the disclosure include combinations of the CDRs and the variable heavy and light chain sequences set forth above.

The disclosure also contemplates fragments of the antibody having binding specificity to IL-6. In one embodiment of the disclosure, antibody fragments of the disclosure comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 218. In another embodiment of the disclosure, antibody fragments of the disclosure comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 219.

In a further embodiment of the disclosure, fragments of the antibody having binding specificity to 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 complementaritydetermining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 218.

In a further embodiment of the disclosure, fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist 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 complementaritydetermining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 219.

The disclosure also contemplates antibody fragments which include one or more of the antibody fragments described herein. In one embodiment of the disclosure, fragments of the antibodies having binding specificity to IL-6 comprise, or alternatively consist 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 complementaritydetermining regions (SEQ ID NO: 220; SEQ ID NO: 221 ; and SEQ ID NO: 222) of the variable light chain region of SEQ ID NO: 218; and the complementarity-determining regions (SEQ ID NO: 223; SEQ ID NO: 224; and SEQ ID NO: 225) of the variable heavy chain region of SEQ ID NO: 219.

In one embodiment of the 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 set forth herein.

In another embodiment, the disclosure includes antibodies having binding specificity to IL-6 and possessing a variable light chain sequence comprising the sequence set forth below: MDTRAPTQLLGLLLLWLPGATFAQVLTQTASPVSAAVGGTVTINCQASQSVYKNNYLSWYQ

QKPGQPPKGLIYSASTLDSGVPLRFSGSGSGTQFTLTISDVQCDDAATYYCLGSYDCSSGD CYA (SEQ ID NO: 234).

The disclosure also includes antibodies having binding specificity to IL-6 and possessing a variable heavy chain sequence comprising the sequence set forth below:

METGLRWLLLVAVLKGVQCQSLEESGGDLVKPEGSLTLTCTASGFSFSSYWMCWVRQAP GKGLEWIACIVTGNGNTYYANWAKGRFTISKTSSTTVTLQMTSLTAADTATYFCAKAYDL (SEQ ID NO: 235).

The 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 complementaritydetermining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 235, or combinations of these polypeptide sequences. In another embodiment of the disclosure, the antibodies of the disclosure include combinations of the CDRs and the variable heavy and light chain sequences set forth above.

In another embodiment, the disclosure contemplates other antibodies, such as for example chimeric 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 complementaritydetermining 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 combinations of these polypeptide sequences. In another embodiment of the disclosure, the antibodies of the disclosure include combinations of the CDRs and the variable heavy and light chain sequences set forth above.

The disclosure also contemplates fragments of the antibody having binding specificity to IL-6. In one embodiment of the disclosure, antibody fragments of the disclosure comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 234. In another embodiment of the disclosure, antibody fragments of the disclosure comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 235.

In a further embodiment of the disclosure, fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist 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.

In a further embodiment of the disclosure, fragments of the antibody having binding specificity to 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 complementaritydetermining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 235.

The disclosure also contemplates antibody fragments which include one or more of the antibody fragments described herein. In one embodiment of the disclosure, fragments of the antibodies having binding specificity to IL-6 comprise, or alternatively consist 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 complementaritydetermining regions (SEQ ID NO: 236; SEQ ID NO: 237; and SEQ ID NO: 238) of the variable light chain region of SEQ ID NO: 234; and the complementarity-determining regions (SEQ ID NO: 239; SEQ ID NO: 240; and SEQ ID NO: 241) of the variable heavy chain region of SEQ ID NO: 235.

In one embodiment of the disclosure, the anti-IL-6 antibody is Ab15, comprising SEQ ID NO: 234 and SEQ ID NO: 235, and having at least one of the biological activities set forth herein.

In another embodiment, the disclosure includes antibodies having binding specificity to IL-6 and possessing a variable light chain sequence comprising the sequence set forth below:

MDTRAPTQLLGLLLLWLPGSTFAAVLTQTPSPVSAAVGGTVSISCQASQSVYDNNYLSWYQ QKPGQPPKLLIYGASTLASGVPSRFKGTGSGTQFTLTITDVQCDDAATYYCAGVFNDDSDD A (SEQ ID NO: 250).

The disclosure also includes antibodies having binding specificity to IL-6 and possessing a variable heavy chain sequence comprising the sequence set forth below:

METGLRWLLLVAVPKGVQCQSLEESGGRLVTPGTPLTLTCTLSGFSLSAYYMSWVRQAPG KGLEWIGFITLSDHISYARWAKGRFTISKTSTTVDLKMTSPTTEDTATYFCARSRGWGAMG RLDL (SEQ ID NO: 251).

The 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 complementaritydetermining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 251 , or combinations of these polypeptide sequences. In another embodiment of the disclosure, the antibodies of the disclosure include combinations of the CDRs and the variable heavy and light chain sequences set forth above.

In another embodiment, the disclosure contemplates other antibodies, such as for example chimeric 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 complementaritydetermining 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 combinations of these polypeptide sequences. In another embodiment of the disclosure, the antibodies of the disclosure include combinations of the CDRs and the variable heavy and light chain sequences set forth above.

The disclosure also contemplates fragments of the antibody having binding specificity to IL-6. In one embodiment of the disclosure, antibody fragments of the disclosure comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 250. In another embodiment of the disclosure, antibody fragments of the disclosure comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 251.

In a further embodiment of the disclosure, fragments of the antibody having binding specificity to 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 complementaritydetermining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 250.

In a further embodiment of the disclosure, fragments of the antibody having binding specificity to 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 complementaritydetermining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 251.

The disclosure also contemplates antibody fragments which include one or more of the antibody fragments described herein. In one embodiment of the disclosure, fragments of the antibodies having binding specificity to IL-6 comprise, or alternatively consist 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 complementaritydetermining regions (SEQ ID NO: 252; SEQ ID NO: 253; and SEQ ID NO: 254) of the variable light chain region of SEQ ID NO: 250; and the complementarity-determining regions (SEQ ID NO: 255; SEQ ID NO: 256; and SEQ ID NO: 257) of the variable heavy chain region of SEQ ID NO: 251. In one embodiment of the disclosure, the anti-IL-6 antibody is Ab16, comprising SEQ ID NO: 250 and SEQ ID NO: 251 , and having at least one of the biological activities set forth herein.

In another embodiment, the disclosure includes antibodies having binding specificity to IL-6 and possessing a variable light chain sequence comprising the sequence set forth below:

MDTRAPTQLLGLLLLWLPGATFAAVLTQTPSPVSAAVGGTVTISCQASQSVYNNKNLAWYQ QKSGQPPKLLIYWASTLASGVSSRFSGSGSGTQFTLTVSGVQCDDAATYYCLGVFDDDAD NA (SEQ ID NO: 266).

The disclosure also includes antibodies having binding specificity to IL-6 and possessing a variable heavy chain sequence comprising the sequence set forth below:

METGLRWLLLVAVLKGVQCQSVEESGGRLVTPGTPLTLTCTASGFSLSSYSMTWVRQAPG KGLEYIGVIGTSGSTYYATWAKGRFTISRTSTTVALKITSPTTEDTATYFCVRSLSSITFL (SEQ ID NO: 267).

The 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 complementaritydetermining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 267, or combinations of these polypeptide sequences. In another embodiment of the disclosure, the antibodies of the disclosure include combinations of the CDRs and the variable heavy and light chain sequences set forth above.

In another embodiment, the disclosure contemplates other antibodies, such as for example chimeric 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 complementaritydetermining 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 combinations of these polypeptide sequences. In another embodiment of the disclosure, the antibodies of the disclosure include combinations of the CDRs and the variable heavy and light chain sequences set forth above.

The disclosure also contemplates fragments of the antibody having binding specificity to IL-6. In one embodiment of the disclosure, antibody fragments of the disclosure comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 266. In another embodiment of the disclosure, antibody fragments of the disclosure comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 267.

In a further embodiment of the disclosure, fragments of the antibody having binding specificity to 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 complementaritydetermining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 266.

In a further embodiment of the disclosure, fragments of the antibody having binding specificity to 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 complementaritydetermining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 267.

The disclosure also contemplates antibody fragments which include one or more of the antibody fragments described herein. In one embodiment of the disclosure, fragments of the antibodies having binding specificity to IL-6 comprise, or alternatively consist 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 complementaritydetermining regions (SEQ ID NO: 268; SEQ ID NO: 269; and SEQ ID NO: 270) of the variable light chain region of SEQ ID NO: 266; and the complementarity-determining regions (SEQ ID NO: 271 ; SEQ ID NO: 272; and SEQ ID NO: 273) of the variable heavy chain region of SEQ ID NO: 267.

In one embodiment of the disclosure, the anti-IL-6 antibody is Ab17, comprising SEQ ID NO: 266 and SEQ ID NO: 267, and having at least one of the biological activities set forth herein.

In another embodiment, the disclosure includes antibodies having binding specificity to IL-6 and possessing a variable light chain sequence comprising the sequence set forth below:

MDTRAPTQLLGLLLLWLPGARCAFELTQTPASVEAAVGGTVTINCQASQNIYRYLAWYQQK PGQPPKFLIYLASTLASGVPSRFKGSGSGTEFTLTISDLECADAATYYCQSYYSSNSVA (SEQ ID NO: 282).

The disclosure also includes antibodies having binding specificity to IL-6 and possessing a variable heavy chain sequence comprising the sequence set forth below:

METGLRWLLLVAVLKGVQCQEQLVESGGDLVQPEGSLTLTCTASELDFSSGYWICWVRQV PGKGLEWIGCIYTGSSGSTFYASWAKGRFTISKTSSTTVTLQMTSLTAADTATYFCARGYS GFGYFKL (SEQ ID NO: 283). The 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 complementaritydetermining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 283, or combinations of these polypeptide sequences. In another embodiment of the disclosure, the antibodies of the disclosure include combinations of the CDRs and the variable heavy and light chain sequences set forth above.

In another embodiment, the disclosure contemplates other antibodies, such as for example chimeric 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 complementaritydetermining 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 combinations of these polypeptide sequences. In another embodiment of the disclosure, the antibodies of the disclosure include combinations of the CDRs and the variable heavy and light chain sequences set forth above.

The disclosure also contemplates fragments of the antibody having binding specificity to IL-6. In one embodiment of the disclosure, antibody fragments of the disclosure comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 282. In another embodiment of the disclosure, antibody fragments of the disclosure comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 283.

In a further embodiment of the disclosure, fragments of the antibody having binding specificity to 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 complementaritydetermining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 282.

In a further embodiment of the disclosure, fragments of the antibody having binding specificity to 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 complementaritydetermining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 283.

The disclosure also contemplates antibody fragments which include one or more of the antibody fragments described herein. In one embodiment of the disclosure, fragments of the antibodies having binding specificity to IL-6 comprise, or alternatively consist 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 complementaritydetermining regions (SEQ ID NO: 284; SEQ ID NO: 285; and SEQ ID NO: 286) of the variable light chain region of SEQ ID NO: 282; and the complementarity-determining regions (SEQ ID NO: 287; SEQ ID NO: 288; and SEQ ID NO: 289) of the variable heavy chain region of SEQ ID NO: 283.

In one embodiment of the 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 set forth herein.

In another embodiment, the disclosure includes antibodies having binding specificity to IL-6 and possessing a variable light chain sequence comprising the sequence set forth below:

MDTRAPTQLLGLLLLWLPGARCAYDMTQTPASVEVAVGGTVTIKCQASEDIYRLLAWYQQK PGQPPKLLIYDSSDLASGVPSRFKGSGSGTEFTLAISGVQCDDAATYYCQQAWSYSDIDNA (SEQ ID NO: 298).

The disclosure also includes antibodies having binding specificity to IL-6 and possessing a variable heavy chain sequence comprising the sequence set forth below:

METGLRWLLLVAVLKGVQCQSVEESGGRLVTPGTPLTLTCTASGFSLSSYYMSWVRQAPG KGLEWIGIITTSGNTFYASWAKGRLTISRTSTTVDLKITSPTTEDTATYFCARTSDIFYYRNL (SEQ ID NO: 299).

The 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 complementaritydetermining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 299, or combinations of these polypeptide sequences. In another embodiment of the disclosure, the antibodies of the disclosure include combinations of the CDRs and the variable heavy and light chain sequences set forth above.

In another embodiment, the disclosure contemplates other antibodies, such as for example chimeric 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 complementaritydetermining 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 combinations of these polypeptide sequences. In another embodiment of the disclosure, the antibodies of the disclosure include combinations of the CDRs and the variable heavy and light chain sequences set forth above.

The disclosure also contemplates fragments of the antibody having binding specificity to IL-6. In one embodiment of the disclosure, antibody fragments of the disclosure comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 298. In another embodiment of the disclosure, antibody fragments of the disclosure comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 299.

In a further embodiment of the disclosure, fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist 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 complementaritydetermining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 298.

In a further embodiment of the disclosure, fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist 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 complementaritydetermining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 299.

The disclosure also contemplates antibody fragments which include one or more of the antibody fragments described herein. In one embodiment of the disclosure, fragments of the antibodies having binding specificity to IL-6 comprise, or alternatively consist 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 complementaritydetermining regions (SEQ ID NO: 300; SEQ ID NO: 301 ; and SEQ ID NO: 302) of the variable light chain region of SEQ ID NO: 298; and the complementarity-determining regions (SEQ ID NO: 303; SEQ ID NO: 304; and SEQ ID NO: 305) of the variable heavy chain region of SEQ ID NO: 299.

In one embodiment of the 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 set forth herein.

In another embodiment, the disclosure includes antibodies having binding specificity to IL-6 and possessing a variable light chain sequence comprising the sequence set forth below:

MDTRAPTQLLGLLLLWLPGATFAAVLTQTASPVSAAVGATVTINCQSSQSVYNDMDLAWFQ QKPGQPPKLLIYSASTLASGVPSRFSGSGSGTEFTLTISGVQCDDAATYYCLGAFDDDADN T (SEQ ID NO: 314). The disclosure also includes antibodies having binding specificity to IL-6 and possessing a variable heavy chain sequence comprising the sequence set forth below:

METGLRWLLLVAVLKGVQCQSVEESGGRLVTPGTPLTLTCTVSGFSLTRHAITWVRQAPGK GLEWIGCIWSGGSTYYATWAKGRFTISKTSTTVDLRITSPTTEDTATYFCARVIGDTAGYAY FTGLDL (SEQ ID NO: 315).

The 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 complementaritydetermining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 315, or combinations of these polypeptide sequences. In another embodiment of the disclosure, the antibodies of the disclosure include combinations of the CDRs and the variable heavy and light chain sequences set forth above.

In another embodiment, the disclosure contemplates other antibodies, such as for example chimeric 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 complementaritydetermining 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 combinations of these polypeptide sequences. In another embodiment of the disclosure, the antibodies of the disclosure include combinations of the CDRs and the variable heavy and light chain sequences set forth above.

The disclosure also contemplates fragments of the antibody having binding specificity to IL-6. In one embodiment of the disclosure, antibody fragments of the disclosure comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 314. In another embodiment of the disclosure, antibody fragments of the disclosure comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 315.

In a further embodiment of the disclosure, fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist 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 complementaritydetermining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 314.

In a further embodiment of the disclosure, fragments of the antibody having binding specificity to 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 complementaritydetermining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 315.

The disclosure also contemplates antibody fragments which include one or more of the antibody fragments described herein. In one embodiment of the disclosure, fragments of the antibodies having binding specificity to IL-6 comprise, or alternatively consist 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 complementaritydetermining regions (SEQ ID NO: 316; SEQ ID NO: 317; and SEQ ID NO: 318) of the variable light chain region of SEQ ID NO: 314; and the complementarity-determining regions (SEQ ID NO: 319; SEQ ID NO: 320; and SEQ ID NO: 321) of the variable heavy chain region of SEQ ID NO: 315.

In one embodiment of the 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 set forth herein.

In another embodiment, the disclosure includes antibodies having binding specificity to IL-6 and possessing a variable light chain sequence comprising the sequence set forth below:

MDTRAPTQLLGLLLLWLPGARCAYDMTQTPASVEVAVGGTVTIKCQASQSVYNWLSWYQ QKPGQPPKLLIYTASSLASGVPSRFSGSGSGTEFTLTISGVECADAATYYCQQGYTSDVDN V (SEQ ID NO: 330).

The disclosure also includes antibodies having binding specificity to IL-6 and possessing a variable heavy chain sequence comprising the sequence set forth below:

METGLRWLLLVAVLKGVQCQSLEEAGGRLVTPGTPLTLTCTVSGIDLSSYAMGWVRQAPG KGLEYIGIISSSGSTYYATWAKGRFTISQASSTTVDLKITSPTTEDSATYFCARGGAGSGGV WLLDGFDP (SEQ ID NO: 331).

The 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 complementaritydetermining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 331 , or combinations of these polypeptide sequences. In another embodiment of the disclosure, the antibodies of the disclosure include combinations of the CDRs and the variable heavy and light chain sequences set forth above. In another embodiment, the disclosure contemplates other antibodies, such as for example chimeric 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 complementaritydetermining 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 combinations of these polypeptide sequences. In another embodiment of the disclosure, the antibodies of the disclosure include combinations of the CDRs and the variable heavy and light chain sequences set forth above.

The disclosure also contemplates fragments of the antibody having binding specificity to IL-6. In one embodiment of the disclosure, antibody fragments of the disclosure comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 330. In another embodiment of the disclosure, antibody fragments of the disclosure comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 331.

In a further embodiment of the disclosure, fragments of the antibody having binding specificity to 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 complementaritydetermining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 330.

In a further embodiment of the disclosure, fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist 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 complementaritydetermining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 331.

The disclosure also contemplates antibody fragments which include one or more of the antibody fragments described herein. In one embodiment of the disclosure, fragments of the antibodies having binding specificity to IL-6 comprise, or alternatively consist 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 complementaritydetermining regions (SEQ ID NO: 332; SEQ ID NO: 333; and SEQ ID NO: 334) of the variable light chain region of SEQ ID NO: 330; and the complementarity-determining regions (SEQ ID NO: 335; SEQ ID NO: 336; and SEQ ID NO: 337) of the variable heavy chain region of SEQ ID NO: 331.

In one embodiment of the 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 set forth herein. In another embodiment, the disclosure includes antibodies having binding specificity to IL-6 and possessing a variable light chain sequence comprising the sequence set forth below:

MDTRAPTQLLGLLLLWLPGAKCADVVMTQTPASVSAAVGGTVTINCQASENIYNWLAWYQ QKPGQPPKLLIYTVGDLASGVSSRFKGSGSGTEFTLTISDLECADAATYYCQQGYSSSYVD NV (SEQ ID NO: 346).

The disclosure also includes antibodies having binding specificity to IL-6 and possessing a variable heavy chain sequence comprising the sequence set forth below:

METGLRWLLLVAVLKGVQCQEQLKESGGRLVTPGTPLTLTCTVSGFSLNDYAVGWFRQAP GKGLEWIGYIRSSGTTAYATWAKGRFTISATSTTVDLKITSPTTEDTATYFCARGGAGSSGV WILDGFAP (SEQ ID NO: 347).

The 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 complementaritydetermining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 347, or combinations of these polypeptide sequences. In another embodiment of the disclosure, the antibodies of the disclosure include combinations of the CDRs and the variable heavy and light chain sequences set forth above.

In another embodiment, the disclosure contemplates other antibodies, such as for example chimeric 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 complementaritydetermining 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 combinations of these polypeptide sequences. In another embodiment of the disclosure, the antibodies of the disclosure include combinations of the CDRs and the variable heavy and light chain sequences set forth above.

The disclosure also contemplates fragments of the antibody having binding specificity to IL-6. In one embodiment of the disclosure, antibody fragments of the disclosure comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 346. In another embodiment of the disclosure, antibody fragments of the disclosure comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 347. In a further embodiment of the disclosure, fragments of the antibody having binding specificity to 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 complementaritydetermining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 346.

In a further embodiment of the disclosure, fragments of the antibody having binding specificity to 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 complementaritydetermining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 347.

The disclosure also contemplates antibody fragments which include one or more of the antibody fragments described herein. In one embodiment of the disclosure, fragments of the antibodies having binding specificity to IL-6 comprise, or alternatively consist 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 complementaritydetermining regions (SEQ ID NO: 348; SEQ ID NO: 349; and SEQ ID NO: 350) of the variable light chain region of SEQ ID NO: 346; and the complementarity-determining regions (SEQ ID NO: 351 ; SEQ ID NO: 352; and SEQ ID NO: 353) of the variable heavy chain region of SEQ ID NO: 347.

In one embodiment of the 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 set forth herein.

In another embodiment, the disclosure includes antibodies having binding specificity to IL-6 and possessing a variable light chain sequence comprising the sequence set forth below:

MDTRAPTQLLGLLLLWLPGATFAQVLTQTPSSVSAAVGGTVTINCQASQSVYQNNYLSWF QQKPGQPPKLLIYGAATLASGVPSRFKGSGSGTQFTLTISDLECDDAATYYCAGAYRDVDS (SEQ ID NO: 362).

The disclosure also includes antibodies having binding specificity to IL-6 and possessing a variable heavy chain sequence comprising the sequence set forth below:

METGLRWLLLVAVLKGVQCQSLEESGGDLVKPGASLTLTCTASGFSFTSTYYIYWVRQAPG KGLEWIACIDAGSSGSTYYATWVNGRFTISKTSSTTVTLQMTSLTAADTATYFCAKWDYGG NVGWGYDL (SEQ ID NO: 363).

The 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 complementaritydetermining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 363, or combinations of these polypeptide sequences. In another embodiment of the disclosure, the antibodies of the disclosure include combinations of the CDRs and the variable heavy and light chain sequences set forth above.

In another embodiment, the disclosure contemplates other antibodies, such as for example chimeric 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 complementaritydetermining 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 combinations of these polypeptide sequences. In another embodiment of the disclosure, the antibodies of the disclosure include combinations of the CDRs and the variable heavy and light chain sequences set forth above.

The disclosure also contemplates fragments of the antibody having binding specificity to IL-6. In one embodiment of the disclosure, antibody fragments of the disclosure comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 362. In another embodiment of the disclosure, antibody fragments of the disclosure comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 363.

In a further embodiment of the disclosure, fragments of the antibody having binding specificity to 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 complementaritydetermining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 362.

In a further embodiment of the disclosure, fragments of the antibody having binding specificity to 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 complementaritydetermining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 363.

The disclosure also contemplates antibody fragments which include one or more of the antibody fragments described herein. In one embodiment of the disclosure, fragments of the antibodies having binding specificity to IL-6 comprise, or alternatively consist 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 complementaritydetermining regions (SEQ ID NO: 364; SEQ ID NO: 365; and SEQ ID NO: 366) of the variable light chain region of SEQ ID NO: 362; and the complementarity-determining regions (SEQ ID NO: 367; SEQ ID NO: 368; and SEQ ID NO: 369) of the variable heavy chain region of SEQ ID NO: 363.

In one embodiment of the 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 set forth herein.

In another embodiment, the disclosure includes antibodies having binding specificity to IL-6 and possessing a variable light chain sequence comprising the sequence set forth below:

MDTRAPTQLLGLLLLWLPGARCAFELTQTPSSVEAAVGGTVTIKCQASQSISSYLAWYQQK PGQPPKFLIYRASTLASGVPSRFKGSGSGTEFTLTISDLECADAATYYCQSYYDSVSNP (SEQ ID NO: 378).

The disclosure also includes antibodies having binding specificity to IL-6 and possessing a variable heavy chain sequence comprising the sequence set forth below:

METGLRWLLLVAVLKGVQCQSLEESGGDLVKPEGSLTLTCKASGLDLGTYWFMCWVRQA PGKGLEWIACIYTGSSGSTFYASWVNGRFTISKTSSTTVTLQMTSLTAADTATYFCARGYSG YGYFKL (SEQ ID NO: 379).

The 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 complementaritydetermining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 379, or combinations of these polypeptide sequences. In another embodiment of the disclosure, the antibodies of the disclosure include combinations of the CDRs and the variable heavy and light chain sequences set forth above.

In another embodiment, the disclosure contemplates other antibodies, such as for example chimeric 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 complementaritydetermining 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 combinations of these polypeptide sequences. In another embodiment of the disclosure, the antibodies of the disclosure include combinations of the CDRs and the variable heavy and light chain sequences set forth above. The disclosure also contemplates fragments of the antibody having binding specificity to IL-6. In one embodiment of the disclosure, antibody fragments of the disclosure comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 378. In another embodiment of the disclosure, antibody fragments of the disclosure comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 379.

In a further embodiment of the disclosure, fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist 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 complementaritydetermining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 378.

In a further embodiment of the disclosure, fragments of the antibody having binding specificity to 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 complementaritydetermining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 379.

The disclosure also contemplates antibody fragments which include one or more of the antibody fragments described herein. In one embodiment of the disclosure, fragments of the antibodies having binding specificity to IL-6 comprise, or alternatively consist 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 complementaritydetermining regions (SEQ ID NO: 380; SEQ ID NO: 381 ; and SEQ ID NO: 382) of the variable light chain region of SEQ ID NO: 378; and the complementarity-determining regions (SEQ ID NO: 383; SEQ ID NO: 384; and SEQ ID NO: 385) of the variable heavy chain region of SEQ ID NO: 379.

In one embodiment of the 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 set forth herein.

In another embodiment, the disclosure includes antibodies having binding specificity to IL-6 and possessing a variable light chain sequence comprising the sequence set forth below:

MDTRAPTQLLGLLLLWLPGVTFAIEMTQSPFSVSAAVGGTVSISCQASQSVYKNNQLSWYQ QKSGQPPKLLIYGASALASGVPSRFKGSGSGTEFTLTISDVQCDDAATYYCAGAITGSIDTD G (SEQ ID NO: 394).

The disclosure also includes antibodies having binding specificity to IL-6 and possessing a variable heavy chain sequence comprising the sequence set forth below: METGLRWLLLVAVLKGVQCQSLEESGGDLVKPGASLTLTCTTSGFSFSSSYFICWVRQAPG KGLEWIACIYGGDGSTYYASWAKGRFTISKTSSTTVTLQMTSLTAADTATYFCAREWAYSQ GYFGAFDL (SEQ ID NO: 395).

The 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 complementaritydetermining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 395, or combinations of these polypeptide sequences. In another embodiment of the disclosure, the antibodies of the disclosure include combinations of the CDRs and the variable heavy and light chain sequences set forth above.

In another embodiment, the disclosure contemplates other antibodies, such as for example chimeric 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 complementaritydetermining 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 combinations of these polypeptide sequences. In another embodiment of the disclosure, the antibodies of the disclosure include combinations of the CDRs and the variable heavy and light chain sequences set forth above.

The disclosure also contemplates fragments of the antibody having binding specificity to IL-6. In one embodiment of the disclosure, antibody fragments of the disclosure comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 394. In another embodiment of the disclosure, antibody fragments of the disclosure comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 395.

In a further embodiment of the disclosure, fragments of the antibody having binding specificity to 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 complementaritydetermining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 394.

In a further embodiment of the disclosure, fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist 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 complementaritydetermining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 395. The disclosure also contemplates antibody fragments which include one or more of the antibody fragments described herein. In one embodiment of the disclosure, fragments of the antibodies having binding specificity to IL-6 comprise, or alternatively consist 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 complementaritydetermining regions (SEQ ID NO: 396; SEQ ID NO: 397; and SEQ ID NO: 398) of the variable light chain region of SEQ ID NO: 394; and the complementarity-determining regions (SEQ ID NO: 399; SEQ ID NO: 400; and SEQ ID NO: 401) of the variable heavy chain region of SEQ ID NO: 395.

In one embodiment of the 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 set forth herein.

In another embodiment, the disclosure includes antibodies having binding specificity to IL-6 and possessing a variable light chain sequence comprising the sequence set forth below:

MDTRAPTQLLGLLLLWLPGARCDVVMTQTPASVEAAVGGTVTIKCQASEDISSYLAWYQQK PGQPPKLLIYAASNLESGVSSRFKGSGSGTEYTLTISDLECADAATYYCQCTYGTISISDGNA (SEQ ID NO: 410).

The disclosure also includes antibodies having binding specificity to IL-6 and possessing a variable heavy chain sequence comprising the sequence set forth below:

METGLRWLLLVAVLKGVQCQSVEESGGRLVTPGTPLTLTCTVSGFSLSSYFMTWVRQAPG EGLEYIGFINPGGSAYYASWVKGRFTISKSSTTVDLKITSPTTEDTATYFCARVLIVSYGAFTI (SEQ ID NO: 411).

The 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 complementaritydetermining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 411 , or combinations of these polypeptide sequences. In another embodiment of the disclosure, the antibodies of the disclosure include combinations of the CDRs and the variable heavy and light chain sequences set forth above.

In another embodiment, the disclosure contemplates other antibodies, such as for example chimeric 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 complementaritydetermining 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 combinations of these polypeptide sequences. In another embodiment of the disclosure, the antibodies of the disclosure include combinations of the CDRs and the variable heavy and light chain sequences set forth above.

The disclosure also contemplates fragments of the antibody having binding specificity to IL-6. In one embodiment of the disclosure, antibody fragments of the disclosure comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 410. In another embodiment of the disclosure, antibody fragments of the disclosure comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 411 .

In a further embodiment of the disclosure, fragments of the antibody having binding specificity to 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 complementaritydetermining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 410.

In a further embodiment of the disclosure, fragments of the antibody having binding specificity to 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 complementaritydetermining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 411.

The disclosure also contemplates antibody fragments which include one or more of the antibody fragments described herein. In one embodiment of the disclosure, fragments of the antibodies having binding specificity to IL-6 comprise, or alternatively consist 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 complementaritydetermining regions (SEQ ID NO: 412; SEQ ID NO: 413; and SEQ ID NO: 414) of the variable light chain region of SEQ ID NO: 410; and the complementarity-determining regions (SEQ ID NO: 415; SEQ ID NO: 416; and SEQ ID NO: 417) of the variable heavy chain region of SEQ ID NO: 411.

In one embodiment of the disclosure, the anti-IL-6 antibody is Ab26, comprising SEQ ID NO: 410 and SEQ ID NO: 41 1 , and having at least one of the biological activities set forth herein.

In another embodiment, the disclosure includes antibodies having binding specificity to IL-6 and possessing a variable light chain sequence comprising the sequence set forth below: MDTRAPTQLLGLLLLWLPGARCDVVMTQTPASVSAAVGGTVTIKCQASEDIESYLAWYQQK PGQPPKLLIYGASNLESGVSSRFKGSGSGTEFTLTISDLECADAATYYCQCTYGIISISDGNA (SEQ ID NO: 426).

The disclosure also includes antibodies having binding specificity to IL-6 and possessing a variable heavy chain sequence comprising the sequence set forth below:

METGLRWLLLVAVLKGVQCQSVEESGGRLVTPGTPLTLTCTVSGFSLSSYFMTWVRQAPG EGLEYIGFMNTGDNAYYASWAKGRFTISKTSTTVDLKITSPTTEDTATYFCARVLVVAYGAF Nl (SEQ ID NO: 427).

The 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 complementaritydetermining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 427, or combinations of these polypeptide sequences. In another embodiment of the disclosure, the antibodies of the disclosure include combinations of the CDRs and the variable heavy and light chain sequences set forth above.

In another embodiment, the disclosure contemplates other antibodies, such as for example chimeric 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 complementaritydetermining 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 combinations of these polypeptide sequences. In another embodiment of the disclosure, the antibodies of the disclosure include combinations of the CDRs and the variable heavy and light chain sequences set forth above.

The disclosure also contemplates fragments of the antibody having binding specificity to IL-6. In one embodiment of the disclosure, antibody fragments of the disclosure comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 426. In another embodiment of the disclosure, antibody fragments of the disclosure comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 427.

In a further embodiment of the disclosure, fragments of the antibody having binding specificity to 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.

In a further embodiment of the disclosure, fragments of the antibody having binding specificity to 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 complementaritydetermining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 427.

The disclosure also contemplates antibody fragments which include one or more of the antibody fragments described herein. In one embodiment of the disclosure, fragments of the antibodies having binding specificity to IL-6 comprise, or alternatively consist 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 complementaritydetermining regions (SEQ ID NO: 428; SEQ ID NO: 429; and SEQ ID NO: 430) of the variable light chain region of SEQ ID NO: 426; and the complementarity-determining regions (SEQ ID NO: 431 ; SEQ ID NO: 432; and SEQ ID NO: 433) of the variable heavy chain region of SEQ ID NO: 427.

In one embodiment of the disclosure, the anti-IL-6 antibody is Ab27, comprising SEQ ID NO: 426 and SEQ ID NO: 427, and having at least one of the biological activities set forth herein.

In another embodiment, the disclosure includes antibodies having binding specificity to IL-6 and possessing a variable light chain sequence comprising the sequence set forth below:

MDTRAPTQLLGLLLLWLPGATFAAVLTQTPSPVSEPVGGTVSISCQSSKSVMNNNYLAWYQ QKPGQPPKLLIYGASNLASGVPSRFSGSGSGTQFTLTISDVQCDDAATYYCQGGYTGYSD HGT (SEQ ID NO: 442).

The disclosure also includes antibodies having binding specificity to IL-6 and possessing a variable heavy chain sequence comprising the sequence set forth below:

METGLRWLLLVAVLKGVQCQSVEESGGRLVKPDETLTLTCTVSGIDLSSYPMNWVRQAPG KGLEWIGFINTGGTIVYASWAKGRFTISKTSTTVDLKMTSPTTEDTATYFCARGSYVSSGYA YYFNV (SEQ ID NO: 443).

The 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 complementaritydetermining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 443, or combinations of these polypeptide sequences. In another embodiment of the disclosure, the antibodies of the disclosure include combinations of the CDRs and the variable heavy and light chain sequences set forth above.

In another embodiment, the disclosure contemplates other antibodies, such as for example chimeric 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 complementaritydetermining 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 combinations of these polypeptide sequences. In another embodiment of the disclosure, the antibodies of the disclosure include combinations of the CDRs and the variable heavy and light chain sequences set forth above.

The disclosure also contemplates fragments of the antibody having binding specificity to IL-6. In one embodiment of the disclosure, antibody fragments of the disclosure comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 442. In another embodiment of the disclosure, antibody fragments of the disclosure comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 443.

In a further embodiment of the disclosure, fragments of the antibody having binding specificity to 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 complementaritydetermining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 442.

In a further embodiment of the disclosure, fragments of the antibody having binding specificity to 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 complementaritydetermining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 443.

The disclosure also contemplates antibody fragments which include one or more of the antibody fragments described herein. In one embodiment of the disclosure, fragments of the antibodies having binding specificity to IL-6 comprise, or alternatively consist 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 complementaritydetermining regions (SEQ ID NO: 444; SEQ ID NO: 445; and SEQ ID NO: 446) of the variable light chain region of SEQ ID NO: 442; and the complementarity-determining regions (SEQ ID NO: 447; SEQ ID NO: 448; and SEQ ID NO: 449) of the variable heavy chain region of SEQ ID NO: 443. In one embodiment of the 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 set forth herein.

In another embodiment, the disclosure includes antibodies having binding specificity to IL-6 and possessing a variable light chain sequence comprising the sequence set forth below:

MDTRAPTQLLGLLLLWLPGATFAAVLTQTPSPVSAAVGGTVSISCQSSQSVYNNNWLSWF QQKPGQPPKLLIYKASTLASGVPSRFKGSGSGTQFTLTISDVQCDDVATYYCAGGYLDSVI (SEQ ID NO: 458).

The disclosure also includes antibodies having binding specificity to IL-6 and possessing a variable heavy chain sequence comprising the sequence set forth below:

METGLRWLLLVAVLKGVQCQSVEESGGRLVTPGTPLTLTCTVSGFSLSTYSINWVRQAPGK GLEWIGIIANSGTTFYANWAKGRFTVSKTSTTVDLKITSPTTEDTATYFCARESGMYNEYGK FNI (SEQ ID NO: 459).

The 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 complementaritydetermining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 459, or combinations of these polypeptide sequences. In another embodiment of the disclosure, the antibodies of the disclosure include combinations of the CDRs and the variable heavy and light chain sequences set forth above.

In another embodiment, the disclosure contemplates other antibodies, such as for example chimeric 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 complementaritydetermining 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 combinations of these polypeptide sequences. In another embodiment of the disclosure, the antibodies of the disclosure include combinations of the CDRs and the variable heavy and light chain sequences set forth above.

The disclosure also contemplates fragments of the antibody having binding specificity to IL-6. In one embodiment of the disclosure, antibody fragments of the disclosure comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 458. In another embodiment of the disclosure, antibody fragments of the disclosure comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 459.

In a further embodiment of the disclosure, fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist 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 complementaritydetermining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 458.

In a further embodiment of the disclosure, fragments of the antibody having binding specificity to 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 complementaritydetermining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 459.

The disclosure also contemplates antibody fragments which include one or more of the antibody fragments described herein. In one embodiment of the disclosure, fragments of the antibodies having binding specificity to IL-6 comprise, or alternatively consist 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 complementaritydetermining regions (SEQ ID NO: 460; SEQ ID NO: 461 ; and SEQ ID NO: 462) of the variable light chain region of SEQ ID NO: 458; and the complementarity-determining regions (SEQ ID NO: 463; SEQ ID NO: 464; and SEQ ID NO: 465) of the variable heavy chain region of SEQ ID NO: 459.

In one embodiment of the 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 set forth herein.

In another embodiment, the disclosure includes antibodies having binding specificity to IL-6 and possessing a variable light chain sequence comprising the sequence set forth below:

MDTRAPTQLLGLLLLWLPGARCASDMTQTPSSVSAAVGGTVTINCQASENIYSFLAWYQQK PGQPPKLLIFKASTLASGVSSRFKGSGSGTQFTLTISDLECDDAATYYCQQGATVYDIDNN (SEQ ID NO: 474).

The disclosure also includes antibodies having binding specificity to IL-6 and possessing a variable heavy chain sequence comprising the sequence set forth below:

METGLRWLLLVAVLKGVQCQSLEESGGRLVTPGTPLTLTCTVSGIDLSAYAMIWVRQAPGE GLEWITIIYPNGITYYANWAKGRFTVSKTSTAMDLKITSPTTEDTATYFCARDAESSKNAYW GYFNV (SEQ ID NO: 475). The 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 complementaritydetermining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 475, or combinations of these polypeptide sequences. In another embodiment of the disclosure, the antibodies of the disclosure include combinations of the CDRs and the variable heavy and light chain sequences set forth above.

In another embodiment, the disclosure contemplates other antibodies, such as for example chimeric 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 complementaritydetermining 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 combinations of these polypeptide sequences. In another embodiment of the disclosure, the antibodies of the disclosure include combinations of the CDRs and the variable heavy and light chain sequences set forth above.

The disclosure also contemplates fragments of the antibody having binding specificity to IL-6. In one embodiment of the disclosure, antibody fragments of the disclosure comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 474. In another embodiment of the disclosure, antibody fragments of the disclosure comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 475.

In a further embodiment of the disclosure, fragments of the antibody having binding specificity to 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 complementaritydetermining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 474.

In a further embodiment of the disclosure, fragments of the antibody having binding specificity to 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 complementaritydetermining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 475.

The disclosure also contemplates antibody fragments which include one or more of the antibody fragments described herein. In one embodiment of the disclosure, fragments of the antibodies having binding specificity to IL-6 comprise, or alternatively consist 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 complementaritydetermining regions (SEQ ID NO: 476; SEQ ID NO: 477; and SEQ ID NO: 478) of the variable light chain region of SEQ ID NO: 474; and the complementarity-determining regions (SEQ ID NO: 479; SEQ ID NO: 480; and SEQ ID NO: 481) of the variable heavy chain region of SEQ ID NO: 475.

In one embodiment of the 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 set forth herein.

In another embodiment, the disclosure includes antibodies having binding specificity to IL-6 and possessing a variable light chain sequence comprising the sequence set forth below:

MDTRAPTQLLGLLLLWLPGARCASDMTQTPSSVSAAVGGTVTINCQASENIYSFLAWYQQK PGQPPKLLIFRASTLASGVSSRFKGSGSGTQFTLTISDLECDDAATYYCQQGATVYDIDNN (SEQ ID NO: 490).

The disclosure also includes antibodies having binding specificity to IL-6 and possessing a variable heavy chain sequence comprising the sequence set forth below:

METGLRWLLLVAVLKGVQCQSLEESGGRLVTPGTPLTLTCTVSGIDLSAYAMIWVRQAPGE GLEWITIIYPNGITYYANWAKGRFTVSKTSTAMDLKITSPTTEDTATYFCARDAESSKNAYW GYFNV (SEQ ID NO: 491).

The 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 complementaritydetermining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 491 , or combinations of these polypeptide sequences. In another embodiment of the disclosure, the antibodies of the disclosure include combinations of the CDRs and the variable heavy and light chain sequences set forth above.

In another embodiment, the disclosure contemplates other antibodies, such as for example chimeric 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 complementaritydetermining 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 combinations of these polypeptide sequences. In another embodiment of the disclosure, the antibodies of the disclosure include combinations of the CDRs and the variable heavy and light chain sequences set forth above.

The disclosure also contemplates fragments of the antibody having binding specificity to IL-6. In one embodiment of the disclosure, antibody fragments of the disclosure comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 490. In another embodiment of the disclosure, antibody fragments of the disclosure comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 491.

In a further embodiment of the disclosure, fragments of the antibody having binding specificity to 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 complementaritydetermining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 490.

In a further embodiment of the disclosure, fragments of the antibody having binding specificity to 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 complementaritydetermining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 491.

The disclosure also contemplates antibody fragments which include one or more of the antibody fragments described herein. In one embodiment of the disclosure, fragments of the antibodies having binding specificity to IL-6 comprise, or alternatively consist 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 complementaritydetermining regions (SEQ ID NO: 492; SEQ ID NO: 493; and SEQ ID NO: 494) of the variable light chain region of SEQ ID NO: 490; and the complementarity-determining regions (SEQ ID NO: 495; SEQ ID NO: 496; and SEQ ID NO: 497) of the variable heavy chain region of SEQ ID NO: 491.

In one embodiment of the 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 set forth herein.

In another embodiment, the disclosure includes antibodies having binding specificity to IL-6 and possessing a variable light chain sequence comprising the sequence set forth below:

MDTRAPTQLLGLLLLWLPGATFAIEMTQTPSPVSAAVGGTVTINCQASESVFNNMLSWYQQ KPGHSPKLLIYDASDLASGVPSRFKGSGSGTQFTLTISGVECDDAATYYCAGYKSDSNDGD NV (SEQ ID NO: 506). The disclosure also includes antibodies having binding specificity to IL-6 and possessing a variable heavy chain sequence comprising the sequence set forth below:

METGLRWLLLVAVLKGVQCQSLEESGGRLVTPGTPLTLTCTVSGFSLNRNSITWVRQAPGE GLEWIGIITGSGRTYYANWAKGRFTISKTSTTVDLKMTSPTTEDTATYFCARGHPGLGSGNI (SEQ ID NO: 507).

The 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 complementaritydetermining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 507, or combinations of these polypeptide sequences. In another embodiment of the disclosure, the antibodies of the disclosure include combinations of the CDRs and the variable heavy and light chain sequences set forth above.

In another embodiment, the disclosure contemplates other antibodies, such as for example chimeric 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 complementaritydetermining 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 combinations of these polypeptide sequences. In another embodiment of the disclosure, the antibodies of the disclosure include combinations of the CDRs and the variable heavy and light chain sequences set forth above.

The disclosure also contemplates fragments of the antibody having binding specificity to IL-6. In one embodiment of the disclosure, antibody fragments of the disclosure comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 506. In another embodiment of the disclosure, antibody fragments of the disclosure comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 507.

In a further embodiment of the disclosure, fragments of the antibody having binding specificity to 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 complementaritydetermining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 506.

In a further embodiment of the disclosure, fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist 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 complementaritydetermining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 507.

The disclosure also contemplates antibody fragments which include one or more of the antibody fragments described herein. In one embodiment of the disclosure, fragments of the antibodies having binding specificity to IL-6 comprise, or alternatively consist 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 complementaritydetermining regions (SEQ ID NO: 508; SEQ ID NO: 509; and SEQ ID NO: 510) of the variable light chain region of SEQ ID NO: 506; and the complementarity-determining regions (SEQ ID NO: 511 ; SEQ ID NO: 512; and SEQ ID NO: 513) of the variable heavy chain region of SEQ ID NO: 507.

In one embodiment of the 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 set forth herein.

In another embodiment, the disclosure includes antibodies having binding specificity to IL-6 and possessing a variable light chain sequence comprising the sequence set forth below:

MDTRAPTQLLGLLLLWLPGATFAQVLTQTASSVSAAVGGTVTINCQSSQSVYNNYLSWYQ QKPGQPPKLLIYTASSLASGVPSRFKGSGSGTQFTLTISEVQCDDAATYYCQGYYSGPIIT (SEQ ID NO: 522).

The disclosure also includes antibodies having binding specificity to IL-6 and possessing a variable heavy chain sequence comprising the sequence set forth below:

METGLRWLLLVAVLKGVQCQSLEESGGRLVTPGTPLTLTCTASGFSLNNYYIQWVRQAPG EGLEWIGIIYAGGSAYYATWANGRFTIAKTSSTTVDLKMTSLTTEDTATYFCARGTFDGYEL (SEQ ID NO: 523).

The 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 complementaritydetermining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 523, or combinations of these polypeptide sequences. In another embodiment of the disclosure, the antibodies of the disclosure include combinations of the CDRs and the variable heavy and light chain sequences set forth above. In another embodiment, the disclosure contemplates other antibodies, such as for example chimeric 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 complementaritydetermining 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 combinations of these polypeptide sequences. In another embodiment of the disclosure, the antibodies of the disclosure include combinations of the CDRs and the variable heavy and light chain sequences set forth above.

The disclosure also contemplates fragments of the antibody having binding specificity to IL-6. In one embodiment of the disclosure, antibody fragments of the disclosure comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 522. In another embodiment of the disclosure, antibody fragments of the disclosure comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 523.

In a further embodiment of the disclosure, fragments of the antibody having binding specificity to 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 complementaritydetermining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 522.

In a further embodiment of the disclosure, fragments of the antibody having binding specificity to 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 complementaritydetermining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 523.

The disclosure also contemplates antibody fragments which include one or more of the antibody fragments described herein. In one embodiment of the disclosure, fragments of the antibodies having binding specificity to IL-6 comprise, or alternatively consist 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 complementaritydetermining regions (SEQ ID NO: 524; SEQ ID NO: 525; and SEQ ID NO: 526) of the variable light chain region of SEQ ID NO: 522; and the complementarity-determining regions (SEQ ID NO: 527; SEQ ID NO: 528; and SEQ ID NO: 529) of the variable heavy chain region of SEQ ID NO: 523.

In one embodiment of the 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 set forth herein. In another embodiment, the disclosure includes antibodies having binding specificity to IL-6 and possessing a variable light chain sequence comprising the sequence set forth below:

MDTRAPTQLLGLLLLWLPGATFAQVLTQTPSPVSVPVGDTVTISCQSSESVYSNNLLSWYQ QKPGQPPKLLIYRASNLASGVPSRFKGSGSGTQFTLTISGAQCDDAATYYCQGYYSGVINS (SEQ ID NO: 538).

The disclosure also includes antibodies having binding specificity to IL-6 and possessing a variable heavy chain sequence comprising the sequence set forth below:

METGLRWLLLVAVLKGVQCQSVEESGGRLVTPGTPLTLTCTVSGFSLSSYFMSWVRQAPG EGLEYIGFINPGGSAYYASWASGRLTISKTSTTVDLKITSPTTEDTATYFCARILIVSYGAFTI (SEQ ID NO: 539).

The 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 complementaritydetermining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 539, or combinations of these polypeptide sequences. In another embodiment of the disclosure, the antibodies of the disclosure include combinations of the CDRs and the variable heavy and light chain sequences set forth above.

In another embodiment, the disclosure contemplates other antibodies, such as for example chimeric 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 complementaritydetermining 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 combinations of these polypeptide sequences. In another embodiment of the disclosure, the antibodies of the disclosure include combinations of the CDRs and the variable heavy and light chain sequences set forth above.

The disclosure also contemplates fragments of the antibody having binding specificity to IL-6. In one embodiment of the disclosure, antibody fragments of the disclosure comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 538. In another embodiment of the disclosure, antibody fragments of the disclosure comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 539. In a further embodiment of the disclosure, fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist 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 complementaritydetermining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 538.

In a further embodiment of the disclosure, fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist 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 complementaritydetermining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 539.

The disclosure also contemplates antibody fragments which include one or more of the antibody fragments described herein. In one embodiment of the disclosure, fragments of the antibodies having binding specificity to IL-6 comprise, or alternatively consist 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 complementaritydetermining regions (SEQ ID NO: 540; SEQ ID NO: 541 ; and SEQ ID NO: 542) of the variable light chain region of SEQ ID NO: 538; and the complementarity-determining regions (SEQ ID NO: 543; SEQ ID NO: 544; and SEQ ID NO: 545) of the variable heavy chain region of SEQ ID NO: 539.

In one embodiment of the 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 set forth herein.

In another embodiment, the disclosure includes antibodies having binding specificity to IL-6 and possessing a variable light chain sequence comprising the sequence set forth below:

MDTRAPTQLLGLLLLWLPGARCAYDMTQTPASVEVAVGGTVTIKCQATESIGNELSWYQQK PGQAPKLLIYSASTLASGVPSRFKGSGSGTQFTLTITGVECDDAATYYCQQGYSSANIDNA (SEQ ID NO: 554).

The disclosure also includes antibodies having binding specificity to IL-6 and possessing a variable heavy chain sequence comprising the sequence set forth below:

METGLRWLLLVAVLKGVQCQSLEESGGRLVTPGTPLTLTCTVSGFSLSKYYMSWVRQAPE KGLKYIGYIDSTTVNTYYATWARGRFTISKTSTTVDLKITSPTSEDTATYFCARGSTYFTDGG HRLDL (SEQ ID NO: 555).

The 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 complementaritydetermining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 555, or combinations of these polypeptide sequences. In another embodiment of the disclosure, the antibodies of the disclosure include combinations of the CDRs and the variable heavy and light chain sequences set forth above.

In another embodiment, the disclosure contemplates other antibodies, such as for example chimeric 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 complementaritydetermining 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 combinations of these polypeptide sequences. In another embodiment of the disclosure, the antibodies of the disclosure include combinations of the CDRs and the variable heavy and light chain sequences set forth above.

The disclosure also contemplates fragments of the antibody having binding specificity to IL-6. In one embodiment of the disclosure, antibody fragments of the disclosure comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 554. In another embodiment of the disclosure, antibody fragments of the disclosure comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 555.

In a further embodiment of the disclosure, fragments of the antibody having binding specificity to 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 complementaritydetermining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 554.

In a further embodiment of the disclosure, fragments of the antibody having binding specificity to 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 complementaritydetermining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 555.

The disclosure also contemplates antibody fragments which include one or more of the antibody fragments described herein. In one embodiment of the disclosure, fragments of the antibodies having binding specificity to IL-6 comprise, or alternatively consist 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 complementaritydetermining regions (SEQ ID NO: 556; SEQ ID NO: 557; and SEQ ID NO: 558) of the variable light chain region of SEQ ID NO: 554; and the complementarity-determining regions (SEQ ID NO: 559; SEQ ID NO: 560; and SEQ ID NO: 561) of the variable heavy chain region of SEQ ID NO: 555.

In one embodiment of the 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 set forth herein.

In another embodiment, the disclosure includes antibodies having binding specificity to IL-6 and possessing a variable light chain sequence comprising the sequence set forth below:

MDTRAPTQLLGLLLLWLPGARCAYDMTQTPASVEVAVGGTVTIKCQATESIGNELSWYQQK PGQAPKLLIYSASTLASGVPSRFKGSGSGTQFTLTITGVECDDAATYYCQQGYSSANIDNA (SEQ ID NO: 570).

The disclosure also includes antibodies having binding specificity to IL-6 and possessing a variable heavy chain sequence comprising the sequence set forth below:

METGLRWLLLVAVLKGVQCQSLEESGGRLVTPGTPLTLTCTVSGFSLSTYNMGWVRQAPG KGLEWIGSITIDGRTYYASWAKGRFTVSKSSTTVDLKMTSLTTGDTATYFCARILIVSYGAFTI (SEQ ID NO: 571).

The 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 complementaritydetermining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 571 , or combinations of these polypeptide sequences. In another embodiment of the disclosure, the antibodies of the disclosure include combinations of the CDRs and the variable heavy and light chain sequences set forth above.

In another embodiment, the disclosure contemplates other antibodies, such as for example chimeric 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 complementaritydetermining 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 combinations of these polypeptide sequences. In another embodiment of the disclosure, the antibodies of the disclosure include combinations of the CDRs and the variable heavy and light chain sequences set forth above. The disclosure also contemplates fragments of the antibody having binding specificity to IL-6. In one embodiment of the disclosure, antibody fragments of the disclosure comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 570. In another embodiment of the disclosure, antibody fragments of the disclosure comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 571.

In a further embodiment of the disclosure, fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist 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 complementaritydetermining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 570.

In a further embodiment of the disclosure, fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist 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 complementaritydetermining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 571.

The disclosure also contemplates antibody fragments which include one or more of the antibody fragments described herein. In one embodiment of the disclosure, fragments of the antibodies having binding specificity to IL-6 comprise, or alternatively consist 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 complementaritydetermining regions (SEQ ID NO: 572; SEQ ID NO: 573; and SEQ ID NO: 574) of the variable light chain region of SEQ ID NO: 570; and the complementarity-determining regions (SEQ ID NO: 575; SEQ ID NO: 576; and SEQ ID NO: 577) of the variable heavy chain region of SEQ ID NO: 571.

In one embodiment of the 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 set forth herein.

Such antibody fragments may be present in one or more of the following non-limiting forms: Fab, Fab', F₍ab')2, Fv and single chain Fv antibody forms. In one embodiment, the anti-IL-6 antibodies described herein further comprises the kappa constant light chain sequence comprising the sequence set forth below:

VAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSK DSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 586).

In another embodiment, the anti-IL-6 antibodies described herein further comprises and the gamma-1 constant heavy chain polypeptide sequence comprising the sequence set forth below: ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG LYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPS VFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTY RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKN QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN VFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 588).

In another embodiment, the disclosure contemplates an isolated anti-IL-6 antibody comprising a VH polypeptide sequence selected from the group consisting of: SEQ ID NO: 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 further comprising a VL polypeptide sequence selected from the group consisting of: SEQ ID NO: 2, 20, 21 , 37, 53, 69, 85, 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 or a variant thereof wherein one or more of the framework residues (FR residues) in said VH or VL polypeptide has been substituted with another amino acid residue resulting in an anti-IL-6 antibody that specifically binds IL-6. The disclosure contemplates humanized and chimeric forms of these antibodies. The chimeric antibodies may include an Fc derived from lgG1 , lgG2, lgG3, lgG4, lgG5, lgG6, lgG7, lgG8, lgG9, lgG10, lgG11 , lgG12, lgG13, lgG14, lgG15, lgG16, lgG17, lgG18 or lgG19 constant regions.

In one embodiment of the disclosure, the antibodies orVH orVL polypeptides originate or are selected from one or more rabbit B cell populations prior to initiation of the humanization process referenced herein.

In another embodiment of the disclosure, the anti-IL-6 antibodies have binding specificity for primate homologs 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 the cynomolgus monkey) and the Rhesus monkey. In another embodiment of the disclosure, the anti-IL-6 antibodies inhibit the association of IL-6 with IL-6R, and/or the production of IL-6/IL- 6R/gp130 complexes and/or the production of IL-6/IL-6R/gp130 multimers and/or antagonizes the biological effects of one or more of the foregoing.

These antibodies thereof may be modified post-translationally to add effector moieties such as chemical linkers, detectable moieties such as for example fluorescent dyes, enzymes, substrates, bioluminescent materials, radioactive materials, and chemiluminescent moieties, or functional moieties such as for example streptavidin, avidin, biotin, a cytotoxin, a cytotoxic agent, and radioactive materials. 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, and 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 (1251), Carbon 14 (14C), Sulfur 35 (35S), Tritium (3H) and Phosphorus 32 (32P).

Regarding functional moieties, exemplary cytotoxic agents include, but are not limited to, methotrexate, aminopterin, 6-mercaptopurine, 6-thioguanine, cytarabine, 5-fluorouracil decarbazine; alkylating agents such as mechlorethamine, thioepa chlorambucil, melphalan, carmustine (BSNU), mitomycin C, lomustine (CCNU), 1 -methylnitrosourea, cyclothosphamide, mechlorethamine, busulfan, dibromomannitol, streptozotocin, mitomycin C, cis-dichlorodiamine platinum (II) (DDP) cisplatin and carboplatin (paraplatin); anthracyclines include daunorubicin (formerly daunomycin), doxorubicin (adriamycin), detorubicin, carminomycin, idarubicin, epirubicin, mitoxantrone and bisantrene; antibiotics include dactinomycin (actinomycin D), bleomycin, calicheamicin, mithramycin, and anthramycin (AMC); and antimytotic agents such as 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, colchicin, dihydroxy anthracin dione, 1 -dehydrotestosterone, glucocorticoids, procaine, tetracaine, lidocaine, propranolol, puromycin, procarbazine, hydroxyurea, asparaginase, corticosteroids, mytotane (O,P'-(DDD)), interferons, and mixtures of these cytotoxic agents.

Further 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 from plants and bacteria such as ricin, diphtheria toxin and Pseudomonas toxin may be conjugated to the humanized antibodies, or binding fragments thereof, to generate 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).

Other cytotoxic agents include cytotoxic ribonucleases as described by Goldenberg in U.S. Pat. No. 6,653,104. Embodiments of the disclosure also relate to radioimmunoconjugates where a radionuclide that emits alpha or beta particles is stably coupled to the antibody, or binding fragments thereof, with or without the use of a complex-forming agent. Such radionuclides include beta-emitters such as Phosphorus-32 (³²P), Scandium-47 (⁴⁷Sc), Copper-67 (⁶⁷Cu), Gallium-67 (⁶⁷Ga), Yttrium-88 (⁸⁸Y), Yttrium-90 (⁹°Y), lodine-125 (¹²⁵l), lodine-131 (¹³¹l), Samarium-153 (¹⁵³Sm), Lutetium-177 (¹⁷⁷Lu), Rhenium-186 (¹⁸⁶Re) or Rhenium-188 (¹⁸⁸Re), and alpha-emitters such as Astatine-211 (²¹¹At), Lead-212 (²¹²Pb), Bismuth-212 (²¹²Bi) or -213 (²¹³Bi) or Actinium-225 (²²⁵Ac).

Methods are known in the art for conjugating an antibody or binding fragment thereof to a detectable moiety and the like, such as for example those methods 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).

Embodiments described herein further include variants and equivalents that are substantially homologous to the antibodies, antibody fragments, diabodies, SMIPs, camelbodies, nanobodies, IgNAR, polypeptides, variable regions and CDRs set forth herein. These may contain, e.g., conservative substitution mutations (/.e., the substitution of one or more amino acids by similar amino acids). For example, conservative substitution refers to the substitution of an amino acid with another within the same general class, e.g., one acidic amino acid with another acidic amino acid, one basic amino acid with another basic amino acid, or one neutral amino acid by another neutral amino acid. What is intended by a conservative amino acid substitution is well known in the art.

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

In another embodiment, the disclosure further contemplates the above-recited polypeptide homologs of the antibody fragments, variable regions and CDRs set forth herein further having anti-IL-6 activity. Non-limiting examples of anti-IL-6 activity are set forth herein.

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

In another embodiment, the disclosure is also directed to an isolated anti-IL-6 antibody comprising the CDRs contained in the VH polypeptide sequences selected from the group consisting of: SEQ ID NO: 3, 18, 19, 22, 38, 54, 70, 86, 102, 117, 1 18, 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 one or more of the CDRs contained in the VL polypeptide sequence consisting of: 2, 20, 21 , 37, 53, 69, 85, 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, such as those of an antibody comprising the VL and VH polypeptides of SEQ ID NO:20 and SEQ ID NO:19.

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

The anti-IL-6 activity of anti-IL-6 antibodies herein be described, in some cases, by their strength of binding or their affinity for IL-6. This also may affect their therapeutic properties. In some cases, anti-IL-6 antibodies bind to IL-6 with a dissociation constant (KD) of less than or equal to 5x10 ⁷, 10⁷, 5x10⁸, 10⁸, 5x10⁹, 10 ⁹, 5x10 ^w, 10 ^w, 5x10 ¹¹, 10 ¹¹, 5x10 ¹², 10 ¹², 5x10' !3, -| Q-13 5_X-| Q-14 -| Q-14 5_X-| Q-15 _{O R} -| Q-15 |_{n some} embodiments, the anti-IL-6 antibodies bind IL- 6 with a dissociation constant of less than or equal to 5x10 ¹⁰. Another method of assessing affinity for IL-6 is to consider the rate of dissociation between IL-6 and an antibody, i.e., the “off-rate.” In some cases, an anti-IL-6 antibody herein has an off-rate of less than or equal to 10-⁴ S-¹ , 5x1 O'⁵ S'¹ , 10'⁵ S'¹ , 5x1 O'⁶ S'¹ , 10⁶ S ¹ , 5x10⁷ S ¹ , or 10 ⁷ S ¹.

The disclosure also contemplates one or more nucleic acid sequences which result in the expression of an anti-IL-6 antibody as set forth above, including those comprising, or alternatively consisting of, yeast or human preferred codons. The disclosure also contemplates vectors (including plasmids or recombinant viral vectors) comprising said nucleic acid sequence(s). The disclosure also contemplates host cells or recombinant host cells expressing at least one of the antibodies set forth above, including a mammalian, yeast, bacterial, and insect cells. In one embodiment, the host cell is a yeast cell. In another embodiment, the yeast cell is a diploidal yeast cell. In one embodiment, the yeast cell is a Pichia yeast.

Polynucleotides Encoding Anti-IL-6 Antibody Polypeptides

Polynucleotides encoding polypeptides of the antibodies having binding specificity to IL-6 are also described herein. In one embodiment of the disclosure, polynucleotides of the disclosure comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable light chain polypeptide sequence of SEQ ID NO: 2:

ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGT

GCCAGATGTGCCTATGATATGACCCAGACTCCAGCCTCGGTGTCTGCAGCTGTGGGAG GCACAGTCACCATCAAGTGCCAGGCCAGTCAGAGCATTAACAATGAATTATCCTGGTAT CAGCAGAAACCAGGGCAGCGTCCCAAGCTCCTGATCTATAGGGCATCCACTCTGGCAT CTGGGGTCTCATCGCGGTTCAAAGGCAGTGGATCTGGGACAGAGTTCACTCTCACCAT CAGCGACCTGGAGTGTGCCGATGCTGCCACTTACTACTGTCAACAGGGTTATAGTCTG AGGAATATTGATAATGCTTTCGGCGGAGGGACCGAGGTGGTGGTCAAACGTACGGTAG CGGCCCCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCC TCTGTTGTGTGCCTGCTGAATAACTT (SEQ ID NO: 10).

In another embodiment of the disclosure, polynucleotides of the disclosure comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable heavy chain polypeptide sequence of SEQ ID NO: 3: ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTCGCTGTGCTCAAAGGTGTCCAGTGTC AGTCGCTGGAGGAGTCCGGGGGTCGCCTGGTCACGCCTGGGACACCCCTGACACTCA CCTGCACAGCCTCTGGATTCTCCCTCAGTAACTACTACGTGACCTGGGTCCGCCAGGC TCCAGGGAAGGGGCTGGAATGGATCGGAATCATTTATGGTAGTGATGAAACGGCCTAC GCGACCTGGGCGATAGGCCGATTCACCATCTCCAAAACCTCGACCACGGTGGATCTGA AAATGACCAGTCTGACAGCCGCGGACACGGCCACCTATTTCTGTGCCAGAGATGATAG TAGTGACTGGGATGCAAAATTTAACTTGTGGGGCCAAGGCACCCTGGTCACCGTCTCG AGCGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCT CTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGG (SEQ ID NO: 11).

In a further embodiment of the disclosure, polynucleotides encoding fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist 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 polynucleotides encoding the complementarity-determining regions (CDRs, or hypervariable regions) of the light chain variable sequence of SEQ ID NO: 2.

In a further embodiment of the disclosure, polynucleotides encoding fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist 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.

The disclosure also contemplates polynucleotide sequences including one or more of the polynucleotide sequences encoding antibody fragments described herein. In one embodiment of the disclosure, polynucleotides encoding fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist of, one, two, three or more, including all of the following polynucleotides encoding antibody fragments: the polynucleotide SEQ ID NO:

10 encoding the light chain variable region of SEQ ID NO: 2; the polynucleotide SEQ ID NO:

11 encoding the heavy chain variable region of SEQ ID NO: 3; polynucleotides encoding the complementarity-determining regions (SEQ ID NO: 12; SEQ ID NO: 13; and SEQ ID NO: 14) of the light chain variable region of SEQ ID NO: 10; and polynucleotides encoding the complementarity-determining regions (SEQ ID NO: 15; SEQ ID NO: 16; and SEQ ID NO: 17) of the heavy chain variable region of SEQ ID NO: 1 1.

The disclosure is further directed to polynucleotides encoding polypeptides of the antibodies having binding specificity to IL-6. In one embodiment of the disclosure, polynucleotides of the disclosure comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable light chain polypeptide sequence of SEQ ID NO: 21 :

ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGT GCCAGATGTGCCTATGATATGACCCAGACTCCAGCCTCTGTGGAGGTAGCTGTGGGAG GCACAGTCACCATCAATTGCCAGGCCAGTGAGACCATTTACAGTTGGTTATCCTGGTAT CAGCAGAAGCCAGGGCAGCCTCCCAAGCTCCTGATCTACCAGGCATCCGATCTGGCAT CTGGGGTCCCATCGCGATTCAGCGGCAGTGGGGCTGGGACAGAGTACACTCTCACCA TCAGCGGCGTGCAGTGTGACGATGCTGCCACTTACTACTGTCAACAGGGTTATAGTGG TAGTAATGTTGATAATGTTTTCGGCGGAGGGACCGAGGTGGTGGTCAAACGTACGGTA GCGGCCCCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGC CTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAG (SEQ ID NO: 29).

In another embodiment of the disclosure, polynucleotides of the disclosure comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable heavy chain polypeptide sequence of SEQ ID NO: 22:

ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTCGCTGTGCTCAAAGGTGTCCAGTGTC AGGAGCAGCTGAAGGAGTCCGGGGGTCGCCTGGTCACGCCTGGGACACCCCTGACAC TTACCTGCACAGCCTCTGGATTCTCCCTCAATGACCATGCAATGGGCTGGGTCCGCCA GGCTCCAGGGAAGGGGCTGGAATACATCGGATTCATTAATAGTGGTGGTAGCGCACGC TACGCGAGCTGGGCAGAAGGCCGATTCACCATCTCCAGAACCTCGACCACGGTGGATC TGAAAATGACCAGTCTGACAACCGAGGACACGGCCACCTATTTCTGTGTCAGAGGGGG TGCTGTTTGGAGTATTCATAGTTTTGATCCCTGGGGCCCAGGGACCCTGGTCACCGTCT CGAGCGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCA CCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAG (SEQ ID NO: 30).

In a further embodiment of the disclosure, polynucleotides encoding fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist 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.

In a further embodiment of the disclosure, polynucleotides encoding fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist 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.

The disclosure also contemplates polynucleotide sequences including one or more of the polynucleotide sequences encoding antibody fragments described herein. In one embodiment of the disclosure, polynucleotides encoding fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist of, one, two, three or more, including all of the following polynucleotides encoding antibody fragments: the polynucleotide SEQ ID NO:

29 encoding the light chain variable region of SEQ ID NO: 21 ; the polynucleotide SEQ ID NO:

30 encoding the heavy chain variable region of SEQ ID NO: 22; polynucleotides encoding the complementarity-determining regions (SEQ ID NO: 31 ; SEQ ID NO: 32; and SEQ ID NO: 33) of the light chain variable region of SEQ ID NO: 29; and polynucleotides encoding the complementarity-determining regions (SEQ ID NO: 34; SEQ ID NO: 35; and SEQ ID NO: 36) of the heavy chain variable region of SEQ ID NO: 30.

The disclosure is further directed to polynucleotides encoding polypeptides of the antibodies having binding specificity to IL-6. In one embodiment of the disclosure, polynucleotides of the disclosure comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable light chain polypeptide sequence of SEQ ID NO: 37:

ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGT GCCACATTTGCCGCCGTGCTGACCCAGACTCCATCTCCCGTGTCTGCAGCTGTGGGAG GCACAGTCAGCATCAGTTGCCAGGCCAGTCAGAGTGTTTATGACAACAACTACTTATCC TGGTTTCAGCAGAAACCAGGGCAGCCTCCCAAGCTCCTGATCTATGGTGCATCCACTC TGGCATCTGGGGTCCCATCGCGGTTCGTGGGCAGTGGATCTGGGACACAGTTCACTCT CACCATCACAGACGTGCAGTGTGACGATGCTGCCACTTACTATTGTGCAGGCGTTTATG ATGATGATAGTGATAATGCCTTCGGCGGAGGGACCGAGGTGGTGGTCAAACGTACGGT AGCGGCCCCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTG CCTCTGTTGTGTGCCTGCTGAATAACTTCT (SEQ ID NO: 45).

In another embodiment of the disclosure, polynucleotides of the disclosure comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable heavy chain polypeptide sequence of SEQ ID NO: 38:

ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTGGCTGTGCTCAAAGGTGTCCAGTGTC AGTCGCTGGAGGAGTCCGGGGGTCGCCTGGTCACCCCTGGGACACCCCTGACACTCA CCTGCACAGCCTCTGGATTCTCCCTCAGTGTCTACTACATGAACTGGGTCCGCCAGGC TCCAGGGAAGGGGCTGGAATGGATCGGATTCATTACAATGAGTGATAATATAAATTACG CGAGCTGGGCGAAAGGCCGATTCACCATCTCCAAAACCTCGACCACGGTGGATCTGAA AATGACCAGTCCGACAACCGAGGACACGGCCACCTATTTCTGTGCCAGGAGTCGTGGC TGGGGTACAATGGGTCGGTTGGATCTCTGGGGCCCAGGCACCCTCGTCACCGTCTCG AGCGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCT

CTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGG (SEQ ID NO: 46).

In a further embodiment of the disclosure, polynucleotides encoding fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist 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 polynucleotides encoding the complementarity-determining regions (CDRs, or hypervariable regions) of the light chain variable sequence of SEQ ID NO: 37.

In a further embodiment of the disclosure, polynucleotides encoding fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist 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.

The disclosure also contemplates polynucleotide sequences including one or more of the polynucleotide sequences encoding antibody fragments described herein. In one embodiment of the disclosure, polynucleotides encoding fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist of, one, two, three or more, including all of the following polynucleotides encoding antibody fragments: the polynucleotide SEQ ID NO:

45 encoding the light chain variable region of SEQ ID NO: 37; the polynucleotide SEQ ID NO:

46 encoding the heavy chain variable region of SEQ ID NO: 38; polynucleotides encoding the complementarity-determining regions (SEQ ID NO: 47; SEQ ID NO: 48; and SEQ ID NO: 49) of the light chain variable region of SEQ ID NO: 37; and polynucleotides encoding the complementarity-determining regions (SEQ ID NO: 50; SEQ ID NO: 51 ; and SEQ ID NO: 52) of the heavy chain variable region of SEQ ID NO: 38.

The disclosure is further directed to polynucleotides encoding polypeptides of the antibodies having binding specificity to IL-6. In one embodiment of the disclosure, polynucleotides of the disclosure comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable light chain polypeptide sequence of SEQ ID NO: 53:

ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGT GCCATATGTGACCCTGTGCTGACCCAGACTCCATCTCCCGTATCTGCACCTGTGGGAG GCACAGTCAGCATCAGTTGCCAGGCCAGTCAGAGTGTTTATGAGAACAACTATTTATCC TGGTTTCAGCAGAAACCAGGGCAGCCTCCCAAGCTCCTGATCTATGGTGCATCCACTC TGGATTCTGGGGTCCCATCGCGGTTCAAAGGCAGTGGATCTGGGACACAGTTCACTCT CACCATTACAGACGTGCAGTGTGACGATGCTGCCACTTACTATTGTGCAGGCGTTTATG ATGATGATAGTGATGATGCCTTCGGCGGAGGGACCGAGGTGGTGGTCAAACGTACGGT AGCGGCCCCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTG CCTCTGTTGTGTGCCTGCTGAATAACTT (SEQ ID NO: 61). In another embodiment of the disclosure, polynucleotides of the disclosure comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable heavy chain polypeptide sequence of SEQ ID NO: 54:

ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTGGCTGTGCTCAAAGGTGTCCAGTGTC AGGAGCAGCTGAAGGAGTCCGGAGGAGGCCTGGTAACGCCTGGAGGAACCCTGACAC TCACCTGCACAGCCTCTGGATTCTCCCTCAATGCCTACTACATGAACTGGGTCCGCCAG GCTCCAGGGAAGGGGCTGGAATGGATCGGATTCATTACTCTGAATAATAATGTAGCTTA CGCGAACTGGGCGAAAGGCCGATTCACCTTCTCCAAAACCTCGACCACGGTGGATCTG AAAATGACCAGTCCGACACCCGAGGACACGGCCACCTATTTCTGTGCCAGGAGTCGTG GCTGGGGTGCAATGGGTCGGTTGGATCTCTGGGGCCATGGCACCCTGGTCACCGTCT CGAGCGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCA CCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGG (SEQ ID NO: 62).

In a further embodiment of the disclosure, polynucleotides encoding fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist 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.

In a further embodiment of the disclosure, polynucleotides encoding fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist 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.

The disclosure also contemplates polynucleotide sequences including one or more of the polynucleotide sequences encoding antibody fragments described herein. In one embodiment of the disclosure, polynucleotides encoding fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist of, one, two, three or more, including all of the following polynucleotides encoding antibody fragments: the polynucleotide SEQ ID NO:

61 encoding the light chain variable region of SEQ ID NO: 53; the polynucleotide SEQ ID NO:

62 encoding the heavy chain variable region of SEQ ID NO: 54; polynucleotides encoding the complementarity-determining regions (SEQ ID NO: 63; SEQ ID NO: 64; and SEQ ID NO: 65) of the light chain variable region of SEQ ID NO: 53; and polynucleotides encoding the complementarity-determining regions (SEQ ID NO: 66; SEQ ID NO: 67; and SEQ ID NO: 68) of the heavy chain variable region of SEQ ID NO: 54.

The disclosure is further directed to polynucleotides encoding polypeptides of the antibodies having binding specificity to IL-6. In one embodiment of the disclosure, polynucleotides of the disclosure comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable light chain polypeptide sequence of SEQ ID NO: 69: ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGT GCCACATTTGCCCAAGTGCTGACCCAGACTCCATCGCCTGTGTCTGCAGCTGTGGGAG GCACAGTCACCATCAACTGCCAGGCCAGTCAGAGTGTTGATGATAACAACTGGTTAGG CTGGTATCAGCAGAAACGAGGGCAGCCTCCCAAGTACCTGATCTATTCTGCATCCACTC TGGCATCTGGGGTCCCATCGCGGTTCAAAGGCAGTGGATCTGGGACACAGTTCACTCT CACCATCAGCGACCTGGAGTGTGACGATGCTGCCACTTACTACTGTGCAGGCGGTTTT AGTGGTAATATCTTTGCTTTCGGCGGAGGGACCGAGGTGGTGGTCAAACGTACGGTAG CGGCCCCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCC TCTGTTGTGTGCCTGCTGAATAACTTCT (SEQ ID NO: 77).

In another embodiment of the disclosure, polynucleotides of the disclosure comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable heavy chain polypeptide sequence of SEQ ID NO: 70:

ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTCGCTGTGCTCAAAGGTGTCCAGTGTC AGTCGGTGGAGGAGTCCGGGGGTCGCCTGGTCACGCCTGGGACACCCCTGACACTCA CCTGCACAGTCTCTGGCTTCTCCCTCAGTAGCTATGCAATGAGCTGGGTCCGCCAGGC TCCAGGAAAGGGGCTGGAGTGGATCGGAATCATTGGTGGTTTTGGTACCACATACTAC GCGACCTGGGCGAAAGGCCGATTCACCATCTCCAAAACCTCGACCACGGTGGATCTGA GAATCACCAGTCCGACAACCGAGGACACGGCCACCTATTTCTGTGCCAGAGGTGGTCC TGGTAATGGTGGTGACATCTGGGGCCAAGGGACCCTGGTCACCGTCTCGAGCGCCTC CACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGG CACAGCGGCCCTGGGCTGCCTGGTCAAGGACT (SEQ ID NO: 78).

In a further embodiment of the disclosure, polynucleotides encoding fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist 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.

In a further embodiment of the disclosure, polynucleotides encoding fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist 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.

The disclosure also contemplates polynucleotide sequences including one or more of the polynucleotide sequences encoding antibody fragments described herein. In one embodiment of the disclosure, polynucleotides encoding fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist of, one, two, three or more, including all of the following polynucleotides encoding antibody fragments: the polynucleotide SEQ ID NO: 77 encoding the light chain variable region of SEQ ID NO: 69; the polynucleotide SEQ ID NO:

78 encoding the heavy chain variable region of SEQ ID NO: 70; polynucleotides encoding the complementarity-determining regions (SEQ ID NO: 79; SEQ ID NO: 80; and SEQ ID NO: 81) of the light chain variable region of SEQ ID NO: 69; and polynucleotides encoding the complementarity-determining regions (SEQ ID NO: 82; SEQ ID NO: 83; and SEQ ID NO: 84) of the heavy chain variable region of SEQ ID NO: 70.

The disclosure is further directed to polynucleotides encoding polypeptides of the antibodies having binding specificity to IL-6. In one embodiment of the disclosure, polynucleotides of the disclosure comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable light chain polypeptide sequence of SEQ ID NO: 85:

ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGT GCCACATTTGCAGCCGTGCTGACCCAGACACCATCGCCCGTGTCTGTACCTGTGGGAG GCACAGTCACCATCAAGTGCCAGTCCAGTCAGAGTGTTTATAATAATTTCTTATCGTGGT ATCAGCAGAAACCAGGGCAGCCTCCCAAGCTCCTGATCTACCAGGCATCCAAACTGGC ATCTGGGGTCCCAGATAGGTTCAGCGGCAGTGGATCTGGGACACAGTTCACTCTCACC ATCAGCGGCGTGCAGTGTGACGATGCTGCCACTTACTACTGTCTAGGCGGTTATGATG ATGATGCTGATAATGCTTTCGGCGGAGGGACCGAGGTGGTGGTCAAACGTACGGTAGC GGCCCCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCT CTGTTGTGTGCCTGCTGAATAACTTC (SEQ ID NO: 93).

In another embodiment of the disclosure, polynucleotides of the disclosure comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable heavy chain polypeptide sequence of SEQ ID NO: 86:

ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTCGCTGTGCTCAAAGGTGTCCAGTGTC AGTCGGTGGAGGAGTCCGGGGGTCGCCTGGTCACGCCTGGGACACCCCTGACGCTCA CCTGCACAGTCTCTGGAATCGACCTCAGTGACTATGCAATGAGCTGGGTCCGCCAGGC TCCAGGGAAGGGGCTGGAATGGATCGGAATCATTTATGCTGGTAGTGGTAGCACATGG TACGCGAGCTGGGCGAAAGGCCGATTCACCATCTCCAAAACCTCGACCACGGTGGATC TGAAAATCACCAGTCCGACAACCGAGGACACGGCCACCTATTTCTGTGCCAGAGATGG ATACGATGACTATGGTGATTTCGATCGATTGGATCTCTGGGGCCCAGGCACCCTCGTC ACCGTCTCGAGCGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCA AGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACT (SEQ ID NO: 94).

In a further embodiment of the disclosure, polynucleotides encoding fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist 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 polynucleotides encoding the complementarity-determining regions (CDRs, or hypervariable regions) of the light chain variable sequence of SEQ ID NO: 85. In a further embodiment of the disclosure, polynucleotides encoding fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist 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.

The disclosure also contemplates polynucleotide sequences including one or more of the polynucleotide sequences encoding antibody fragments described herein. In one embodiment of the disclosure, polynucleotides encoding fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist of, one, two, three or more, including all of the following polynucleotides encoding antibody fragments: the polynucleotide SEQ ID NO:

93 encoding the light chain variable region of SEQ ID NO: 85; the polynucleotide SEQ ID NO:

94 encoding the heavy chain variable region of SEQ ID NO: 86; polynucleotides encoding the complementarity-determining regions (SEQ ID NO: 95; SEQ ID NO: 96; and SEQ ID NO: 97) of the light chain variable region of SEQ ID NO: 85; and polynucleotides encoding the complementarity-determining regions (SEQ ID NO: 98; SEQ ID NO: 99; and SEQ ID NO: 100) of the heavy chain variable region of SEQ ID NO: 86.

The disclosure is further directed to polynucleotides encoding polypeptides of the antibodies having binding specificity to IL-6. In one embodiment of the disclosure, polynucleotides of the disclosure comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable light chain polypeptide sequence of SEQ ID NO: 101 :

ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGT GCCAGATGTGCCTATGATATGACCCAGACTCCAGCCTCGGTGTCTGCAGCTGTGGGAG GCACAGTCACCATCAAATGCCAGGCCAGTCAGAGCATTAACAATGAATTATCCTGGTAT CAGCAGAAATCAGGGCAGCGTCCCAAGCTCCTGATCTATAGGGCATCCACTCTGGCAT CTGGGGTCTCATCGCGGTTCAAAGGCAGTGGATCTGGGACAGAGTTCACTCTCACCAT CAGCGACCTGGAGTGTGCCGATGCTGCCACTTACTACTGTCAACAGGGTTATAGTCTG AGGAATATTGATAATGCTTTCGGCGGAGGGACCGAGGTGGTGGTCAAACGTACGGTAG CGGCCCCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCC TCTGTTGTGTGCCTGCTGAATAACTTC (SEQ ID NO: 109).

In another embodiment of the disclosure, polynucleotides of the disclosure comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable heavy chain polypeptide sequence of SEQ ID NO: 102:

ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTCGCTGTGCTCTCAGGTGTCCAGTGTC AGTCGCTGGAGGAGTCCGGGGGTCGCCTGGTCACGCCTGGGACACCCCTGACACTCA CCTGCACAGCCTCTGGATTCTCCCTCAGTAACTACTACATGACCTGGGTCCGCCAGGC TCCAGGGAAGGGGCTGGAATGGATCGGAATGATTTATGGTAGTGATGAAACAGCCTAC GCGAACTGGGCGATAGGCCGATTCACCATCTCCAAAACCTCGACCACGGTGGATCTGA AAATGACCAGTCTGACAGCCGCGGACACGGCCACCTATTTCTGTGCCAGAGATGATAG TAGTGACTGGGATGCAAAATTTAACTTGTGGGGCCAAGGGACCCTCGTCACCGTCTCG AGCGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCT CTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGG (SEQ ID NO: 110).

In a further embodiment of the disclosure, polynucleotides encoding fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist 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 polynucleotides encoding the complementarity-determining regions (CDRs, or hypervariable regions) of the light chain variable sequence of SEQ ID NO: 101.

In a further embodiment of the disclosure, polynucleotides encoding fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist 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.

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

The disclosure is further directed to polynucleotides encoding polypeptides of the antibodies having binding specificity to IL-6. In one embodiment of the disclosure, polynucleotides of the disclosure comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable light chain polypeptide sequence of SEQ ID NO: 122:

ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGT GCCACATTTGCAGCCGTGCTGACCCAGACACCATCACCCGTGTCTGCAGCTGTGGGAG GCACAGTCACCATCAGTTGCCAGTCCAGTCAGAGTGTTGGTAATAACCAGGACTTATCC TGGTTTCAGCAGAGACCAGGGCAGCCTCCCAAGCTCCTGATCTACGAAATATCCAAACT GGAATCTGGGGTCCCATCGCGGTTCAGCGGCAGTGGATCTGGGACACACTTCACTCTC ACCATCAGCGGCGTACAGTGTGACGATGCTGCCACTTACTACTGTCTAGGCGGTTATG ATGATGATGCTGATAATGCT (SEQ ID NO: 130). In another embodiment of the disclosure, polynucleotides of the disclosure comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable heavy chain polypeptide sequence of SEQ ID NO: 123:

ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTCGCTGTGCTCAAAGGTGTCCAGTGTC ACTCGGTGGAGGAGTCCGGGGGTCGCCTGGTCACGCCTGGGACACCCCTGACACTCA CCTGCACAGTCTCTGGATTCTCCCTCAGTAGTCGTACAATGTCCTGGGTCCGCCAGGC TCCAGGGAAGGGGCTGGAGTGGATCGGATACATTTGGAGTGGTGGTAGCACATACTAC GCGACCTGGGCGAAAGGCCGATTCACCATCTCCAAAACCTCGACCACGGTGGATCTGA AAATCACCAGTCCGACAACCGAGGACACGGCCACCTATTTCTGTGCCAGATTGGGCGA TACTGGTGGTCACGCTTATGCTACTCGCTTAAATCTC (SEQ ID NO: 131).

In a further embodiment of the disclosure, polynucleotides encoding fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist 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.

In a further embodiment of the disclosure, polynucleotides encoding fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist 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.

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

The disclosure is further directed to polynucleotides encoding polypeptides of the antibodies having binding specificity to IL-6. In one embodiment of the disclosure, polynucleotides of the disclosure comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable light chain polypeptide sequence of SEQ ID NO: 138: ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGT GCCACATTTGCAGCCGTGCTGACCCAGACACCATCGTCCGTGTCTGCAGCTGTGGGAG GCACAGTCAGCATCAGTTGCCAGTCCAGTCAGAGTGTTTATAGTAATAAGTACCTAGCC TGGTATCAGCAGAAACCAGGGCAGCCTCCCAAGCTCCTGATCTACTGGACATCCAAAC TGGCATCTGGGGCCCCATCACGGTTCAGCGGCAGTGGATCTGGGACACAATTCACTCT CACCATCAGCGGCGTGCAGTGTGACGATGCTGCCACTTACTACTGTCTAGGCGCTTAT GATGATGATGCTGATAATGCT (SEQ ID NO: 146).

In another embodiment of the disclosure, polynucleotides of the disclosure comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable heavy chain polypeptide sequence of SEQ ID NO: 139:

ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTCGCTGTGCTCAAAGGTGTCCAGTGTC AGTCGGTGGAAGAGTCCGGGGGTCGCCTGGTCAAGCCTGACGAAACCCTGACACTCA CCTGCACAGCCTCTGGATTCTCCCTGGAGGGCGGCTACATGACCTGGGTCCGCCAGG CTCCAGGGAAGGGGCTGGAATGGATCGGAATCAGTTATGATAGTGGTAGCACATACTA CGCGAGCTGGGCGAAAGGCCGATTCACCATCTCCAAGACCTCGTCGACCACGGTGGA TCTGAAAATGACCAGTCTGACAACCGAGGACACGGCCACCTATTTCTGCGTCAGATCAC TAAAATATCCTACTGTTACTTCTGATGACTTG (SEQ ID NO: 147).

In a further embodiment of the disclosure, polynucleotides encoding fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist 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 polynucleotides encoding the complementarity-determining regions (CDRs, or hypervariable regions) of the light chain variable sequence of SEQ ID NO: 138.

In a further embodiment of the disclosure, polynucleotides encoding fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist 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.

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

The disclosure is further directed to polynucleotides encoding polypeptides of the antibodies having binding specificity to IL-6. In one embodiment of the disclosure, polynucleotides of the disclosure comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable light chain polypeptide sequence of SEQ ID NO: 154:

ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGT GCCACATTTGCAGCCGTGCTGACCCAGACACCATCACCCGTGTCTGCAGCTGTGGGAG GCACAGTCACCATCAGTTGCCAGTCCAGTCAGAGTGTTTATAATAATAACGACTTAGCC TGGTATCAGCAGAAACCAGGGCAGCCTCCTAAACTCCTGATCTATTATGCATCCACTCT GGCATCTGGGGTCCCATCGCGGTTCAAAGGCAGTGGATCTGGGACACAGTTCACTCTC ACCATCAGCGGCGTGCAGTGTGACGATGCTGCCGCTTACTACTGTCTAGGCGGTTATG ATGATGATGCTGATAATGCT (SEQ ID NO: 162).

In another embodiment of the disclosure, polynucleotides of the disclosure comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable heavy chain polypeptide sequence of SEQ ID NO: 155:

ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTCGCTGTGCTCAAAGGTGTCCAGTGTC AGTCGGTGGAGGAGTCCGGGGGTCGCCTGGTCACGCCTGGGACACCCCTGACACTCA CCTGCACAGTATCTGGATTATCCCTCAGTAGCAATACAATAAACTGGGTCCGCCAGGCT CCAGGGAAGGGGCTGGAGTGGATCGGATACATTTGGAGTGGTGGTAGTACATACTACG CGAGCTGGGTGAATGGTCGATTCACCATCTCCAAAACCTCGACCACGGTGGATCTGAA AATCACCAGTCCGACAACCGAGGACACGGCCACCTATTTCTGTGCCAGAGGGGGTTAC GCTAGTGGTGGTTATCCTTATGCCACTCGGTTGGATCTC (SEQ ID NO: 163).

In a further embodiment of the disclosure, polynucleotides encoding fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist 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.

In a further embodiment of the disclosure, polynucleotides encoding fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist 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.

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

The disclosure is further directed to polynucleotides encoding polypeptides of the antibodies having binding specificity to IL-6. In one embodiment of the disclosure, polynucleotides of the disclosure comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable light chain polypeptide sequence of SEQ ID NO: 170:

ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGT GCCACATTTGCAGCCGTGCTGACCCAGACACCATCCTCCGTGTCTGCAGCTGTGGGAG GCACAGTCACCATCAATTGCCAGTCCAGTCAGAGTGTTTATAATAACGACTACTTATCCT GGTATCAACAGAGGCCAGGGCAACGTCCCAAGCTCCTAATCTATGGTGCTTCCAAACT GGCATCTGGGGTCCCGTCACGGTTCAAAGGCAGTGGATCTGGGAAACAGTTTACTCTC ACCATCAGCGGCGTGCAGTGTGACGATGCTGCCACTTACTACTGTCTGGGCGATTATG ATGATGATGCTGATAATACT (SEQ ID NO: 178).

In another embodiment of the disclosure, polynucleotides of the disclosure comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable heavy chain polypeptide sequence of SEQ ID NO: 171 :

ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTCGCTGTGCTCAAAGGTGTCCAGTGTC AGTCGCTGGAGGAGTCCGGGGGTCGCCTGGTCACGCCTGGGACACCCCTGACACTCA CTTGCACAGTCTCTGGATTCACCCTCAGTACCAACTACTACCTGAGCTGGGTCCGCCA GGCTCCAGGGAAGGGGCTAGAATGGATCGGAATCATTTATCCTAGTGGTAACACATATT GCGCGAAGTGGGCGAAAGGCCGATTCACCATCTCCAAAACCTCGTCGACCACGGTGG ATCTGAAAATGACCAGTCCGACAACCGAGGACACAGCCACGTATTTCTGTGCCAGAAAT TATGGTGGTGATGAAAGTTTG (SEQ ID NO: 179).

In a further embodiment of the disclosure, polynucleotides encoding fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist 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. In a further embodiment of the disclosure, polynucleotides encoding fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist 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.

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

The disclosure is further directed to polynucleotides encoding polypeptides of the antibodies having binding specificity to IL-6. In one embodiment of the disclosure, polynucleotides of the disclosure comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable light chain polypeptide sequence of SEQ ID NO: 186:

ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGT GCCAGATGTGATGTTGTGATGACCCAGACTCCAGCCTCCGTGGAGGCAGCTGTGGGA GGCACAGTCACCATCAAGTGCCAGGCCAGTGAGACCATTGGCAATGCATTAGCCTGGT ATCAGCAGAAATCAGGGCAGCCTCCCAAGCTCCTGATCTACAAGGCATCCAAACTGGC ATCTGGGGTCCCATCGCGGTTCAAAGGCAGTGGATCTGGGACAGAGTACACTCTCACC ATCAGCGACCTGGAGTGTGCCGATGCTGCCACTTACTACTGTCAATGGTGTTATTTTGG TGATAGTGTT (SEQ ID NO: 194).

In another embodiment of the disclosure, polynucleotides of the disclosure comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable heavy chain polypeptide sequence of SEQ ID NO: 187:

ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTCACTGTGCTCAAAGGTGTCCAGTGTC AGGAGCAGCTGGTGGAGTCCGGGGGAGGCCTGGTCCAGCCTGAGGGATCCCTGACA CTCACCTGCACAGCCTCTGGATTCGACTTCAGTAGCGGCTACTACATGTGCTGGGTCC GCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGCGTGTATTTTCACTATTACTACTAA CACTTACTACGCGAGCTGGGCGAAAGGCCGATTCACCATCTCCAAGACCTCGTCGACC ACGGTGACTCTGCAAATGACCAGTCTGACAGCCGCGGACACGGCCACCTATCTCTGTG CGAGAGGGATTTATTCTGATAATAATTATTATGCCTTG (SEQ ID NO: 195). In a further embodiment of the disclosure, polynucleotides encoding fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist 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.

In a further embodiment of the disclosure, polynucleotides encoding fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist 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.

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

The disclosure is further directed to polynucleotides encoding polypeptides of the antibodies having binding specificity to IL-6. In one embodiment of the disclosure, polynucleotides of the disclosure comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable light chain polypeptide sequence of SEQ ID NO: 202:

ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGT GCCAGATGTGATGTTGTGATGACCCAGACTCCAGCCTCCGTGGAGGCAGCTGTGGGA GGCACAGTCACCATCAAGTGCCAGGCCAGTGAGAGCATTGGCAATGCATTAGCCTGGT ATCAGCAGAAACCAGGGCAGCCTCCCAAGCTCCTGATCTACAAGGCATCCACTCTGGC ATCTGGGGTCCCATCGCGGTTCAGCGGCAGTGGATCTGGGACAGAGTTCACTCTCACC ATCAGCGGCGTGCAGTGTGCCGATGCTGCCGCTTACTACTGTCAATGGTGTTATTTTGG TGATAGTGTT (SEQ ID NO: 210).

In another embodiment of the disclosure, polynucleotides of the disclosure comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable heavy chain polypeptide sequence of SEQ ID NO: 203: ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTCGCTGTGCTCAAAGGTGTCCAGTGTC AGCAGCAGCTGGTGGAGTCCGGGGGAGGCCTGGTCAAGCCGGGGGCATCCCTGACA CTCACCTGCAAAGCCTCTGGATTCTCCTTCAGTAGCGGCTACTACATGTGCTGGGTCC GCCAGGCTCCAGGGAAGGGGCTGGAGTCGATCGCATGCATTTTTACTATTACTGATAA CACTTACTACGCGAACTGGGCGAAAGGCCGATTCACCATCTCCAAGCCCTCGTCGCCC ACGGTGACTCTGCAAATGACCAGTCTGACAGCCGCGGACACGGCCACCTATTTCTGTG CGAGGGGGATTTATTCTACTGATAATTATTATGCCTTG (SEQ ID NO: 211).

In a further embodiment of the disclosure, polynucleotides encoding fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist 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.

In a further embodiment of the disclosure, polynucleotides encoding fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist 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.

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

The disclosure is further directed to polynucleotides encoding polypeptides of the antibodies having binding specificity to IL-6. In one embodiment of the disclosure, polynucleotides of the disclosure comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable light chain polypeptide sequence of SEQ ID NO: 218:

ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGT GCCAGATGTGATGTTGTGATGACCCAGACTCCAGCCTCCGTGGAGGCAGCTGTGGGA GGCACAGTCACCATCAAGTGCCAGGCCAGTCAGAGCGTTAGTAGCTACTTAAACTGGT ATCAGCAGAAACCAGGGCAGCCTCCCAAGCTCCTGATCTACAGGGCATCCACTCTGGA ATCTGGGGTCCCATCGCGGTTCAAAGGCAGTGGATCTGGGACAGAGTTCACTCTCACC ATCAGCGACCTGGAGTGTGCCGATGCTGCCACTTACTACTGTCAATGTACTTATGGTAC TAGTAGTAGTTATGGTGCTGCT (SEQ ID NO: 226).

In another embodiment of the disclosure, polynucleotides of the disclosure comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable heavy chain polypeptide sequence of SEQ ID NO: 219:

ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTCGCTGTGCTCAAAGGTGTCCAGTGTC AGTCGGTGGAGGAGTCCGGGGGTCGCCTGGTCACGCCTGGGACACCCCTGACACTCA CCTGCACCGTCTCTGGTATCTCCCTCAGTAGCAATGCAATAAGCTGGGTCCGCCAGGC TCCAGGGAAGGGGCTGGAATGGATCGGAATCATTAGTTATAGTGGTACCACATACTAC GCGAGCTGGGCGAAAGGCCGATTCACCATCTCCAAAACCTCGTCGACCACGGTGGATC TGAAAATCACTAGTCCGACAACCGAGGACACGGCCACCTACTTCTGTGCCAGAGATGA CCCTACGACAGTTATGGTTATGTTGATACCTTTTGGAGCCGGCATGGACCTC (SEQ ID NO: 227).

In a further embodiment of the disclosure, polynucleotides encoding fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist 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.

In a further embodiment of the disclosure, polynucleotides encoding fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist 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.

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

The disclosure is further directed to polynucleotides encoding polypeptides of the antibodies having binding specificity to IL-6. In one embodiment of the disclosure, polynucleotides of the disclosure comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable light chain polypeptide sequence of SEQ ID NO: 234:

ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGT GCCACATTTGCCCAAGTGCTGACCCAGACTGCATCGCCCGTGTCTGCAGCTGTGGGAG GCACAGTCACCATCAACTGCCAGGCCAGTCAGAGTGTTTATAAGAACAACTACTTATCC TGGTATCAGCAGAAACCAGGGCAGCCTCCCAAAGGCCTGATCTATTCTGCATCGACTC TAGATTCTGGGGTCCCATTGCGGTTCAGCGGCAGTGGATCTGGGACACAGTTCACTCT CACCATCAGCGACGTGCAGTGTGACGATGCTGCCACTTACTACTGTCTAGGCAGTTAT GATTGTAGTAGTGGTGATTGTTATGCT (SEQ ID NO: 242).

In another embodiment of the disclosure, polynucleotides of the disclosure comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable heavy chain polypeptide sequence of SEQ ID NO: 235:

ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTCGCTGTGCTCAAAGGTGTCCAGTGTC AGTCGTTGGAGGAGTCCGGGGGAGACCTGGTCAAGCCTGAGGGATCCCTGACACTCA CCTGCACAGCCTCTGGATTCTCCTTCAGTAGCTACTGGATGTGCTGGGTCCGCCAGGC TCCAGGGAAGGGGCTGGAGTGGATCGCATGCATTGTTACTGGTAATGGTAACACTTAC TACGCGAACTGGGCGAAAGGCCGATTCACCATCTCCAAAACCTCGTCGACCACGGTGA CTCTGCAAATGACCAGTCTGACAGCCGCGGACACGGCCACCTATTTTTGTGCGAAAGC CTATGACTTG (SEQ ID NO: 243).

In a further embodiment of the disclosure, polynucleotides encoding fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist 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.

In a further embodiment of the disclosure, polynucleotides encoding fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist 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.

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

The disclosure is further directed to polynucleotides encoding polypeptides of the antibodies having binding specificity to IL-6. In one embodiment of the disclosure, polynucleotides of the disclosure comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable light chain polypeptide sequence of SEQ ID NO: 250:

ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGT TCCACATTTGCCGCCGTGCTGACCCAGACTCCATCTCCCGTGTCTGCAGCTGTGGGAG GCACAGTCAGCATCAGTTGCCAGGCCAGTCAGAGTGTTTATGACAACAACTATTTATCC TGGTATCAGCAGAAACCAGGACAGCCTCCCAAGCTCCTGATCTATGGTGCATCCACTCT GGCATCTGGGGTCCCATCGCGGTTCAAAGGCACGGGATCTGGGACACAGTTCACTCTC ACCATCACAGACGTGCAGTGTGACGATGCTGCCACTTACTATTGTGCAGGCGTTTTTAA TGATGATAGTGATGATGCC (SEQ ID NO: 258).

In another embodiment of the disclosure, polynucleotides of the disclosure comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable heavy chain polypeptide sequence of SEQ ID NO: 251 :

ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTCGCTGTGCCCAAAGGTGTCCAGTGTC AGTCGCTGGAGGAGTCCGGGGGTCGCCTGGTCACGCCTGGGACACCCCTGACACTCA CCTGCACACTCTCTGGATTCTCCCTCAGTGCATACTATATGAGCTGGGTCCGCCAGGCT CCAGGGAAGGGGCTGGAATGGATCGGATTCATTACTCTGAGTGATCATATATCTTACGC GAGGTGGGCGAAAGGCCGATTCACCATCTCCAAAACCTCGACCACGGTGGATCTGAAA ATGACCAGTCCGACAACCGAGGACACGGCCACCTATTTCTGTGCCAGGAGTCGTGGCT GGGGTGCAATGGGTCGGTTGGATCTC (SEQ ID NO: 259).

In a further embodiment of the disclosure, polynucleotides encoding fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist 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.

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

The disclosure is further directed to polynucleotides encoding polypeptides of the antibodies having binding specificity to IL-6. In one embodiment of the disclosure, polynucleotides of the disclosure comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable light chain polypeptide sequence of SEQ ID NO: 266:

ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGT GCCACATTCGCAGCCGTGCTGACCCAGACACCATCGCCCGTGTCTGCGGCTGTGGGA GGCACAGTCACCATCAGTTGCCAGGCCAGTCAGAGTGTTTATAACAACAAAAATTTAGC CTGGTATCAGCAGAAATCAGGGCAGCCTCCCAAGCTCCTGATCTACTGGGCATCCACT CTGGCATCTGGGGTCTCATCGCGGTTCAGCGGCAGTGGATCTGGGACACAGTTCACTC TCACCGTCAGCGGCGTGCAGTGTGACGATGCTGCCACTTACTACTGTCTAGGCGTTTTT GATGATGATGCTGATAATGCT (SEQ ID NO: 274).

In another embodiment of the disclosure, polynucleotides of the disclosure comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable heavy chain polypeptide sequence of SEQ ID NO: 267:

ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTCGCTGTGCTCAAAGGTGTCCAATGTC AGTCGGTGGAGGAGTCCGGGGGTCGCCTGGTCACGCCTGGGACACCCCTGACACTCA CCTGCACAGCCTCTGGATTCTCCCTCAGTAGCTACTCCATGACCTGGGTCCGCCAGGC TCCAGGGAAGGGGCTGGAATATATCGGAGTCATTGGTACTAGTGGTAGCACATACTAC GCGACCTGGGCGAAAGGCCGATTCACCATCTCCAGAACCTCGACCACGGTGGCTCTG AAAATCACCAGTCCGACAACCGAGGACACGGCCACCTATTTCTGTGTCAGGAGTCTTTC TTCTATTACTTTCTTG (SEQ ID NO: 275).

In a further embodiment of the disclosure, polynucleotides encoding fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist 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. In a further embodiment of the disclosure, polynucleotides encoding fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist 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.

The disclosure also contemplates polynucleotide sequences including one or more of the polynucleotide sequences encoding antibody fragments described herein. In one embodiment of the disclosure, polynucleotides encoding fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist of, one, two, three or more, including all of the following polynucleotides encoding antibody fragments: the polynucleotide SEQ ID NO: 274 encoding the light chain variable region of SEQ ID NO: 266; the polynucleotide SEQ ID NO: 275 encoding the heavy chain variable region of SEQ ID NO: 267; polynucleotides encoding the complementarity-determining regions (SEQ ID NO: 276; SEQ ID NO: 277; and SEQ ID NO: 278) of the light chain variable region of SEQ ID NO: 266; and polynucleotides encoding the complementarity-determining regions (SEQ ID NO: 279; SEQ ID NO: 280; and SEQ ID NO: 281) of the heavy chain variable region of SEQ ID NO: 267.

The disclosure is further directed to polynucleotides encoding polypeptides of the antibodies having binding specificity to IL-6. In one embodiment of the disclosure, polynucleotides of the disclosure comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable light chain polypeptide sequence of SEQ ID NO: 282:

ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGT GCCAGATGTGCATTCGAATTGACCCAGACTCCAGCCTCCGTGGAGGCAGCTGTGGGA GGCACAGTCACCATCAATTGCCAGGCCAGTCAGAACATTTATAGATACTTAGCCTGGTA TCAGCAGAAACCAGGGCAGCCTCCCAAGTTCCTGATCTATCTGGCATCTACTCTGGCAT CTGGGGTCCCATCGCGGTTTAAAGGCAGTGGATCTGGGACAGAGTTCACTCTCACCAT CAGCGACCTGGAGTGTGCCGATGCTGCCACTTACTACTGTCAAAGTTATTATAGTAGTA ATAGTGTCGCT (SEQ ID NO: 290).

In another embodiment of the disclosure, polynucleotides of the disclosure comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable heavy chain polypeptide sequence of SEQ ID NO: 283:

ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTCGCTGTGCTCAAAGGTGTCCAGTGTC AGGAGCAGCTGGTGGAGTCCGGGGGAGACCTGGTCCAGCCTGAGGGATCCCTGACAC TCACCTGCACAGCTTCTGAGTTAGACTTCAGTAGCGGCTACTGGATATGCTGGGTCCG CCAGGTTCCAGGGAAGGGGCTGGAGTGGATCGGATGCATTTATACTGGTAGTAGTGGT AGCACTTTTTACGCGAGTTGGGCGAAAGGCCGATTCACCATCTCCAAAACCTCGTCGA CCACGGTGACTCTGCAAATGACCAGTCTGACAGCCGCGGACACGGCCACCTATTTCTG

TGCGAGAGGTTATAGTGGCTTTGGTTACTTTAAGTTG (SEQ ID NO: 291).

In a further embodiment of the disclosure, polynucleotides encoding fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist of, one or more of the polynucleotide sequences of SEQ ID NO: 292; SEQ ID NO: 293; and SEQ ID NO: 294 which correspond to polynucleotides encoding the complementarity-determining regions (CDRs, or hypervariable regions) of the light chain variable sequence of SEQ ID NO: 282.

In a further embodiment of the disclosure, polynucleotides encoding fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist of, one or more of the polynucleotide sequences of SEQ ID NO: 295; SEQ ID NO: 296; and SEQ ID NO: 297 which correspond to polynucleotides encoding the complementarity-determining regions (CDRs, or hypervariable regions) of the heavy chain variable sequence of SEQ ID NO: 283.

The disclosure also contemplates polynucleotide sequences including one or more of the polynucleotide sequences encoding antibody fragments described herein. In one embodiment of the disclosure, polynucleotides encoding fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist of, one, two, three or more, including all of the following polynucleotides encoding antibody fragments: the polynucleotide SEQ ID NO: 290 encoding the light chain variable region of SEQ ID NO: 282; the polynucleotide SEQ ID NO: 291 encoding the heavy chain variable region of SEQ ID NO: 283; polynucleotides encoding the complementarity-determining regions (SEQ ID NO: 292; SEQ ID NO: 293; and SEQ ID NO: 294) of the light chain variable region of SEQ ID NO: 282; and polynucleotides encoding the complementarity-determining regions (SEQ ID NO: 295; SEQ ID NO: 296; and SEQ ID NO: 297) of the heavy chain variable region of SEQ ID NO: 283.

The disclosure is further directed to polynucleotides encoding polypeptides of the antibodies having binding specificity to IL-6. In one embodiment of the disclosure, polynucleotides of the disclosure comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable light chain polypeptide sequence of SEQ ID NO: 298:

ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGT GCCAGATGTGCCTATGATATGACCCAGACTCCAGCCTCTGTGGAGGTAGCTGTGGGAG GCACAGTCACCATCAAGTGCCAGGCCAGTGAGGACATTTATAGGTTATTGGCCTGGTAT CAACAGAAACCAGGGCAGCCTCCCAAGCTCCTGATCTATGATTCATCCGATCTGGCATC TGGGGTCCCATCGCGGTTCAAAGGCAGTGGATCTGGGACAGAGTTCACTCTCGCCATC AGCGGTGTGCAGTGTGACGATGCTGCCACTTACTACTGTCAACAGGCTTGGAGTTATA GTGATATTGATAATGCT (SEQ ID NO: 306). In another embodiment of the disclosure, polynucleotides of the disclosure comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable heavy chain polypeptide sequence of SEQ ID NO: 299:

ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTCGCTGTGCTCAAAGGTGTCCAGTGTC AGTCGGTGGAGGAGTCCGGGGGTCGCCTGGTCACGCCGGGGACACCCCTGACACTCA CCTGCACAGCCTCTGGATTCTCCCTCAGTAGCTACTACATGAGCTGGGTCCGCCAGGC TCCAGGGAAGGGGCTGGAATGGATCGGAATCATTACTACTAGTGGTAATACATTTTACG CGAGCTGGGCGAAAGGCCGGCTCACCATCTCCAGAACCTCGACCACGGTGGATCTGA AAATCACCAGTCCGACAACCGAGGACACGGCCACCTATTTCTGTGCCAGAACTTCTGAT ATTTTTTATTATCGTAACTTG (SEQ ID NO: 307).

In a further embodiment of the disclosure, polynucleotides encoding fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist of, one or more of the polynucleotide sequences of SEQ ID NO: 308; SEQ ID NO: 309; and SEQ ID NO: 310 which correspond to polynucleotides encoding the complementarity-determining regions (CDRs, or hypervariable regions) of the light chain variable sequence of SEQ ID NO: 298.

In a further embodiment of the disclosure, polynucleotides encoding fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist of, one or more of the polynucleotide sequences of SEQ ID NO: 31 1 ; SEQ ID NO: 312; and SEQ ID NO: 313 which correspond to polynucleotides encoding the complementarity-determining regions (CDRs, or hypervariable regions) of the heavy chain variable sequence of SEQ ID NO: 299.

The disclosure also contemplates polynucleotide sequences including one or more of the polynucleotide sequences encoding antibody fragments described herein. In one embodiment of the disclosure, polynucleotides encoding fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist of, one, two, three or more, including all of the following polynucleotides encoding antibody fragments: the polynucleotide SEQ ID NO: 306 encoding the light chain variable region of SEQ ID NO: 298; the polynucleotide SEQ ID NO: 307 encoding the heavy chain variable region of SEQ ID NO: 299; polynucleotides encoding the complementarity-determining regions (SEQ ID NO: 308; SEQ ID NO: 309; and SEQ ID NO: 310) of the light chain variable region of SEQ ID NO: 298; and polynucleotides encoding the complementarity-determining regions (SEQ ID NO: 311 ; SEQ ID NO: 312; and SEQ ID NO: 313) of the heavy chain variable region of SEQ ID NO: 299.

The disclosure is further directed to polynucleotides encoding polypeptides of the antibodies having binding specificity to IL-6. In one embodiment of the disclosure, polynucleotides of the disclosure comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable light chain polypeptide sequence of SEQ ID NO: 314: ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGT GCCACGTTTGCAGCCGTGCTGACCCAGACTGCATCACCCGTGTCTGCCGCTGTGGGA GCCACAGTCACCATCAACTGCCAGTCCAGTCAGAGTGTTTATAATGACATGGACTTAGC CTGGTTTCAGCAGAAACCAGGGCAGCCTCCCAAGCTCCTGATCTATTCTGCATCCACTC TGGCATCTGGGGTCCCATCGCGGTTCAGCGGCAGTGGATCTGGGACAGAGTTCACTCT CACCATCAGCGGCGTGCAGTGTGACGATGCTGCCACTTACTACTGTCTAGGCGCTTTT GATGATGATGCTGATAATACT (SEQ ID NO: 322).

In another embodiment of the disclosure, polynucleotides of the disclosure comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable heavy chain polypeptide sequence of SEQ ID NO: 315:

ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTCGCTGTGCTCAAAGGTGTCCAGTGTC AGTCGGTGGAGGAGTCCGGGGGTCGCCTGGTCACGCCTGGGACACCCCTGACACTCA CCTGCACAGTCTCTGGATTCTCCCTCACTAGGCATGCAATAACCTGGGTCCGCCAGGC TCCAGGGAAGGGGCTGGAATGGATCGGATGCATTTGGAGTGGTGGTAGCACATACTAC GCGACCTGGGCGAAAGGCCGATTCACCATCTCCAAAACCTCGACCACGGTGGATCTCA GAATCACCAGTCCGACAACCGAGGACACGGCCACCTACTTCTGTGCCAGAGTCATTGG CGATACTGCTGGTTATGCTTATTTTACGGGGCTTGACTTG (SEQ ID NO: 323).

In a further embodiment of the disclosure, polynucleotides encoding fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist of, one or more of the polynucleotide sequences of SEQ ID NO: 324; SEQ ID NO: 325; and SEQ ID NO: 326 which correspond to polynucleotides encoding the complementarity-determining regions (CDRs, or hypervariable regions) of the light chain variable sequence of SEQ ID NO: 314.

In a further embodiment of the disclosure, polynucleotides encoding fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist of, one or more of the polynucleotide sequences of SEQ ID NO: 327; SEQ ID NO: 328; and SEQ ID NO: 329 which correspond to polynucleotides encoding the complementarity-determining regions (CDRs, or hypervariable regions) of the heavy chain variable sequence of SEQ ID NO: 315.

The disclosure also contemplates polynucleotide sequences including one or more of the polynucleotide sequences encoding antibody fragments described herein. In one embodiment of the disclosure, polynucleotides encoding fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist of, one, two, three or more, including all of the following polynucleotides encoding antibody fragments: the polynucleotide SEQ ID NO: 322 encoding the light chain variable region of SEQ ID NO: 314; the polynucleotide SEQ ID NO: 323 encoding the heavy chain variable region of SEQ ID NO: 315; polynucleotides encoding the complementarity-determining regions (SEQ ID NO: 324; SEQ ID NO: 325; and SEQ ID NO: 326) of the light chain variable region of SEQ ID NO: 314; and polynucleotides encoding the complementarity-determining regions (SEQ ID NO: 327; SEQ ID NO: 328; and SEQ ID NO: 329) of the heavy chain variable region of SEQ ID NO: 315.

The disclosure is further directed to polynucleotides encoding polypeptides of the antibodies having binding specificity to IL-6. In one embodiment of the disclosure, polynucleotides of the disclosure comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable light chain polypeptide sequence of SEQ ID NO: 330:

ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGT GCCAGATGTGCCTATGATATGACCCAGACTCCAGCCTCTGTGGAGGTAGCTGTGGGAG GCACAGTCACCATCAAGTGCCAGGCCAGTCAGAGTGTTTATAATTGGTTATCCTGGTAT CAGCAGAAACCAGGGCAGCCTCCCAAGCTCCTGATCTATACTGCATCCAGTCTGGCAT CTGGGGTCCCATCGCGGTTCAGTGGCAGTGGATCTGGGACAGAGTTCACTCTCACCAT CAGCGGCGTGGAGTGTGCCGATGCTGCCACTTACTACTGTCAACAGGGTTATACTAGT GATGTTGATAATGTT (SEQ ID NO: 338).

In another embodiment of the disclosure, polynucleotides of the disclosure comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable heavy chain polypeptide sequence of SEQ ID NO: 331 :

ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTCGCTGTGCTCAAAGGTGTCCAGTGTC AGTCGCTGGAGGAGGCCGGGGGTCGCCTGGTCACGCCTGGGACACCCCTGACACTCA CCTGCACAGTCTCTGGAATCGACCTCAGTAGCTATGCAATGGGCTGGGTCCGCCAGGC TCCAGGGAAGGGGCTGGAATACATCGGAATCATTAGTAGTAGTGGTAGCACATACTAC GCGACCTGGGCGAAAGGCCGATTCACCATCTCACAAGCCTCGTCGACCACGGTGGAT CTGAAAATTACCAGTCCGACAACCGAGGACTCGGCCACATATTTCTGTGCCAGAGGGG GTGCTGGTAGTGGTGGTGTTTGGCTGCTTGATGGTTTTGATCCC (SEQ ID NO: 339).

In a further embodiment of the disclosure, polynucleotides encoding fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist of, one or more of the polynucleotide sequences of SEQ ID NO: 340; SEQ ID NO: 341 ; and SEQ ID NO: 342 which correspond to polynucleotides encoding the complementarity-determining regions (CDRs, or hypervariable regions) of the light chain variable sequence of SEQ ID NO: 330.

In a further embodiment of the disclosure, polynucleotides encoding fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist of, one or more of the polynucleotide sequences of SEQ ID NO: 343; SEQ ID NO: 344; and SEQ ID NO: 345 which correspond to polynucleotides encoding the complementarity-determining regions (CDRs, or hypervariable regions) of the heavy chain variable sequence of SEQ ID NO: 331.

The disclosure also contemplates polynucleotide sequences including one or more of the polynucleotide sequences encoding antibody fragments described herein. In one embodiment of the disclosure, polynucleotides encoding fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist of, one, two, three or more, including all of the following polynucleotides encoding antibody fragments: the polynucleotide SEQ ID NO: 338 encoding the light chain variable region of SEQ ID NO: 330; the polynucleotide SEQ ID NO: 339 encoding the heavy chain variable region of SEQ ID NO: 331 ; polynucleotides encoding the complementarity-determining regions (SEQ ID NO: 340; SEQ ID NO: 341 ; and SEQ ID NO: 342) of the light chain variable region of SEQ ID NO: 330; and polynucleotides encoding the complementarity-determining regions (SEQ ID NO: 343; SEQ ID NO: 344; and SEQ ID NO: 345) of the heavy chain variable region of SEQ ID NO: 331 .

The disclosure is further directed to polynucleotides encoding polypeptides of the antibodies having binding specificity to IL-6. In one embodiment of the disclosure, polynucleotides of the disclosure comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable light chain polypeptide sequence of SEQ ID NO: 346:

ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGT GCCAAATGTGCCGATGTTGTGATGACCCAGACTCCAGCCTCCGTGTCTGCAGCTGTGG GAGGCACAGTCACCATCAATTGCCAGGCCAGTGAGAACATTTATAATTGGTTAGCCTGG TATCAGCAGAAACCAGGGCAGCCTCCCAAGCTCCTGATCTATACTGTAGGCGATCTGG CATCTGGGGTCTCATCGCGGTTCAAAGGCAGTGGATCTGGGACAGAGTTCACTCTCAC CATCAGCGACCTGGAGTGTGCCGATGCTGCCACTTACTATTGTCAACAGGGTTATAGTA GTAGTTATGTTGATAATGTT (SEQ ID NO: 354).

In another embodiment of the disclosure, polynucleotides of the disclosure comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable heavy chain polypeptide sequence of SEQ ID NO: 347:

ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTCGCTGTGCTCAAAGGTGTCCAGTGTC AGGAGCAGCTGAAGGAGTCCGGGGGTCGCCTGGTCACGCCTGGGACACCCCTGACAC TCACCTGCACAGTCTCTGGATTCTCCCTCAATGACTATGCAGTGGGCTGGTTCCGCCA GGCTCCAGGGAAGGGGCTGGAATGGATCGGATACATTCGTAGTAGTGGTACCACAGC CTACGCGACCTGGGCGAAAGGCCGATTCACCATCTCCGCTACCTCGACCACGGTGGAT CTGAAAATCACCAGTCCGACAACCGAGGACACGGCCACCTATTTCTGTGCCAGAGGGG GTGCTGGTAGTAGTGGTGTGTGGATCCTTGATGGTTTTGCTCCC (SEQ ID NO: 355).

In a further embodiment of the disclosure, polynucleotides encoding fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist of, one or more of the polynucleotide sequences of SEQ ID NO: 356; SEQ ID NO: 357; and SEQ ID NO: 358 which correspond to polynucleotides encoding the complementarity-determining regions (CDRs, or hypervariable regions) of the light chain variable sequence of SEQ ID NO: 346. In a further embodiment of the disclosure, polynucleotides encoding fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist of, one or more of the polynucleotide sequences of SEQ ID NO: 359; SEQ ID NO: 360; and SEQ ID NO: 361 which correspond to polynucleotides encoding the complementarity-determining regions (CDRs, or hypervariable regions) of the heavy chain variable sequence of SEQ ID NO: 347.

The disclosure also contemplates polynucleotide sequences including one or more of the polynucleotide sequences encoding antibody fragments described herein. In one embodiment of the disclosure, polynucleotides encoding fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist of, one, two, three or more, including all of the following polynucleotides encoding antibody fragments: the polynucleotide SEQ ID NO: 354 encoding the light chain variable region of SEQ ID NO: 346; the polynucleotide SEQ ID NO: 355 encoding the heavy chain variable region of SEQ ID NO: 347; polynucleotides encoding the complementarity-determining regions (SEQ ID NO: 356; SEQ ID NO: 357; and SEQ ID NO: 358) of the light chain variable region of SEQ ID NO: 346; and polynucleotides encoding the complementarity-determining regions (SEQ ID NO: 359; SEQ ID NO: 360; and SEQ ID NO: 361) of the heavy chain variable region of SEQ ID NO: 347.

The disclosure is further directed to polynucleotides encoding polypeptides of the antibodies having binding specificity to IL-6. In one embodiment of the disclosure, polynucleotides of the disclosure comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable light chain polypeptide sequence of SEQ ID NO: 362:

ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGT GCCACATTTGCTCAAGTGCTGACCCAGACTCCATCCTCCGTGTCTGCAGCTGTGGGAG GCACAGTCACCATCAATTGCCAGGCCAGTCAGAGTGTTTATCAGAACAACTACTTATCC TGGTTTCAGCAGAAACCAGGGCAGCCTCCCAAGCTCCTGATCTATGGTGCGGCCACTC TGGCATCTGGGGTCCCATCGCGGTTCAAAGGCAGTGGATCTGGGACACAGTTCACTCT CACCATCAGCGACCTGGAGTGTGACGATGCTGCCACTTACTACTGTGCAGGCGCTTAT AGGGATGTGGATTCT (SEQ ID NO: 370).

In another embodiment of the disclosure, polynucleotides of the disclosure comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable heavy chain polypeptide sequence of SEQ ID NO: 363:

ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTCGCTGTGCTCAAAGGTGTCCAGTGTC AGTCGTTGGAGGAGTCCGGGGGAGACCTGGTCAAGCCTGGGGCATCCCTGACACTCA CCTGCACAGCCTCTGGATTCTCCTTTACTAGTACCTACTACATCTACTGGGTCCGCCAG GCTCCAGGGAAGGGGCTGGAGTGGATCGCATGTATTGATGCTGGTAGTAGTGGTAGCA CTTACTACGCGACCTGGGTGAATGGCCGATTCACCATCTCCAAAACCTCGTCGACCAC GGTGACTCTGCAAATGACCAGTCTGACAGCCGCGGACACGGCCACCTATTTCTGTGCG AAATGGGATTATGGTGGTAATGTTGGTTGGGGTTATGACTTG (SEQ ID NO: 371). In a further embodiment of the disclosure, polynucleotides encoding fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist of, one or more of the polynucleotide sequences of SEQ ID NO: 372; SEQ ID NO: 373; and SEQ ID NO: 374 which correspond to polynucleotides encoding the complementarity-determining regions (CDRs, or hypervariable regions) of the light chain variable sequence of SEQ ID NO: 362.

In a further embodiment of the disclosure, polynucleotides encoding fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist of, one or more of the polynucleotide sequences of SEQ ID NO: 375; SEQ ID NO: 376; and SEQ ID NO: 377 which correspond to polynucleotides encoding the complementarity-determining regions (CDRs, or hypervariable regions) of the heavy chain variable sequence of SEQ ID NO: 363.

The disclosure also contemplates polynucleotide sequences including one or more of the polynucleotide sequences encoding antibody fragments described herein. In one embodiment of the disclosure, polynucleotides encoding fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist of, one, two, three or more, including all of the following polynucleotides encoding antibody fragments: the polynucleotide SEQ ID NO: 370 encoding the light chain variable region of SEQ ID NO: 362; the polynucleotide SEQ ID NO: 371 encoding the heavy chain variable region of SEQ ID NO: 363; polynucleotides encoding the complementarity-determining regions (SEQ ID NO: 372; SEQ ID NO: 373; and SEQ ID NO: 374) of the light chain variable region of SEQ ID NO: 362; and polynucleotides encoding the complementarity-determining regions (SEQ ID NO: 375; SEQ ID NO: 376; and SEQ ID NO: 377) of the heavy chain variable region of SEQ ID NO: 363.

The disclosure is further directed to polynucleotides encoding polypeptides of the antibodies having binding specificity to IL-6. In one embodiment of the disclosure, polynucleotides of the disclosure comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable light chain polypeptide sequence of SEQ ID NO: 378:

ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGT GCCAGATGTGCATTCGAATTGACCCAGACTCCATCCTCCGTGGAGGCAGCTGTGGGAG GCACAGTCACCATCAAGTGCCAGGCCAGTCAGAGCATTAGTAGTTACTTAGCCTGGTAT CAGCAGAAACCAGGGCAGCCTCCCAAGTTCCTGATCTACAGGGCGTCCACTCTGGCAT CTGGGGTCCCATCGCGATTCAAAGGCAGTGGATCTGGGACAGAGTTCACTCTCACCAT CAGCGACCTGGAGTGTGCCGATGCTGCCACTTACTACTGTCAAAGCTATTATGATAGTG TTTCAAATCCT (SEQ ID NO: 386).

In another embodiment of the disclosure, polynucleotides of the disclosure comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable heavy chain polypeptide sequence of SEQ ID NO: 379: ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTCGCTGTGCTCAAAGGTGTCCAGTGTC AGTCGTTGGAGGAGTCCGGGGGAGACCTGGTCAAGCCTGAGGGATCCCTGACACTCA CCTGCAAAGCCTCTGGACTCGACCTCGGTACCTACTGGTTCATGTGCTGGGTCCGCCA GGCTCCAGGGAAGGGGCTGGAGTGGATCGCTTGTATTTATACTGGTAGTAGTGGTTCC ACTTTCTACGCGAGCTGGGTGAATGGCCGATTCACCATCTCCAAAACCTCGTCGACCA CGGTGACTCTGCAAATGACCAGTCTGACAGCCGCGGACACGGCCACTTATTTTTGTGC GAGAGGTTATAGTGGTTATGGTTATTTTAAGTTG (SEQ ID NO: 387).

In a further embodiment of the disclosure, polynucleotides encoding fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist of, one or more of the polynucleotide sequences of SEQ ID NO: 388; SEQ ID NO: 389; and SEQ ID NO: 390 which correspond to polynucleotides encoding the complementarity-determining regions (CDRs, or hypervariable regions) of the light chain variable sequence of SEQ ID NO: 378.

In a further embodiment of the disclosure, polynucleotides encoding fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist of, one or more of the polynucleotide sequences of SEQ ID NO: 391 ; SEQ ID NO: 392; and SEQ ID NO: 393 which correspond to polynucleotides encoding the complementarity-determining regions (CDRs, or hypervariable regions) of the heavy chain variable sequence of SEQ ID NO: 379.

The disclosure also contemplates polynucleotide sequences including one or more of the polynucleotide sequences encoding antibody fragments described herein. In one embodiment of the disclosure, polynucleotides encoding fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist of, one, two, three or more, including all of the following polynucleotides encoding antibody fragments: the polynucleotide SEQ ID NO: 386 encoding the light chain variable region of SEQ ID NO: 378; the polynucleotide SEQ ID NO: 387 encoding the heavy chain variable region of SEQ ID NO: 379; polynucleotides encoding the complementarity-determining regions (SEQ ID NO: 388; SEQ ID NO: 389; and SEQ ID NO: 390) of the light chain variable region of SEQ ID NO: 378; and polynucleotides encoding the complementarity-determining regions (SEQ ID NO: 391 ; SEQ ID NO: 392; and SEQ ID NO: 393) of the heavy chain variable region of SEQ ID NO: 379.

The disclosure is further directed to polynucleotides encoding polypeptides of the antibodies having binding specificity to IL-6. In one embodiment of the disclosure, polynucleotides of the disclosure comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable light chain polypeptide sequence of SEQ ID NO: 394:

ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGT GTCACATTTGCCATCGAAATGACCCAGAGTCCATTCTCCGTGTCTGCAGCTGTGGGAG GCACAGTCAGCATCAGTTGCCAGGCCAGTCAGAGTGTTTATAAGAACAACCAATTATCC TGGTATCAGCAGAAATCAGGGCAGCCTCCCAAGCTCCTGATCTATGGTGCATCGGCTC TGGCATCTGGGGTCCCATCGCGGTTCAAAGGCAGTGGATCTGGGACAGAGTTCACTCT CACCATCAGCGACGTGCAGTGTGACGATGCTGCCACTTACTACTGTGCAGGCGCTATT ACTGGTAGTATTGATACGGATGGT (SEQ ID NO: 402).

In another embodiment of the disclosure, polynucleotides of the disclosure comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable heavy chain polypeptide sequence of SEQ ID NO: 395:

ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTCGCTGTGCTCAAAGGTGTCCAGTGTC AGTCGTTGGAGGAGTCCGGGGGAGACCTGGTCAAGCCTGGGGCATCCCTGACACTCA CCTGCACAACTTCTGGATTCTCCTTCAGTAGCAGCTACTTCATTTGCTGGGTCCGCCAG GCTCCAGGGAAGGGGCTGGAGTGGATCGCATGCATTTATGGTGGTGATGGCAGCACA TACTACGCGAGCTGGGCGAAAGGCCGATTCACCATCTCCAAAACCTCGTCGACCACGG TGACGCTGCAAATGACCAGTCTGACAGCCGCGGACACGGCCACCTATTTCTGTGCGAG AGAATGGGCATATAGTCAAGGTTATTTTGGTGCTTTTGATCTC (SEQ ID NO: 403).

In a further embodiment of the disclosure, polynucleotides encoding fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist of, one or more of the polynucleotide sequences of SEQ ID NO: 404; SEQ ID NO: 405; and SEQ ID NO: 406 which correspond to polynucleotides encoding the complementarity-determining regions (CDRs, or hypervariable regions) of the light chain variable sequence of SEQ ID NO: 394.

In a further embodiment of the disclosure, polynucleotides encoding fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist of, one or more of the polynucleotide sequences of SEQ ID NO: 407; SEQ ID NO: 408; and SEQ ID NO: 409 which correspond to polynucleotides encoding the complementarity-determining regions (CDRs, or hypervariable regions) of the heavy chain variable sequence of SEQ ID NO: 395.

The disclosure also contemplates polynucleotide sequences including one or more of the polynucleotide sequences encoding antibody fragments described herein. In one embodiment of the disclosure, polynucleotides encoding fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist of, one, two, three or more, including all of the following polynucleotides encoding antibody fragments: the polynucleotide SEQ ID NO: 402 encoding the light chain variable region of SEQ ID NO: 394; the polynucleotide SEQ ID NO: 403 encoding the heavy chain variable region of SEQ ID NO: 395; polynucleotides encoding the complementarity-determining regions (SEQ ID NO: 404; SEQ ID NO: 405; and SEQ ID NO: 406) of the light chain variable region of SEQ ID NO: 394; and polynucleotides encoding the complementarity-determining regions (SEQ ID NO: 407; SEQ ID NO: 408; and SEQ ID NO: 409) of the heavy chain variable region of SEQ ID NO: 395.

The disclosure is further directed to polynucleotides encoding polypeptides of the antibodies having binding specificity to IL-6. In one embodiment of the disclosure, polynucleotides of the disclosure comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable light chain polypeptide sequence of SEQ ID NO: 410:

ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGT GCCAGATGTGATGTTGTGATGACCCAGACTCCAGCCTCCGTGGAGGCAGCTGTGGGA GGCACAGTCACCATCAAGTGCCAGGCCAGTGAGGATATTAGTAGCTACTTAGCCTGGT ATCAGCAGAAACCAGGGCAGCCTCCCAAGCTCCTGATCTATGCTGCATCCAATCTGGA ATCTGGGGTCTCATCGCGATTCAAAGGCAGTGGATCTGGGACAGAGTACACTCTCACC ATCAGCGACCTGGAGTGTGCCGATGCTGCCACCTATTACTGTCAATGTACTTATGGTAC TATTTCTATTAGTGATGGTAATGCT (SEQ ID NO: 418).

In another embodiment of the disclosure, polynucleotides of the disclosure comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable heavy chain polypeptide sequence of SEQ ID NO: 41 1 :

ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTCGCTGTGCTCAAAGGTGTCCAATGTC AGTCGGTGGAGGAGTCCGGGGGTCGCCTGGTCACGCCTGGGACACCCCTGACACTCA CCTGCACAGTCTCTGGATTCTCCCTCAGTAGCTACTTCATGACCTGGGTCCGCCAGGC TCCAGGGGAGGGGCTGGAATACATCGGATTCATTAATCCTGGTGGTAGCGCTTACTAC GCGAGCTGGGTGAAAGGCCGATTCACCATCTCCAAGTCCTCGACCACGGTAGATCTGA AAATCACCAGTCCGACAACCGAGGACACGGCCACCTATTTCTGTGCCAGGGTTCTGAT TGTTTCTTATGGAGCCTTTACCATC (SEQ ID NO: 419).

In a further embodiment of the disclosure, polynucleotides encoding fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist of, one or more of the polynucleotide sequences of SEQ ID NO: 420; SEQ ID NO: 421 ; and SEQ ID NO: 422 which correspond to polynucleotides encoding the complementarity-determining regions (CDRs, or hypervariable regions) of the light chain variable sequence of SEQ ID NO: 410.

In a further embodiment of the disclosure, polynucleotides encoding fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist of, one or more of the polynucleotide sequences of SEQ ID NO: 423; SEQ ID NO: 424; and SEQ ID NO: 425 which correspond to polynucleotides encoding the complementarity-determining regions (CDRs, or hypervariable regions) of the heavy chain variable sequence of SEQ ID NO: 411.

The disclosure also contemplates polynucleotide sequences including one or more of the polynucleotide sequences encoding antibody fragments described herein. In one embodiment of the disclosure, polynucleotides encoding fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist of, one, two, three or more, including all of the following polynucleotides encoding antibody fragments: the polynucleotide SEQ ID NO: 418 encoding the light chain variable region of SEQ ID NO: 410; the polynucleotide SEQ ID NO: 419 encoding the heavy chain variable region of SEQ ID NO: 41 1 ; polynucleotides encoding the complementarity-determining regions (SEQ ID NO: 420; SEQ ID NO: 421 ; and SEQ ID NO: 422) of the light chain variable region of SEQ ID NO: 410; and polynucleotides encoding the complementarity-determining regions (SEQ ID NO: 423; SEQ ID NO: 424; and SEQ ID NO: 425) of the heavy chain variable region of SEQ ID NO: 411 .

The disclosure is further directed to polynucleotides encoding polypeptides of the antibodies having binding specificity to IL-6. In one embodiment of the disclosure, polynucleotides of the disclosure comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable light chain polypeptide sequence of SEQ ID NO: 426:

ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGT GCCAGATGTGATGTTGTGATGACCCAGACTCCAGCCTCCGTGTCTGCAGCTGTGGGAG GCACAGTCACCATCAAGTGCCAGGCCAGTGAGGACATTGAAAGCTATCTAGCCTGGTA TCAGCAGAAACCAGGGCAGCCTCCCAAGCTCCTGATCTATGGTGCATCCAATCTGGAA TCTGGGGTCTCATCGCGGTTCAAAGGCAGTGGATCTGGGACAGAGTTCACTCTCACCA TCAGCGACCTGGAGTGTGCCGATGCTGCCACTTACTATTGTCAATGCACTTATGGTATT

ATTAGTATTAGTGATGGTAATGCT (SEQ ID NO: 434).

In another embodiment of the disclosure, polynucleotides of the disclosure comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable heavy chain polypeptide sequence of SEQ ID NO: 427:

ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTCGCTGTGCTCAAAGGTGTCCAGTGTC AGTCGGTGGAGGAGTCCGGGGGTCGCCTGGTCACGCCTGGGACACCCCTGACACTCA CCTGCACAGTGTCTGGATTCTCCCTCAGTAGCTACTTCATGACCTGGGTCCGCCAGGC TCCAGGGGAGGGGCTGGAATACATCGGATTCATGAATACTGGTGATAACGCATACTAC GCGAGCTGGGCGAAAGGCCGATTCACCATCTCCAAAACCTCGACCACGGTGGATCTGA AAATCACCAGTCCGACAACCGAGGACACGGCCACCTATTTCTGTGCCAGGGTTCTTGTT GTTGCTTATGGAGCCTTTAACATC (SEQ ID NO: 435).

In a further embodiment of the disclosure, polynucleotides encoding fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist of, one or more of the polynucleotide sequences of SEQ ID NO: 436; SEQ ID NO: 437; and SEQ ID NO: 438 which correspond to polynucleotides encoding the complementarity-determining regions (CDRs, or hypervariable regions) of the light chain variable sequence of SEQ ID NO: 426.

In a further embodiment of the disclosure, polynucleotides encoding fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist of, one or more of the polynucleotide sequences of SEQ ID NO: 439; SEQ ID NO: 440; and SEQ ID NO: 441 which correspond to polynucleotides encoding the complementarity-determining regions (CDRs, or hypervariable regions) of the heavy chain variable sequence of SEQ ID NO: 427. The disclosure also contemplates polynucleotide sequences including one or more of the polynucleotide sequences encoding antibody fragments described herein. In one embodiment of the disclosure, polynucleotides encoding fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist of, one, two, three or more, including all of the following polynucleotides encoding antibody fragments: the polynucleotide SEQ ID NO: 434 encoding the light chain variable region of SEQ ID NO: 426; the polynucleotide SEQ ID NO: 435 encoding the heavy chain variable region of SEQ ID NO: 427; polynucleotides encoding the complementarity-determining regions (SEQ ID NO: 436; SEQ ID NO: 437; and SEQ ID NO: 438) of the light chain variable region of SEQ ID NO: 426; and polynucleotides encoding the complementarity-determining regions (SEQ ID NO: 439; SEQ ID NO: 440; and SEQ ID NO: 441) of the heavy chain variable region of SEQ ID NO: 427.

The disclosure is further directed to polynucleotides encoding polypeptides of the antibodies having binding specificity to IL-6. In one embodiment of the disclosure, polynucleotides of the disclosure comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable light chain polypeptide sequence of SEQ ID NO: 442:

ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGT GCCACATTTGCCGCCGTGCTGACCCAGACTCCATCTCCCGTGTCTGAACCTGTGGGAG GCACAGTCAGCATCAGTTGCCAGTCCAGTAAGAGTGTTATGAATAACAACTACTTAGCC TGGTATCAGCAGAAACCAGGGCAGCCTCCCAAGCTCCTGATCTATGGTGCATCCAATC TGGCATCTGGGGTCCCATCACGGTTCAGCGGCAGTGGATCTGGGACACAGTTCACTCT CACCATCAGCGACGTGCAGTGTGACGATGCTGCCACTTACTACTGTCAAGGCGGTTAT ACTGGTTATAGTGATCATGGGACT (SEQ ID NO: 450).

In another embodiment of the disclosure, polynucleotides of the disclosure comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable heavy chain polypeptide sequence of SEQ ID NO: 443:

ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTCGCTGTGCTCAAAGGTGTCCAGTGTC AGTCGGTGGAGGAGTCCGGGGGTCGCCTGGTCAAGCCTGACGAAACCCTGACACTCA CCTGCACAGTCTCTGGAATCGACCTCAGTAGCTATCCAATGAACTGGGTCCGCCAGGC TCCAGGGAAGGGGCTGGAATGGATCGGATTCATTAATACTGGTGGTACCATAGTCTAC GCGAGCTGGGCAAAAGGCCGATTCACCATCTCCAAAACCTCGACCACGGTGGATCTGA AAATGACCAGTCCGACAACCGAGGACACGGCCACCTATTTCTGTGCCAGAGGCAGTTA TGTTTCATCTGGTTATGCCTACTATTTTAATGTC (SEQ ID NO: 451).

In a further embodiment of the disclosure, polynucleotides encoding fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist of, one or more of the polynucleotide sequences of SEQ ID NO: 452; SEQ ID NO: 453; and SEQ ID NO: 454 which correspond to polynucleotides encoding the complementarity-determining regions (CDRs, or hypervariable regions) of the light chain variable sequence of SEQ ID NO: 442. In a further embodiment of the disclosure, polynucleotides encoding fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist of, one or more of the polynucleotide sequences of SEQ ID NO: 455; SEQ ID NO: 456; and SEQ ID NO: 457 which correspond to polynucleotides encoding the complementarity-determining regions (CDRs, or hypervariable regions) of the heavy chain variable sequence of SEQ ID NO: 443.

The disclosure also contemplates polynucleotide sequences including one or more of the polynucleotide sequences encoding antibody fragments described herein. In one embodiment of the disclosure, polynucleotides encoding fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist of, one, two, three or more, including all of the following polynucleotides encoding antibody fragments: the polynucleotide SEQ ID NO: 450 encoding the light chain variable region of SEQ ID NO: 442; the polynucleotide SEQ ID NO: 451 encoding the heavy chain variable region of SEQ ID NO: 443; polynucleotides encoding the complementarity-determining regions (SEQ ID NO: 452; SEQ ID NO: 453; and SEQ ID NO: 454) of the light chain variable region of SEQ ID NO: 442; and polynucleotides encoding the complementarity-determining regions (SEQ ID NO: 455; SEQ ID NO: 456; and SEQ ID NO: 457) of the heavy chain variable region of SEQ ID NO: 443.

The disclosure is further directed to polynucleotides encoding polypeptides of the antibodies having binding specificity to IL-6. In one embodiment of the disclosure, polynucleotides of the disclosure comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable light chain polypeptide sequence of SEQ ID NO: 458:

ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGT GCCACATTTGCCGCCGTGCTGACCCAGACTCCATCTCCCGTGTCTGCAGCTGTGGGAG GCACAGTCAGCATCAGTTGCCAGTCCAGTCAGAGTGTTTATAATAACAACTGGTTATCC TGGTTTCAGCAGAAACCAGGGCAGCCTCCCAAGCTCCTGATCTACAAGGCATCCACTC TGGCATCTGGGGTCCCATCGCGGTTCAAAGGCAGTGGATCTGGGACACAGTTCACTCT CACCATCAGCGACGTGCAGTGTGACGATGTTGCCACTTACTACTGTGCGGGCGGTTAT CTTGATAGTGTTATT (SEQ ID NO: 466).

In another embodiment of the disclosure, polynucleotides of the disclosure comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable heavy chain polypeptide sequence of SEQ ID NO: 459:

ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTCGCTGTGCTCAAAGGTGTCCAGTGTC AGTCGGTGGAGGAGTCCGGGGGTCGCCTGGTCACGCCTGGGACACCCCTGACACTCA CCTGCACAGTCTCTGGATTCTCCCTCAGTACCTATTCAATAAACTGGGTCCGCCAGGCT CCAGGGAAGGGCCTGGAATGGATCGGAATCATTGCTAATAGTGGTACCACATTCTACG CGAACTGGGCGAAAGGCCGATTCACCGTCTCCAAAACCTCGACCACGGTGGATCTGAA AATCACCAGTCCGACAACCGAGGACACGGCCACCTATTTCTGTGCCAGAGAGAGTGGA ATGTACAATGAATATGGTAAATTTAACATC (SEQ ID NO: 467). In a further embodiment of the disclosure, polynucleotides encoding fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist of, one or more of the polynucleotide sequences of SEQ ID NO: 468; SEQ ID NO: 469; and SEQ ID NO: 470 which correspond to polynucleotides encoding the complementarity-determining regions (CDRs, or hypervariable regions) of the light chain variable sequence of SEQ ID NO: 458.

In a further embodiment of the disclosure, polynucleotides encoding fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist of, one or more of the polynucleotide sequences of SEQ ID NO: 471 ; SEQ ID NO: 472; and SEQ ID NO: 473 which correspond to polynucleotides encoding the complementarity-determining regions (CDRs, or hypervariable regions) of the heavy chain variable sequence of SEQ ID NO: 459.

The disclosure also contemplates polynucleotide sequences including one or more of the polynucleotide sequences encoding antibody fragments described herein. In one embodiment of the disclosure, polynucleotides encoding fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist of, one, two, three or more, including all of the following polynucleotides encoding antibody fragments: the polynucleotide SEQ ID NO: 466 encoding the light chain variable region of SEQ ID NO: 458; the polynucleotide SEQ ID NO: 467 encoding the heavy chain variable region of SEQ ID NO: 459; polynucleotides encoding the complementarity-determining regions (SEQ ID NO: 468; SEQ ID NO: 469; and SEQ ID NO: 470) of the light chain variable region of SEQ ID NO: 458; and polynucleotides encoding the complementarity-determining regions (SEQ ID NO: 471 ; SEQ ID NO: 472; and SEQ ID NO: 473) of the heavy chain variable region of SEQ ID NO: 459.

The disclosure is further directed to polynucleotides encoding polypeptides of the antibodies having binding specificity to IL-6. In one embodiment of the disclosure, polynucleotides of the disclosure comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable light chain polypeptide sequence of SEQ ID NO: 474:

ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGT GCCAGATGTGCCTCTGATATGACCCAGACTCCATCCTCCGTGTCTGCAGCTGTGGGAG GCACAGTCACCATCAATTGCCAGGCCAGTGAGAACATTTATAGCTTTTTGGCCTGGTAT CAGCAGAAACCAGGGCAGCCTCCCAAGCTCCTGATCTTCAAGGCTTCCACTCTGGCAT CTGGGGTCTCATCGCGGTTCAAAGGCAGTGGATCTGGGACACAGTTCACTCTCACCAT CAGCGACCTGGAGTGTGACGATGCTGCCACTTACTACTGTCAACAGGGTGCTACTGTG TATGATATTGATAATAAT (SEQ ID NO: 482).

In another embodiment of the disclosure, polynucleotides of the disclosure comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable heavy chain polypeptide sequence of SEQ ID NO: 475: ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTCGCTGTGCTCAAAGGTGTCCAGTGTC AGTCGCTGGAGGAGTCCGGGGGTCGCCTGGTCACGCCTGGGACACCCCTGACACTCA CCTGCACAGTTTCTGGAATCGACCTCAGTGCCTATGCAATGATCTGGGTCCGCCAGGC TCCAGGGGAGGGGCTGGAATGGATCACAATCATTTATCCTAATGGTATCACATACTACG CGAACTGGGCGAAAGGCCGATTCACCGTCTCCAAAACCTCGACCGCGATGGATCTGAA AATCACCAGTCCGACAACCGAGGACACGGCCACCTATTTCTGTGCCAGAGATGCAGAA AGTAGTAAGAATGCTTATTGGGGCTACTTTAACGTC (SEQ ID NO: 483).

In a further embodiment of the disclosure, polynucleotides encoding fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist of, one or more of the polynucleotide sequences of SEQ ID NO: 484; SEQ ID NO: 485; and SEQ ID NO: 486 which correspond to polynucleotides encoding the complementarity-determining regions (CDRs, or hypervariable regions) of the light chain variable sequence of SEQ ID NO: 474.

In a further embodiment of the disclosure, polynucleotides encoding fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist of, one or more of the polynucleotide sequences of SEQ ID NO: 487; SEQ ID NO: 488; and SEQ ID NO: 489 which correspond to polynucleotides encoding the complementarity-determining regions (CDRs, or hypervariable regions) of the heavy chain variable sequence of SEQ ID NO: 475.

The disclosure also contemplates polynucleotide sequences including one or more of the polynucleotide sequences encoding antibody fragments described herein. In one embodiment of the disclosure, polynucleotides encoding fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist of, one, two, three or more, including all of the following polynucleotides encoding antibody fragments: the polynucleotide SEQ ID NO: 482 encoding the light chain variable region of SEQ ID NO: 474; the polynucleotide SEQ ID NO: 483 encoding the heavy chain variable region of SEQ ID NO: 475; polynucleotides encoding the complementarity-determining regions (SEQ ID NO: 484; SEQ ID NO: 485; and SEQ ID NO: 486) of the light chain variable region of SEQ ID NO: 474; and polynucleotides encoding the complementarity-determining regions (SEQ ID NO: 487; SEQ ID NO: 488; and SEQ ID NO: 489) of the heavy chain variable region of SEQ ID NO: 475.

The disclosure is further directed to polynucleotides encoding polypeptides of the antibodies having binding specificity to IL-6. In one embodiment of the disclosure, polynucleotides of the disclosure comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable light chain polypeptide sequence of SEQ ID NO: 490:

ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGT GCCAGATGTGCCTCTGATATGACCCAGACTCCATCCTCCGTGTCTGCAGCTGTGGGAG GCACAGTCACCATCAATTGCCAGGCCAGTGAGAACATTTATAGCTTTTTGGCCTGGTAT CAGCAGAAACCAGGGCAGCCTCCCAAGCTCCTGATCTTCAGGGCTTCCACTCTGGCAT CTGGGGTCTCATCGCGGTTCAAAGGCAGTGGATCTGGGACACAGTTCACTCTCACCAT CAGCGACCTGGAGTGTGACGATGCTGCCACTTACTACTGTCAACAGGGTGCTACTGTG

TATGATATTGATAATAAT (SEQ ID NO: 498).

In another embodiment of the disclosure, polynucleotides of the disclosure comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable heavy chain polypeptide sequence of SEQ ID NO: 491 :

ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTCGCTGTGCTCAAAGGTGTCCAGTGTC AGTCGCTGGAGGAGTCCGGGGGTCGCCTGGTCACGCCTGGGACACCCCTGACACTCA CCTGCACAGTTTCTGGAATCGACCTCAGTGCCTATGCAATGATCTGGGTCCGCCAGGC TCCAGGGGAGGGGCTGGAATGGATCACAATCATTTATCCTAATGGTATCACATACTACG CGAACTGGGCGAAAGGCCGATTCACCGTCTCCAAAACCTCGACCGCGATGGATCTGAA AATCACCAGTCCGACAACCGAGGACACGGCCACCTATTTCTGTGCCAGAGATGCAGAA AGTAGTAAGAATGCTTATTGGGGCTACTTTAACGTC (SEQ ID NO: 499).

In a further embodiment of the disclosure, polynucleotides encoding fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist of, one or more of the polynucleotide sequences of SEQ ID NO: 500; SEQ ID NO: 501 ; and SEQ ID NO: 502 which correspond to polynucleotides encoding the complementarity-determining regions (CDRs, or hypervariable regions) of the light chain variable sequence of SEQ ID NO: 490.

In a further embodiment of the disclosure, polynucleotides encoding fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist of, one or more of the polynucleotide sequences of SEQ ID NO: 503; SEQ ID NO: 504; and SEQ ID NO: 505 which correspond to polynucleotides encoding the complementarity-determining regions (CDRs, or hypervariable regions) of the heavy chain variable sequence of SEQ ID NO: 491.

The disclosure also contemplates polynucleotide sequences including one or more of the polynucleotide sequences encoding antibody fragments described herein. In one embodiment of the disclosure, polynucleotides encoding fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist of, one, two, three or more, including all of the following polynucleotides encoding antibody fragments: the polynucleotide SEQ ID NO: 498 encoding the light chain variable region of SEQ ID NO: 490; the polynucleotide SEQ ID NO: 499 encoding the heavy chain variable region of SEQ ID NO: 491 ; polynucleotides encoding the complementarity-determining regions (SEQ ID NO: 500; SEQ ID NO: 501 ; and SEQ ID NO: 502) of the light chain variable region of SEQ ID NO: 490; and polynucleotides encoding the complementarity-determining regions (SEQ ID NO: 503; SEQ ID NO: 504; and SEQ ID NO: 505) of the heavy chain variable region of SEQ ID NO: 491 .

The disclosure is further directed to polynucleotides encoding polypeptides of the antibodies having binding specificity to IL-6. In one embodiment of the disclosure, polynucleotides of the disclosure comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable light chain polypeptide sequence of SEQ ID NO: 506:

ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGT GCCACATTTGCCATTGAAATGACCCAGACTCCATCCCCCGTGTCTGCCGCTGTGGGAG GCACAGTCACCATCAATTGCCAGGCCAGTGAGAGTGTTTTTAATAATATGTTATCCTGG TATCAGCAGAAACCAGGGCACTCTCCTAAGCTCCTGATCTATGATGCATCCGATCTGGC ATCTGGGGTCCCATCGCGGTTCAAAGGCAGTGGATCTGGGACACAGTTCACTCTCACC ATCAGTGGCGTGGAGTGTGACGATGCTGCCACTTACTATTGTGCAGGGTATAAAAGTG ATAGTAATGATGGCGATAATGTT (SEQ ID NO: 514).

In another embodiment of the disclosure, polynucleotides of the disclosure comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable heavy chain polypeptide sequence of SEQ ID NO: 507:

ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTCGCTGTGCTCAAAGGTGTCCAGTGTC AGTCGCTGGAGGAGTCCGGGGGTCGCCTGGTCACGCCTGGGACACCCCTGACACTCA CCTGCACAGTCTCTGGATTCTCCCTCAACAGGAATTCAATAACCTGGGTCCGCCAGGCT CCAGGGGAGGGGCTGGAATGGATCGGAATCATTACTGGTAGTGGTAGAACGTACTACG CGAACTGGGCAAAAGGCCGATTCACCATCTCCAAAACCTCGACCACGGTGGATCTGAA AATGACCAGTCCGACAACCGAGGACACGGCCACCTATTTCTGTGCCAGAGGCCATCCT GGTCTTGGTAGTGGTAACATC (SEQ ID NO: 515).

In a further embodiment of the disclosure, polynucleotides encoding fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist of, one or more of the polynucleotide sequences of SEQ ID NO: 516; SEQ ID NO: 517; and SEQ ID NO: 518 which correspond to polynucleotides encoding the complementarity-determining regions (CDRs, or hypervariable regions) of the light chain variable sequence of SEQ ID NO: 506.

In a further embodiment of the disclosure, polynucleotides encoding fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist of, one or more of the polynucleotide sequences of SEQ ID NO: 519; SEQ ID NO: 520; and SEQ ID NO: 521 which correspond to polynucleotides encoding the complementarity-determining regions (CDRs, or hypervariable regions) of the heavy chain variable sequence of SEQ ID NO: 507.

The disclosure also contemplates polynucleotide sequences including one or more of the polynucleotide sequences encoding antibody fragments described herein. In one embodiment of the disclosure, polynucleotides encoding fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist of, one, two, three or more, including all of the following polynucleotides encoding antibody fragments: the polynucleotide SEQ ID NO: 514 encoding the light chain variable region of SEQ ID NO: 506; the polynucleotide SEQ ID NO: 515 encoding the heavy chain variable region of SEQ ID NO: 507; polynucleotides encoding the complementarity-determining regions (SEQ ID NO: 516; SEQ ID NO: 517; and SEQ ID NO: 518) of the light chain variable region of SEQ ID NO: 506; and polynucleotides encoding the complementarity-determining regions (SEQ ID NO: 519; SEQ ID NO: 520; and SEQ ID NO: 521) of the heavy chain variable region of SEQ ID NO: 507.

The disclosure is further directed to polynucleotides encoding polypeptides of the antibodies having binding specificity to IL-6. In one embodiment of the disclosure, polynucleotides of the disclosure comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable light chain polypeptide sequence of SEQ ID NO: 522:

ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGT GCCACATTTGCGCAAGTGCTGACCCAGACTGCATCGTCCGTGTCTGCAGCTGTGGGAG GCACAGTCACCATCAATTGCCAGTCCAGTCAGAGTGTTTATAATAACTACTTATCCTGGT ATCAGCAGAAACCAGGGCAGCCTCCCAAGCTCCTGATCTATACTGCATCCAGCCTGGC ATCTGGGGTCCCATCGCGGTTCAAAGGCAGTGGATCTGGGACACAGTTCACTCTCACC ATCAGCGAAGTGCAGTGTGACGATGCTGCCACTTACTACTGTCAAGGCTATTATAGTGG TCCTATAATTACT (SEQ ID NO: 530).

In another embodiment of the disclosure, polynucleotides of the disclosure comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable heavy chain polypeptide sequence of SEQ ID NO: 523:

ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTCGCTGTGCTCAAAGGTGTCCAGTGTC AGTCGCTGGAGGAGTCCGGGGGTCGCCTGGTCACGCCTGGGACACCCCTGACACTCA CCTGCACAGCCTCTGGATTCTCCCTCAATAACTACTACATACAATGGGTCCGCCAGGCT CCAGGGGAGGGGCTGGAATGGATCGGGATCATTTATGCTGGTGGTAGCGCATACTAC GCGACCTGGGCAAACGGCCGATTCACCATCGCCAAAACCTCGTCGACCACGGTGGAT CTGAAGATGACCAGTCTGACAACCGAGGACACGGCCACCTATTTCTGTGCCAGAGGGA CATTTGATGGTTATGAGTTG (SEQ ID NO: 531).

In a further embodiment of the disclosure, polynucleotides encoding fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist of, one or more of the polynucleotide sequences of SEQ ID NO: 532; SEQ ID NO: 533; and SEQ ID NO: 534 which correspond to polynucleotides encoding the complementarity-determining regions (CDRs, or hypervariable regions) of the light chain variable sequence of SEQ ID NO: 522.

In a further embodiment of the disclosure, polynucleotides encoding fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist of, one or more of the polynucleotide sequences of SEQ ID NO: 535; SEQ ID NO: 536; and SEQ ID NO: 537 which correspond to polynucleotides encoding the complementarity-determining regions (CDRs, or hypervariable regions) of the heavy chain variable sequence of SEQ ID NO: 523. The disclosure also contemplates polynucleotide sequences including one or more of the polynucleotide sequences encoding antibody fragments described herein. In one embodiment of the disclosure, polynucleotides encoding fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist of, one, two, three or more, including all of the following polynucleotides encoding antibody fragments: the polynucleotide SEQ ID NO: 530 encoding the light chain variable region of SEQ ID NO: 522; the polynucleotide SEQ ID NO: 531 encoding the heavy chain variable region of SEQ ID NO: 523; polynucleotides encoding the complementarity-determining regions (SEQ ID NO: 532; SEQ ID NO: 533; and SEQ ID NO: 534) of the light chain variable region of SEQ ID NO: 522; and polynucleotides encoding the complementarity-determining regions (SEQ ID NO: 535; SEQ ID NO: 536; and SEQ ID NO: 537) of the heavy chain variable region of SEQ ID NO: 523.

The disclosure is further directed to polynucleotides encoding polypeptides of the antibodies having binding specificity to IL-6. In one embodiment of the disclosure, polynucleotides of the disclosure comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable light chain polypeptide sequence of SEQ ID NO: 538:

ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGT GCCACATTTGCCCAAGTGCTGACCCAGACTCCATCCCCTGTGTCTGTCCCTGTGGGAG ACACAGTCACCATCAGTTGCCAGTCCAGTGAGAGCGTTTATAGTAATAACCTCTTATCC TGGTATCAGCAGAAACCAGGGCAGCCTCCCAAGCTCCTGATCTACAGGGCATCCAATC TGGCATCTGGTGTCCCATCGCGGTTCAAAGGCAGTGGATCTGGGACACAGTTCACTCT CACCATCAGCGGCGCACAGTGTGACGATGCTGCCACTTACTACTGTCAAGGCTATTATA GTGGTGTCATTAATAGT (SEQ ID NO: 546).

In another embodiment of the disclosure, polynucleotides of the disclosure comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable heavy chain polypeptide sequence of SEQ ID NO: 539:

ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTCGCTGTGCTCAAAGGTGTCCAGTGTC AGTCGGTGGAGGAGTCCGGGGGTCGCCTGGTCACGCCTGGGACACCCCTGACACTCA CCTGCACAGTGTCTGGATTCTCCCTCAGTAGCTACTTCATGAGCTGGGTCCGCCAGGC TCCAGGGGAGGGGCTGGAATACATCGGATTCATTAATCCTGGTGGTAGCGCATACTAC GCGAGCTGGGCGAGTGGCCGACTCACCATCTCCAAAACCTCGACCACGGTAGATCTGA AAATCACCAGTCCGACAACCGAGGACACGGCCACCTATTTCTGTGCCAGGATTCTTATT GTTTCTTATGGAGCCTTTACCATC (SEQ ID NO: 547).

In a further embodiment of the disclosure, polynucleotides encoding fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist of, one or more of the polynucleotide sequences of SEQ ID NO: 548; SEQ ID NO: 549; and SEQ ID NO: 550 which correspond to polynucleotides encoding the complementarity-determining regions (CDRs, or hypervariable regions) of the light chain variable sequence of SEQ ID NO: 538. In a further embodiment of the disclosure, polynucleotides encoding fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist of, one or more of the polynucleotide sequences of SEQ ID NO: 551 ; SEQ ID NO: 552; and SEQ ID NO: 553 which correspond to polynucleotides encoding the complementarity-determining regions (CDRs, or hypervariable regions) of the heavy chain variable sequence of SEQ ID NO: 539.

The disclosure also contemplates polynucleotide sequences including one or more of the polynucleotide sequences encoding antibody fragments described herein. In one embodiment of the disclosure, polynucleotides encoding fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist of, one, two, three or more, including all of the following polynucleotides encoding antibody fragments: the polynucleotide SEQ ID NO: 546 encoding the light chain variable region of SEQ ID NO: 538; the polynucleotide SEQ ID NO: 547 encoding the heavy chain variable region of SEQ ID NO: 539; polynucleotides encoding the complementarity-determining regions (SEQ ID NO: 548; SEQ ID NO: 549; and SEQ ID NO: 550) of the light chain variable region of SEQ ID NO: 538; and polynucleotides encoding the complementarity-determining regions (SEQ ID NO: 551 ; SEQ ID NO: 552; and SEQ ID NO: 553) of the heavy chain variable region of SEQ ID NO: 539.

The disclosure is further directed to polynucleotides encoding polypeptides of the antibodies having binding specificity to IL-6. In one embodiment of the disclosure, polynucleotides of the disclosure comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable light chain polypeptide sequence of SEQ ID NO: 554:

ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGT GCCAGATGTGCCTATGATATGACCCAGACTCCAGCCTCTGTGGAGGTAGCTGTGGGAG GCACAGTCACCATCAAGTGCCAGGCCACTGAGAGCATTGGCAATGAGTTATCCTGGTA TCAGCAGAAACCAGGGCAGGCTCCCAAGCTCCTGATCTATTCTGCATCCACTCTGGCA TCTGGGGTCCCATCGCGGTTCAAAGGCAGTGGATCTGGGACACAGTTCACTCTCACCA TCACCGGCGTGGAGTGTGATGATGCTGCCACTTACTACTGTCAACAGGGTTATAGTAGT GCTAATATTGATAATGCT (SEQ ID NO: 562).

In another embodiment of the disclosure, polynucleotides of the disclosure comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable heavy chain polypeptide sequence of SEQ ID NO: 555:

ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTCGCTGTGCTCAAAGGTGTCCAGTGTC AGTCGCTGGAGGAGTCCGGGGGTCGCCTGGTCACGCCTGGGACACCCCTGACACTCA CCTGCACCGTCTCTGGATTCTCCCTCAGTAAGTACTACATGAGCTGGGTCCGCCAGGC TCCAGAGAAGGGGCTGAAATACATCGGATACATTGATAGTACTACTGTTAATACATACTA CGCGACCTGGGCGAGAGGCCGATTCACCATCTCCAAAACCTCGACCACGGTGGATCT GAAGATCACCAGTCCGACAAGTGAGGACACGGCCACCTATTTCTGTGCCAGAGGAAGT

ACTTATTTTACTGATGGAGGCCATCGGTTGGATCTC (SEQ ID NO: 563).

In a further embodiment of the disclosure, polynucleotides encoding fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist of, one or more of the polynucleotide sequences of SEQ ID NO: 564; SEQ ID NO: 565; and SEQ ID NO: 566 which correspond to polynucleotides encoding the complementarity-determining regions (CDRs, or hypervariable regions) of the light chain variable sequence of SEQ ID NO: 554.

In a further embodiment of the disclosure, polynucleotides encoding fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist of, one or more of the polynucleotide sequences of SEQ ID NO: 567; SEQ ID NO: 568; and SEQ ID NO: 569 which correspond to polynucleotides encoding the complementarity-determining regions (CDRs, or hypervariable regions) of the heavy chain variable sequence of SEQ ID NO: 555.

The disclosure also contemplates polynucleotide sequences including one or more of the polynucleotide sequences encoding antibody fragments described herein. In one embodiment of the disclosure, polynucleotides encoding fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist of, one, two, three or more, including all of the following polynucleotides encoding antibody fragments: the polynucleotide SEQ ID NO: 562 encoding the light chain variable region of SEQ ID NO: 554; the polynucleotide SEQ ID NO: 563 encoding the heavy chain variable region of SEQ ID NO: 555; polynucleotides encoding the complementarity-determining regions (SEQ ID NO: 564; SEQ ID NO: 565; and SEQ ID NO: 566) of the light chain variable region of SEQ ID NO: 554; and polynucleotides encoding the complementarity-determining regions (SEQ ID NO: 567; SEQ ID NO: 568; and SEQ ID NO: 569) of the heavy chain variable region of SEQ ID NO: 555.

The disclosure is further directed to polynucleotides encoding polypeptides of the antibodies having binding specificity to IL-6. In one embodiment of the disclosure, polynucleotides of the disclosure comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable light chain polypeptide sequence of SEQ ID NO: 570:

ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGT GCCAGATGTGCCTATGATATGACCCAGACTCCAGCCTCTGTGGAGGTAGCTGTGGGAG GCACAGTCACCATCAAGTGCCAGGCCACTGAGAGCATTGGCAATGAGTTATCCTGGTA TCAGCAGAAACCAGGGCAGGCTCCCAAGCTCCTGATCTATTCTGCATCCACTCTGGCA TCTGGGGTCCCATCGCGGTTCAAAGGCAGTGGATCTGGGACACAGTTCACTCTCACCA TCACCGGCGTGGAGTGTGATGATGCTGCCACTTACTACTGTCAACAGGGTTATAGTAGT GCTAATATTGATAATGCT (SEQ ID NO: 578). In another embodiment of the disclosure, polynucleotides of the disclosure comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable heavy chain polypeptide sequence of SEQ ID NO: 571 :

ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTCGCTGTGCTCAAAGGTGTCCAGTGTC AGTCGCTGGAGGAGTCCGGGGGTCGCCTGGTAACGCCTGGGACACCCCTGACACTCA CCTGCACAGTCTCTGGATTCTCCCTCAGTACCTACAACATGGGCTGGGTCCGCCAGGC TCCAGGGAAGGGGCTGGAATGGATCGGAAGTATTACTATTGATGGTCGCACATACTAC GCGAGCTGGGCGAAAGGCCGATTCACCGTCTCCAAAAGCTCGACCACGGTGGATCTG AAAATGACCAGTCTGACAACCGGGGACACGGCCACCTATTTCTGTGCCAGGATTCTTAT TGTTTCTTATGGGGCCTTTACCATC (SEQ ID NO: 579).

In a further embodiment of the disclosure, polynucleotides encoding fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist of, one or more of the polynucleotide sequences of SEQ ID NO: 580; SEQ ID NO: 581 ; and SEQ ID NO: 582 which correspond to polynucleotides encoding the complementarity-determining regions (CDRs, or hypervariable regions) of the light chain variable sequence of SEQ ID NO: 570.

In a further embodiment of the disclosure, polynucleotides encoding fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist of, one or more of the polynucleotide sequences of SEQ ID NO: 583; SEQ ID NO: 584; and SEQ ID NO: 585 which correspond to polynucleotides encoding the complementarity-determining regions (CDRs, or hypervariable regions) of the heavy chain variable sequence of SEQ ID NO: 571.

The disclosure also contemplates polynucleotide sequences including one or more of the polynucleotide sequences encoding antibody fragments described herein. In one embodiment of the disclosure, polynucleotides encoding fragments of the antibody having binding specificity to IL-6 comprise, or alternatively consist of, one, two, three or more, including all of the following polynucleotides encoding antibody fragments: the polynucleotide SEQ ID NO: 578 encoding the light chain variable region of SEQ ID NO: 570; the polynucleotide SEQ ID NO: 579 encoding the heavy chain variable region of SEQ ID NO: 571 ; polynucleotides encoding the complementarity-determining regions (SEQ ID NO: 580; SEQ ID NO: 581 ; and SEQ ID NO: 582) of the light chain variable region of SEQ ID NO: 570; and polynucleotides encoding the complementarity-determining regions (SEQ ID NO: 583; SEQ ID NO: 584; and SEQ ID NO: 585) of the heavy chain variable region of SEQ ID NO: 571 .

In another embodiment of the disclosure, polynucleotides of the disclosure further comprise, the following polynucleotide sequence encoding the kappa constant light chain sequence of SEQ ID NO: 586:

GTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAAC TGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGA AGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACA GCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACG AGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCAC AAAGAGCTTCAACAGGGGAGAGTGT (SEQ ID NO: 587).

In another embodiment of the disclosure, polynucleotides of the disclosure further comprise, the following polynucleotide sequence encoding the gamma-1 constant heavy chain polypeptide sequence of SEQ ID NO: 588:

GCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTG GGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGG TGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTAC AGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGG CACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAG AGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTG AACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCAT GATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCC TGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAG CCGCGGGAGGAGCAGTACGCCAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTG CACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCC CAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGT GTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTG CCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCA GCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTC CTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCAT GCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTC TCCGGGTAAA (SEQ ID NO: 589).

In one embodiment, the disclosure is directed to an isolated polynucleotide comprising a polynucleotide encoding an anti-IL-6 VH antibody amino acid sequence selected from SEQ ID NO: 3, 18, 19, 22, 38, 54, 70, 86, 102, 1 17, 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 or encoding a variant thereof wherein at least one framework residue (FR residue) has been substituted with an amino acid present at the corresponding position in a rabbit anti-IL-6 antibody VH polypeptide or a conservative amino acid substitution.

In another embodiment, the disclosure is directed to an isolated polynucleotide comprising the polynucleotide sequence encoding an anti-IL-6 VL antibody amino acid sequence of 2, 20, 21 , 37, 53, 69, 85, 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 or encoding a variant thereof wherein at least one framework residue (FR residue) has been substituted with an amino acid present at the corresponding position in a rabbit anti-IL- 6 antibody VL polypeptide or a conservative amino acid substitution.

In yet another embodiment, the disclosure is directed to one or more heterologous polynucleotides comprising a sequence encoding the polypeptides contained in SEQ ID NO:2 and SEQ ID NO:3; SEQ ID NO:2 and SEQ ID NO:18; SEQ ID NO:2 and SEQ ID NO:19; SEQ ID NQ:20 and SEQ ID NO:3; SEQ ID NQ:20 and SEQ ID NO:18; SEQ ID NQ:20 and SEQ ID NO:19; SEQ ID NO:21 and SEQ ID NO:22; SEQ ID NO:37 and SEQ ID NO:38; SEQ ID NO:53 and SEQ ID NO:54; SEQ ID NO:69 and SEQ ID NQ:70; SEQ ID NO:85 and SEQ ID NO:86; SEQ ID NQ:101 and SEQ ID NQ:102; SEQ ID NQ:101 and SEQ ID NO:117; SEQ ID NQ:101 and SEQ ID NO:1 18; SEQ ID NO:1 19 and SEQ ID NQ:102; SEQ ID NO:119 and SEQ ID NO:117; SEQ ID NO:119 and SEQ ID NO:118; SEQ ID NO:122 and SEQ ID NO:123; SEQ ID NO:138 and SEQ ID NO:139; SEQ ID NO:154 and SEQ ID NO:155; SEQ ID NQ:170 and SEQ ID NO:171 ; SEQ ID NO:186 and SEQ ID NO:187; SEQ ID NQ:202 and SEQ ID NQ:203; SEQ ID NO:218 and SEQ ID NO:219; SEQ ID NO:234 and SEQ ID NO:235; SEQ ID NQ:250 and SEQ ID NO:251 ; SEQ ID NO:266 and SEQ ID NO:267; SEQ ID NO:282 and SEQ ID NO:283; SEQ ID NO:298 and SEQ ID NO:299; SEQ ID NO:314 and SEQ ID NO:315; SEQ ID NQ:330 and SEQ ID NO:331 ; SEQ ID NO:346 and SEQ ID NO:347; SEQ ID NO:362 and SEQ ID NO:363; SEQ ID NO:378 and SEQ ID NO:379; SEQ ID NO:394 and SEQ ID NO:395; SEQ ID NO:410 and SEQ ID NO:411 ; SEQ ID NO:426 and SEQ ID NO:427; SEQ ID NO:442 and SEQ ID NO:443; SEQ ID NO:458 and SEQ ID NO:459; SEQ ID NO:474 and SEQ ID NO:475; SEQ ID NQ:490 and SEQ ID NO:491 ; SEQ ID NQ:506 and SEQ ID NQ:507; SEQ ID NO:522 and SEQ ID NO:523; SEQ ID NO:538 and SEQ ID NO:539; SEQ ID NO:554 and SEQ ID NO:555; or SEQ ID NQ:570 and SEQ ID NO:571 .

In another embodiment, the disclosure is directed to an isolated polynucleotide that expresses a polypeptide containing at least one CDR polypeptide derived from an anti-IL-6 antibody wherein said expressed polypeptide alone specifically binds IL-6 or specifically binds IL-6 when expressed in association with another polynucleotide sequence that expresses a polypeptide containing at least one CDR polypeptide derived from an anti-IL-6 antibody wherein said at least one CDR is selected from those contained in the VL or VH polypeptides contained in SEQ ID NO: 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; 571 ; 2, 20, 21 , 37, 53, 69, 85, 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.

Host cells and vectors comprising said polynucleotides are also contemplated.

The disclosure further contemplates vectors comprising the polynucleotide sequences encoding the variable heavy and light chain polypeptide sequences, as well as the individual complementarity determining regions (CDRs, or hypervariable regions) set forth herein, as well as host cells comprising said sequences. In one embodiment of the disclosure, the host cell is a yeast cell. In another embodiment of the disclosure, the yeast host cell belongs to the genus Pichia.

Administration

As noted above, antibodies herein may be administered in a therapeutically effective amount in order for use in treating myocarditis in a human subject in need thereof. In some embodiments, administration is subcutaneous. In some cases, administration is intravenous. In other cases, an alternative form of administration, such as intra-nasal or inhalation may be used. A therapeutically effective amount may comprise a concentration of between 0.3 and 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. The dosage of the antibody may comprise from 3, 4, 5, 6, 7, 8, 9, 10, 12, 12.5, 15, 20, 24, 25, 36, 40, 60, or 100 mg, or may comprise any amount intervening the foregoing mg values. In a one embodiment of the disclosure, the anti-IL-6 or anti-IL-6R antibodies described herein may be administered to a recipient subject with a frequency of once every twenty-six weeks or less, such as once every sixteen weeks or less, once every eight weeks or less, once every six weeks, once every four weeks or monthly, once every three weeks, or once every two weeks or biweekly, for example. In one embodiment, the antibody is administered every 4 weeks or monthly. In some embodiments, the antibody is administered for at least 4, 6, 9, 10, 12, 14, 16, 18, 20, 22, 24, or 36 months. In some cases, the antibody is administered for at least 3 months, at least 6 months, at least 9 months, at least 1 year, or at least 2 years.

It is understood that the effective dosage may depend on recipient subject attributes, such as, for example, age, gender, pregnancy status, body mass index, lean body mass, condition or conditions for which the composition is given, other health conditions of the recipient subject that may affect metabolism or tolerance of the composition, levels of IL-6 in the recipient subject, and resistance to the composition (for example, arising from the patient developing antibodies against the composition). A person of skill in the art would be able to determine an effective dosage and frequency of administration through routine experimentation, for example guided by the disclosure herein and the teachings in Goodman, L. S., Gilman, A., Brunton, L. L., Lazo, J. S., & Parker, K. L. (2006). Goodman & Gilman's the pharmacological basis of therapeutics. New York: McGraw-Hill; Howland, R. D., Mycek, M. J., Harvey, R. A., Champe, P. C., & Mycek, M. J. (2006). Pharmacology. Lippincott's illustrated reviews. Philadelphia: Lippincott Williams & Wilkins; and Golan, D. E. (2008). Principles of pharmacology: the pathophysiologic basis of drug therapy. Philadelphia, Pa., [etc.]: Lippincott Williams & Wilkins.

Pharmaceutical Compositions

In some embodiments of the disclosure, the anti-IL-6 or anti-IL-6R antibodies are administered to a subject in a pharmaceutical composition. A “pharmaceutical composition” refers to a chemical or biological composition suitable for administration to a mammal. Such compositions may be specifically formulated for administration via one or more of a number of routes, including but not limited to buccal, epicutaneous, epidural, inhalation, intraarterial, intracardial, intracerebroventricular, intradermal, intramuscular, intranasal, intraocular, intraperitoneal, intraspinal, intrathecal, intravenous, oral, parenteral, rectally via an enema or suppository, subcutaneous, subdermal, sublingual, transdermal, and transmucosal. In addition, administration can occur by means of injection, powder, liquid, gel, drops, or other means of administration.

The antibodies in some cases are administered in a composition containing pharmaceutical excipient” or a “pharmaceutically acceptable excipient”. A “pharmaceutical excipient” or a “pharmaceutically acceptable excipient” is a carrier, usually a liquid, in which an active therapeutic agent is formulated. In one embodiment of the disclosure, the active therapeutic agent is a humanized antibody described herein. The excipient generally does not provide any pharmacological activity to the formulation, though it may provide chemical and/or biological stability, and release characteristics. Exemplary formulations can be found, for example, in Remington’s Pharmaceutical Sciences, 19th Ed., Grennaro, A., Ed., 1995 which is incorporated by reference.

As used herein “pharmaceutically acceptable carrier” or “excipient” includes any and all liquid or solid filler, diluent, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and combinations thereof that are physiologically compatible. In one embodiment, the carrier is suitable for parenteral administration. Alternatively, the carrier can be suitable for intravenous, intraperitoneal, intramuscular, or sublingual administration. Pharmaceutically acceptable carriers include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the pharmaceutical compositions of the disclosure is contemplated. Supplementary active compounds can also be incorporated into the compositions.

Pharmaceutical compositions typically must be sterile and stable under the conditions of manufacture and storage. In some embodiments, the pharmaceutical composition is present in lyophilized form. The composition can be formulated as a solution, microemulsion, liposome, or other ordered structure suitable to high drug concentration. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof. The disclosure further contemplates the inclusion of a stabilizer in the pharmaceutical composition.

In some embodiments, isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride are included in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, monostearate salts and gelatin. Moreover, the alkaline polypeptide can be formulated in a time release formulation, for example in a composition which includes a slow release polymer. The active compounds can be prepared with carriers that will protect the compound against rapid release, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, polylactic acid and polylactic, polyglycolic copolymers (PLG). Many methods for the preparation of such formulations are known to those skilled in the art.

The compounds can be administered by a variety of dosage forms. Any biologically- acceptable dosage form known to persons of ordinary skill in the art, and combinations thereof, are contemplated. Examples of such dosage forms include, without limitation, reconstitutable powders, elixirs, liquids, solutions, suspensions, emulsions, powders, granules, particles, microparticles, dispersible granules, cachets, inhalants, aerosol inhalants, patches, particle inhalants, implants, depot implants, injectables (including subcutaneous, intramuscular, intravenous, and intradermal), infusions, and combinations thereof.

“Parenteral” refers to a route of administration that is generally associated with injection, including intraorbital, infusion, intraarterial, intracapsular, intracardiac, intradermal, intramuscular, intraperitoneal, intrapulmonary, intraspinal, intrasternal, intrathecal, intrauterine, intravenous, subarachnoid, subcapsular, subcutaneous, transmucosal, or transtracheal. In some embodiments, the administration is by subcutaneous or intravenous administration. Via the parenteral route, the compositions may be in the form of solutions or suspensions for infusion or for injection, or as lyophilized powders. Via the parenteral route, the compositions may be in the form of solutions or suspensions for infusion or for injection. Via the enteral route, the pharmaceutical compositions can be in the form of tablets, gel capsules, sugar-coated tablets, syrups, suspensions, solutions, powders, granules, emulsions, microspheres or nanospheres or lipid vesicles or polymer vesicles allowing controlled release. Typically, the compositions are administered by injection. Methods for these administrations are known to one skilled in the art.

Other Anti-Myocarditis Agents or Therapies

In some embodiments, one or more additional therapeutic agents, such as other anti- myocartitis agents may be administered along with the anti-IL-6 or anti-IL-6R antibody. Thus, for example, these may include a corticosteroid, an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin II receptor blocker (ARB), a beta blocker, an intravenous IgG (MG) or subcutaneous IgG (SCIG), and/or a diuretic. Such agents may be administered in conjunction with the antibody, such as at the same time (i.e., simultaneously) or during the same treatment visit or on the same day, or they may be administered sequentially, such as with an intervening period of several hours, or at least one day. In some cases, a pharmaceutical composition may comprise both the antibody and at least one other antimyocarditis agent.

In some embodiments, the pharmaceutical composition may be administered with one or more additional myocarditis treatments such as mechanical support In some embodiments, the mechanical support comprises one or more of extracorporeal membrane oxygenation (ECMO), intra-aortic balloon pump (IABP), and hemodynamic stabilization (e.g., with a heart pump, such as an IMPELLA® device (ABIOMED®, Massachusetts).

The above description of various illustrated embodiments of the disclosure is not intended to be exhaustive or to limit the disclosure to the precise form disclosed. While specific embodiments of, and examples for, the disclosure are described herein for illustrative purposes, various equivalent modifications are possible within the scope of the disclosure, as those skilled in the relevant art will recognize. The teachings provided herein of the disclosure can be applied to other purposes, other than the examples described above.

These and other changes can be made to the disclosure in light of the above detailed description. In general, in the following claims, the terms used should not be construed to limit the disclosure to the specific embodiments disclosed in the specification and the claims. Accordingly, the disclosure is not limited by the disclosure, but instead the scope of the disclosure is to be determined entirely by the following claims.

The disclosure may be practiced in ways other than those particularly described in the foregoing description and examples. Numerous modifications and variations of the disclosure are possible in light of the above teachings and, therefore, are within the scope of the appended claims.

The entire disclosure of each document cited (including patents, patent applications, journal articles, abstracts, manuals, books, or other disclosures) is herein incorporated by reference in their entireties.

The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the subject disclosure, and are not intended to limit the scope of what is regarded as the disclosure. Efforts have been made to ensure accuracy with respect to the numbers used (e.g., amounts, temperature, concentrations, etc.) but some experimental errors and deviations should be allowed for. Unless otherwise indicated, parts are parts by weight, molecular weight is average molecular weight, temperature is in degrees centigrade; and pressure is at or near atmospheric. EXAMPLES

Example 1. Efficacy of Clazakizumab (Anti-IL-6) Murine Surrogate in Viral (CVB3- Induced) Myocarditis Model

42 Balb/c mice are administered 2.8 x 103 PFU 2^nd heart passaged ATCC coxsackievirus B3 (CVB3) at day 0. Mice were administered a low dose of 5 mg/kg i.p. (14 mice) or a high dose of 50 mg/kg i.p. (14 mice) of a murine anti-IL-6 antibody , or a high dose isotype control (14 mice) after a baseline echocardiogram at days 4, 7, 1 1 , 18, 25, and 31. Due to severe mortality/morbidity in treatment groups, the experiment ended early (day 20/21 post infection). In the CVB3 myocarditis model, cardiac inflammation (myocarditis) is expected to peak about day 7, fibrosis is expected to start at day 14. Further, IL-6 cytokine was known to peak around day 14, and cardiac dysfunction starts at day 14. CVB3 myocarditis model was established as reported by Fairweather et al., Methods 2007 Jan; 41 (1):118-122.

Cardiac function by echocardiography was measured on days 0, 4, 7, 11 , and 18. Histology of cardiac tissues and plasma cytokines, chemokine levels, and RNA sequence analysis of heart were analyzed on day 21 .

Example 2. Efficacy of Anti-IL-6 Murine Surrogate in Experimental Autoimmune Myocarditis (EAM)

Goal: To examine the efficacy of anti-mouse IL-6 antibody treatment on cardiac and plasma outcomes in experimental autoimmune myocarditis (EAM).

Experimental Outline: Prior to immunization and baseline echocardiograms, 33 BALB/c mice were randomly assigned to isotype control, or 5 mg/kg or 25 mg/kg anti-IL-6 treatment groups (11 per group). Baseline echocardiograms were measured. Mice were treated with two subcutaneous immunizations of an emulsion of 150 pg of Myosin peptide and M.Tb (myobacterium tuberculosis) supplemented CFA (complete Freud adjuvant) on days 0 and 7. Mice were also given pertussis toxin intraperitoneally at day 0. Mice were treated with either isotype control or anti-IL-6 on days 7, 10, 14, 21 , 28, and 35. Echocardiograms were obtained again on days 7, 14, 21 , 28, 35, and 42 post first immunization. Mice were sacrificed on day 43. See Figure 1 .

Baseline measurements: Trans-thoracic echocardiography was performed on conscious mice using ACUSON Sequoia™ C256 imaging system (Siemens Medical Solutions USA, Inc.) equipped with a 13 MHz transducer. In conscious mice, the heart was imaged in the 2D mode in the parasternal short-axis view. From the M-mode, the left ventricular wall thickness and chamber dimensions was measured; interventricular septal (IVS) wall thickness, posterior wall (PW) thickness, and end-left ventricular diameter in systolic and diastolic. From these parameters, left ventricular (LV) shortening fraction (SF), LV ejection fraction (EF), and LV mass was calculated. There were no statistically significant differences in baseline weight and cardiac function (measured by ejection fraction (EF) and fractional shortening (FS or SF)) between groups.

Anatomical measurements: Animals were weighed on days 7, 10, 14, 21 , 28, 35, and 42 to determine the body weight. Treatment with 5 mg/kg or 25 mg/kg of anti-IL-6 significantly protected against weight loss on days 10 and 14 (Figure 2). Treatment with the low dose and high dose of anti-IL-6 antibody significantly protected against weight loss on days 10 and 14, compared to isotype control group (Figure 2). The protection against weight loss extended until day 21 with the low dose anti-IL-6 antibody group. Mice that received the high dose anti- IL-6 treatment had a statistically significant increase in the heart weight/spleen weight, spleen/body weight, and spleen/tibia length ratios (Figures 3A to 3E) as compared to isotype control.

Fibrosis Scoring: Mice were euthanized by cervical dislocation under Avertin® (tribromoethanol) anesthesia and after retroorbital blood collection. Hearts were perfused using continuous flow of 1X PBS for 10 minutes. Resected hearts were cut longitudinally. The half heart with left ventricle (LV) was fixed and 5 pm thick slide sections were stained with H&E (hematoxylin and eosin). Intracardiac fibrosis was assessed by staining of heart sections with Masson’s Trichrome blue and hydroxyproline determination. The scoring system for inflammation and fibrosis will be as follows: grade 0 - no inflammation; grade 1 - less than 10 percent of the heart section is involved; grade 2 - 10 to 30 percent; grade 3 - 30 to 50 percent; grade 4 - 50 to 90 percent; and grade 5 - more than 90 percent. Scoring of blinded slides was done by two independent investigators.

Nonparametric fibrosis scores were not significantly different between groups (see Figure 4). A Matlab code was used to separate fibrotic area from healthy tissue based on set hue and saturation values to calculate the area of the heart that is fibrotic. Then the high dose anti-IL- 6 treatment had significantly less fibrotic area compared to isotype control, particularly in the ventricles.

Echocardiography. Trans-thoracic echocardiography was performed on conscious mice using ACUSON Sequoia™ C256 imaging system equipped with a 13 MHz transducer (Siemens Medical Solutions USA, Inc.). In conscious mice, the heart was imaged in the 2D mode in the parasternal short-axis view. From the M-mode, the left ventricular wall thickness and chamber dimensions was measured; interventricular septal (IVS) wall thickness, posterior wall (PW) thickness, and end-left ventricular diameter in systolic and diastolic. From these parameters, left ventricular (LV) shortening fraction (SF), LV ejection fraction (EF) and LV mass was calculated.

For ejection fraction (EF) changes (Figure5A), and fractional shortening (FS or SF) changes (Figure 5B), all groups saw decline in cardiac function between baseline and day 42. The high dose (25 mg/kg) anti-IL-6 group saw less of a decline in EF and FS across time compared to isotype control. Post-hoc analysis shows statistically significant differences in EF and FS between Isotype and 25mg/kg anti-IL-6 on days 14 and 42.

For left ventricular internal diameter (LVID), all groups saw an increase in LVID end diastole (LVID;d) (Figure 6A) and LVID end systole (LVID;s) (Figure 6B) between baseline and day 42. The high dose (25 mg/kg) anti-IL-6 group saw less of a decline in EF and FS across time compared to isotype control. Linear mixed effect (LME) model (repeated measures ANOVA) analysis and Dunnett test (with Kenward-Roger degrees of freedom adjustment) showed statistically significant differences in EF and FS between Isotype control and 25 mg/kg anti-IL- 6 on days 14, 28 and 42 (Figures 5A and 5B). Low dose (5 mg/kg) anti-IL-6 showed statistically significant differences in EF and FS compared to Isotype control on day 28).

For left ventricular internal diameter (LVID), all groups saw an increase in LVID end diastole (LVID;d) (Figure 6A) and LVID end systole (LVID;s) (Figure 6B) between baseline and day 42. The high dose anti-IL-6 group saw significantly less increase in LVID;d (Figure 6A) and LVID;s (Figure 6B) compared to isotype control on days 28 and 42.

For interventricular septum (IVS), all groups saw a decline in IVS end diastole (IVS;d) (Figure 7 A) and IVS end systole (IVS;s) (Figure 7B) between baseline and day 42. Linear mixed effect model (repeated measures ANOVA) and Dunnett test (with Kenward-Roger degrees of freedom adjustment) analysis showed statistically significant differences in IVS;d between Isotype control and 5 mg/kg anti-IL-6 on day 14 (Figure 7A). IVS;s was statistically significant between Isotype control and 5 mg/kg anti-IL-6 on days 21 and 28 (Figure 7B).

All groups saw a decline in left ventricular posterior wall (LVPW) thickness end diastole (LVPW;d) (Figure 8A) and LVPW end systole (LVPW;s) (Figure 8B) between baseline and day 42. There were no differences between treatment groups in the change of LVPW over time.

Plasma assays: Plasma cytokines and chemokines were measured using commercial ELISA kits. One way ANOVA with Tukey’s multiple comparisons was used for all plasma assay results in Figures 9 to 15A-D. Note that the dotted line means limit of detection for all measurements.

IL-6: IL-6 levels (pg/mL) were greater in the treatment groups than isotype control (Figure 9). This may be due to the detection of IL-6 antibody immune complexes by the assay.

Disease markers: Plasma levels of CRP, Myosin IgG and serum amyloid A (SAA) were significantly lower in low and high dose anti-IL-6 antibody treated groups compared to isotype control (Figures 18A-C). No difference was observed in Troponin IgG levels between treatment groups. D show plasma assays of inflammatory cytokines granulocyte macrophage colony-stimulating factor (GM-CSF) (Fig. 1 1 A), Interleukin 1 A (IL-1 A) (Fig. 1 1 B), IL-1 B (Fig. 11 C), and TNFa (Fig. 11 D). GM-CSF levels were significantly increased in the plasma of anti-IL-6 treated mice as compared to isotype (Fig. 11 A). No significant difference was observed between the treatment groups for other cytokines.

T cell cytokines: Figures 12A to 12C show plasma levels of T cell cytokines IL-2 (Fig. 12A), IL-7 (Fig. 12B), and IL-10 (Fig. 12C). Figure 13A shows plasma levels of Th1-related T cell cytokines IFNy and IL-12 (p70), Figure 13B shows plasma levels of Th2-related T cell cytokines IL-4, IL-5 and IL-13, and Figure 13C shows plasma levels of Th3-related T cell cytokines IL-17A. IL-13 levels were significantly elevated in the plasma of anti-IL-6 treated mice (Fig. 13B) as compared to the isotype control group. IL-12 (p70) was also significantly higher in the 25 mg/kg anti-IL-6 group than the isotype control group, but almost all the values were below the limit of detection (Fig. 13A).

Chemokines: Figures 14A to 14E show plasma assays of chemokines CXCL1 (KC) (Fig. 14A), CXCL2 (MIP-2) (Fig. 14B), CXCL5 (LIX) (Fig. 14C), CCL2 (MCP-1) (Fig. 14D), and CXCL16 (Fig. 14E). There were no differences in chemokine levels between the groups.

Biomarkers: Figures 15A to 15D show plasma assays of follistatin (Fig. 15A), placenta growth factor 2 (PIGF-2) (Fig. 15B), NT-proBNP (Fig. 15C), and fibrinogen (Fig. 15D). No difference were observed between the treatment groups were observed. Endocan-1 , LIGHT, Oncostatin M, sCD40L, Troponin I, Troponin T were all undetectable in the plasma.

Example 3. Administration of Clazakizumab for Treatment of Acute or Subacute Myocarditis

A therapeutic composition comprising clazakizumab contained in phosphate buffered saline is administered via subcutaneous or intravenous administration to patients with acute or subacute myocarditis at antibody dosages of 5 to 12.5 mg. These antibody compositions are administered every 4 weeks or monthly for several months or years.

In these patients, the acute or subacute myocarditis is caused by viral infection or autoimmune disease.

Priorto administration ofthe humanized antibody serum levels of IL-6 and CRP are measured.

Weekly after antibody administration serum levels of IL-6 and CRP are measured.

Example 4. Administration of An Anti-IL-6 or Anti-IL-6R Antibody for Treatment of Acute or Subacute Myocarditis A therapeutic composition comprising an anti-IL-6 or anti-IL-6R antibody contained in phosphate buffered saline is administered via subcutaneous or intravenous administration to patients with acute or subacute myocarditis at antibody dosages of less than or equal to 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 12.5, 15, 20 or 25 mg. These antibody compositions are administered every 4 weeks or monthly for several months or years.

Priorto administration ofthe humanized antibody serum levels of IL-6 and CRP are measured. Weekly after antibody administration serum levels of IL-6 and CRP are measured. The foregoing written specification is considered to be sufficient to enable one skilled in the art to practice the embodiments. The foregoing description and Examples detail certain embodiments and describes the best mode contemplated by the inventors. It will be appreciated, however, that no matter how detailed the foregoing may appear in text, the embodiment may be practiced in many ways and should be construed in accordance with the appended claims and any equivalents thereof. References cited herein are incorporated herein by reference.

Claims

Claims

1. A method of treating myocarditis in a human subject in need thereof, comprising subcutaneously or intravenously administering to the human subject a therapeutically effective amount of an anti-IL-6 antibody once every 4 weeks or monthly.

2. 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 4 weeks or monthly.

3. The method of claim 1 or 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 variably 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 the preceding claims, wherein the antibody comprises the heavy chain polypeptide of SEQ ID NO: 704 and comprises the light chain polypeptide of SEQ ID NO: 702.

5. The method or use of any one of the preceding claims, wherein the antibody comprises human lgG1 constant regions.

6. The method or use of any one of the preceding claims, wherein the antibody is clazakizumab.

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

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

9. The method or use of any one of the preceding claims, 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. 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 . 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. The method or use of any one of the preceding claims, wherein the antibody is administered for at least 4, 6, 9, 10,

12, 14, 16, 18, 20, 22, 24, or 36 months.

13. The method or use of any one of the preceding claims, wherein the antibody is clazakizumab and is administered at a dose of 5 to 12.5 mg subcutaneously or intravenously every 4 weeks or monthly, optionally wherein 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. The method or use of any one of the preceding claims, wherein the human subject has an elevated pre-treatment serum C-reactive protein (CRP) level, optionally wherein the CRP level is determined by an hs-CRP test.

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

16. The method or use of any one of the preceding claims, wherein the human subject has an elevated pre-treatment serum IL-6 level.

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

18. The method or use of any one of the preceding claims, wherein the CRP level after treatment is decreased by at least 50%, 70%, 80%, or 90 % as compared to the pretreatment CRP level.

19. The method or use of any one of the preceding claims, wherein the method or use further comprises determining serum IL-6 or serum CRP level at least once post-treatment.

20. The method or use of any one of the preceding claims, wherein the human subject pretreatment has been diagnosed with reduced ejection fraction (such as < 45%), ventricular arrhythmia such as sustained ventricular arrhythmia, heart failure, chest pain, and/or cardiogenic shock.

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

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, an intravenous IgG (MG), a subcutaneous IgG (SCIG), and/or a diuretic.

23. The method or use of any one of the preceding claims, wherein the myocarditis is caused by one or more of the following: viral infection, bacterial infection, fungal infection, parasites, one or more medications, drugs, toxins, or chemicals, radiation, autoimmune disease or other inflammatory disease, or insect or other animal bite or sting.

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

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

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

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

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

29. The method of any one of the preceding claims, wherein the human subject has no active virus infection.

30. A method of treating acute or subacute myocarditis caused by viral infection or autoimmune disease in a human subject in need thereof, comprising administering subcutaneously or intravenously to the human subject a dose of less than 30 mg clazakizumab every 4 weeks or monthly.

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

33. The method of any one of claims 30-32, wherein the 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. The method of any one of claims 30-33, wherein the human subject pre-treatment has been diagnosed with reduced ejection fraction (such as < 45%), ventricular arrhythmia such as sustained ventricular arrhythmia, heart failure, presence of anti-cardiac antibodies (for example anti-myosin antibodies), increase in Troponin (Troponin I and T) levels, chest pain, and/or cardiogenic shock.

35. The method of any one of claims 30-34, wherein the treating comprises chronic care.

36. The method of any one of claims 30 to 35, wherein the human subject has no active

5 virus infection.