Methods for the prevention and treatment of long covid and related symptoms

Abstract

The present disclosure provides methods of preventing or treating a patient having Long COVID comprising subcutaneously administering to a patient in need thereof a therapeutically effective dose of an anti -interleukin-6 (anti-IL-6) antibody. The method described herein can prevent or treat Long COVID associated symptoms or diseases such as postural orthostatic tachycardia syndrome (POTS), brain fog, post-exertional malaise, aerobic metabolism impairment or deficiency, Chronic Fatigue Syndrome (CFS), fibromyalgia, and Mast cell activation syndrome (MCAS).

Description

157570.604279 METHODS FOR THE PREVENTION AND TREATMENT OF LONG COVID AND RELATED SYMPTOMS CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the priority of U.S. provisional application Ser. No. U.S. 63 / 607,366, filed December 7, 2023, which are incorporated herein by reference in its entirety for all purposes. REFERENCE TO AN ELECTRONIC SEQUENCE LISTING

[0002] The contents of the electronic sequence listing (TOUR_006_00US_SeqList_ST26.xml; Size: 13,983 bytes; and Date of Creation: November 21, 2023) are herein incorporated by reference in their entirety. TECHNICAL FIELD

[0003] The disclosure relates to therapeutic antibody molecules and treatments for Long COVID and related symptoms. BACKGROUND

[0004] Long COVID, or post-COVID-19 syndrome (PCS), is defined by National Institute for Health and Care Research and the WHO as the signs and symptoms of the disease that continue for more than 12 weeks after the initial acute COVID-19 infection. There have been over 577 million cases of COVID-19 worldwide. The number of patients with acute COVID-19 that go on to develop PCS has ranged from 3.0% to 14.1% with over 1 million people in the US only reporting Long COVID symptoms. Incidence of Long COVID will remain high due to recurrent waves of COVID and continually emerging new variants.

[0005] The symptoms of Long COVID include fatigue, breathlessness, brain fog, anosmia and mental health problems. These symptoms can cause debilitating functional and psychological limitations and have been shown to persist for up to 2 years. This has led to many people with Long COVID being unable to work or care for others for a prolonged157570.604279 period. The potential impact of Long COVID on national health services, economies and population health is significant.

[0006] To date, no targeted therapy has been proven to have sufficient benefit in improving recovery from COVID-19 or Long COVID. There remains an unmet need to develop effective treatment for Long COVID. SUMMARY

[0007] Provided herein is a method of preventing or treating a patient having Long COVID comprising administering to a patient in need thereof a therapeutically effective dose of an anti-interleukin-6 (anti-IL-6) antibody, wherein the anti-IL-6 antibody comprises a heavy chain variable region comprising HCDR1, HCDR2, and HCDR3, and a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein: (a) HCDR1 comprises SEQ ID NO: 2, or has an amino acid sequence which differs from SEQ ID NO: 2 at one, two, or three amino acid positions, HCDR2 comprises SEQ ID NO: 3, or has an amino acid sequence which differs from SEQ ID NO: 3 at one, two, or three amino acid positions, and HCDR3 comprises SEQ ID NO: 4, or has an amino acid sequence which differs from SEQ ID NO: 4 at one, two, or three amino acid positions; and (b) LCDR1 comprises SEQ ID NO: 8, or has an amino acid sequence which differs from SEQ ID NO:8 at one, two, or three amino acid positions, LCDR2 comprises SEQ ID NO: 9, or has an amino acid sequence which differs from SEQ ID NO: 9 at one, two, or three amino acid positions, and LCDR3 comprises SEQ ID NO: 10, or has an amino acid sequence which differs from SEQ ID NO: 10 at one, two, or three amino acid positions.

[0008] In some embodiments, the anti-IL-6 antibody comprises HCDR1 of SEQ ID NO: 2, HCDR2 of SEQ ID NO: 3, HCDR3 of SEQ ID NO: 4, LCDR1 of SEQ ID NO: 8, LCDR2 of SEQ ID NO: 9, and LCDR3 of SEQ ID NO: 10.

[0009] In some embodiments, the anti-IL-6 antibody comprises the heavy chain variable region comprising a polypeptide having at least 95% identity to SEQ ID NO: 5 and the light chain variable region comprising a polypeptide having at least 95% identity to SEQ157570.604279 ID NO: 11. In some embodiments, the anti-IL-6 antibody comprises the heavy chain variable region comprising a polypeptide having the sequence of SEQ ID NO: 5 and the light chain variable region comprising a polypeptide having the sequence of SEQ ID NO: 11.

[0010] In some embodiments, the anti-IL-6 antibody comprises a heavy chain polypeptide comprising a polypeptide having at least 95% identity to SEQ ID NO: 1 and a light chain polypeptide comprising a polypeptide having at least 95% identity to SEQ ID NO: 7. In some embodiments, the anti-IL-6 antibody comprises the heavy chain polypeptide having the sequence of SEQ ID NO: 1 and the light chain polypeptide having the sequence of SEQ ID NO: 7.

[0011] In some embodiments, the therapeutically effective dose is between about 10 mg to about 200 mg. In some embodiments, the therapeutically effective dose is about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 120 mg, about 140 mg, about 160 mg, about 180 mg, or about 200 mg. In some embodiments, the therapeutically effective dose is about 50 mg. In some embodiments, the therapeutically effective dose is about 100 mg.

[0012] In some embodiments, the therapeutically effective dose is administered from every 1 month to every 12 months. In some embodiments, the therapeutically effective dose is administered every 1 month, every 2 months, every 3 months, every 4 months, every 5 months, every 6 months, every 7 months, every 8 month, every 9 months, every 10 months, every 11 months, or every 12 months. In some embodiments, the therapeutically effective dose is administered every 3 months.

[0013] In some embodiments, the therapeutically effective dose is a single dose between about 10 mg to about 200 mg. In some embodiments, the therapeutically effective dose is a single dose of about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 120 mg, about 140 mg, about 160 mg, about 180 mg, or about 200 mg. In some embodiments, the single dose is administered after a period of about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 week, about 7 weeks, about 8 weeks, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 1.5 years, about 2157570.604279 years, about 3 years, or greater than 3 years after an acute, symptomatic or asymptomatic SARS-CoV-2 infection. In some embodiments, the single dose is administered within 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks after onset of an acute, symptomatic or asymptomatic SARS-CoV-2 infection to prevent Long COVID.

[0014] In some embodiments, the therapeutically effective dose is comprised of a primary dose and a booster dose. In some embodiments, the booster dose is identical to the primary dose. In some embodiments, the booster dose and primary dose are different. In some embodiments, the primary dose and the booster dose are between about 10 mg to about 200 mg each. In some embodiments, the primary dose and the booster dose are about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 120 mg, about 140 mg, about 160 mg, about 180 mg, or about 200 mg each. In some embodiments, the primary dose and the booster dose are about 1 month, about 2 month, about 3 months, about 4 months, about 5 months, about 6 months, or about 12 months apart. In some embodiments, the primary dose and the booster dose are about 3 months apart. In some embodiments, the primary dose is administered after a period of about 1 week, about 2 weeks, about 3 weeks about 4 weeks, about 5 weeks, about 6 week, about 7 weeks, about 8 weeks, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 1.5 years, about 2 years, about 3 years, or more after an acute, symptomatic or asymptomatic SARS-CoV-2 infection. In some embodiments, the primary dose is administered after a period of about at least 6 months after an acute, symptomatic or asymptomatic SARS-CoV-2 infection.

[0015] In some embodiments, the therapeutically effective dose is administered subcutaneously.

[0016] In some embodiments, the patient having Long COVID has a baseline serum level of IL-6 ≥ about 5.0, 10.0, 15.0, 20.0, 30.0, or 40.0 pg / mL. In some embodiments, the method described herein further comprises determining the baseline level of IL-6 in a serum sample obtained from the patient having Long COVID, and administering to the patient a therapeutically effective dose of the anti-IL-6 antibody if the baseline level of IL- 6 in the serum sample is ≥ about 5.0, 10.0, 15.0, 20.0, 30.0, or 40.0 pg / mL. In some157570.604279 embodiments, methods of the present disclosure comprises the treatment of subjects with a baseline serum level of IL-6 that is not elevated.

[0017] In some embodiments, the method leads to improved functional capacity within about 72 weeks, about 64 weeks, about 56 weeks, about 48 weeks, about 44 weeks, about 40 weeks, about 32 weeks, about 20 weeks, about 16 weeks, about 12 weeks, about 8 weeks, or about 4 weeks after receiving treatment. In some embodiments, the improvement is sustained for at least about 6 months, about 9 months, about 12 months, or about 18 months.

[0018] In some embodiments, the method leads to improved functional capacity as measured by cardiopulmonary exercise testing (CPET) compared to baseline. In some embodiments, the method leads to improved functional capacity as measured by CPET or by 2-day CPET compared to baseline at the 2-day CPET Day 1 and / or 2-day CPET Day 2 measurements.

[0019] In some embodiments, the method leads to an increase in peak VO2based upon CPET, 2-day CPET Day 1 and / or 2-day CPET Day 2 measurements by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% relative to baseline. In some embodiments, the method leads to an increase in peak VO2of about +3, or about +2, or about +1.5 mL / kg / min relative to baseline.

[0020] In some embodiments, the method leads to an increase in VO2at ventilatory anaerobic threshold (VAT) based upon CPET, 2-day CPET Day 1 and / or 2-day CPET Day 2 measurements by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% relative to baseline.

[0021] In some embodiments, the method leads to a mean increase in peak workload based upon CPET, 2-day CPET Day 1 and / or 2-day CPET Day 2 measurements by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% relative to baseline.157570.604279

[0022] In some embodiments, the method leads to a mean increase from baseline in peak workload based upon CPET, 2-day CPET Day 1 and / or 2-day CPET Day 2 measurements by at least 5 Watts (W), at least 10 W, at least 15 W, at least 20 W, at least 25 W, at least 30 W, at least 35 W, at least 40 W, at least 45 W, at least 50 W, at least 55 W, at least 60 W, at least 65 W, at least 70W, at least 75 W, at least 80 W, at least 85 W, at least 90 W, at least 95 W, or at least 100 W relative to baseline.

[0023] In some embodiments, the method leads to a mean increase in workload at VAT based upon CPET, 2-day CPET Day 1 and / or 2-day CPET Day 2 measurements by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% relative to baseline.

[0024] In some embodiments, the method leads to a mean increase from baseline in workload at VAT based upon CPET, 2-day CPET Day 1 and / or 2-day CPET Day 2 measurements by at least 5 Watts (W), at least 10 W, at least 15 W, at least 20 W, at least 25 W, at least 30 W, at least 35 W, at least 40 W, at least 45 W, at least 50 W, at least 55 W, at least 60 W, at least 65 W, at least 70W, at least 75 W, at least 80 W, at least 85 W, at least 90 W, at least 95 W, or at least 100 W relative to baseline.

[0025] In some embodiments, the method leads to resolution of post-exertional malaise in at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% of patients who had post-exertional malaise as at baseline.

[0026] In some embodiments, the method leads to a mean increase relative to baseline in the SF-36 score by at least 5, at least 10, at least 15, at least 20, at least 25, at least 30, at least 35, at least 40, at least 45, or at least 50 in the overall score or in at least one of the domains comprising the overall SF-36. In some embodiments, the at least one of the domains is selected from physical functioning, role limitations due to physical health, role limitations due to emotional problems, energy / fatigue, emotional well-being, social functioning, pain, and general health.157570.604279

[0027] In some embodiments, the method leads to a mean increase in the Karnofsky Performance Scale by at least 10, at least 20, at least 30, at least 40, or at least 50 relative to baseline.

[0028] In some embodiments, the method leads to a mean increase in the Functional Capacity Scale by at least 10, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90, or at least 100 relative to baseline.

[0029] In some embodiments, the method leads to a mean increase in the Fatigue Severity Scale by at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10 relative to baseline.

[0030] In some embodiments, the method leads to resolution of POTS as determined by the 10-minute standing test in at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% of patients who had POTS at baseline.

[0031] In some embodiments, the method leads to resolution of POTS as determined by the tilt table test in at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% of patients who had POTS at baseline.

[0032] In some embodiments, the method leads to an increase in a score as measured by PASAT by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% relative to baseline.

[0033] In some embodiments, the method leads to a reduction in high-sensitivity CRP (hsCRP) concentrations by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 98%relative to baseline.

[0034] In some embodiments, the method leads to a reduction in high-sensitivity CRP (hsCRP) concentrations to < 2 mg / L in at least 10%, at least 15%, at least 20%, at least157570.604279 25%, at least 30%, at least 35%, at least 40%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% of patients with hsCRP at least 2.0 mg / L at baseline.

[0035] In some embodiments, the method leads to a reduction in serum IL-6 levels by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% relative to baseline.

[0036] In some embodiments, the method leads to a reduction in serum free fatty acids (FFAs) levels by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% relative to baseline.

[0037] In some embodiments, the method leads to a reduction in serum kynurenine levels by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% relative to baseline.

[0038] In some embodiments, the methods described herein further comprise a step of treating a subject with an additional form of therapy. In some embodiments, the additional form of therapy comprises administering one or more therapeutic agents in addition to the anti-IL-6 antibody as described herein. The therapeutic agents include, but are not limited to, a second antibody (e.g., an anti-IL-1 antibody, anti-TNF-alpha antibody, anti-FcRn antibody, anti-CD20 antibody, complement pathway inhibitor, anti-IL17a antibody), a soluble receptor (e.g., soluble IL-1 receptor, soluble TNF-alpha receptor), other anti- inflammatory agent (e.g., corticosteroid, 6-mercaptopurine, mycophenolate mofetil), intravenous immunoglobulin (IVIg), plasmapheresis, antiviral agent against SARS-CoV-2 (e.g., nirmatrelvir / ritonavir, monoclonal antibody against SARS-CoV-2, polyclonal antibodies against SARS-CoV-2, convalescent plasma), other immunomodulatory or anti- infection agent (e.g., interferon beta, interferon gamma, ribavirin, other antiviral agent), or adjunctive medication (e.g., metformin, angiotensin-converting enzyme (ACE)-inhibitor, angiotensin receptor blocker (ARB), antidepressant, anabolic steroid, GLP-1 receptor agonist, GIP receptor agonist, glucagon, or dietary supplement).157570.604279

[0039] In some embodiments, the methods described herein further comprise a step of treating a subject with an additional form of rehabilitation therapy or intervention. Rehabilitation therapy or interventions include but are not limited to prolonged rest, physical therapy, occupational therapy, relaxation techniques, sleep therapy, cognitive rehabilitation, energy-saving techniques, activities of daily living training, nutrition, and / or breathing exercise.

[0040] In some embodiments, the methods described herein are utilized to prevent or treat a symptom or disease associated with Long COVID. In some embodiments, the symptom or disease associated with Long COVID comprises postural orthostatic tachycardia syndrome (POTS), brain fog, post exertional malaise, aerobic metabolism impairment or deficiency, chronic fatigue syndrome (CFS), fibromyalgia, and mast cell activation syndrome (MCAS).

[0041] In some embodiments, provided are pharmacologically active agents, compositions, methods and / or dosing schedules that have certain advantages compared to the agents, compositions, methods and / or dosing schedules that are currently used and / or known in the art, including the ability to dose less frequently or to administer lower doses to obtain equivalent effects in inhibiting IL-6 mediated signaling. BRIEF DESCRIPTION OF THE DRAWINGS

[0042] FIGs. 1A and 1B presents a normal exertion-rest cycle (FIG. 1A), wherein intramyocellular lipids (IMCL) can be fully repleted through rest and an abnormal exertion rest cycle (FIG.1B) with marked IL-6 elevation, wherein IMCLs are only partially repleted due to IL-6 induced IMCL usage even during periods of rest.

[0043] FIG.2 illustrate a progressive depletion of IMCL stores that may result in very low levels of these lipid reserves within skeletal myocytes.

[0044] FIG. 3 illustrates the abnormally low pre-exertion baseline wherein IMCL stores cannot be repleted to a normal level such that subsequent exertion may cause rapid IMCL exhaustion.

[0045] FIG. 4 illustrates a vicious cycle wherein IMCL stores are severely depleted, making replenishment exceedingly difficult.157570.604279

[0046] FIG. 5 depicts the methods of the present disclosure utilized to block IL-6 and to disrupt the vicious cycle.

[0047] FIG. 6 shows that IL-6 blockage allows restoration of IMCL stores and aerobic metabolism capacity.

[0048] FIG. 7 presents the schematic for an example of a phase II randomized, double- blind, placebo-controlled trial of administration of TOUR006 in patients with Long COVID. DETAILED DESCRIPTION OVERVIEW

[0049] Provided herein are methods of preventing or treating a condition associated with IL-6 elevations comprising subcutaneously administering to a patient in need thereof a therapeutically effective dose of an anti-interleukin-6 (anti-IL-6) antibody. Further provided herein are pharmacologically active agents, compositions, methods and / or dosing schedules for the prevention and treatment of a condition associated with IL-6 elevations. In some embodiments, the conditions associated with IL-6 elevations include, but is not limited to, Long COVID, postural orthostatic tachycardia syndrome (POTS), brain fog, post-exertional malaise (PEM), aerobic metabolism impairment or deficiency, Chronic Fatigue Syndrome (CFS), fibromyalgia, and Mast cell activation syndrome (MCAS). DEFINITIONS

[0050] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the disclosure belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of particular embodiments, preferred embodiments of compositions, methods and materials are described herein. For the purposes of the present disclosure, the following terms are defined below. Additional definitions are set forth throughout this disclosure.

[0051] The articles “a,” “an,” and “the” are used herein to refer to one or to more than one (i.e., to at least one, or to one or more) of the grammatical object of the article. By way of example, “an element” means one element or one or more elements.157570.604279

[0052] The use of the alternative (e.g., “or”) should be understood to mean either one, both, or any combination thereof of the alternatives.

[0053] The term “and / or” should be understood to mean either one, or both of the alternatives.

[0054] Throughout this application, the term “about” is used to indicate that a value includes the inherent variation of error for the device or the method being employed to determine the value, or the variation that exists among the samples being measured. Unless otherwise stated or otherwise evident from the context, the term “about” means within 10% above or below the reported numerical value (except where such number would exceed 100% of a possible value or go below 0%). When used in conjunction with a range or series of values, the term “about” applies to the endpoints of the range or each of the values enumerated in the series, unless otherwise indicated. As used in this application, the terms “about” and “approximately” are used as equivalents.

[0055] As used herein, a numerical range, e.g., 1 to 5, about 1 to 5, or about 1 to about 5, refers to each numerical value encompassed by the range. For example, in one non-limiting and merely illustrative embodiment, the range “1 to 5” is equivalent to the expression 1, 2, 3, 4, 5; or 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, or 5.0; or 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, or 5.0.

[0056] As used herein, the term “substantially” refers to a quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length that is 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or higher compared to a reference quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length. In one embodiment, “substantially the same” refers to a quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length that produces an effect, e.g., a physiological effect, that is approximately the same as a reference quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length.

[0057] As used herein, the term “baseline” refers to the initial or starting point against which variations or changes are measured. The baseline may encompass a set of parameters, conditions, or values that serve as a reference for comparison. In some157570.604279 embodiments, the baseline may represent the pre-treatment state prior to treatment with the IL-6 inhibitor.

[0058] Reference throughout this specification to “one embodiment,” “an embodiment,” “a particular embodiment,” “a related embodiment,” “a certain embodiment,” “an additional embodiment,” or “a further embodiment” or combinations thereof means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the foregoing phrases in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. It is also understood that the positive recitation of a feature in one embodiment, serves as a basis for excluding the feature in a particular embodiment. Long COVID

[0059] As used herein, “COVID-19” refers to coronavirus disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

[0060] As used herein, “Long COVID-19” or “Long COVID” refers to a condition wherein a subject continues to experience COVID-19 symptoms for longer than usual after initially contracting the SARS-CoV-2 virus. Long COVID is also known as post-COVID-19 syndrome, post-acute sequelae of COVID-19 (PASC), chronic COVID syndrome (CCS), and long-haul COVID. Long COVID, or post-COVID-19 syndrome (PCS), is defined by National Institute for Health and Care Research and the WHO as the signs and symptoms of the disease that continue for more than 12 weeks after the initial acute COVID-19 infection. COVID-19 symptoms include, but are not limited to, fatigue, brain fog, headaches, dizziness, and / or shortness of breath.

[0061] In some embodiments, the methods of the present disclosure are utilized to prevent or treat Long COVID. A subgroup of patients with Long COVID has experienced complication of endurance failure, often accompanied by a phenomenon called post- exertional malaise (PEM). PEM is characterized by a significant and prolonged endurance impairment following even minor exertion. In severe cases, individuals may find themselves confined to beds for days or longer. This condition leads to a debilitating impairment in an individual’s capacity for physical activity, making it challenging to work157570.604279 or perform even the most basic activities of daily living. For those who experience the severe form of post-exertional malaise, the functional impairment may even surpass the limitations seen in some stroke patients (Walker et al., BMJ Open, 2023; 13). PEM is commonly associated with other manifestations of Long COVID, including postural orthostatic tachycardia (POTS), and cognitive difficulties referred to as “brain fog.”

[0062] Evidence suggests that PEM is primarily driven by a profound deficiency in aerobic metabolism (Singh et al., Chest.2022; 161(1): 54-63; Aparisi et al. Front Med (Lausanne), 2022; 9: 924819; Joseph et al., Chest. 2023 Sep; 164(3): 717–726). Aerobic metabolism is a crucial energy-produced process that relies on oxygen to break down nutrients, such as glucose and fatty acids, to generate ATP, the cell’s primary source of energy. Decreased fatty acid oxidation and premature lactate production during exercise in patients with Long COVID reveal profound deficit in aerobic metabolism in Long COVID (Boer, et al., Am J Respir Crit Care Med, 2022 Jan 1; 205(1): 126–129).

[0063] The slow but steady source for Fatty acids (FFAs) derives from FFA uptake from bloodstream; the fast source of FFAs derives from intramyocellular lipid (IMCL) breakdown. IMCL complements supply from FFA uptake into cells from bloodstream and can serve as a “loading dose” provider to rapidly elevate FFA concentration in mitochondria. In a normal exertion rest cycle, IMCL can be fully repleted through rest (FIG. 1A).

[0064] IMCL breakdown is mainly modulated by the adrenergic system and other mediators. However, in the context of particularly vigorous physical activity (based upon exertion intensity and / or duration), evidence from previous studies indicate that IL-6 is likely a major, if the not the predominant, mediator that facilitates IMCL breakdown. There is a large body of evidence for this IMCL-modulating role of IL-6 in humans. IL-6 levels acutely increase in response to surge in energy demand. IL-6 production in skeletal muscle is triggered by glycogen depletion (i.e., indicator that glucose fuel source is insufficient to meet demands) (Steensberg, et al., J Physiol.2001 Dec 1; 537(Pt 2): 633–639). IL-6 levels increase exponentially (i.e., nonlinear) during intensive & prolonged exercise (Ostrowski, et al., J Physiol. 1998 Dec 15; 513(Pt 3): 889–894). Magnitude of IL-6 surge correlates with both intensity & duration of exercise (Ostrowski, et al., European Journal of Applied Physiology, 2000, 83, 512–515). It is noted that more than 100-fold increase in IL-6 in157570.604279 systemic circulation can be observed from marathons (Ostrowski, et al., J Physiol. 1999 Feb 15; 515(Pt 1): 287–291). Further, IL-6 drives IMCL usage to release FFAs in skeletal muscle. Acute IL-6 treatment increases fatty acid turnover in elderly humans in vivo and in tissue culture in vitro (Petersen, et al., Am J Physiol Endocrinol Metab 288: E155-E162, 2005). IL-6 selectively stimulates fatty acid release in human skeletal muscle (Wolsk, et al., Am J Physiol Endocrinol Metab 299: E832-E840, 2010). Additionally, blocking endogenous IL-6 significantly suppresses the surge in FFA release induced by significant exertion (Trinh, et al., Cell Report Medicine, 2021, Vol. 2, Issue 9).

[0065] IL-6 elevations are common in acute COVID-19. Even mild COVID-19 leads to IL-6 elevations, with a subset of patients with marked elevations. IL-6 levels remain elevated in many patients during acute recovery / resolution phase after infection. A study using Elecsys IL-6 on samples from 817 apparently healthy individuals shows the upper limit of the reference range for IL-6 in the serum is 7 pg / mL (95th percentile) ( Fact Sheet for Health Care Providers: Elecsys IL-6–Roche Diagnostics. US Food and Drug Administration Web site. https: / / www.fda.gov / media / 138594 / download. June 2, 2020. Accessed September 2020). By contrast, the pooled estimate of IL-6 for Long COVID-19 patients reveals a mean value of 20.92 pg / ml (95% CI = 9.30– 32.54 pg / ml, I2 = 100%, P < 0.01) (Yin, et al., 2023, Infect Dis Poverty 12, 43). Without being bound by theory, elevated IL-6 results in IMCL breakdown and FFA release in patients with acute COVID-19 even when they are at rest. In an exertion-rest cycle with marked IL-6 elevation, IMCLs are only partially repleted due to IL-6 induced IMCL usage even during periods of rest (FIG. 1B). Without being bound by theory, prolonged IL-6 elevation in Long COVID may lead to repeated IL-6-induced IMCL utilization during rest. Over time, this progressive depletion of IMCL stores may result in very low levels of these lipid reserves within muscle cells while in a pre-exertion resting state (FIG.2). Subsequent exertion may cause rapid and complete or near-complete IMCL exhaustion, which can preclude aerobic metabolism and clinically present as post exertional malaise (FIG. 3).

[0066] Without being bound by theory, a vicious cycle occurs when IMCL stores are severely depleted, making replenishment exceedingly difficult (FIG. 4). Systemic IL-6 elevations occur during acute COVID and in acute post-COVID recovery phase. In a subset of patients, IL-6 levels remain high enough to induce a state in which skeletal muscles157570.604279 behave as if they are in a constant state of high energy demand, akin to running a marathon even at rest. This constant demand leads to significant IMCL utilization, even during periods of rest. When individuals with IL-6 elevation engage in exertion, the net depletion of IMCLs is further exacerbated and the amount of IMCL restoration during a typical period of rest will be only partial and insufficient. Over time, there will be gradual depletion of IMCLs, eventually resulting in severe or even complete exhaustion of IMCL stores within skeletal muscle. In turn, this loss of IMCLs as a source of FFAs for use leads to severe impairment in aerobic metabolism in skeletal muscle. Clinically, this phenomenon presents as profound endurance failure. Once IMCLs have reached extremely low levels, even minimal exertion triggers a local surge of IL-6 within skeletal muscle because the shortage of FFAs leads to greater and premature reliance upon glycogen, thereby leading to rapid glycogen depletion. Glycogen depletion in turn will lead to production of IL-6. Thus, a self-sustained loop is fostered. As a result, even if systemic inflammation may have resolved (and thus, no significant IL-6 elevation systemically), the IMCL- deprived state can still be sustained through a vicious cycle.

[0067] The vicious cycle as shown in FIG. 4 robustly explains the key observations of endurance failure commonly seen in Long COVID. It often begins with a latency period following the initial COVID-19 infection, where individuals may briefly feel like they are on the path to recovery. However, beneath this surface, metabolic and immunological dysregulations (e.g., marked FFA release at rest; IL-6 elevations) set the stage for what follows. The inability to restore IMCL stores in skeletal muscle to normal states leads to susceptibility for rapid exhaustion (and thus loss of FFA supply needed for aerobic metabolism) following even minor amounts of exertion. Manifesting as post-exertional malaise, this phenomenon subjects individuals to severe and prolonged symptom exacerbation following even minor physical or mental exertion. This, in turn, leads to a profound loss of endurance capacity, significantly impairing an individual’s ability to engage in everyday activities or exercise. Further, it is extremely difficult to recover from a low endurance state, even after prolonged rest. The vicious cycle, fueled by local IL-6 surges within skeletal muscle upon even minor exertion, hampers the ability of affected patients to regain their previous endurance capacity.157570.604279

[0068] In some embodiments, the methods of the present disclosure are utilized to break the vicious cycle and address the underlying IL-6 driven IMCL depletion process in individuals, especially those with Long COVID.

[0069] In some embodiments, the methods of the present disclosure are utilized to block IL-6 in Long COVID and to disrupt the vicious cycle (FIG.5). The primary objectives are to achieve escape velocity for IMCL repletion and to block the IL-6 surges arising from IMCL exhaustion. This approach has additional impact if systemic IL-6 levels are elevated due to persistent background inflammation. Without being bound by theory, IL-6 blockage allows restoration of IMCL stores and aerobic metabolism capacity (FIG. 6).

[0070] In some embodiments, the methods of the present disclosure are utilized to treat a patient having Long COVID. In some embodiments, the patient has a baseline serum level of IL-6 that is ≥ about 1.5, about 2, about 2.5, or about 3 times the upper limit of normal. In the art, the recognized upper limit of normal for the serum level of IL-6 is defined at about 7 pg / mL. ( Fact Sheet for Health Care Providers: Elecsys IL-6–Roche Diagnostics. US Food and Drug Administration Web site. www.fda.gov / media / 138594 / download. June 2, 2020. Accessed September 2020). It is to be understood that the upper limit of normal for the serum level of IL-6 may be varied, taking into consideration different factors such as subject demographics, health conditions, or specific assay methodologies. For instance, the upper limit of normal for the serum level of IL-6 may be 7 pg / mL, with an acceptable variation of ± 5 pg / mL. In some embodiments, the patient has a baseline serum level of IL-6 that is ≥ about 10.5 pg / mL, about 14 pg / mL, about 17.5 pg / mL, or about 21 pg / mL. In some embodiments, the patient has a baseline serum level of IL-6 that is ≥ about 5.0, about 10.0, about 15.0, about 20.0, about 30.0, or about 40.0 pg / mL. In some embodiments, the methods of the present disclosure comprises a step of selecting a subject having a baseline serum level of IL-6 that is ≥ about 1.5 times the upper limit of normal. In some embodiments, the methods of the present disclosure comprises a step of selecting a subject having a baseline serum level of IL-6 that is elevated above the normal range. In some embodiments, methods of the present disclosure comprises the treatment of subjects with a baseline serum level of IL-6 that is not elevated (i.e., the baseline serum level of IL-6 is in the normal range), as it is possible for local IL-6 activity within skeletal muscle to drive157570.604279 IMCL usage and Long COVID pathogenesis even if the systemically circulating levels of IL-6 are not abnormal or elevated.

[0071] In some embodiments, the methods described herein further comprise a step of treating a subject with an additional form of therapy. In some embodiments, the additional form of therapy comprises administering one or more therapeutic agents in addition to the anti-IL-6 antibody as described herein. The therapeutic agents include, but are not limited to, a second antibody (e.g., an anti-IL-1 antibody, anti-TNF-alpha antibody, anti-FcRn antibody, anti-CD20 antibody, complement pathway inhibitor, anti-IL17a antibody), a soluble receptor (e.g., soluble IL-1 receptor, soluble TNF-alpha receptor), other anti- inflammatory agent (e.g., corticosteroid, 6-mercaptopurine, mycophenolate mofetil), intravenous immunoglobulin (IVIg), plasmapheresis, antiviral agent against SARS-CoV-2 (e.g., nirmatrelvir / ritonavir, monoclonal antibody against SARS-CoV-2, polyclonal antibodies against SARS-CoV-2, convalescent plasma), other immunomodulatory or anti- infection agent (e.g., interferon beta, interferon gamma, ribavirin, other antiviral agent), or adjunctive medication (e.g., metformin, angiotensin-converting enzyme (ACE)-inhibitor, angiotensin receptor blocker (ARB), antidepressant, anabolic steroid, GLP-1 receptor agonist, GIP receptor agonist, glucagon, or dietary supplement).

[0072] In some embodiments, the methods described herein further comprise a step of treating a subject with an additional form of rehabilitation therapy or intervention. Rehabilitation therapy or interventions include but are not limited to prolonged rest, physical therapy, occupational therapy, relaxation techniques, sleep therapy, cognitive rehabilitation, energy-saving techniques, activities of daily living training, nutrition, and / or breathing exercise.

[0073] In some embodiments, the methods described herein are utilized to prevent Long COVID in patients having SARS-CoV-2 infection. In some embodiments, patients receive treatment within about 1 weeks, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 3 months, about 4 months, about 5 months, or about 6 months after an acute, symptomatic or asymptomatic SARS- CoV-2 infection. In some embodiments, patients who satisfy one or more of the following criteria are eligible for treatment: age at least 40 years old; female; comorbidities such as obesity, metabolic syndrome, diabetes; likely to engage in intensive exertion over the next157570.604279 several weeks or months, such as physically demanding work or endurance athletics; history of chronic fatigue syndrome, post-exertional malaise, Brain Fog, POTS, fibromyalgia, mast cell activation syndrome (e.g., had such an episode previously or such a prior episode is still persisting); early onset of symptoms of post-exertional malaise, POTS, or brain Fog. (e.g., symptoms may be mild but have started, and so treatment is given in order to stop and reverse this process before those symptoms become more severe and / or persistent); medical history of joint hypermobility or Ehlers-Danlos Syndrome; moderate, severe or critical COVID infection (based upon CDC criteria); persisted COVID symptoms beyond 14 days after symptom onset; persisted COVID test positivity (by PCR or rapid antigen test) beyond 14 days after symptom onset or first positive test result, whichever happened earlier; viral re-activation during or after COVID occurs (observed clinically and / or by test positivity) for at least one of the following viruses: EBV, CMV, HSV-1, HSV-6, and VZV; and biomarker positivity for abnormally elevated CRP, IL-6, kynurenine, FFA or lactate. Postural Orthostatic Tachycardia Syndrome (POTS)

[0074] In some embodiments, the methods of the present disclosure are utilized to prevent or treat POTS associated with Long COVID. In some embodiments, the methods of the present disclosure are utilized to treat POTS and other orthostatic intolerance conditions. In some embodiments, the methods of the present disclosure are utilized to block IL-6 in POTS.

[0075] POTS is a chronic multisystem disorder involving a broad array of symptoms. POTS patients can present with a myriad of symptoms including lightheadedness, tachycardia, presyncope, headache and difficulty concentrating. POTS can be triggered by a number of precipitants, such as infection. There is evidence that the coronavirus that causes COVID-19 may also trigger POTS in people with Long COVID. POTS is considered to be a major phenotype in the new post-acute COVID-19 syndrome, with an estimated prevalence of ~30% among highly symptomatic patients (Fedorowski, et al., Nature Reviews Cardiology, 2023, 20, 281–282).

[0076] POTS can be confirmed by an appropriately performed active standing test. Heart rate and blood pressure are measured after resting lying down, then immediately upon standing and after 2, 5 and 10 minutes. The syndrome includes an exaggerated chronotropic157570.604279 response to standing of >30 bpm with maintained blood pressure and chronic symptoms of orthostatic intolerance and fatigue, in the absence of other explanatory pathologies (Fedorowski, et al., J. Intern. Med., 2019, 285, 352–366).

[0077] Under normal physiology conditions, contractions of soleus muscle drive venous return of blood to the heart. Soleus is highly dependent upon aerobic metabolism. Without being bound by theory, POTS is driven by a deficiency in aerobic metabolism caused by a shortage of IMCL (due to IL-6 mediated IMCL breakdown). This deficiency leads to calf muscle pump impairment, which in turn results in insufficient venous return. Among a subset of POTS in which low venous return is the primary defect, impaired calf muscle pump activity is observed (Stewart, et al., Am J Physiol Heart Circ Physiol, 2004, 286: 1216-1222). Impaired venous return is common in Long COVID. POTS is also observed in chronic fatigue syndrome and joint hypermobility syndrome (Lewis, et al, J Intern Med 2013; 273: 501–510; Kanjwal, et al., Indian Pacing Electrophysiol J. 2010; 10(4): 173–178.).

[0078] IL-6 elevation has been observed in patients with POTS (Okamoto, et al., Am J Physiol Heart Circ Physiol. 2015 Dec 15; 309(12): H2098–H2107). Without being bound by theory, IL-6 blockade suppresses inappropriate IMCL breakdown and thereby allows restoration of aerobic metabolism capacity and amelioration of POTS.

[0079] In some embodiments, a patient having POTS has a baseline serum level of IL-6 that is ≥ about 10.5 pg / mL, about 14 pg / mL, about 17.5 pg / mL, or about 21 pg / mL. In some embodiments, methods of the present disclosure comprises the treatment of subjects with a baseline serum level of IL-6 that is not elevated (i.e., the baseline serum level of IL-6 is in the normal range), as it is possible for local IL-6 activity within skeletal muscle to drive IMCL usage and POTS pathogenesis even if the systemically circulating levels of IL-6 are not abnormal or elevated.

[0080] In some embodiments, provided herein are methods of treating a patient having POTS, comprising determining the baseline level of IL-6 in a serum sample obtained from the patient having POTS, and administering to the patient a therapeutically effective dose of anti-IL-6 antibody described herein if the baseline level of IL-6 in the serum sample is elevated above normal range. In some embodiments, methods of the present disclosure comprises the treatment of subjects with a baseline serum level of IL-6 that is not elevated157570.604279 (i.e., the baseline serum level of IL-6 is in the normal range), as it is possible for local IL- 6 activity to drive IMCL usage and POTS pathogenesis even if the systemically circulating levels of IL-6 are not abnormal or elevated.

[0081] In some embodiments, the methods described herein further comprise a step of treating a subject with an additional form of therapy. In some embodiments, the additional form of therapy comprises administering one or more therapeutic agents in addition to the anti-IL-6 antibody as described herein. The therapeutic agents include, but are not limited to, a second antibody (e.g., an anti-IL-1 antibody, anti-TNF-alpha antibody, anti-FcRn antibody, anti-CD20 antibody, complement pathway inhibitor, anti-IL17a antibody), a soluble receptor (e.g., soluble IL-1 receptor, soluble TNF-alpha receptor), other anti- inflammatory agent (e.g., corticosteroid, 6-mercaptopurine, mycophenolate mofetil), intravenous immunoglobulin (IVIg), plasmapheresis, antiviral agent against SARS-CoV-2 (e.g., nirmatrelvir / ritonavir, monoclonal antibody against SARS-CoV-2, polyclonal antibodies against SARS-CoV-2, convalescent plasma), other immunomodulatory or anti- infection agent (e.g., interferon beta, interferon gamma, ribavirin, other antiviral agent), adjunctive medication (e.g., metformin, angiotensin-converting enzyme (ACE)-inhibitor, angiotensin receptor blocker (ARB), antidepressant, anabolic steroid, GLP-1 receptor agonist, GIP receptor agonist, glucagon, or dietary supplement), POTS medication (e.g., Beta-blockers or calcium channel blockers to lower heart rate, Fludrocortisone or midodrine to help with blood pressure).

[0082] In some embodiments, the methods described herein further comprise a step of treating a subject with an additional form of rehabilitation therapy or intervention. Rehabilitation therapy or interventions include but are not limited to prolonged rest, physical therapy, occupational therapy, relaxation techniques, sleep therapy, cognitive rehabilitation, energy-saving techniques, activities of daily living training, nutrition, and / or breathing exercise. Brain Fog

[0083] In some embodiments, the methods of the present disclosure are utilized to prevent or treat brain fog associated with Long COVID. In some embodiments, the methods of the present disclosure are utilized to treat brain fog. In some embodiments, the methods of the present disclosure are utilized to block IL-6 in brain fog.157570.604279

[0084] Brain fog is characterized by confusion, forgetfulness, and a lack of focus and mental clarity. Conditions that can cause brain fog, include, stress, anxiety, depression, lack of sleep, hormonal changes (e.g. menopause, perimenopause, pregnancy, birth control medications), medications (e.g., chemotherapy, oxybutynin, diphenhydramine, amitriptyline), underactive thyroid, nutritional deficiency ( e.g., low levels of Vitamin B12), food intolerance, allergy, chronic infection (e.g., candidiasis), multiple sclerosis, chronic fatigue syndrome, fibromyalgia, mechanical ventilation and metal poisoning (e.g., mercury, cadmium, lead). More recently, patients recovering from COVID-19 report experiencing brain fog, which can reflect a wide variety of neurological and psychological symptoms linked to COVID-19.

[0085] Cognitive impairment in brain fog can be measured by methods known in the art, such as for example, the Paced Auditory Serial Addition Test (PASAT) and the Digit Span Test.

[0086] Brain fog can be treated by treating the underlining condition, such as treating the underactive thyroid with thyroid hormone. However, brain fog caused by chemotherapy, mechanical ventilation and Covid-19 have few if any treatment options.

[0087] Brain fog often co-associates with post-exertional malaise and / or POTS. ADHD (continual energy usage from nonstop cognitive multitasking) patients have increased incidence of brain fog, which is analogous to joint hypermobility syndrome and post- exertional malaise & POTS. It is noted that IL-6 levels increase following intense cognitive tasks (e.g., study of college students taking an exam) and lactate elevation in CSF is observed in brain fog associated with Long COVID & CFS. Without being bound by theory, similar to Long COVID, elevated IL-6 in the brain, or in other organ systems interfacing directly or indirectly with the brain, results in the breakdown of lipid droplets in astrocytes or other cells located adjacent to and / or interacting with neurons. These lipid droplets are analogous to IMCLs present in skeletal muscles, and the release of FFA. Released FFAs are converted to ketone bodies which are then provided to neurons for aerobic energy. It is hypothesized that prolonged IL-6 elevation may result in the depletion of lipid droplets. Without being bound by theory, aerobic metabolism deficit from shortage of lipid droplets in the brain leads to cognitive impairment in patients experiencing brain fog and vulnerability to energy-intensive cognitive tasks. Without being bound by theory,157570.604279 IL-6 blockage allows restoration of aerobic metabolism capacity and amelioration of brain fog.

[0088] In some embodiments, provided herein are methods of treating a patient having brain fog, comprising determining the baseline level of IL-6 in a serum sample obtained from the patient having POTS, and administering to the patient a therapeutically effective dose of anti-IL-6 antibody described herein if the baseline level of IL-6 in the serum sample is elevated above the normal range. In some embodiments, methods of the present disclosure comprises the treatment of subjects with a baseline serum level of IL-6 that is not elevated (i.e., the baseline serum level of IL-6 is in the normal range), as it is possible for local IL-6 activity to drive IMCL usage and brain fog pathogenesis even if the systemically circulating levels of IL-6 are not abnormal or elevated.

[0089] In some embodiments, the methods described herein further comprise a step of treating a subject with an additional form of therapy. In some embodiments, the additional form of therapy comprises administering one or more therapeutic agents in addition to the anti-IL-6 antibody as described herein. The therapeutic agents include, but are not limited to, a second antibody (e.g., an anti-IL-1 antibody, anti-TNF-alpha antibody, anti-FcRn antibody, anti-CD20 antibody, complement pathway inhibitor, anti-IL17a antibody), a soluble receptor (e.g., soluble IL-1 receptor, soluble TNF-alpha receptor), other anti- inflammatory agent (e.g., corticosteroid, 6-mercaptopurine, mycophenolate mofetil), intravenous immunoglobulin (IVIg), plasmapheresis, antiviral agent against SARS-CoV-2 (e.g., nirmatrelvir / ritonavir, monoclonal antibody against SARS-CoV-2, polyclonal antibodies against SARS-CoV-2, convalescent plasma), other immunomodulatory or anti- infection agent (e.g., interferon beta, interferon gamma, ribavirin, other antiviral agent), or adjunctive medication (e.g., metformin, angiotensin-converting enzyme (ACE)-inhibitor, angiotensin receptor blocker (ARB), antidepressant, anabolic steroid, GLP-1 receptor agonist, GIP receptor agonist, glucagon, or dietary supplement).

[0090] In some embodiments, the methods described herein further comprise a step of treating a subject with an additional form of rehabilitation therapy or intervention. Rehabilitation therapy or interventions include but are not limited to prolonged rest, physical therapy, occupational therapy, relaxation techniques, sleep therapy, cognitive157570.604279 rehabilitation, energy-saving techniques, activities of daily living training, nutrition, and / or breathing exercise. Chronic Fatigue Syndrome (CFS)

[0091] In some embodiments, the methods of the present disclosure are utilized to prevent or treat a patient having CFS associated with Long COVID. In some embodiments, the methods of the present disclosure are utilized to treat Chronic Fatigue Syndrome (CFS). In some embodiments, the methods of the present disclosure are utilized to block IL-6 in CFS.

[0092] Chronic Fatigue Syndrome (CFS) is defined as greater than 6 months of persistent fatigue that is experienced physically and cognitively. The following symptoms are concurrently present in CFS: pharyngeal pain, cervical or axillary lymphadenopathy, myalgia, polyarthritis without erythema or edema, headache, non-restful sleep, prolonged post-exercise fatigue, and / or debilitating cognitive impairments in short-term memory and concentration. Up to 85% of patients with CFS describe experiencing cognitive impairments (Grafman, et al., J. Neurol. Neurosurg. Psychiatry, 1993,56, 684–689.). These cognitive impairments have subjectively been described by patients with CFS as brain fog as described above.

[0093] CFS often occurs after an initial “infectious-like” illness characterized by respiratory and gastrointestinal symptoms, fatigue, myalgias and other symptoms as well as fever and lymphadenopathy (Komaroff et al., Rev Infect Dis. (1991) 13:S8–11). Several stressors including exercise, prolonged upright position, cognitive and emotional upset typically produce a worsening of all of the symptoms of the illness. Post-exertional malaise (PEM) is a prominent feature of CFS and is also commonly reported by the majority of individuals with Long COVID (Institute of Medicine. Beyond Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: Redefining an Illness. Washington, DC: The National Academies Press (2015)). A recent meta-analysis of 21 studies has reported a long list of overlapping symptoms between CFS and Long COVID, including fatigue, PEM, headaches, sleep disorder, impaired reasoning, impaired memory, impaired attention, secondary depression, secondary activity, myalgia / arthralgia, muscle weakness, hot and cold spells, poor appetite, orthostatic intolerance, palpitations, breathlessness, nausea and diarrhea, chills, and cough (Wong, et al., Medicina (Kaunas) (2021)). Both CFS and Long COVID share a wide range of the underlying objective biological abnormalities157570.604279 involving the central and autonomic nervous systems, the immune system, reactivation of latent infectious agents, the gut microbiome, energy metabolism, a hypometabolic state, redox imbalance, and various cardiac, pulmonary and vascular abnormalities (Komaroff, et al., Front. Med., 02 June 2023). Much like in Long COVID, CFS involves a self- reinforcing vicious pathophysiological cycle that could lead to persisting illness.

[0094] It has been found that plasma IL-6 levels are reportedly higher in patients with CFS than in healthy controls (Broderick et al., Brain Behav Immun. 2010;24:1209–1217). Plasma IL-6 levels exhibit a dose–effect relationship with CFS severity. It is reported that increased plasma IL-6 levels are observed in patients with severe CFS and relatively lower levels of it are present in those with moderate CFS (Hardcastle et al,. Int J Med Sci. 2015;12:764–772). It is also reported that dynamic changes in IL-6 levels align with CFS progression, including lower levels in early CFS stages and increased levels with disease progression (Russell et al., BMC Immunol. 2016;17:3). Moreover, IL-6 reportedly plays an important role in the main symptoms of CFS, such as hyperalgesia, fatigue, sleep impairment, and depression. It is also found that increased IL-6 levels contribute to the pathogenesis of fibromyalgia, the main symptoms of which are chronic diffuse muscle pain, fatigue, and skin sensitivity (Wallace et al., Rheumatology. 2001;40:743–749). Without being bound by theory, IL-6 blockade allows restoration of aerobic metabolism capacity and amelioration of CFS symptoms.

[0095] In some embodiments, the patient has a baseline serum level of IL-6 that is ≥ about 10.5 pg / mL, about 14 pg / mL, about 17.5 pg / mL, or about 21 pg / mL. In some embodiments, the patient has a baseline serum level of IL-6 that is ≥ about 5.0, about 10.0, about 15.0, about 20.0, about 30.0, or about 40.0 pg / mL. In some embodiments, the patient has a baseline serum level of IL-6 that is not elevated (i.e., the baseline serum level of IL-6 is in the normal range).

[0096] In some embodiments, provided herein are methods of treating a patient having CFS, comprising determining the baseline level of IL-6 in a serum sample obtained from the patient having CFS, and administering to the patient a therapeutically effective dose of anti-IL-6 antibody described herein if the baseline level of IL-6 in the serum sample is elevated above the normal range. In some embodiments, methods of the present disclosure comprises the treatment of subjects with a baseline serum level of IL-6 that is not elevated157570.604279 (i.e., the baseline serum level of IL-6 is in the normal range), as it is possible for local IL- 6 activity to drive IMCL usage and brain fog pathogenesis even if the systemically circulating levels of IL-6 are not abnormal or elevated.

[0097] In some embodiments, the methods described herein further comprise a step of treating a subject with an additional form of therapy. In some embodiments, the additional form of therapy comprises administering one or more therapeutic agents in addition to the anti-IL-6 antibody as described herein. The therapeutic agents include, but are not limited to, a second antibody (e.g., an anti-IL-1 antibody, anti-TNF-alpha antibody, anti-FcRn antibody, anti-CD20 antibody, complement pathway inhibitor, anti-IL17a antibody), a soluble receptor (e.g., soluble IL-1 receptor, soluble TNF-alpha receptor), other anti- inflammatory agent (e.g., corticosteroid, 6-mercaptopurine, mycophenolate mofetil), intravenous immunoglobulin (IVIg), plasmapheresis, antiviral agent against SARS-CoV-2 (e.g., nirmatrelvir / ritonavir, monoclonal antibody against SARS-CoV-2, polyclonal antibodies against SARS-CoV-2, convalescent plasma), other immunomodulatory or anti- infection agent (e.g., interferon beta, interferon gamma, ribavirin, other antiviral agent), adjunctive medication (e.g., metformin, angiotensin-converting enzyme (ACE)-inhibitor, angiotensin receptor blocker (ARB), antidepressant, anabolic steroid, GLP-1 receptor agonist, GIP receptor agonist, glucagon, or dietary supplement), POTS medication (e.g., Beta-blockers or calcium channel blockers to lower heart rate, Fludrocortisone or midodrine to help with blood pressure).

[0098] In some embodiments, the methods described herein further comprise a step of treating a subject with an additional form of rehabilitation therapy or intervention. Rehabilitation therapy or interventions include but are not limited to prolonged rest, physical therapy, occupational therapy, relaxation techniques, sleep therapy, cognitive rehabilitation, energy-saving techniques, activities of daily living training, nutrition, and / or breathing exercise. Mast cell activation syndrome (MCAS)

[0099] In some embodiments, the methods of the present disclosure are utilized to prevent or treat a patient having MCAS associated with Long COVID. In some embodiments, the methods of the present disclosure are utilized to treat Mast cell activation syndrome157570.604279 (MCAS). In some embodiments, the methods of the present disclosure are utilized to block IL-6 in MCAS.

[0100] Mast cells play a key role in the inflammatory process. They are found in the perivascular spaces of most tissues and contain pro-inflammatory and vasoactive mediators, such as serine proteases, tryptase, histamine, serotonin, proteoglycans, thromboxane, prostaglandin D2, leukotriene C4, platelet-activating factor, and eosinophil chemotactic factor. When activated, mast cells rapidly release granules and various hormone mediators into the interstitium, a process referred to as degranulation. Degranulation of mast cells can be caused by physical or chemical injury, crosslinking of immunoglobulin G receptors, or by activated complement proteins.

[0101] Systemic mast cell related disorders may result from excessive proliferation of mast cells or abnormal release of pro-inflammatory and vasoactive mediators. Symptoms of systemic mast cell related disorders include pruritus, flushing, nausea, vomiting, diarrhea, headaches, abdominal pain, vascular instability, urticaria, itching, and anaphylaxis. Accumulation of mast cells in the skin, gastrointestinal tract, bone marrow, liver, spleen, and lymph nodes may result in a particular systemic mast cell related disorder, systemic mastocytosis, or mastocytosis.

[0102] There is an activated condition of mast cells in Long COVID-19, with abnormal granulation and excessive inflammatory cytokine release. A study indicates that patients with Long COVID suffer the same clinical symptoms as patients with mast cell activation syndrome (MCAS), such as physical weakness, brain fog, tachycardia, insomnia, shortness of breath, migraines, paresthesia, arthralgia, dizziness, eye complaints, nasal complaints, tinnitus, dry mouth, constipation, easy bruising, flushing, vertigo, wheezing, bone pain, weight loss, rashes, abdominal pain, and skin lesions (Weinstock et al,. Int J InfectDis 2021;112:217–226). Without being bound by theory, a persistent inflammatory statein Long COVID will activate specific mast cell genes that will cause an abnormal mast cell activation. Activation of toll-like receptors in SARS-CoV2 infection causes the formation of autoantibodies that could interact with and then activate mast cell immunoglobulin receptors. The location of mast cells in the pulmonary perivascular space, where mast cell maturation occurs, also puts these cells in the front line of immune hyper-responsive condition caused by COVID-19. In addition, mast cell stimulation will release many pro-157570.604279 inflammatory cytokines, such as platelet-activating factor, histamine, heparin, tryptase, prostaglandins, leukotriene, and chemokines (IL-1β and IL-6) ( Umesh et al,. Infection 2022;50:1053–1066; Davis et al., Nat Rev Microbiol 2023;21:133–146).

[0103] Activated mast cells increase IL-6 mRNA associated with protein kinase C (PKC) activity. IL-6 also up-regulates histamine production rather than increases its storage and is an important inducing factor for the expression of immunoglobulin E (IgE) Fc epsilon RI (Conti, et al., Allergy Asthma Proc, 2002 Sep-Oct;23(5):331-5). In turn, IL-6 increases mast cell proliferation and formation of a more reactive phenotype enabled by suppressing proteolytic cleavage of sIL-6R from IL-6R (Desai, et al., J Allergy Clin Immunol. 2016 Jun; 137(6): 1863–1871). Without being bound by theory, IL-6 blockade might prevent or ameliorate MCAS and MC-related diseases associated with elevated IL-6 including mastocytosis.

[0104] In some embodiments, provided herein are methods of treating a patient having MCAS, comprising determining the baseline level of IL-6 in a serum sample obtained from the patient having MCAS, and administering to the patient a therapeutically effective dose of anti-IL-6 antibody described herein if the baseline level of IL-6 in the serum sample is elevated above the normal range. In some embodiments, methods of the present disclosure comprises the treatment of subjects with a baseline serum level of IL-6 that is not elevated (i.e., the baseline serum level of IL-6 is in the normal range), as it is possible for local IL- 6 activity to drive mast cell pathogenesis even if the systemically circulating levels of IL- 6 are not abnormal or elevated..

[0105] In some embodiments, the methods described herein further comprise a step of treating a subject with an additional form of therapy. In some embodiments, the additional form of therapy comprises administering one or more therapeutic agents in addition to the anti-IL-6 antibody as described herein. The therapeutic agents include, but are not limited to, a second antibody (e.g., an anti-IL-1 antibody, anti-TNF-alpha antibody, anti-FcRn antibody, anti-CD20 antibody, complement pathway inhibitor, anti-IL17a antibody), a soluble receptor (e.g., soluble IL-1 receptor, soluble TNF-alpha receptor), other anti- inflammatory agent (e.g., corticosteroid, 6-mercaptopurine, mycophenolate mofetil), intravenous immunoglobulin (IVIg), plasmapheresis, antiviral agent against SARS-CoV-2 (e.g., nirmatrelvir / ritonavir, monoclonal antibody against SARS-CoV-2, polyclonal157570.604279 antibodies against SARS-CoV-2, convalescent plasma), other immunomodulatory or anti- infection agent (e.g., interferon beta, interferon gamma, ribavirin, other antiviral agent), adjunctive medication (e.g., metformin, angiotensin-converting enzyme (ACE)-inhibitor, angiotensin receptor blocker (ARB), antidepressant, anabolic steroid, GLP-1 receptor agonist, GIP receptor agonist, glucagon, or dietary supplement), POTS medication (e.g., Beta-blockers or calcium channel blockers to lower heart rate, Fludrocortisone or midodrine to help with blood pressure), or MCAS medication (e.g., antihistamines (H1 and H2 blockers), inhibition of synthesis of mediators (zileuton and aspirin), inhibition of mediator release (sodium-cromoglycate), and inhibition of degranulation of mast cells by anti-IgE).

[0106] In some embodiments, the methods described herein further comprise a step of treating a subject with an additional form of rehabilitation therapy or intervention. Rehabilitation therapy or interventions include but are not limited to prolonged rest, physical therapy, occupational therapy, relaxation techniques, sleep therapy, cognitive rehabilitation, energy-saving techniques, activities of daily living training, nutrition, and / or breathing exercise. Conditions related to IL-6 elevations

[0107] In some embodiments, the methods of the present disclosure are utilized to prevent or treat a condition related to IL-6 elevations. In some embodiments, the condition related to IL-6 elevations is selected from fatigue, inability to exercise or be active because of fatigue, low exercise tolerance because of fatigue, shortness of breath or difficulty breathing, persistent chest pain or pressure, cough, heart palpitations, diarrhea, partial or complete loss of sense of smell, tachycardia, hair loss, blurry vision, neuropathy in feet and hands, partial or complete loss of sense of taste, nausea or vomiting, clogged ears, dry eyes, tremors or shakiness, floaters or flashes of light in vision, rash, tinnitus or humming in ears, changed sense of taste, dry or peeling skin, phantom smells, costochondritis, low blood oxygen, COVID toes, thrush, dyspnea, phlegm in back of throat, constant thirst, muscle twitching, heat intolerance, abnormally low temperature, cold burning feeling in lungs, goiter or lump in throat, dry scalp or dandruff, anemia, elevated thyroid, sicca syndrome, red eyes, dysgeusia, sputum production, lack of appetite, vertigo, muscle pain, cognitive problems, problems with concentration, problems with thinking, chills, sweats, sleep157570.604279 problems, muscle or body aches, difficulty concentrating or focusing, headache, difficulty sleeping, anxiety, memory problems, dizziness, joint pain, sore throat, night sweats, fever or chills, congested or runny nose, sadness, reflux or heartburn, changing symptoms, abdominal pain, lower back pain, shortness of breath or exhaustion from bending over, weight gain, calf cramps, sleeping more than normal, upper back pain, nerve sensations, sharp or sudden chest pain, confusion, feeling irritable, weight loss, post nasal drip, dry throat, high blood pressure, swollen hands or feet, mouth sores or sore tongue, neck muscle pain, hot blood rush, bone aches in extremities, feeling of burning skin, extreme pressure at base of head or occipital nerve, swollen lymph nodes, brain pressure, kidney pain, spikes in blood pressure, hand or wrist pain, bulging veins, mid-back pain at base of ribs, burning sensations, painful scalp, jaw pain, arrhythmia, cracked or dry lips, foot pain, eye stye or infection, low blood pressure, kidney issues or protein in urine, urinary tract infection, hormone imbalances, drastic personality change, gastroesophageal reflux disease with excessive salivation, herpes infection, EBV infection, trigeminal neuralgia, bilateral neck throbbing around lymph nodes, syncope, sadness, chest pain, rhinitis, and myalgia. ANTI-IL-6 ANTIBODIES

[0108] Provided herein are antibodies and antigen-binding fragments thereof that specifically bind IL-6. Antibodies and antigen-binding fragments disclosed herein specifically bind human IL-6. In some embodiments, an antibody may be specific for only human IL-6 and may exhibit no non-human cross-reactivity.

[0109] As used herein, the term “antibody” refers to immunoglobulin (Ig) molecules and immunologically active portions or fragments of immunoglobulin molecules, i.e., molecules that contain an antigen-binding site that specifically binds (immunoreacts with) an antigen (e.g., IL-6). By “specifically binds” or “immunoreacts with” is meant that the antibody reacts with one or more antigenic determinants of the desired antigen and does not react with other polypeptides. In some embodiments, an antibody is said to specifically bind an antigen when it preferentially recognizes its target antigen in a complex mixture of proteins and / or macromolecules. In some embodiments, an antibody “specifically binds” IL-6 if the antibody binds IL-6 with greater affinity, greater avidity, more readily and / or for greater duration than it binds other polypeptides.157570.604279 The term “antibody” broadly refers to an immunoglobulin (Ig) molecule, generally, comprising four polypeptide chains, two heavy (H) chains and two light (L) chains, or any functional fragment, mutant, variant, or derivative thereof, that retains the essential target binding features of an Ig molecule. Such mutant, variant, or derivative antibody formats are known in the art.

[0110] In a full-length antibody, each heavy chain comprises a heavy chain variable region (abbreviated herein as VH region) and a heavy chain constant region. The heavy chain constant region comprises three domains, CH1, CH2 and CH3. Each light chain comprises a light chain variable region (abbreviated herein as VL region) and a light chain constant region. The light chain constant region comprises one domain, CL. The VH and VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDRs), interspersed with regions that are more conserved, termed framework regions (FRs). Each VH region and VL region is composed of three CDRs and four FRs, arranged from amino-terminus to carboxyl-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.

[0111] As used herein, the term “HCDR” refers to a heavy chain complementarity determining region. As used herein, the term “LCDR” refers to a light chain complementarity determining region.

[0112] The term “Fc region” is used to define a C-terminal region of an immunoglobulin heavy chain. The “Fc region” may be a native sequence Fc region or a variant Fc region. Although the boundaries of the Fc region of an immunoglobulin heavy chain might vary, the human IgG heavy chain Fc region is usually defined to stretch from an amino acid residue at position Cys226, or from Pro230, to the carboxyl-terminus thereof. The numbering of the residues in the Fc region is according to the EU numbering system. The Fc region of an immunoglobulin generally comprises two constant domains, CH2 and CH3. An Fc region can be present in dimer or monomeric form. The Fc region binds to various cell receptors, such as Fc receptors, and other immune molecules, such as complement proteins.

[0113] Immunoglobulin molecules can be of any type (e.g., IgG, IgE, IgM, IgD, IgA or IgY) and class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1 or IgA2) or subclass. IgG, IgD, and IgE antibodies generally contain two identical heavy chains and two identical light chains157570.604279 and two antigen combining domains, each composed of a VH) and a VL. Generally IgA antibodies are composed of two monomers, each monomer composed of two heavy chains and two light chains (as for IgG, IgD, and IgE antibodies); in this way the IgA molecule has four antigen binding domains, each again composed of a VH and a VL. Certain IgA antibodies are monomeric in that they are composed of two heavy chains and two light chains. Secreted IgM antibodies are generally composed of five monomers, each monomer composed of two heavy chains and two light chains (as for IgG and IgE antibodies). Thus, the IgM molecule has ten antigen binding domains, each again composed of a VH and a VL. A cell surface form of IgM has a two heavy chain / two light chain structure similar to IgG, IgD and IgE antibodies.

[0114] The terms “specific binding affinity” or “specifically binds” or “specifically bound” or “specific binding” or “specifically targets” as used herein, describe binding of an antibody or antigen binding fragment thereof to an antigen at greater binding affinity than background binding. A binding domain “specifically binds” to IL6 polypeptide if it binds to or associates with IL6 with an affinity or Ka (i.e., an equilibrium association constant of a particular binding interaction with units of 1 / M) of, for example, greater than or equal to about 105M-1. In certain embodiments, a binding domain (or a fusion protein thereof) binds to a target with a Ka greater than or equal to about 106M-1, 107M-1, 108M-1, 109M-1, 1010M-1, 1011M-1, 1012M-1, or 1013M-1. “High affinity” binding domains (or single chain fusion proteins thereof) refers to those binding domains with a Ka of at least 107M-1, at least 108M-1, at least 109M-1, at least 1010M-1, at least 1011M-1, at least 1012M-1, at least 1013M-1, or greater.

[0115] The term “antigen-binding portion” or “antigen-binding fragment” of an antibody (or “antibody portion” or “antibody fragment”), as used herein, refers to one or more fragments of an antibody that retain the ability to specifically bind to an antigen (e.g., IL- 6). It has been shown that the antigen-binding function of an antibody can be performed by portions or fragments of a full-length antibody. Examples of binding fragments encompassed within the term “antigen binding portion” of an antibody include (i) a Fab fragment, a monovalent fragment consisting of the VL, VH, CL and CH1 domains; (ii) a F(ab')2fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; (iii) a Fd fragment consisting of the VH and CH1 domains; (iv)157570.604279 a Fv fragment consisting of the VL and VH domains of a single arm of an antibody, (v) a dAb (domain antibody) fragment (Ward et al., (1989) Nature 341:544-546; WO 90 / 05144 A1, each herein incorporated by reference in its entirety), which comprises a single variable domain; and (vi) an isolated complementarity determining region (CDR). The disclosure also encompasses a Fab' fragment. Fab' fragments can be formed by the reduction of F(ab')2fragments. Fab' is derived from F(ab')2; therefore, it may contain a small portion of Fc. Furthermore, although the two domains of the Fv fragment, VL and VH, are coded for by separate genes, they can be joined, using recombinant methods, by a synthetic linker that enables them to be made as a single protein chain in which the VL and VH domains pair to form monovalent molecules (known as single chain Fv (scFv). See e.g., Bird et al. (1988) Science 242:423-426; Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85:5879- 5883. Such single chain antibodies are also intended to be encompassed within the term “antigen-binding portion” of an antibody. In some embodiments, scFv molecules may be incorporated into a fusion protein. In some embodiments, provided herein is a single chain camelid antibody. In some embodiments, provided herein is a shark heavy chain antibody (V-NAR). See, English et al. (2020) Antibody Therapeutics, 3(1):1-9. Examples of antigen-binding portions are known in the art (Kontermann and Dubel eds., Antibody Engineering (2001) Springer-Verlag. New York.790 pp.). In some embodiments, provided herein is a single domain antibody. In general, the term “antibody” when used herein encompasses an “antibody fragment”. An antibody fragment generally retains the antigen- binding properties of a full-length antibody.

[0116] Antibodies and antibody portions provided herein may be in multispecific (e.g., bispecific or trispecific) formats. Such multispecific molecules specifically bind to two or more different molecular targets or epitopes. In some embodiments, an antibody or an antigen-binding portion is a bispecific molecule that binds specifically to a first antigen and a second antigen, wherein the first antigen is IL-6 and the second antigen is not IL-6. In some embodiments, an antibody or an antigen-binding portion is a diabody. Diabodies are bivalent, bispecific antibodies in which VH and VL regions are expressed on a single polypeptide chain, but using a linker that is too short to allow for pairing between the two regions on the same chain, thereby forcing the regions to pair with complementary domains of another chain and creating two antigen-binding sites (see e.g., Holliger et al. (1993)157570.604279 Proc. Natl. Acad. Sci. USA 90:6444-6448; Poljak et al. (1994) Structure 2:1121-1123). In some embodiments, an antibody or an antigen-binding portion is a triabody, a tetrabody, a bis-scFv or a tandem scFv. In some embodiments, an antibody or an antigen-binding portion is a dual affinity re-targeting protein.

[0117] In some embodiments, an anti-IL-6 antigen-binding portion disclosed herein is a Fab, a F(ab')2, a Fab', a Fv, a scFv, a Fd, a single domain antibody, a single chain camelid antibody, a diabody, a triabody, a tetrabody or a bis-scFv.

[0118] As used herein, the terms “immunological binding” and “immunological binding properties” refer to the non-covalent interactions of the type which occur between an immunoglobulin molecule (e.g., antibody or antigen-binding portion thereof) and an antigen for which the immunoglobulin is specific. The strength, or affinity of immunological binding interactions can be expressed in terms of the dissociation constant (Kd) of the interaction, wherein a smaller Kdrepresents a greater affinity. Immunological binding properties of selected polypeptides can be quantified using methods well known in the art. One such method entails measuring the rates of antigen-binding site / antigen complex formation and dissociation, wherein those rates depend on the concentrations of the complex partners, the affinity of the interaction, and geometric parameters that equally influence the rate in both directions. Thus, both the “on rate constant” (Kon) and the “off rate constant” (Koff) can be determined by calculation of the concentrations and the actual rates of association and dissociation. (See, Malmqvist, Nature 361:186-187 (1993)). The ratio of Koff / Konenables the cancellation of all parameters not related to affinity, and is equal to the dissociation constant Kd. (See, Davies et al. (1990) Annual Rev Biochem 59:439-473). An antibody or antigen-binding portion provided herein is said to specifically bind IL-6 when the equilibrium binding constant (Kd) is 10 M, preferably 10 nM, more preferably 10 nM, and most preferably 100 pM to about 1 pM, as measured by assays such as radioligand binding assays or similar assays known to those skilled in the art.

[0119] In some embodiments, an anti-IL-6 antibody provided herein is monovalent or bivalent and comprises a single or double chain. Functionally, the binding affinity of an antibody may be within the range of about 10-5M to 10-12M. For example, the binding affinity of an antibody is from about 10-6M to 10-12M, from about 10-7M to 10-12M, from about 10-8M to 10-12M, from about 10-9M to 10-12M, from about 10-5M to 10-11M, from157570.604279 about 10-6M to 10-11M, from about 10-7M to 10-11M, from about 10-8M to 10-11M, from about 10-9M to 10-11M, from about 10-10M to 10-11M, from about 10-5M to 10-10M, from about 10-6M to 10-10M, from about 10-7M to 10-10M, from about 10-8M to 10-10M, from about 10-9M to 10-10M, from about 10-5M to 10-9M, from about 10-6M to 10-9M, from about 10-7M to 10-9M, from about 10-8M to 10-9M, from about 10-5M to 10-8M, from about 10-6M to 10-8M, from about 10-7M to 10-8M, from about 10-5M to 10-7M, from about 10-6M to 10-7M or from about 10-5M to 10-6M.

[0120] A human anti-IL-6 monoclonal antibody (PF-04236921) was described in US8,188,235, which is incorporated herein by reference in its entirety. The human anti-IL- 6 monoclonal antibody is a fully human immunoglobulin G2 monoclonal antibody that binds to human IL-6 and has a Kd of about 6 pM and a half-life of 36–51 days. In phase I trials in healthy volunteers and patients with rheumatoid arthritis (protocol B0151001, NCT00838565 and NCT01166555), intravenous and subcutaneous (SC) the human anti- IL-6 monoclonal antibody (PF-04236921) was well tolerated and caused sustained suppression of C-reactive protein (CRP), a marker for inflammation that is transcriptionally controlled by IL-6. PF-04236921 has also been investigated in a phase II trial in patients with systemic lupus erythematosus (SLE; NCT01405196). While the study did not meet the primary end point, improvement was noted in the primary as well as key secondary end points with 10 mg. Overall, the human anti-IL-6 monoclonal antibody demonstrated desirable pharmacokinetic (PK) and pharmacodynamic (PD) properties supporting sustained target inhibition, and low incidence of immunogenicity upon single and multiple dose administration. See Danese, et al., Randomised trial and open-label extension study of an anti-interleukin-6 antibody in Crohn's disease (ANDANTE I and II), Gut 2019;68:40– 48; Li etal, Pharmacokinetics and C‐reactive protein modelling of anti‐interleukin‐6 antibody (PF‐04236921) in healthy volunteers and patients with autoimmune disease, Br J Clin Pharmacol. 2018 Sep; 84(9): 2059–2074. Further, the PK and PD profile of the human anti-IL-6 monoclonal antibody offer potential for attaining necessary level of IL-6 suppression in skeletal muscle. Moreover, long serum half-life of the human anti-IL-6 monoclonal antibody permits the use of a lower dose and less frequent dosing. For example, the human anti-IL-6 monoclonal antibody can be administered following a “vaccination-like” dosing regimen (e.g., a primary dose followed by a booster dose 3157570.604279 months after the primary dose), which substantially decreases drug administration burden. The reduced drug administration burden is especially beneficial for patients with Long COVID, considering the potential challenges they may face in visiting healthcare provides due to severe limitations in their physical activity capacity. Additionally, a low total dose regimen provides the opportunity for a scalable drug supply to meet global demand.

[0121] The amino acid and nucleic acid sequences of the human anti-IL-6 antibody (TOUR006) are provided in Table 1. Table 1. Amino acid and nucleic acid sequences of human anti-IL-6 antibody Antibody name Anti-IL-6 antibody (TOUR006)157570.604279 Table 1. Amino acid and nucleic acid sequences of human anti-IL-6 antibody Antibody name Anti-IL-6 antibody (TOUR006)n and light chain, respectively.157570.604279

[0122] Provided herein is a method of preventing or treating a patient having Long COVID comprising subcutaneously administering to a patient in need thereof a therapeutically effective dose of an anti-IL-6 antibody described herein. In some embodiments, the anti- IL-6 antibody described herein is utilized to prevent or treat a symptom or disease associated with Long COVID selected from postural orthostatic tachycardia syndrome (POTS), brain fog, chronic fatigue syndrome (CFS) and mast cell activation syndrome (MCAS). In some embodiments, the anti-IL-6 antibody described herein is utilized to treat POTS, brain fog, CFS or MCAS.

[0123] In some embodiments, the anti-IL-6 antibody comprises a heavy chain variable region comprising HCDR1, HCDR2, and HCDR3, and a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein: (a) HCDR1 comprises SEQ ID NO: 2, or has an amino acid sequence which differs from SEQ ID NO:2 at one, two, or three amino acid positions, HCDR2 comprises SEQ ID NO: 3, or has an amino acid sequence which differs from SEQ ID NO: 3 at one, two, or three amino acid positions, and HCDR3 comprises SEQ ID NO: 4, or has an amino acid sequence which differs from SEQ ID NO: 4 at one, two, or three amino acid positions; and (b) LCDR1 comprises SEQ ID NO: 8, or has an amino acid sequence which differs from SEQ ID NO:8 at one, two, or three amino acid positions, LCDR2 comprises SEQ ID NO: 9, or has an amino acid sequence which differs from SEQ ID NO: 9 at one, two, or three amino acid positions, and LCDR3 comprises SEQ ID NO: 10, or has an amino acid sequence which differs from SEQ ID NO: 10 at one, two, or three amino acid positions.

[0124] In some embodiments, the anti-IL-6 antibody comprises HCDR1 of SEQ ID NO: 2, HCDR2 of SEQ ID NO: 3, HCDR3 of SEQ ID NO: 4, LCDR1 of SEQ ID NO: 8, LCDR2 of SEQ ID NO: 9, and LCDR3 of SEQ ID NO: 10.

[0125] In some embodiments, the anti-IL-6 antibody comprises the heavy chain variable region comprising a polypeptide having at least about 95%, about 96%, about 97%, about 98% or about 99% identity to SEQ ID NO: 5 and the light chain variable region comprising a polypeptide having at least about 95%, about 96%, about 97%, about 98% or about 99% identity to SEQ ID NO: 11. In some embodiments, the anti-IL-6 antibody comprises the157570.604279 heavy chain variable region comprising a polypeptide having the sequence of SEQ ID NO: 5 and the light chain variable region comprising a polypeptide having the sequence of SEQ ID NO: 11.

[0126] In some embodiments, the anti-IL-6 antibody comprises a heavy chain polypeptide comprising a polypeptide having at least about 95%, about 96%, about 97%, about 98% or about 99% identity to SEQ ID NO: 1 and a light chain polypeptide comprising a polypeptide having at least about 95%, about 96%, about 97%, about 98% or about 99% identity to SEQ ID NO: 7. In some embodiments, the anti-IL-6 antibody comprises the heavy chain polypeptide having the sequence of SEQ ID NO: 1 and the light chain polypeptide having the sequence of SEQ ID NO: 7.

[0127] In some embodiments, the anti-IL-6 antibody or an antigen-binding portion comprises human IgG2 constant regions.

[0128] As used herein, the term “conservative substitution” refers to replacement of an amino acid with another amino acid which does not significantly deleteriously change the functional activity. A preferred example of a “conservative substitution” is the replacement of one amino acid with another amino acid which has a value ≥ 0 in the following BLOSUM 62 substitution matrix (see Henikoff & Henikoff, 1992, PNAS 89: 10915- 10919): A R N D C Q E G H I L K M F P S T W Y V A 4 -1 -2 -2 0 -1 -1 0 -2 -1 -1 -1 -1 -2 -1 1 0 -3 -2 0 R -1 5 0 -2 -3 1 0 -2 0 -3 -2 2 -1 -3 -2 -1 -1 -3 -2 -3 N -2 0 6 1 -3 0 0 0 1 -3 -3 0 -2 -3 -2 1 0 -4 -2 -3 D -2 -2 1 6 -3 0 2 -1 -1 -3 -4 -1 -3 -3 -1 0 -1 -4 -3 -3 C 0 -3 -3 -3 9 -3 -4 -3 -3 -1 -1 -3 -1 -2 -3 -1 -1 -2 -2 -1 Q -1 1 0 0 -3 5 2 -2 0 -3 -2 1 0 -3 -1 0 -1 -2 -1 -2 E -1 0 0 2 -4 2 5 -2 0 -3 -3 1 -2 -3 -1 0 -1 -3 -2 -2 G 0 -2 0 -1 -3 -2 -2 6 -2 -4 -4 -2 -3 -3 -2 0 -2 -2 -3 -3 H -2 0 1 -1 -3 0 0 -2 8 -3 -3 -1 -2 -1 -2 -1 -2 -2 2 -3 I -1 -3 -3 -3 -1 -3 -3 -4 -3 4 2 -3 1 0 -3 -2 -1 -3 -1 3 L -1 -2 -3 -4 -1 -2 -3 -4 -3 2 4 -2 2 0 -3 -2 -1 -2 -1 1 K -1 2 0 -1 -3 1 1 -2 -1 -3 -2 5 -1 -3 -1 0 -1 -3 -2 -2 M -1 -1 -2 -3 -1 0 -2 -3 -2 1 2 -1 5 0 -2 -1 -1 -1 -1 1 F -2 -3 -3 -3 -2 -3 -3 -3 -1 0 0 -3 0 6 -4 -2 -2 1 3 -1 P -1 -2 -2 -1 -3 -1 -1 -2 -2 -3 -3 -1 -2 -4 7 -1 -1 -4 -3 -2157570.604279 S 1 -1 1 0 -1 0 0 0 -1 -2 -2 0 -1 -2 -1 4 1 -3 -2 -2 T 0 -1 0 -1 -1 -1 -1 -2 -2 -1 -1 -1 -1 -2 -1 1 5 -2 -2 0 W -3 -3 -4 -4 -2 -2 -3 -2 -2 -3 -2 -3 -1 1 -4 -3 -2 11 2 -3-1 V 0 -3 -3 -3 -1 -2 -2 -3 -3 3 1 -2 1 -1 -2 -2 0 -3 -1 4

[0129] Calculations of sequence homology or identity (the terms are used interchangeably herein) between sequences may be performed as follows.

[0130] To determine the percent identity of two amino acid sequences, or of two nucleic acid sequences, the sequences are aligned for optimal comparison purposes (e.g., gaps can be introduced in one or both of a first and a second amino acid or nucleic acid sequence for optimal alignment and non-homologous sequences can be disregarded for comparison purposes). In a preferred embodiment, the length of a reference sequence aligned for comparison purposes is at least about 30%, preferably at least about 40%, more preferably at least about 50%, even more preferably at least about 60%, and even more preferably at least about 70%, about 75%, about 80%, about 82%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100% of the length of the reference sequence. The amino acid residues or nucleotides at corresponding amino acid positions or nucleotide positions are then compared. When a position in the first sequence is occupied by the same amino acid residue or nucleotide as the corresponding position in the second sequence, then the molecules are identical at that position (as used herein amino acid or nucleic acid “identity” is equivalent to amino acid or nucleic acid “homology”). The percent identity between the two sequences is a function of the number of identical positions shared by the sequences, considering the number of gaps, and the length of each gap, which need to be introduced for optimal alignment of the two sequences.

[0131] The comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm. In some embodiments, the percent identity between two amino acid sequences is determined using the Needleman et al. ((1970) J. Mol. Biol. 48:444-453) algorithm which has been incorporated into the GAP program in the GCG software package, using either a BLOSUM 62 matrix or a PAM250 matrix, and a gap weight of 16, 14, 12, 10, 8, 6, or 4 and a length weight of 1, 2,157570.604279 3, 4, 5, or 6. In some embodiments, the percent identity between two nucleotide sequences is determined using the GAP program in the GCG software package, using a NWSgapdna.CMP matrix and a gap weight of 40, 50, 60, 70, or 80 and a length weight of 1, 2, 3, 4, 5, or 6. One set of parameters (and the one that can be used if the practitioner is uncertain about what parameters should be applied to determine if a molecule is within a sequence identity or homology limitation of the invention) is a BLOSUM 62 scoring matrix with a gap penalty of 12, a gap extend penalty of 4, and a frameshift gap penalty of 5.

[0132] In some embodiments, the percent identity between two amino acid or nucleotide sequences can be determined using the algorithm of Meyers et al. ((1989) CABIOS 4:11- 17) which has been incorporated into the ALIGN program (version 2.0), using a PAM120 weight residue table, a gap length penalty of 12 and a gap penalty of 4.

[0133] In some embodiments, the anti-IL-6 antibody provided herein is monoclonal.

[0134] In some embodiments, the anti-IL-6 antibody provided herein is chimeric. The term “chimeric” is intended to refer to an antibody molecule, or an antigen-binding portion thereof, in which the variable domain sequences are derived from one species and at least one constant region sequence is derived from another species. For example, one or all the variable domains of the light chain(s) and / or one or all the variable domains of the heavy chain(s) of a mouse antibody (e.g., a mouse monoclonal antibody) may each be joined to a human constant region, such as, without limitation an IgG1, IgG2, or an IgG4 human constant region. Examples of chimeric antibodies and suitable techniques for their generation are provided in U.S. 4,816,567; U.S. 4,975,369; and U.S. 4,816,397, each of which is incorporated herein by reference in its entirety.

[0135] In some embodiments, the anti-IL-6 antibody provided herein is humanized. The term “humanized” is intended to refer to an antibody that has been engineered to comprise one or more human framework regions in the variable domain together with non-human (e.g., mouse, rat, or hamster) CDRs of the heavy and / or light chain. In some embodiments, a humanized antibody comprises sequences that are entirely human except for the CDRs. In some embodiments, the VH domain, the VL domain, or both the VH domain and the VL domain of an anti-IL-6 antibody or antigen-binding portion provided herein comprise one or more human framework region amino acid sequences. In some embodiments, a humanized antibody comprises sequences that are entirely human except for the CDRs,157570.604279 which are the CDRs of antibody 32G8H6. Examples of humanized antibodies and suitable techniques for their generation are provided in Hwang et al., Methods 36:35, 2005; Queen et al., Proc. Natl. Acad. Sci. USA, 86:10029-10033, 1989; Jones et al., Nature, 321:522-25, 1986; Riechmann et al., Nature, 332:323-27, 1988; Verhoeyen et al., Science, 239:1534- 36, 1988; Orlandi et al., Proc. Natl. Acad. Sci. USA, 86:3833-37, 1989; U.S. 5,225,539; U.S. 5,530,101; U.S.5,585,089; U.S.5,693,761; U.S. 5,693,762; U.S.6,180,370; and WO 90 / 07861, each of which is incorporated herein by reference in its entirety.

[0136] In some embodiments, humanization comprises removal of post-translational modification (PTM) sites in the variable domain sequences (e.g., in the CDR or framework sequences) of a non-human antibody. For example, one or more PTM sites in CDR sequences may be removed by substituting certain amino acid residues. In some embodiments, humanization comprises CDR grafting and back mutation.

[0137] In some embodiments, the anti-IL-6 antibody comprises an immunoglobulin constant region. In some embodiments, the immunoglobulin constant region is IgG, IgE, IgM, IgD, IgA or IgY. In some embodiments, the immunoglobulin constant region is IgG1, IgG2, IgG3, IgG4, IgA1 or IgA2. In some embodiments, the immunoglobulin constant region is immunologically inert. In some embodiments, the immunoglobulin constant region comprises one or more mutations to reduce or prevent FcγR binding, antibody- dependent cell-mediated cytotoxicity activity, and / or complement-dependent cytotoxicity activity. In some embodiments, the immunoglobulin constant region is a wild-type human IgG1 constant region, a wild-type human IgG2 constant region, a wild-type human IgG4 constant region, a human IgG1 constant region comprising the amino acid substitutions L234A, L235A and G237A, a human IgG1 constant region comprising the amino acid substitutions L234A, L235A, G237A and P331S or a human IgG4 constant region comprising the amino acid substitution S228P, wherein numbering is according to the EU numbering system. In some embodiments, a position of an amino acid residue in a constant region of an immunoglobulin molecule is numbered according to EU nomenclature (Ward et al., 1995 Therap. Immunol. 2:77-94).

[0138] In some embodiments, the anti-IL-6 antibody may comprise an immunoglobulin light chain constant region that is a kappa light chain constant region or a lambda light chain constant region.157570.604279

[0139] In some embodiments, the anti-IL-6 antibody may comprise a human IgG4 constant region comprising the amino acid substitution S228P and a kappa light chain constant region.

[0140] Further provided herein is an immunoconjugate comprising an anti-IL-6 antibody or an antigen-binding portion linked to a therapeutic agent. In some embodiments, the therapeutic agent is a small molecule drug. PHARMACEUTICAL COMPOSITIONS

[0141] The anti-IL-6 antibodies and antigen-binding portions described herein (also referred to herein as “active compounds”) can be incorporated into pharmaceutical compositions suitable for administration. Such compositions typically comprise an anti- IL-6 antibody or antigen-binding portion (or an immunoconjugate comprising said antibody or portion), and a pharmaceutically acceptable carrier, diluent or excipient. As used herein, the term “pharmaceutically acceptable” refers to molecular entities and compositions that do not generally produce allergic or other serious adverse reactions when administered using routes well known in the art. Molecular entities and compositions approved by a regulatory agency of the U.S. federal or state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans are considered to be “pharmaceutically acceptable.” As used herein, the term “pharmaceutically acceptable carrier” is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. Suitable carriers are described in the most recent edition of Remington's Pharmaceutical Sciences, a standard reference text in the field, which is incorporated herein by reference. Some examples of such carriers or diluents include, but are not limited to, water, saline, Ringer's solutions, dextrose solution, and 5% human serum albumin. Liposomes and non- aqueous vehicles such as fixed oils may also be used. 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 compositions is contemplated. Supplementary active compounds can also be incorporated into the compositions.157570.604279

[0142] Provided herein is a pharmaceutical composition comprising (i) an anti-IL-6 antibody, wherein the antibody comprises a heavy chain variable region comprising HCDR1, HCDR2, and HCDR3, and a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein: (a) HCDR1 comprises SEQ ID NO: 2, or has an amino acid sequence which differs from SEQ ID NO:2 at one, two, or three amino acid positions, and HCDR2 comprises SEQ ID NO: 3, or has an amino acid sequence which differs from SEQ ID NO: 3 at one, two, or three amino acid positions, and HCDR3 comprises SEQ ID NO: 4, or has an amino acid sequence which differs from SEQ ID NO: 4 at one, two, or three amino acid positions; and (b) LCDR1 comprises SEQ ID NO: 8, or has an amino acid sequence which differs from SEQ ID NO:8 at one, two, or three amino acid positions, and LCDR2 comprises SEQ ID NO: 9, or has an amino acid sequence which differs from SEQ ID NO: 9 at one, two, or three amino acid positions, and LCDR3 comprises SEQ ID NO: 10, or has an amino acid sequence which differs from SEQ ID NO: 10 at one, two, or three amino acid positions; and (ii) a pharmaceutically acceptable carrier, diluent or excipient.

[0143] A pharmaceutical composition disclosed herein may be formulated to be compatible with its intended route of administration. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (i.e., topical), transmucosal, and rectal administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfate; chelating agents such as ethylenediaminetetraacetic acid (EDTA); buffers such as acetates, citrates or phosphates, and agents for the adjustment of tonicity such as sodium chloride or dextrose. The pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.

[0144] Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL®(BASF,157570.604279 Parsippany, N.J.) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent that easy syringeability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.

[0145] Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, methods of preparation are vacuum drying and freeze-drying that yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.

[0146] Oral compositions generally include an inert diluent or an edible carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and / or adjuvant materials can be included as part of the composition. The157570.604279 tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primojel®, or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.

[0147] For administration by inhalation, the compounds may be delivered in the form of an aerosol spray from pressured container or dispenser which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer.

[0148] Systemic administration can also be by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives. Transmucosal administration can be accomplished through the use of nasal sprays or suppositories. For transdermal administration, the active compounds are formulated into ointments, salves, gels, or creams as generally known in the art.

[0149] The pharmaceutical agents can also be prepared in the form of suppositories (e.g., with conventional suppository bases such as cocoa butter and other glycerides) or retention enemas for rectal delivery.

[0150] In some embodiments, the active compounds are prepared with carriers that will protect the compound against rapid elimination from the body, 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, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. The materials can also be obtained commercially. Liposomal suspensions can also be used as pharmaceutically acceptable carriers.

[0151] It is especially advantageous to formulate oral or parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to157570.604279 produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the invention are dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and the limitations inherent in the art of compounding such an active compound for the treatment of individuals.

[0152] In some embodiments, the anti-IL-6 antibody of the present disclosure is formulated in a aqueous solution. In some embodiments, the aqueous solution comprises the anti-IL-6 antibody at a concentration ranging from about 50 mg / mL to about 150 mg / mL. In some embodiments, the aqueous solution comprises the anti-IL-6 antibody described herein at a concentration of about 50 mg / mL, about 55 mg / mL, about 60 mg / mL, 65 mg / mL, about 70 mg / mL, about 75 mg / mL, about 80 mg / mL, about 85 mg / mL, about 90 mg / mL, about 95 mg / mL, about 100 mg / mL, about 105 mg / mL, about 110 mg / mL, about 115 mg / mL about 120 mg / mL, about 125 mg / mL, about 130 mg / mL, about 135 mg / mL, about 140 mg / mL, about 145 mg / mL, or about 150 mg / mL.

[0153] In some embodiments, a buffer is selected from phosphate buffers, histidine, sodium citrate, HEPES, Tris, Bicine, glycine, N-glycylglycine, sodium acetate, sodium carbonate, glycylglycine, lysine, arginine, sodium phosphate, and any combination thereof. Exemplary concentrations of buffers for formulations of the present disclosure are from about 5 mM to about 100 mM, about 50 mM, about 10 mM to about 40 mM, or about 20 mM. In some embodiments, histidine is included at about 5 mM, about 10 mM, about 20 mM, about 30 mM, about 40 mM, or about 50 mM.

[0154] In some embodiments, a sweetening agent is selected from sucrose and saccharin. In some embodiments, sucrose is included at about 50 mg / mL, about 60 mg / mL, about 80 mg / mL, about 90 mg / mL, or about 100 mg / mL.

[0155] In some embodiments, a tonicity adjusting agent is selected from sodium chloride, potassium chloride, dextrose, mannitol, glycerin, sorbitol, and any combination thereof. In some embodiments, mannitol is included at about 10 mg / mL, about 15 mg / mL, about 20 mg / mL, about 25 mg / mL, about 30 mg / mL, about 35 mg / mL, about 40 mg / mL, about 45 mg / mL, or about 50 mg / mL.

[0156] In some embodiments, a chelating agents is selected from ethylenediaminetetraacetic acid (EDTA), disodium edetate, calcium EDTA, and any157570.604279 combination thereof. In some embodiments, EDTA is included at about 0.01 mg / mL, about 0.02 mg / mL, 0.03mg / mL, about 0.04 mg / mL, 0.05mg / mL, about 0.06 mg / mL, 0.07mg / mL, about 0.08 mg / mL, about 0.09 mg / mL, or 0.10 mg / mL.

[0157] In some embodiments, a surfactant is selected from polysorbate 80, sodium lauryl sulfate (SDS), Tween 80, and any combination thereof. In some embodiments, polysorbate 80 is included at about 0.1 mg / mL, about 0.2 mg / mL, 0.3mg / mL, about 0.4 mg / mL, 0.5mg / mL, about 0.6 mg / mL, 0.7mg / mL, about 0.8 mg / mL, about 0.9 mg / mL, or about 1.0 mg / mL.

[0158] In some embodiments, the formulation has a pH value ranging from about 5.0 to about 8.0. In some embodiments, the formulation has a pH value of about 5.0, about 5.1, about 5.2, about 5.3, about 5.4, about 5.5, about 5.6, about 5.7, about 5.8, about 5.9, about 6.0, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, about 7.5, about 7.6, about 7.7, about 7.8, about 7.9, or about 8.0.

[0159] In some embodiments, TOUR006 is formulated at a concentration of 85 mg / mL with 20 mM histidine, 63.2 mg / mL sucrose, 16.8 mg / mL mannitol, 0.05 mg / mL EDTA, and 0.2 mg / mL polysorbate 80, pH 5.8. After reconstitution with water for injection, each single use vial contains 106 mg of TOUR006 in 1.25 mL of aqueous solution.

[0160] The pharmaceutical compositions provided herein can be included in a container, pack, or dispenser together with instructions for administration. USES OF ANTIBODIES

[0161] Provided herein are methods and uses of the anti-IL-6 antibodies, anti-IL-6 antigen- binding portions, immunoconjugates and pharmaceutical compositions described herein for providing a therapeutic benefit to a subject with a condition associated with IL-6elevations. In some embodiments, the condition is selected from Long COVID, posturalorthostatic tachycardia syndrome (POTS), brain fog, post exertional malaise, aerobic metabolism impairment or deficiency, Chronic Fatigue Syndrome (CFS), fibromyalgia, and Mast cell activation syndrome (MCAS).

[0162] Provided herein is an anti-IL-6 antibody or an anti-IL-6 antigen-binding portion, an immunoconjugate or a pharmaceutical composition described herein, for use as a medicament.157570.604279

[0163] As used herein, the term “effective amount”, “therapeutically effective amount” or “therapeutically effective dose” refers to the amount of a pharmaceutical agent, e.g., an anti-IL-6 antibody or an antigen-binding portion thereof, which is sufficient to reduce or ameliorate the severity and / or duration of a disorder, e.g., Long COVID, or one or more symptoms thereof, prevent the advancement of a disorder, cause regression of a disorder, prevent the recurrence, development, onset or progression of one or more symptoms associated with a disorder, detect a disorder, or enhance or improve the prophylactic or therapeutic effect(s) of another therapy (e.g., prophylactic or therapeutic agent). In some embodiments, the therapeutically effective dose of said anti-IL-6 antibody is effective to change one or more biomarkers of IL-6 mediated signaling including, but not limited to, total sIL-6R, total IL-6, C-reactive protein (CRP), an / or autoantibody, for unexpectedly prolonged periods of time.

[0164] As used herein, the terms “treat,” “treating,” “treatment,” and the like refer to reducing or ameliorating a disorder, and / or signs or symptoms associated therewith, or slowing or halting the progression thereof. 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.

[0165] As used herein, the term “prevent,” “prevention,” and the like refers to stopping something from happening, or taking advance measures against something possible or probable from happening. In the context of medicine, “prevention” generally refers to action taken to decrease the chance of getting a disease or disorder, and / or signs orsymptoms associated therewith. A “preventive” or “prophylactic” treatment is a treatmentadministered to a subject who does not exhibit signs, or exhibits only early signs, of a disease or disorder. A prophylactic or preventative treatment is administered for the purpose of decreasing the risk of developing pathology associated with developing the disease or disorder.

[0166] As used herein, “pre-treatment” means prior to the first administration of an anti- IL-6 antibody according the methods described herein. Pre-treatment does not exclude, and often includes, the prior administration of treatments other than an anti-IL-6 antibody.

[0167] As used herein, “post-treatment” means after the administration of an anti-IL-6 antibody according the methods described herein. Post-treatment includes after any157570.604279 administration of an anti-IL-6 antibody at any dosage described herein. Post-treatment also includes after the treatment phase of an anti-IL-6 antibody.

[0168] The actual amount administered, and rate and time-course of administration, will depend on the nature and severity of what is being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the composition, the method of administration, the scheduling of administration and other factors known to medical practitioners. Prescription of treatment, e.g. decisions on dosage etc., is within the responsibility of general practitioners and other medical doctors and may depend on the severity of the symptoms and / or progression of a disease being treated. Appropriate doses of antibody molecules are well known in the art (Ledermann J.A. et al., 1991, Int. J. Cancer 47: 659-664; Bagshawe K.D. et al., 1991, Antibody, Immunoconjugates and Radiopharmaceuticals 4: 915-922). Specific dosages may be indicated herein or in the Physician’s Desk Reference (2003) as appropriate for the type of medicament being administered may be used. A therapeutically effective amount or suitable dose of an antibody molecule may be determined by comparing its in vitro activity and in vivo activity in an animal model. Methods for extrapolation of effective dosages in mice and other test animals to humans are known. The precise dose will depend upon a number of factors, including whether the antibody is for prevention or for treatment, the size and location of the area to be treated, the precise nature of the antibody (e.g., whole antibody, fragment) and the nature of any detectable label or other molecule attached to the antibody.

[0169] A typical antibody dose will be in the range 100 μg to 1 g for systemic applications, and 1 μg to 1 mg for intradermal injection. An initial higher loading dose, followed by one or more lower doses, may be administered. In some embodiments, the antibody is a whole antibody, e.g., the IgG1, IgG2 or IgG4 isotype. This is a dose for a single treatment of an adult subject, which may be proportionally adjusted for children and infants, and also adjusted for other antibody formats in proportion to molecular weight. Treatments may be repeated at daily, twice-weekly, weekly or monthly intervals, at the discretion of the physician. The treatment schedule for a subject may be dependent on the pharmacokinetic and pharmacodynamic properties of the antibody composition, the route of administration and the nature of the condition being treated.157570.604279

[0170] In some embodiments, the therapeutically effective dose is between about 10 mg to about 200 mg. In some embodiments, the therapeutically effective dose is about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 120 mg, about 140 mg, about 160 mg, about 180 mg, or about 200 mg. In some embodiments, the therapeutically effective dose is about 50 mg. In some embodiments, the therapeutically effective dose is about 100 mg.

[0171] In some embodiments, the therapeutically effective dose is administered from every 1 month to every 12 months. In some embodiments, the therapeutically effective dose is administered every 1 month, every 2 months, every 3 months, every 4 months, every 5 months, every 6 months, every 7 months, every 8 month, every 9 months, every 10 months, every 11 months, or every 12 months. In some embodiments, the therapeutically effective dose is administered every 3 months.

[0172] In some embodiments, the anti-IL-6 antibody or antibody fragment of the present disclosure is administered after a period of about 1 week, or about 2 weeks, or about 3 weeks, or about 4 weeks, or about 5 weeks, or about 6 weeks, or about 7 weeks, about 8 weeks, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 1.5 years, about 2 years, about 3 years, or more after an acute, symptomatic or asymptomatic SARS-CoV-2 infection. In some embodiments, the anti-IL-6 antibody or antibody fragment of the present disclosure is administered within 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks after onset of the SARS-CoV-2 infection to prevent Long COVID.

[0173] In some embodiments, the therapeutically effective dose is a single dose of about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 120 mg, about 140 mg, about 160 mg, about 180 mg, or about 200 mg. In some embodiments, the single dose is administered after a period of about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 week, about 7 weeks, about 8 weeks, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 1.5 years, about 2 years, about 3 years, or greater than 3 years after an acute, symptomatic or asymptomatic SARS-CoV-2157570.604279 infection. In some embodiments, the single dose is administered within 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks after onset of an acute, symptomatic or asymptomatic SARS-CoV-2 infection to prevent Long COVID.

[0174] In some embodiments, according to the methods of the present disclosure, anti-IL- 6 antibody or antibody fragment of the present disclosure is administered following a “vaccination-like” dosing regimen. For example, the “vaccination-like” dosing regimen contains a primary dose followed by a booster dose. In some embodiments, the therapeutically effective dose comprise a primary dose and a booster dose. In some embodiments, the booster dose is identical to the primary dose. In some embodiments, the primary dose and the booster dose are 50 mg each. In some embodiments, the primary dose and the booster dose are about 1 month, about 2 month, about 3 months, about 4 months, about 5 months, or about 6 months apart. In some embodiments, the primary dose and the booster dose are about 3 months apart. In some embodiments, the primary dose is administered after a period of about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 week, about 7 weeks, or about 8 weeks after an acute, symptomatic or asymptomatic SARS-CoV-2 infection. In some embodiments, the primary dose is administered after a period of about 4 weeks after an acute, symptomatic or asymptomatic SARS-CoV-2 infection.

[0175] In some embodiments, the methods described herein further comprise a step of treating a subject with an additional form of therapy. In some embodiments, the additional form of therapy comprises administering one or more therapeutic agents in addition to the anti-IL-6 antibody as described herein. The therapeutic agents include, but are not limited to, a second antibody (e.g., an anti-IL-1 antibody, anti-TNF-alpha antibody, anti-FcRn antibody, anti-CD20 antibody, complement pathway inhibitor, anti-IL17a antibody), a soluble receptor (e.g., soluble IL-1 receptor, soluble TNF-alpha receptor), other anti- inflammatory agent (e.g., corticosteroid, 6-mercaptopurine, mycophenolate mofetil), intravenous immunoglobulin (IVIg), plasmapheresis, antiviral agent against SARS-CoV-2 (e.g., nirmatrelvir / ritonavir, monoclonal antibody against SARS-CoV-2, polyclonal antibodies against SARS-CoV-2, convalescent plasma), other immunomodulatory or anti- infection agent (e.g., interferon beta, interferon gamma, ribavirin, other antiviral agent), or adjunctive medication (e.g., metformin, angiotensin-converting enzyme (ACE)-inhibitor,157570.604279 angiotensin receptor blocker (ARB), antidepressant, anabolic steroid, GLP-1 receptor agonist, GIP receptor agonist, glucagon, or dietary supplement).

[0176] In some embodiments, the methods described herein further comprise a step of treating a subject with an additional form of rehabilitation therapy or intervention. Rehabilitation therapy or interventions include but are not limited to prolonged rest, physical therapy, occupational therapy, relaxation techniques, sleep therapy, cognitive rehabilitation, energy-saving techniques, activities of daily living training, nutrition, and / or breathing exercise.

[0177] In some embodiments, a subject is a human, a non-human primate, a pig, a horse, a cow, a dog, a cat, a guinea pig, a mouse or a rat. In some embodiments, a subject is an adult human. In some embodiments, a subject is a pediatric human. CLINICAL OUTCOMES

[0178] In some embodiments, according to the methods of the disclosure, administration of anti-IL-6 antibody or antibody fragment results in an improvement in one or more outcomes when compared to baseline. Non-limiting examples of patient outcomes include: CPET or 2-day CPET test parameters including but not limited to: peak oxygen consumption (VO2peak), VO2at ventilatory anaerobic threshold (VAT), peak workload, workload at VAT, , 10-minute standing test for POTS, tilt table testing to evaluate POTS, cognitive test scores, high-sensitivity CRP (hsCRP), serum (or other blood-based sample) FFAs level, serum (or other blood-based sample) lactate level and serum (or other blood- based sample) kynurenine level.

[0179] In some embodiments, baselines are measured 1 day, or 2 days, or 3 days, or 4 days, or 5 days, 6 days, or 1 week, or 2 weeks, or 3 weeks, or 4 weeks, or 5 weeks, or 6 weeks, or 7 weeks, or 8 weeks prior to initiation of treatment according to the methods of the disclosure.

[0180] In some embodiments, outcomes are measured about 1 month, or about 2 month, or about 3 month, or about 4 months, or about 5 months, or about 6 months, or about 7 months, or about 8 months, or about 9 months, or about 10 months, or about 11 months, or about 12 months, or more months after initiation of treatment according to the methods of the disclosure.157570.604279

[0181] In some embodiments, the methods of the disclosure result in an improvement in outcomes about 1 month, or about 2 month, or about 3 month, or about 4 months, or about 5 months, or about 6 months, or about 7 months, or about 8 months, or about 9 months, or about 10 months, or about 11 months, or about 12 months, or more months after initiation of treatment according to the methods of the disclosure.

[0182] In some embodiments, the methods of the disclosure lead to improved functional capacity as measured by cardiopulmonary exercise testing (CPET) or 2-day CPET compared to baseline. CPET can be conducted using a standardized treadmill or bicycle ergometer at baseline and after initiation of treatment. The same modality (treadmill or upright bicycle) must be used for all CPETs conducted for a given participant. Participants will be encouraged to perform maximally to achieve their expected peak exercise heart rate(HR) and exertion level. In some embodiments, CPET parameters are measured by CPETat baseline before treatment initiation and at an endpoint after treatment (CPETmeasurement). In some embodiments, CPET parameters are measured by 2-day CPET.The 2-day CPET protocol is described in Institute of Medicine The National Academies Collection: Reports funded by National Institutes of Health. In: Committee on the Diagnostic Criteria for Myalgic Encephalomyelitis / Chronic Fatigue S, Board on the Health of Select P, editor. Beyond Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: Redefining an Illness. Washington, DC: National Academies Press; (2015), 82–4, the contents of which are expressly incorporated by reference in its entirety for any purpose. In a 2-day CPET, baseline and endpoint CPET parameters are determined with the first test (2-day CEPT Day 1 measurement), which also serves as a standardized stressor to elicit a post-exertional symptom flare. The second exercise test is conducted 24h later (2-day CEPT Day 2 measurement). The 2-day CEPT Day 2 measurement provides a metric of change in physiological function due to the post-exertional response, and can indicatemagnitude of impairment associated with a patient’s compromised recovery. The 2-dayCPET methodology is useful for assessing impaired recovery because CPET measures are readily reproduced in both healthy and diseased populations. Therefore, a failure to reproduce CPET measures on a subsequent test, despite peak effort on both tests, indicates a derangement of homeostasis. Throughout this specification, the improvements in CPET parameters can be determined by comparing the endpoint relative to baseline based on the157570.604279 CPET measurement, 2-day CPET Day 1 measurement, and / or 2-day CPET Day 2 measurement.

[0183] In some embodiments, the CPET or 2-day CPET is performed via bicycle test as described in Evers, et al., Can Respir J. 2022, the contents of which are expressly incorporated by reference in its entirety for any purpose. The CPET or 2-day CPET performance parameters include, but not limited to the following: peak oxygen consumption (VO2peak), VO2at ventilatory anaerobic threshold (VAT), peak workload and workload at VAT.

[0184] Oxygen consumption (VO2) is the volume of O2extracted from the air inhaled during pulmonary ventilation in a period of time. In practice, maximum VO2(VO2max) is defined as the highest value reached, despite progressive increase of the load applied, with the development of a plateau in the VO2curve during an incremental exercise test. When no plateau can be identified, the highest value obtained at the end of an exhausting exercise is characterized as peak VO2, which, in practice, is used as VO2max. Peak VO2is an objective measure of maximum energy producing capacity. The response is influenced by a central mechanism (cardiovascular and / or pulmonary) and peripheral function (skeletal muscle). The normal values depend on several factors, such as: age, sex, weight, height, physical activity level, genetic variability and ethnicity. Different equations to predict the normal values of VO2max or peak VO2have been determined from different populations. In general, when assessing peak VO2levels, an increase in peak VO2of 2.0 mL / kg / min or more from baseline is considered a clinical improvement, a decrease in peak VO2of 2.0 mL / kg / min or more from baseline is considered a clinical regression, and a less than 2.0 mL / kg / min variance in peak VO2is considered no clinical change. In some embodiments, the methods of the disclosure lead to an increase in peak VO2compared to baseline. In some embodiments, the methods of the disclosure lead to an increase in peak VO2by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% relative to baseline. In some embodiments, the methods of the disclosure lead to an increase in peak VO2of about +3, or about +2, or about +1.5 mL / kg / min relative to baseline.157570.604279

[0185] VO2at anaerobic threshold is the volume of oxygen at anaerobic threshold, which is the point which ventilation starts to increase at a faster rate than oxygen consumption, when the work rate is reached at which blood lactic acid starts to accumulate, and is due to ATP synthesis from anaerobic glycolysis in muscles. The VO2and work intensity at anaerobic threshold are important indices of capacity to do continuous work, as activity above the anaerobic threshold is rapidly fatiguing and cannot be sustained. Anaerobic threshold (also known as ventilatory threshold or ventilatory anaerobic threshold) is the exercise intensity at which the anaerobic contribution to energy generation is significant enough to cause non-linear increases in muscle and blood pH, lactate and carbon dioxide concentration. This transition is typically identified using serial measures of blood lactate obtained throughout an incremental exercise test to ascertain at which VO2a non-linear increase in blood lactate occurs. The ventilatory stimulus of carbon dioxide causes a similar response in expired ventilation to that of blood lactate. This makes the ventilatory threshold a good non-invasive metric for the anaerobic threshold, which is referred to as the ventilatory anaerobic threshold (VAT). In some embodiments, the methods of the disclosure lead to an increase in VO2at VAT compared to baseline. In some embodiments, the methods of the disclosure lead to an increase in VO2at VAT by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% relative to baseline.

[0186] Workload measures the power output produced by the participant during exertion. In cycling CPET, workload is measured by force x cycling velocity and is quantified in watts (W) or in kilopond meters / min (kpm / min; 1 W  =  6 kpm / min). A peak workload is measured when maximal exertion is reached. In some embodiments, the method leads to an increase in peak workload (based upon CPET, 2-day CPET Day 1 and / or 2-day CPET Day 2 measurements) by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% relative to baseline. In some embodiments, the method leads to a mean increase from baseline in peak workload (based upon CPET, 2-day CPET Day 1 and / or 2-day CPET Day 2 measurements) by at least 5 Watts (W), at least 10 W, at least 15 W, at least 20 W, at157570.604279 least 25 W, at least 30 W, at least 35 W, at least 40 W, at least 45 W, at least 50 W, at least 55 W, at least 60 W, at least 65 W, at least 70W, at least 75 W, at least 80 W, at least 85 W, at least 90 W, at least 95 W, or at least 100 W relative to baseline.

[0187] Workload at ventilatory anerobic threshold (VAT) signifies the highest workload that can be sustained for prolonged duration without major elevation in lactate. In some embodiments, the methods of the disclosure lead to an increase in workload at VAT compared to baseline. In some embodiments, the methods of the disclosure lead to an increase in workload at VAT (based upon CPET, 2-day CPET Day 1 and / or 2-day CPET Day 2 measurements) by at least 5%, 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% relative to baseline. In some embodiments, the methods of the disclosure lead to a mean increase from baseline in workload at VAT (based upon CPET, 2-day CPET Day 1 and / or 2-day CPET Day 2 measurements) by at least 5 Watts (W), at least 10 W, at least 15 W, at least 20 W, at least 25 W, at least 30 W, at least 35 W, at least 40 W, at least 45 W, at least 50 W, at least 55 W, at least 60 W, at least 65 W, at least 70W, at least 75 W, at least 80 W, at least 85 W, at least 90 W, at least 95 W, or at least 100 W relative to baseline.

[0188] In some embodiments, the methods of the disclosure lead to resolution of post- exertional malaise (PEM) in at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% of patients who had PEM as at baseline. PEM can be objectively measured by a 2-day CPET (e.g., VO2max). PEM can also be assessed using self-report data, such as DePaul Post-Exertional Malaise Questionnaire (DPEMQ) (Leonard, et al., J Health Psychol. 2021 Feb; 26(2): 238–248).

[0189] In some embodiments, the methods of the disclosure lead to a mean increase from baseline in the 36-item short-form health survey (SF-36) score by at least 5, at least 10, at least 15, at least 20, at least 25, at least 30, at least 35, at least 40, at least 45, or at least 50 in the overall score or in at least one of the domains comprising the overall SF-36, including physical functioning, role limitations due to physical health, role limitations due to157570.604279 emotional problems, energy / fatigue, emotional well-being, social functioning, pain, and general health. The SF-36 was designed for use in clinical practice and research, health policy evaluations, and general population surveys (Ware Jr et al., Med Care. 1992 Jun;30(6):473-83). The SF-36 survey has 36 questions. Answers to the questions yield the following eight domains (scored from 0 (worst) to 100 (best) and two summary physical and metal component scores: (1) limitations in physical activities because of health problems; (2) limitations in social activities because of physical or emotional problems; (3) limitations in usual role activities because of physical health problems; (4) bodily pain; (5) general mental health (psychological distress and well-being); (6) limitations in usual role activities because of emotional problems; (7) vitality (energy and fatigue); and (8) general health perceptions. These are calculated based on positively weighting four physical domains and negatively weighting four mental domains (or vice versa) on a scale of 0 to 50–with normative values equal to 50.

[0190] In some embodiments, the methods of the disclosure lead to a mean increase from baseline by at least 10, at least 20, at least 30, at least 40, or at least 50 in the Karnofsky Performance Scale. The Karnofsky Performance Scale allows patients to be classified as to their functional impairment. This can be used to compare effectiveness of different therapies and to assess the prognosis in individual patients. The Karnofsky Performance Scale runs from 100 to 0, where 100 is normal health and 0 is death (www.npcrc.org / files / news / karnofsky_performance_scale.pdf).

[0191] In some embodiments, the methods of the disclosure lead to a mean increase from baseline by at least 10, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90, or at least 100 in the Functional Capacity Scale. The assessment of functional capacity reflects the ability to perform activities of daily living that require sustained aerobic metabolism. The functional capacity can be measured using the Functional Capacity Scale (www.nova.edu / nim / patients / forms / functional-capacity- scale.pdf). Each scale is scored by means of 10 points (from 10 to 1), where 10 indicates no symptoms and 0 is no energy

[0192] In some embodiments, the methods of the disclosure lead to a mean increase from baseline by at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10 in the Fatigue Severity Scale. The Fatigue Severity Scale (FSS)157570.604279 is a method of evaluating the impact of fatigue on you. The FSS is a short questionnaire that requires participants to rate their level of fatigue. The FSS questionnaire contains nine statements that rate the severity of fatigue symptoms (www.mercy.net / content / dam / mercy / en / pdf / fatigue-severity-scale-epworth-sleepiness- scale-questionaire.pdf). Each statement can be assigned a number from 1 to 7, based on how accurately it reflects participants’ condition during the past week and the extent to which participants agree or disagree that the statement applies to them, where 7 indicates strong agreement with the statement and 1 indicates strong disagreement.

[0193] In some embodiments, the methods of the disclosure lead to resolution of Postural Orthostatic Tachycardia Syndrome (POTS) as determined by the 10-minute standing test in at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% of patients who had POTS at baseline. In some embodiments, the method leads to resolution of POTS as determined by the tilt table test in at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% of patients who had POTS at baseline. In some embodiments, POTS is diagnosed using a 10-minute standing test or a head-up tilt table test. POTS is present when there is an increase in heart rate of 30 BPM within the 10 min period that lasts longer than 1 min; 40 BPM for children and adolescents. If the resting heart rate is below 60 then 60 should be used as the supine heart rate. For clarity, if the heart rate goes up only one time during the test and does not remain up until the next minute the test is not diagnostic of POTS.

[0194] In some embodiments, the methods of the disclosure lead to an improved score as measured by a cognitive test. In some embodiments, the cognitive test is a paced auditory serial addition test (PASAT). PASAT has been used to investigate cognitive processing including attention and working memory in different neurological dysfunctions (Tombaugh TN, Arch Clin Neuropsychol, 2006;21(1):53–76). The design of the PASAT is described in Nikravesh, et al., Med J Islam Repub Iran. 2017; 31: 61, the contents of which are expressly incorporated by reference in its entirety for any purpose. In some embodiments, PASAT is presented in the form of recorded 61 single-digit numbers (1 to157570.604279 9). A participant repeatedly adds the 2 recent digits. The psychometric properties of PASAT including convergent validity (using the digit memory span tasks), divergent validity (using results in the control group and treatment group), and face validity are recorded. In some embodiments, the methods of the disclosure lead to an increase in scores as measured by PASAT by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% relative to baseline.

[0195] In some embodiments, the methods of the disclosure lead to a mean or median reduction of high-sensitivity CRP (hsCRP) or CRP serum (or other blood sample) concentrations by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% relative to baseline. In some embodiments, the methods of the disclosure lead to a reduction in hsCRP concentrations to < 2 mg / L in at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% of patients with hsCRP at least 2.0 mg / L at baseline. As used herein, the term “C-reactive protein (CRP)” refers to a marker of inflammation. CRP levels increase in response to inflammation, and can be measured with a hsCRP (high-sensitivity C-reactive protein) test.

[0196] In some embodiments, the methods of the disclosure lead to a reduction in serum (or other blood sample) IL-6 levels by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% relative to baseline. The serum IL-6 level can be measured by methods known in the art, such as a IL-6 ELISA kit.

[0197] In some embodiments, the methods of the disclosure lead to a reduction in serum (or other blood sample) free fatty acids (FFAs) levels by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%,157570.604279 at least 95%, or at least 98% relative to baseline. The serum FFAs level can be measured by methods known in the art, such as GC-MS.

[0198] In some embodiments, the methods of the disclosure lead to a reduction in serum (or other blood sample) lactate levels by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% relative to baseline

[0199] In some embodiments, the methods of the disclosure lead to a reduction in serum (or other blood sample) kynurenine levels by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% relative to baseline. Kynurenine is an aromatic, non-proteinogenic amino acid, and a metabolite of tryptophan metabolism. The term “kynurenine”, as used herein, refers to all metabolites of the tryptophan / kynurenine pathway. Thus, kynurenine and / or its derivatives are included in said term. In some embodiments, the level of kynurenine is at least two times higher in a patient having Long COVID than a health control. The serum kynurenine level can be measured by methods known in the art, such as a kynurenine ELISA kit.

[0200] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. All documents, or portions of documents, cited herein, including but not limited to patents, patent applications, articles, books, and treatises, are hereby expressly incorporated by reference in their entirety for any purpose. In the event that one or more of the incorporated documents or portions of documents define a term that contradicts that term’s definition in the application, the definition that appears in this application controls. However, mention of any reference, article, publication, patent, patent publication, and patent application cited herein is not, and should not be taken as an acknowledgment, or any form of suggestion, that they constitute valid prior art or form part of the common general knowledge in any country in the world.

[0201] In the present description, any concentration range, percentage range, ratio range, or integer range is to be understood to include the value of any integer within the recited157570.604279 range and, when appropriate, fractions thereof (such as one tenth and one hundredth of an integer), unless otherwise indicated. It should be understood that the terms “a” and “an” as used herein refer to “one or more” of the enumerated components unless otherwise indicated. The use of the alternative (e.g., “or”) should be understood to mean either one, both, or any combination thereof of the alternatives. As used herein, the terms “include” and “comprise” are used synonymously.

[0202] The disclosure will be further clarified by the following examples, which are intended to be purely exemplary of the disclosure and in no way limiting. EXAMPLES Example 1: Phase II study to evaluate the administration of human anti-IL6 antibody in patients with Long COVID, including endurance failure

[0203] A Phase II trial will be conducted to evaluate the efficacy and safety of human anti- IL6 antibody TOUR006 as disclosed herein in patients with Long COVID including endurance failure. The study will be a randomized, double-blind, placebo-controlled trial designed to evaluate the effects of TOUR006 at two dosing regimens in participants with Long COVID. Study population

[0204] Participants must meet all of the following criteria to participate in the study: Documented h / o COVID preceding endurance failure Endurance failure similar to IOM criteria for Chronic Fatigue Syndrome (e.g., > 6 months, severe fatigue not substantially alleviated by rest or sleep, post-exertional malaise, etc.) Evidence of IL-6 pathway activation (e.g., elevated IL-6 and / or hsCRP). Potential for other biomarker enrichment (e.g., serum basal FFAs, kynurenine etc.) Major impairment in workload at anaerobic threshold on screening CPET Exclude patients at elevated risk for safety complications (e.g., immunocompromised patients) Dose Regimens

[0205] The study schematic is shown in FIG. 7. The eligible patents will be randomized 1:1:1 to 1 of 2 dosing regimens of TOUR006 or placebo. The treatment arms are as follows:157570.604279 Treatment Arm A (a single dose of 50 mg TOUR006 administered subcutaneously) o Participants will receive TOUR00650 mg injections on Study Days 1; matching placebo injections will be administered on Study Day 1. o Total cumulative TOUR006 dose: 50 mg Treatment Arm B (two doses of 50 mg TOUR006 administered subcutaneously 3 months apart) o Participants will receive TOUR00650 mg injections on Study Days 1 and 90; matching placebo injections will be administered on Study Days 1 and 90. o Total cumulative TOUR006 dose: 100 mg Placebo: administered subcutaneously every 90 days

[0206] Approximately 180 participants (60 per treatment arm) will be randomized. After the screening period, randomized participants will be dosed with TOUR006 or placebo. Participants will be followed for pharmacokinetic and pharmacodynamic endpoints through Study Day 180 and followed for safety until Study Day 365. The primary pharmacodynamic endpoint evaluation will occur at Study Day 180. Study Endpoints

[0207] The primary endpoints of this study would be CPET parameters including Peak VO2, VO2at anaerobic threshold, Peak Workload, and Workload at anaerobic threshold as measured by CPET or 2-day CPET. The secondary endpoints include other CPET parameters; assessments for POTS (e.g., 10 min standing test) & brain fog (e.g., PASAT) in patients with these manifestations. Additional efficacy endpoints include assessments of quality of life, activities of daily living, and fatigue; such assessments include but are not limited to: SF-36, Karnofsky Performance Scale, Functional Capacity Scale, and Fatigue Severity Scale.

[0208] The safety endpoints include proportion of participants with adverse events (AEs), serious AEs (SAEs), severe AEs, and AEs leading to discontinuation; description and frequency of events of special interest by treatment group; and description of additional safety assessments by treatment group and dose, e.g., vital signs, electrocardiogram and anti-drug antibodies.157570.604279

[0209] The pharmacokinetic / pharmacodynamic endpoints are as follows: The effects of TOUR006 over time on absolute serum concentrations of TOUR006. Pharmacokinetic parameters of TOUR006. The effects of TOUR006 over time on absolute concentrations for serum high- sensitivity C-reactive protein (hs-CRP). The effects of TOUR006 over time on absolute concentrations for serum IL-6. Mean change from baseline in serum concentration of TOUR006. Mean change from baseline in serum hs-CRP. Mean change from baseline in serum IL-6. Percentage of participants with anti-drug antibody (ADA).

[0210] The treatment result may be achieved within 72 weeks, 64 weeks, 56 weeks, 48 weeks, 44 weeks, 40 weeks, 32 weeks, 20 weeks, 16 weeks, 12 weeks, 8 weeks, or 4 weeks. The treatment result may also be achieved during a long-term treatment (e.g. more than 24 weeks, more than 48 weeks, more than 72 weeks, or more than 96 weeks after treatment initiation). Example 2: Phase II study to evaluate the administration of human anti-IL6 antibody in patients with severe Long COVID including endurance failure

[0211] A Phase II trial will be conducted to evaluate the efficacy and safety of human anti- IL6 antibody TOUR006 as disclosed herein in patients with severe Long COVID, including endurance failure. The study will be an open-label trial designed to evaluate the effects of TOUR006 in participants with severe Long COVID. Study population

[0212] Participants must meet all of the following criteria to participate in the study: Documented h / o COVID preceding endurance failure Endurance failure similar to IOM criteria for Chronic Fatigue Syndrome (e.g., > 6 months, severe fatigue not substantially alleviated by rest or sleep, post-exertional malaise, etc.) Evidence of IL-6 pathway activation (e.g., elevated IL-6 and / or hsCRP). Potential for other biomarker enrichment (e.g., serum basal FFAs, kynurenine etc.)157570.604279 Severe functional limitation (e.g., unable to leave home unassisted more often than once per month, unable to undergo CPET, bedridden for at least 50% of the day on average). Exclude patients at elevated risk for safety complications (e.g., immunocompromised patients) Dose Regimens

[0213] The eligible patents will be treated with TOUR006 in open-label fashion: Single treatment Arm (two doses of 50 mg TOUR006 administered subcutaneously 3 months apart) o Participants will receive TOUR00650 mg injections on Study Days 1 and 90 o Total cumulative TOUR006 dose: 100 mg An alternative approach to this study design could be a randomized open-label scheme in which patients are randomized to receive subcutaneously administered TOUR006 as two doses of 50 mg given 3 months apart or as a single dose of 50 mg.

[0214] Approximately 30 participants will be enrolled. After the screening period, randomized participants will be dosed with TOUR006. Participants will be followed for pharmacokinetic and pharmacodynamic endpoints through Study Day 180 and followed for safety until Study Day 365. The primary pharmacodynamic endpoint evaluation will occur at Study Day 180. Study Endpoints

[0215] Key efficacy endpoints of this study include assessments of quality of life, activities of daily living, and fatigue; such assessments include but are not limited to: SF-36, Karnofsky Performance Scale, Functional Capacity Scale, and Fatigue Severity Scale. The secondary endpoints include CPET parameters; assessments for POTS (e.g., 10 min standing test) & brain fog (e.g., PASAT) in patients with these manifestations.

[0216] The safety endpoints include proportion of participants with adverse events (AEs), serious AEs (SAEs), severe AEs, and AEs leading to discontinuation; description and frequency of events of special interest by treatment group; and description of additional157570.604279 safety assessments by treatment group and dose, e.g., vital signs, electrocardiogram and anti-drug antibodies.

[0217] The pharmacokinetic / pharmacodynamic endpoints are as follows: The effects of TOUR006 over time on absolute serum concentrations of TOUR006. Pharmacokinetic parameters of TOUR006. The effects of TOUR006 over time on absolute concentrations for serum high- sensitivity C-reactive protein (hs-CRP). The effects of TOUR006 over time on absolute concentrations for serum IL-6. Mean change from baseline in serum concentration of TOUR006. Mean change from baseline in serum hs-CRP. Mean change from baseline in serum IL-6. Percentage of participants with anti-drug antibody (ADA).

[0218] The treatment result may be achieved within 72 weeks, 64 weeks, 56 weeks, 48 weeks, 44 weeks, 40 weeks, 32 weeks, 20 weeks, 16 weeks, 12 weeks, 8 weeks, or 4 weeks. The treatment result may also be achieved during a long-term treatment (e.g. more than 24 weeks, more than 48 weeks, more than 72 weeks, or more than 96 weeks after treatment initiation). Example 3: Clinical study to evaluate the administration of human anti-IL6 antibody in patients with CFS

[0219] A clinical study will be conducted to evaluate the efficacy and safety of human anti- IL6 antibody TOUR006 as disclosed herein in patients with chronic fatigue syndrome (CFS). The study is a randomized, double-blind, placebo-controlled trial designed to evaluate the effects of TOUR006 at two dosing regimens in participants with CFS. Study population

[0220] Participants must meet all of the following criteria to participate in the study: Evidence for Chronic Fatigue Syndrome (e.g., > 6 months, severe fatigue not substantially alleviated by rest or sleep, post-exertional malaise, etc.) Evidence of IL-6 pathway activation (e.g., elevated IL-6 and / or hsCRP). Potential for other biomarker enrichment (e.g., serum basal FFAs, kynurenine etc.)157570.604279 Major impairment in workload at anaerobic threshold on screening CPET Exclude patients at elevated risk for safety complications (e.g., immunocompromised patients) Dose Regimens

[0221] The eligible patents will be randomized 1:1:1 to 1 of 2 dosing regimens of TOUR006 or placebo (see treatment arms below). The treatment arms are as follows: Treatment Arm A (a single dose of 50 mg TOUR006 administered subcutaneously) o Participants will receive TOUR00650 mg injections on Study Days 1; matching placebo injections will be administered on Study Day 1. o Total cumulative TOUR006 dose: 50 mg Treatment Arm B (two doses of 50 mg TOUR006 administered subcutaneously 3 months apart) o Participants will receive TOUR00650 mg injections on Study Days 1 and 90; matching placebo injections will be administered on Study Days 1 and 90. o Total cumulative TOUR006 dose: 100 mg Placebo: administered subcutaneously every 90 days

[0222] Approximately 180 participants (60 per treatment arm) will be randomized. After the screening period, randomized participants will be dosed with TOUR006 or placebo. Participants will be followed for pharmacokinetic and pharmacodynamic endpoints through Study Day 180 and followed for safety until Study Day 365. The primary pharmacodynamic endpoint evaluation will occur at Study Day 180. Study Endpoints

[0223] The primary endpoints of this study would be CPET parameters including Peak VO2, VO2at anaerobic threshold, Peak Workload, and Workload at anaerobic threshold as measured by CPET or 2-day CPET. Additional efficacy endpoints include assessments of quality of life, activities of daily living, and fatigue; such assessments include but are not limited to: SF-36, Karnofsky Performance Scale, Functional Capacity Scale, and Fatigue Severity Scale. The secondary endpoints include CPET; assessments for POTS (e.g., 10 min standing test) & brain fog (e.g., PASAT) in patients with these manifestations.157570.604279

[0224] The safety endpoints include proportion of participants with adverse events (AEs), serious AEs (SAEs), severe AEs, and AEs leading to discontinuation; description and frequency of events of special interest by treatment group; and description of additional safety assessments by treatment group and dose, e.g., vital signs, electrocardiogram, and anti-drug antibodies.

[0225] The pharmacokinetic / pharmacodynamic endpoints are as follows: The effects of TOUR006 over time on absolute serum concentrations of TOUR006. Pharmacokinetic parameters of TOUR006. The effects of TOUR006 over time on absolute concentrations for serum high- sensitivity C-reactive protein (hs-CRP). The effects of TOUR006 over time on absolute concentrations for serum IL-6. Mean change from baseline in serum concentration of TOUR006. Mean change from baseline in serum hs-CRP. Mean change from baseline in serum IL-6. Percentage of participants with anti-drug antibody (ADA).

[0226] The treatment result may be achieved within 72 weeks, 64 weeks, 56 weeks, 48 weeks, 44 weeks, 40 weeks, 32 weeks, 20 weeks, 16 weeks, 12 weeks, 8 weeks, or 4 weeks. The treatment result may also be achieved during a long-term treatment (e.g. more than 24 weeks, more than 48 weeks, more than 72 weeks, or more than 96 weeks after treatment initiation). Example 4: Clinical study to evaluate the administration of human anti-IL6 antibody in patients with POTS

[0227] A clinical study will be conducted to evaluate the efficacy and safety of human anti- IL6 antibody TOUR006 as disclosed herein in patients with postural orthostatic tachycardia syndrome (POTS). The study is a randomized, double-blind, placebo-controlled trial designed to evaluate the effects of TOUR006 at two dosing regimens in participants with POTS. Study population

[0228] Participants must meet all of the following criteria to participate in the study:157570.604279 Evidence for POTS (e.g., lightheadedness, tachycardia, presyncope, headache, difficulty concentrating, etc.), with positive test on the 10-minute standing test. Evidence of IL-6 pathway activation (e.g., elevated IL-6 and / or hsCRP). Potential for other biomarker enrichment. Exclude patients at elevated risk for safety complications (e.g., immunocompromised patients) Dose Regimens

[0229] The eligible patents will be randomized 1:1:1 to 1 of 2 dosing regimens of TOUR006 or placebo (see treatment arms below). The treatment arms are as follows: Treatment Arm A (a single dose of 50 mg TOUR006 administered subcutaneously) o Participants will receive TOUR00650 mg injections on Study Days 1; matching placebo injections will be administered on Study Day 1. o Total cumulative TOUR006 dose: 50 mg Treatment Arm B (two doses of 50 mg TOUR006 administered subcutaneously 3 months apart) o Participants will receive TOUR00650 mg injections on Study Days 1 and 90; matching placebo injections will be administered on Study Days 1 and 90. o Total cumulative TOUR006 dose: 100 mg Placebo: administered subcutaneously every 90 days

[0230] Approximately 180 participants (60 per treatment arm) will be randomized. After the screening period, randomized participants will be dosed with TOUR006 or placebo. Participants will be followed for pharmacokinetic and pharmacodynamic endpoints through Study Day 180 and followed for safety until Study Day 365. The primary pharmacodynamic endpoint evaluation will occur at Study Day 180. Study Endpoints

[0231] The primary endpoint of this study would be heart rates as measured in the 10-min standing test and evaluating for resolution of POTS (as defined by no longer having a positive 10-minute standing test result). The safety endpoints include proportion of participants with adverse events (AEs), serious AEs (SAEs), severe AEs, and AEs leading157570.604279 to discontinuation; description and frequency of events of special interest by treatment group; and description of additional safety assessments by treatment group and dose, e.g., vital signs, electrocardiogram, and anti-drug antibodies.

[0232] The pharmacokinetic / pharmacodynamic endpoints are as follows: The effects of TOUR006 over time on absolute serum concentrations of TOUR006. Pharmacokinetic parameters of TOUR006. The effects of TOUR006 over time on absolute concentrations for serum high- sensitivity C-reactive protein (hs-CRP). The effects of TOUR006 over time on absolute concentrations for serum IL-6. Mean change from baseline in serum concentration of TOUR006. Mean change from baseline in serum hs-CRP. Mean change from baseline in serum IL-6. Percentage of participants with anti-drug antibody (ADA).

[0233] The treatment result may be achieved within 72 weeks, 64 weeks, 56 weeks, 48 weeks, 44 weeks, 40 weeks, 32 weeks, 20 weeks, 16 weeks, 12 weeks, 8 weeks, or 4 weeks. The treatment result may also be achieved during a long-term treatment (e.g. more than 24 weeks, more than 48 weeks, more than 72 weeks, or more than 96 weeks after treatment initiation). Example 5: Clinical study to evaluate the administration of human anti-IL6 antibody in patients with brain fog

[0234] A clinical study will be conducted to confirm the efficacy of human anti-IL6 antibody TOUR006 as disclosed herein in patients with brain fog. The study is a randomized, double-blind, placebo-controlled trial designed to evaluate the effects of TOUR006 at two dosing regimens in participants with brain fog. Study population

[0235] Participants must meet all of the following criteria to participate in the study: Evidence for brain fog (e.g., problems in concentration in studies and / or work; exhibiting reluctance or difficulty in acquiring new skills; finding multitasking jobs daunting; confusion; short-term memory loss; not able to give attention to a particular thing for a long time; slow in completing usual tasks; difficulty in157570.604279 recalling a conversation or finding the right word to form a sentence; forgetfulness with image or list of words; fatigue, mild depression, and anxiety, etc.) Evidence of IL-6 pathway activation (e.g., elevated IL-6 and / or hsCRP). Potential for other biomarker enrichment (e.g., kynurenine, free fatty acids, lactate). Abnormal PASAT result. Exclude patients at elevated risk for safety complications (e.g., immunocompromised patients) Dose Regimens

[0236] The eligible patents will be randomized 1:1:1 to 1 of 2 dosing regimens of TOUR006 or placebo (see treatment arms below). The treatment arms are as follows: Treatment Arm A (a single dose of 50 mg TOUR006 administered subcutaneously) o Participants will receive TOUR00650 mg injections on Study Days 1; matching placebo injections will be administered on Study Day 1. o Total cumulative TOUR006 dose: 50 mg Treatment Arm B (two doses of 50 mg TOUR006 administered subcutaneously 3 months apart) o Participants will receive TOUR00650 mg injections on Study Days 1 and 90; matching placebo injections will be administered on Study Days 1 and 90. o Total cumulative TOUR006 dose: 100 mg Placebo: administered subcutaneously every 90 days

[0237] Approximately 180 participants (60 per treatment arm) will be randomized. After the screening period, randomized participants will be dosed with TOUR006 or placebo. Participants will be followed for pharmacokinetic and pharmacodynamic endpoints through Study Day 180 and followed for safety until Study Day 365. The primary pharmacodynamic endpoint evaluation will occur at Study Day 180. Study Endpoints

[0238] The primary endpoint of this study would be test scores as measured by the Paced Auditory Serial Addition Test (PASAT). The safety endpoints include proportion of participants with adverse events (AEs), serious AEs (SAEs), severe AEs, and AEs leading157570.604279 to discontinuation; description and frequency of events of special interest by treatment group; and description of additional safety assessments by treatment group and dose, e.g., vital signs, electrocardiogram, and anti-drug antibodies.

[0239] The pharmacokinetic / pharmacodynamic endpoints are as follows: The effects of TOUR006 over time on absolute serum concentrations of TOUR006. Pharmacokinetic parameters of TOUR006. The effects of TOUR006 over time on absolute concentrations for serum high- sensitivity C-reactive protein (hs-CRP). The effects of TOUR006 over time on absolute concentrations for serum IL-6. Mean change from baseline in serum concentration of TOUR006. Mean change from baseline in serum hs-CRP. Mean change from baseline in serum IL-6. Percentage of participants with anti-drug antibody (ADA).

[0240] The treatment result may be achieved within 72 weeks, 64 weeks, 56 weeks, 48 weeks, 44 weeks, 40 weeks, 32 weeks, 20 weeks, 16 weeks, 12 weeks, 8 weeks, or 4 weeks. The treatment result may also be achieved during a long-term treatment (e.g. more than 24 weeks, more than 48 weeks, more than 72 weeks, or more than 96 weeks after treatment initiation). INCORPORATION BY REFERENCE

[0241] All references, articles, publications, patents, patent publications, and patent applications cited herein are incorporated by reference in their entireties for all purposes. However, mention of any reference, article, publication, patent, patent publication, and patent application cited herein is not, and should not be taken as an acknowledgment or any form of suggestion that they constitute valid prior art or form part of the common general knowledge in any country in the world.

Claims

157570.604279 CLAIMS What is claimed is:

1. A method of preventing or treating a patient having Long COVID comprising administering to a patient in need thereof a therapeutically effective dose of an anti- interleukin-6 (anti-IL-6) antibody, wherein the anti-IL-6 antibody comprises a heavy chain variable region comprising HCDR1, HCDR2, and HCDR3, and a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein: (a) HCDR1 comprises SEQ ID NO: 2, or has an amino acid sequence which differs from SEQ ID NO:2 at one, two, or three amino acid positions, HCDR2 comprises SEQ ID NO: 3, or has an amino acid sequence which differs from SEQ ID NO: 3 at one, two, or three amino acid positions, and HCDR3 comprises SEQ ID NO: 4, or has an amino acid sequence which differs from SEQ ID NO: 4 at one, two, or three amino acid positions; and (b) LCDR1 comprises SEQ ID NO: 8, or has an amino acid sequence which differs from SEQ ID NO:8 at one, two, or three amino acid positions, LCDR2 comprises SEQ ID NO: 9, or has an amino acid sequence which differs from SEQ ID NO: 9 at one, two, or three amino acid positions, and LCDR3 comprises SEQ ID NO: 10, or has an amino acid sequence which differs from SEQ ID NO: 10 at one, two, or three amino acid positions.

2. The method of claim 1, wherein the anti-IL-6 antibody comprises HCDR1 of SEQ ID NO: 2, HCDR2 of SEQ ID NO: 3, HCDR3 of SEQ ID NO: 4, LCDR1 of SEQ ID NO: 8, LCDR2 of SEQ ID NO: 9, and LCDR3 of SEQ ID NO:

10.

3. The method of claim 1 or 2, wherein the anti-IL-6 antibody comprises the heavy chain variable region comprising a polypeptide having at least 95% identity to SEQ ID NO: 5 and the light chain variable region comprising a polypeptide having at least 95% identity to SEQ ID NO: 11.157570.604279 4. The method of claim 3, wherein the anti-IL-6 antibody comprises the heavy chain variable region comprising a polypeptide having the sequence of SEQ ID NO: 5 and the light chain variable region comprising a polypeptide having the sequence of SEQ ID NO:

11.

5. The method of any one of the preceding claims, wherein the anti-IL-6 antibody comprises a heavy chain polypeptide comprising a polypeptide having at least 95% identity to SEQ ID NO: 1 and a light chain polypeptide comprising a polypeptide having at least 95% identity to SEQ ID NO:

7.

6. The method of claim 5, wherein the anti-IL-6 antibody comprises the heavy chain polypeptide having the sequence of SEQ ID NO: 1 and the light chain polypeptide having the sequence of SEQ ID NO:

7.

7. The method of any one of the preceding claims, wherein the therapeutically effective dose is between about 10 mg to about 200 mg.

8. The method of claim 7, wherein the therapeutically effective dose is about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 120 mg, about 140 mg, about 160 mg, about 180 mg, or about 200 mg.

9. The method of claim 8, wherein the therapeutically effective dose is about 50 mg.

10. The method of claim 8, wherein the therapeutically effective dose is about 100 mg.

11. The method of any one of the preceding claims, wherein the therapeutically effective dose is administered from every 1 month to every 12 months.

12. The method of claim 11, wherein the therapeutically effective dose is administered every 1 month, every 2 months, every 3 months, every 4 months, every 5 months,157570.604279 every 6 months, every 7 months, every 8 month, every 9 months, every 10 months, every 11 months, or every 12 months.

13. The method of claim 12, wherein the therapeutically effective dose is administered every 3 months.

14. The method of any one of the preceding claims, wherein the therapeutically effective dose is a single dose of 10 mg to about 200 mg.

15. The method of any one of the preceding claims, wherein the therapeutically effective dose is a single dose of about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 120 mg, about 140 mg, about 160 mg, about 180 mg, or about 200 mg.

16. The method of claim 14 or 15, wherein the single dose is administered after a period of about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 week, about 7 weeks, about 8 weeks, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 1.5 years, about 2 years, about 3 years after an acute, symptomatic or asymptomatic SARS-CoV-2 infection.

17. The method of claim 14 or 15, wherein the single dose is administered within 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks after onset of an acute, symptomatic or asymptomatic SARS-CoV-2 infection to prevent Long COVID.

18. The method of any one of the preceding claims, wherein the therapeutically effective dose comprise a primary dose and a booster dose.

19. The method of claim 18, wherein the booster dose is identical to the primary dose.

20. The method of claim 18, wherein the booster dose and the primary dose are different.157570.604279 21. The method of any one of claims 18-20, wherein the primary dose and the booster dose are between about 10 mg to about 200 mg.

22. The method of claim 21, wherein the primary dose and the booster dose are about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 120 mg, about 140 mg, about 160 mg, about 180 mg, or about 200 mg each.

23. The method of any one of claims 18-22, wherein the primary dose and the booster dose are about 1 month, about 2 month, about 3 months, about 4 months, about 5 months, or about 6 months apart.

24. The method of any one of claims 18-23, wherein the primary dose and the booster dose are about 3 months apart.

25. The method of any one of claims 18-24, wherein the primary dose is administered after a period of about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 week, about 7 weeks, about 8 weeks, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 1.5 years, about 2 years, about 3 years after an acute, symptomatic or asymptomatic SARS-CoV-2 infection.

26. The method of any one of claims 18-24, wherein the primary dose is administered after a period of about at least 6 months after an acute, symptomatic or asymptomatic SARS-CoV-2 infection.

27. The method of any one of the preceding claims, wherein the therapeutically effective dose is administered subcutaneously.157570.604279 28. The method of any one of the preceding claims, wherein the patient having Long COVID has a baseline serum level of IL-6 ≥ about 5.0, about 10.0, about 15.0, about 20.0, about 30.0, or about 40.0 pg / mL.

29. The method of any one of the preceding claims, further comprising determining the baseline level of IL-6 in a serum sample obtained from the patient having Long COVID, and administering to the patient a therapeutically effective dose of the anti- IL-6 antibody if the baseline level of IL-6 in the serum sample is ≥ about 5.0, about 10.0, about 15.0, about 20.0, about 30.0, or about 40.0 pg / mL.

30. The method of any one of the preceding claims, wherein the patient having Long COVID has a baseline serum level of IL-6 that is not elevated.

31. The method of any of the preceding claims, wherein the method leads to improved functional capacity as measured by cardiopulmonary exercise testing (CPET) or 2-day CPET compared to baseline.

32. The method of any of the preceding claims, wherein the method leads to an increase in peak VO2based upon CPET, 2-day CPET Day 1 and / or 2-day CPET Day 2 measurements by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% relative to baseline.

33. The method of any of the preceding claims, wherein the method leads to an increase in peak VO2based upon CPET, 2-day CPET Day 1 and / or 2-day CPET Day 2 measurements of about +3, or about +2, or about +1.5 mL / kg / min relative to baseline.

34. The method of any of the preceding claims, wherein the method leads to an increase in VO2at VAT based upon CPET, 2-day CPET Day 1 and / or 2-day CPET Day 2 measurements by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at157570.604279 least 30%, at least 35%, at least 40%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% relative to baseline.

35. The method of any of the preceding claims, wherein the method leads to a mean increase in peak workload based upon CPET, 2-day CPET Day 1 and / or 2-day CPET Day 2 measurements by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% relative to baseline.

36. The method of any of the preceding claims, wherein the method leads to a mean increase in peak workload based upon CPET, 2-day CPET Day 1 and / or 2-day CPET Day 2 measurements by at least 5 Watts (W), at least 10 W, at least 15 W, at least 20 W, at least 25 W, at least 30 W, at least 35 W, at least 40 W, at least 45 W, at least 50 W, at least 55 W, at least 60 W, at least 65 W, at least 70W, at least 75 W, at least 80 W, at least 85 W, at least 90 W, at least 95 W, or at least 100 W relative to baseline.

37. The method of any of the preceding claims, wherein the method leads to a mean increase in workload at VAT based upon CPET, 2-day CPET Day 1 and / or 2-day CPET Day 2 measurements by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% relative to baseline.

38. The method of any of the preceding claims, wherein the method leads to a mean increase in workload at VAT based upon CPET, 2-day CPET Day 1 and / or 2-day CPET Day 2 measurements by at least 5 Watts (W), at least 10 W, at least 15 W, at least 20 W, at least 25 W, at least 30 W, at least 35 W, at least 40 W, at least 45 W, at least 50 W, at least 55 W, at least 60 W, at least 65 W, at least 70W, at least 75 W, at157570.604279 least 80 W, at least 85 W, at least 90 W, at least 95 W, or at least 100 W relative to baseline.

39. The method of any of the preceding claims, wherein the method leads to resolution of post-exertional malaise in at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% of patients who had post-exertional malaise as at baseline.

40. The method of any of the preceding claims, wherein the method leads to a mean increase relative to baseline in the SF-36 score by at least 5, at least 10, at least 15, at least 20, at least 25, at least 30, at least 35, at least 40, at least 45, or at least 50 in the overall score or in at least one of the domains comprising the overall SF-36.

41. The method of claim 40, wherein the at least one of the domains is selected from physical functioning, role limitations due to physical health, role limitations due to emotional problems, energy / fatigue, emotional well-being, social functioning, pain, and general health.

42. The method of any of the preceding claims, wherein the method leads to a mean increase in the Karnofsky Performance Scale by at least 10, at least 20, at least 30, at least 40, or at least 50 relative to baseline.

43. The method of any of the preceding claims, wherein the method leads to a mean increase in the Functional Capacity Scale by at least 10, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90, or at least 100 relative to baseline.

44. The method of any of the preceding claims, wherein the method leads to a mean increase in the Fatigue Severity Scale by at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10 relative to baseline.157570.604279 45. The method of any of the preceding claims, wherein the method leads to resolution of POTS as determined by the 10-minute standing test in at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% of patients who had POTS at baseline.

46. The method of any of the preceding claims, wherein the method leads to resolution of POTS as determined by the tilt table test in at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% of patients who had POTS at baseline.

47. The method of any of the preceding claims, wherein the method leads to an increase in a score as measured by PASAT by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% relative to baseline.

48. The method of any of the preceding claims, wherein the method leads to a reduction in high-sensitivity CRP (hsCRP) concentrations by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 98%relative to baseline.

49. The method of any of the preceding claims, wherein the method leads to a reduction in hsCRP concentrations to < 2 mg / L in at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% of patients with hsCRP at least 2.0 mg / L at baseline.157570.604279 50. The method of any of the preceding claims, wherein the method leads to a reduction in serum IL-6 levels by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% relative to baseline.

51. The method of any of the preceding claims, wherein the method leads to a reduction in serum free fatty acids (FFAs) levels by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% relative to baseline.

52. The method of any of the preceding claims, wherein the method leads to a reduction in serum kynurenine levels by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% relative to baseline.

53. The method of any of the preceding claims, wherein the method prevents or treats a symptom or disease associated with Long COVID.

54. The method of claim 39, wherein the symptom or disease associated with Long COVID comprises postural orthostatic tachycardia syndrome (POTS), brain fog, post- exertional malaise, aerobic metabolism impairment or deficiency, chronic fatigue syndrome (CFS), fibromyalgia, and mast cell activation syndrome (MCAS).

55. The method of any of the preceding claims, further comprising administering one or more therapeutic agents selected from a second antibody, a soluble receptor, an anti- inflammatory agent, an intravenous immunoglobulin (IVIg), plasmapheresis, an antiviral agent against SARS-CoV-2, an immunomodulatory or anti-infection agent, and an adjunctive medication.157570.604279 56. The method of claim 55, wherein the second antibody comprises an anti-IL-1 antibody, an anti-TNF-alpha antibody, an anti-FcRn antibody, an anti-CD20 antibody, a complement pathway inhibitor, or an anti-IL17a antibody.

57. The method of claim 55, wherein the soluble receptor comprises a soluble IL-1 receptor, or a soluble TNF-alpha receptor.

58. The method of claim 55, wherein the anti-inflammatory agent comprises corticosteroid, 6-mercaptopurine, or mycophenolate mofetil.

59. The method of claim 55, wherein the antiviral agent against SARS-CoV-2 comprises nirmatrelvir / ritonavir, a monoclonal antibody against SARS-CoV-2, a polyclonal antibody against SARS-CoV-2, or convalescent plasma.

60. The method of claim 55, wherein the immunomodulatory or anti-infection agent comprises interferon beta, interferon gamma, ribavirin, or an antiviral agent.

61. The method of claim 55, wherein the adjunctive medication comprises metformin, an angiotensin-converting enzyme (ACE)-inhibitor, an angiotensin receptor blocker (ARB), an antidepressant, an anabolic steroid, a GLP-1 receptor agonist, a GIP receptor agonist, glucagon, or a dietary supplement.

62. The method of any of the preceding claims, further comprising treating the patient with a rehabilitation therapy or intervention.

63. The method of claim 62, wherein the rehabilitation therapy or intervention comprises prolonged rest, physical therapy, occupational therapy, relaxation techniques, sleep therapy, cognitive rehabilitation, energy-saving techniques, activities of daily living training, nutrition, and / or breathing exercise.

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