Treatment of fibromyalgia

Abstract

The present invention provides a method for treating or preventing fibromyalgia syndrome (FMS) in an individual, the method comprising administering to the individual a therapeutically effective amount of an FcRn antagonist, wherein the FcRn antagonist is rozanolixizumab.

Description

[Technical Field]

[0001] Technical Field The present invention relates to the treatment of fibromyalgia syndrome (FMS).

[0002] Background technology Fibromyalgia syndrome (FMS) is a highly prevalent (2-3% of the adult population) complex syndrome characterized primarily by the presence of chronic widespread pain but also incorporating a wide range of other symptoms that negatively impact function and quality of life, including severe fatigue, cognitive impairment, and sleep disturbances (Hauser et al., 2015). This can impair work capacity, leading to reduced productivity and high healthcare costs (White et al., 2008). The direct and indirect impacts of FMS are higher among patients with more severe disease (Chandran et al., 2012).

[0003] Challenges surround the diagnosis of FMS. There is no definitive clinical test, and as a result, it often takes patients more than two years to receive a diagnosis, often involving multiple consultations with different physicians. The lack of specific disease biomarkers also hinders patient stratification, affecting all areas of FMS research. Current clinical practice recommendations and guidelines for FMS include non-pharmacological and pharmacological strategies focused on reducing symptoms and improving function. Pharmacological agents include tricyclic antidepressants, antiepileptic drugs, selective serotonin reuptake inhibitors, and norepinephrine / serotonin reuptake inhibitors. While the U.S. Food and Drug Administration has approved pregabalin, duloxetine, and milnacipran for the treatment of fibromyalgia in adults, the modest efficacy of available therapies in many patients highlights unmet clinical need for this patient population. Patients with severe FMS are distinguished by higher scores on pain and other measures, as well as significantly increased disability and depression (Chandran et al., 2012). Patients with severe FMS have unmet need due to the limited treatment options available.

[0004] The FcRn receptor rescues IgG from intracellular lysosomal degradation by recycling it from sorting endosomes to the cell surface (Anderson et al., 2006). This is accomplished by IgG binding to the FcRn receptor. Thus, in effect, FcRn salvages IgG, protecting it from degradation and returning it to the circulation. Albumin is similarly recycled by FcRn, albeit via a different binding site on the FcRn molecule. Knocking out or blocking FcRn has been shown to eliminate this recycling, resulting in endosomal catabolism of IgG and a significant reduction in IgG concentrations in both the vascular and extravascular (tissue) compartments. In effect, blocking FcRn promotes the clearance of endogenous IgG.

[0005] Summary of the Invention The present invention provides a method for treating or preventing fibromyalgia syndrome (FMS) in an individual, comprising administering to the individual a therapeutically effective amount of an FcRn antagonist, wherein the FcRn antagonist: (a) a heavy chain or heavy chain fragment having a variable region, the variable region comprising three CDRs having the sequences shown in SEQ ID NO: 4 for CDR H1, SEQ ID NO: 5 for CDR H2, and SEQ ID NO: 6 for CDR H3; (b) a light chain or light chain fragment having a variable region, the variable region comprising three CDRs having the sequences shown in SEQ ID NO: 9 for CDR L1, SEQ ID NO: 10 for CDR L2, and SEQ ID NO: 11 for CDR L3; The method further provides an anti-FcRn antibody or FcRn-binding antibody fragment comprising:

[0006] The FMS treated by the present invention is typically severe FMS. Patients with severe FMS are distinguished by their higher scores on pain and other scales, for example, individuals have a pain intensity of greater than 5 and less than 10 (i.e., greater than or equal to 6 and less than 10) on the Pain Numerical Rating Scale (Pain NRS), and / or a Brief Pain Inventory-Short Form (BPI-SF) interference score of 6 or greater. Patients may also have a Fibromyalgia Questionnaire (FIQR) score of 64 or greater and / or a Fatigue Numerical Rating Scale (Fatigue NRS) score of 5 or greater.

[0007] The anti-FcRn antibody can be rozanolixizumab (sold under the trade name RYSTIGGO®).

[0008] The dose of the anti-FcRn antibody or FcRn-binding fragment thereof is typically 1 mg / kg to 50 mg / kg, 4 mg / kg to 20 mg / kg, or 7 mg / kg to 10 mg / kg. The dose may be 420 mg, 560 mg, or 840 mg. In one embodiment, the dose is 560 mg.

[0009] An anti-FcRn antibody or an FcRn-binding fragment thereof can be administered, for example, once a day, three times a week, twice a week, once a week, once every two weeks, once every three weeks, once a month, once every six weeks, once every two months, once every three months, once every four months, once every five months, or once every six months.

[0010] The method may further include administering a therapeutically effective amount of a second agent for treating FMS, such as an analgesic, an antidepressant, a dopaminergic agent, an antiseizure agent, an antihistamine, a hypnotic, a muscle relaxant, and an antipsychotic agent. [Brief explanation of the drawings]

[0011] [Figure 1](c) Administration of IgG from a human FMS patient to mice resulted in a statistically significant decrease in total activity, distance traveled, and speed in the open field test compared with mice administered IgG from a healthy control. Treatment of mice receiving IgG from an FMS patient with 30 mg / kg of an anti-mouse FcRn antibody (UCB4470) resulted in a statistically significant increase in total activity, distance traveled, and speed compared with mice receiving an isotype control antibody (UCB101.4 30 mg / kg) and IgG from an FMS patient. [Figure 2] This figure shows that in the cold allodynia test, all mice showed a reduction in latency after treatment with antibody (UCB101.4 or UCB4470) and administration of IgG from HC or FMS pooled samples on day 3 compared to baseline on day 0. This reduction was similar across all groups. Mice receiving IgG from FMS patients treated with an isotype control antibody (UCB101.4) (FMA and FMB groups) showed an overall reduction in latency from day 3 to day 9 compared to mice receiving IgG from HCs. This suggests that IgG from FMS patients sensitizes recipient mice to cold stimuli. Treatment with UCB4470 tended to inhibit this hypersensitivity when mice received IgG from the FMA pool. However, this trend was not observed with UCB4470 when mice received IgG from the FMB pool. [Figure 3] Figure 1 is a schematic diagram of a Phase 2, multicenter, randomized, double-blind, placebo-controlled, proof-of-concept study to evaluate the efficacy, safety, PK (pharmacokinetics), and PD (pharmacodynamics) of rozanolixizumab for the treatment of severe FMS. The primary endpoint is the mean BPI-SF interference score after 12 weeks of double-blind treatment. EOS = end of study; QW = once weekly; sc = subcutaneous.

[0012] Detailed Description of the Invention Introduction Current treatments for FMS, such as analgesics, focus on relieving specific symptoms of FMS, particularly pain, without treating the underlying cause of FMS. In contrast, the treatment of the present invention can treat the potential cause of FMS, namely serum IgG autoantibodies. The present invention inhibits the binding of IgG autoantibodies to the FcRn receptor, thereby inhibiting their salvage and promoting their removal from serum.

[0013] General definition Unless otherwise defined, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0014] In general, the term "comprising" is intended to mean including, but not limited to. For example, the phrase "an antibody comprising a heavy chain" should be interpreted to mean that the antibody has heavy chain sequence elements, but that the antibody may include additional elements. In some aspects of the invention, the word "comprising" may be replaced with the phrase "consisting of." The term "consisting of" is intended to be limiting.

[0015] In some aspects of the present invention, the word "comprising" may be replaced with the phrase "consisting essentially of." The term "consisting essentially of" means that certain additional components may be present, i.e., components that do not materially affect the essential characteristics of the subject matter.

[0016] For the purposes of the present invention, the term "fragment" refers to a contiguous portion of a sequence. For example, a 50 amino acid fragment of SEQ ID NO:1 refers to 50 contiguous amino acids of SEQ ID NO:1.

[0017] The term "about" used in the context of describing a decrease in a subject's IgG levels indicates that the decrease can be a defined percentage, plus or minus 10%, more specifically, plus or minus 5%, or even more specifically, plus or minus a single percentage point. For example, a reference to a decrease in a subject's IgG levels of "about" 70% can refer to a 60-80% decrease, more specifically, a 65-75% decrease, or even more specifically, a 69-71% decrease.

[0018] The singular forms "a," "an," and "the" include plural referents unless the content clearly dictates otherwise. Thus, for example, a reference to an "amino acid" includes two or more instances or versions of that amino acid.

[0019] All publications, patents, and patent applications cited herein, whether supra or infra, are hereby incorporated by reference in their entirety.

[0020] Fibromyalgia Syndrome (FMS) Fibromyalgia syndrome (FMS), also known as fibromyalgia, is a highly prevalent (2–3% of the adult population) complex syndrome characterized primarily by the presence of chronic widespread pain but also incorporating a wide range of other symptoms that negatively impact function and quality of life, such as severe fatigue, cognitive impairment, and sleep disturbances (Hauser et al., 2015). This can impair work capacity, leading to reduced productivity and high medical costs (White et al., 2008). Direct and indirect costs associated with FMS are higher among patients with more severe disease (Chandran et al., 2012).

[0021] Symptoms of FMS include pain, tingling, burning, stabbing, hyperalgesia, allodynia, stiffness, muscle spasms, fatigue, reduced sleep quality, memory impairment, attention deficit, concentration deficit, speech disorders, headaches, migraines, constipation, diarrhea, dizziness, clumsiness, anxiety, and depression.

[0022] In one embodiment, treating FMS with a method according to the invention comprises reducing or eliminating one or more symptoms of FMS.

[0023] As used herein, "treating" and "treatment" refer to reducing the severity of FMS, and "preventing" or "prevention" refers to reducing or delaying the onset of symptoms of FMS. One skilled in the art will appreciate that any degree of protection or amelioration from FMS or its associated symptoms is beneficial to a subject, such as a human patient. A patient's quality of life is improved by reducing the severity of symptoms and / or delaying the onset of symptoms to any degree in a subject.

[0024] Thus, the method in one aspect is performed as soon as possible after a subject is determined to have or be at risk of having FMS, particularly severe FMS.

[0025] In various aspects, an FcRn antagonist, such as an FcRn antibody or FcRn-binding fragment thereof, is administered using a dosing regimen that achieves an improvement in BPI-SF score, FIQR score, pain NRS score, or fatigue NRS score compared to pre-treatment (baseline), where improvement is a decrease in the relevant score compared to baseline. The improvement in score can be observed, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 weeks after the first administration of the antagonist. In one example, the improvement in score compared to baseline is observed 10, 12, or 24 weeks after the first administration of the FcRn antagonist.

[0026] Alternatively or additionally, the FcRn antagonist, e.g., an FcRn antibody or an FcRn-binding fragment thereof, is administered using a dosing regimen that achieves a reduction in IgG serum levels and / or a reduction in FMS-specific autoantibody levels (e.g., antibodies that bind to cells of the dorsal root ganglion) levels compared to before treatment (baseline). The reduction in levels can be observed, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 24 weeks after the initial administration of the antibody or antigen-binding fragment thereof. In one example, the reduction in serum IgG levels is observed 10, 12, or 24 weeks after the initial administration of the antibody or FcRn-binding fragment thereof. The IgG serum levels and / or FMS-specific autoantibody levels (e.g., antibodies that bind to cells of the dorsal root ganglion) levels may be reduced by at least 50%, at least 55%, at least 60%, at least 65%, or at least 70%, particularly compared to baseline.

[0027] Dosage The precise therapeutically effective amount for a human subject depends on the severity of the disease state, the subject's general health, the subject's age, weight, and sex, diet, time and frequency of administration, drug combinations, sensitivities, and tolerance / response to treatment. Generally, a therapeutically effective amount of an FcRn antagonist, e.g., an anti-FcRn antibody or fragment thereof, is 4 mg / kg to 50 mg / kg (e.g., 4 mg / kg to 25 mg / kg, e.g., about 7 mg / kg, 10 mg / kg, 15 mg / kg, or 20 mg / kg). Compositions can conveniently be provided in dosage forms containing a predetermined amount of an active FcRn antagonist of the present disclosure per dose.

[0028] Dose ranges and regimens for all embodiments described herein include, but are not limited to, doses ranging from 100 mg to 4000 mg (e.g., doses of 280 mg, 420 mg, 560 mg, 840 mg, 1120 mg, or 1400 mg). Doses may be given every 1 to 10 weeks. In one embodiment, doses are given once a week. Doses may be given by any route of administration, such as either subcutaneous or intravenous administration. For example, doses may be given by subcutaneous infusion. In one embodiment, a 560 mg dose is given every 1 to 10 weeks.

[0029] Thus, the present invention provides a method for treating or preventing fibromyalgia syndrome (FMS) in a human in need thereof, comprising administering to the human at least three doses, preferably at least six doses, of an anti-FcRn antibody or an FcRn-binding fragment thereof, wherein each dose is a 560 mg dose.

[0030] In one aspect of the invention, the 560 mg dose is administered once a week, once every two weeks, once every three weeks, once a month, once every six weeks, or once every two months. Preferably, the 560 mg dose is administered once a week.

[0031] In one embodiment of the present invention, the dose is given once a week in a treatment course lasting 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 weeks. More than one treatment course may be given. There may be an interval between one or more treatment courses. For example, the first weekly dose of a subsequent treatment course may start 1 month, 2 months, 3 months, 4 months, 5 months, or 6 months after the last dose of the previous weekly treatment course.

[0032] In one embodiment of the present invention, the method comprises administering up to 3 doses, up to 6 doses, up to 12 doses, up to 18 doses, up to 24 doses, up to 36 doses, up to 48 doses, or up to 96 doses of an anti-FcRn antagonist to a human. In one embodiment of the present invention, the method comprises administering 3 to 48 doses, 3 to 36 doses, 3 to 24 doses, 3 to 12 doses, or 3 to 6 doses of an anti-FcRn antibody or an FcRn-binding fragment thereof to a human. In one embodiment of the present invention, the method comprises administering 6 to 48 doses, 6 to 36 doses, 6 to 24 doses, or 6 to 12 doses of an anti-FcRn antibody or an FcRn-binding fragment thereof to a human.

[0033] In one embodiment of the invention, the method comprises administering to a human one dose of an anti-FcRn antibody or antigen-binding fragment thereof once a week for 12 or 24 weeks, each dose being 560 mg. In one embodiment of the invention, the method comprises administering to a human one dose of an anti-FcRn antibody or FcRn-binding fragment thereof once a week for at least 12 weeks, each dose being 560 mg. Administration may be subcutaneous.

[0034] In one embodiment, the dose is selected based on the patient's response. For example, the dose can be selected to achieve a 30-90% (e.g., 50-80% or approximately 70%) reduction in the patient's serum IgG levels. Alternatively, the dose can be selected to achieve a satisfactory level of improvement in the BPI-SF score, FIQR score, pain NRS score, or fatigue NRS score compared to pre-treatment (baseline). For example, if the dose does not result in a satisfactory reduction in serum IgG and / or a satisfactory improvement in the BPI-SF score, FIQR score, pain NRS score, or fatigue NRS score compared to pre-treatment (baseline), a higher dose can be selected. In one embodiment of the invention where the 560 mg dose does not achieve a satisfactory reduction in the BPI-SF score, FIQR score, pain NRS score, or fatigue NRS score, the dose can be increased to 1.2-fold, 1.5-fold, 1.8-fold, or 2.0-fold the original dose. For example, the dose can be increased to 840 mg.

[0035] In one embodiment of the invention where a dose achieves less than a 70% reduction in serum IgG levels, the dose can be increased. For example, the dose can be increased to 1.2, 1.5, 1.8, or 2.0 times the original dose. In one embodiment of the invention where a 560 mg dose achieves less than a 70% reduction in serum IgG levels, the dose can be increased to 840 mg.

[0036] In one embodiment of the invention where the dose achieves a greater than 70% reduction, the dose can be reduced. For example, the dose can be reduced to 0.75, 0.5, or 0.25 times the original dose. In one embodiment of the invention where a 560 mg dose achieves a greater than 70% reduction in IgG levels, the dose can be reduced to 420 mg.

[0037] In one example, the present invention also provides a method for treating or preventing fibromyalgia syndrome (FMS) in a human in need thereof, comprising administering at least three doses, preferably at least six doses, of an anti-FcRn antibody or antigen-binding fragment thereof to the human, wherein each dose is selected from 280 mg, 315 mg, 350 mg, 385 mg, 420 mg, 455 mg, 490 mg, 525 mg, 560 mg, 595 mg, 630 mg, 665 mg, 700 mg, 735 mg, 770 mg, 805 mg, 840 mg, 875 mg, 910 mg, 945 mg, 980 mg, 1015 mg, 1050 mg, 1085 mg, and 1120 mg, and wherein the anti-FcRn antibody or FcRn-binding fragment thereof optionally comprises a heavy chain comprising the sequence set forth in SEQ ID NO: 1 and a light chain comprising the sequence set forth in SEQ ID NO: 2. Again, the dose may be selected based on the patient's weight.

[0038] In one example, doses across weight strata can be utilized as follows (equivalent to approximately 7 mg / kg): Weight 40-<49kg: Administered dose 280mg Weight 49~<69kg: Administered dose 420mg Weight 69-<89kg: Administered dose 560mg Body weight 89-<109 kg; Administered dose 700 mg Body weight 109-<129 kg; Administered dose 840 mg Weight 129-<149 kg; Administered dose 980 mg Weight 149-<169 kg; Administered dose 1120 mg Body weight ≥ 169 kg; administered dose 1260 mg

[0039] These doses may be administered, for example, subcutaneously at weekly intervals for, for example, 12 weeks.

[0040] In one example, doses across weight categories can be utilized as follows (equivalent to approximately 10 mg / kg): Weight 40-<49kg: Administered dose 420mg Weight 49~<63kg: Administered dose 560mg Weight 63 to <77 kg: Administered dose 700 mg Body weight 77 to <91 kg; Administered dose 840 mg Body weight 91 to <105 kg; Administered dose 980 mg Body weight 105-<119 kg; Administered dose 1120 mg Weight 119-<133 kg; Administered dose 1260 mg Body weight 133-<147 kg; Administered dose 1400 mg Weight 147-<161 kg; Administered dose 1540 mg Body weight ≥ 161 kg; administered dose 1680 mg

[0041] These doses may also be administered subcutaneously, for example, at weekly intervals, for example, for 12 weeks.

[0042] In one example, a dose equivalent to approximately 7 mg / kg is used. In one example, for a body weight of 40-49 kg, the dose is 280 mg. In one example, for a body weight of 49 kg or greater but less than 69 kg, the dose is 420 mg. In one example, for a body weight of 69 kg or greater but less than 89 kg, the dose is 560 mg. In one example, for a body weight of 89 kg or greater but less than 109 kg, the dose is 700 mg. In one example, for a body weight of 109 kg or greater but less than 129 kg, the dose is 840 mg. In one example, for a body weight of 129 kg or greater but less than 149 kg, the dose is 980 mg. In one example, for a body weight of 149 kg or greater but less than 169 kg, the dose is 1120 mg. In one example, for a body weight of 169 kg or greater, the dose is 1260 mg.

[0043] Accordingly, in one example, the present invention also provides a method for treating or preventing fibromyalgia syndrome (FMS) in a human in need thereof, comprising administering at least three doses, preferably at least six doses, and more preferably at least 12 doses of an anti-FcRn antibody or an FcRn-binding fragment thereof to the human, wherein the dose is 280 mg for a body weight of 40 to 49 kg, 420 mg for a body weight of 49 kg or more but less than 69 kg, 560 mg for a body weight of 69 kg or more but less than 89 kg, 700 mg for a body weight of 89 kg or more but less than 109 kg, 840 mg for a body weight of 109 kg or more but less than 129 kg, 980 mg for a body weight of 129 kg or more but less than 149 kg, 1120 mg for a body weight of 149 kg or more but less than 169 kg, and 1260 mg for a body weight of 169 kg or more.

[0044] Alternatively, one of the following doses across weight groups can be used: · Body weight ≥ 35~< 70kg: Administered dose 420mg; Body weight ≥ 70 kg: 560 mg administered dose; or Weight ≥ 35~< 70kg: Administered dose 420mg Weight ≥ 70~< 100kg: Administered dose 560mg Body weight ≥ 100 kg: Administered dose 840 mg; or Weight ≥ 35~< 50kg: Administered dose 420mg Weight ≥ 50~< 100kg: Administered dose 560mg Body weight ≥ 100 kg: Administered dose 840 mg; or Weight <50kg: Administered dose 420mg Weight 50kg~<100kg: Administered dose 560mg Body weight 100 kg: Administered dose 840 mg; or Weight ≥ 35~< 50kg: Administered dose 280mg Weight ≥ 50~< 70kg: Administered dose 420mg Body weight ≥ 70~< 100kg: Administered dose 560mg Body weight ≥ 100 kg: Administered dose 840 mg Weight ≥ 35~< 50kg: Administered dose 420mg Weight ≥ 50~< 70kg: Administered dose 560mg Body weight ≥ 70~< 100kg: Administered dose 840mg Body weight ≥ 100 kg: Administered dose 1120 mg

[0045] In one embodiment, patients are given a lower initial dose followed by successively higher doses. Alternatively, the following doses across weight groups can be used: · Body weight ≥ 35~< 70kg: the first dose administered is 280mg, and subsequent doses are 420mg; · Body weight ≥ 70 kg: First dose administered is 420 mg, subsequent doses are 560 mg.

[0046] In one embodiment, patients are given a lower initial dose before subsequently receiving higher doses. For example, the following doses across weight groups can be used: · Body weight ≥ 35~< 70 kg: the first dose administered is 420 mg, and subsequent doses are 280 mg; · Body weight ≥ 70 kg: First dose administered is 560 mg, subsequent doses are 420 mg.

[0047] Severe FMS Generalized pain is generally considered to be the most debilitating symptom experienced by patients with fibromyalgia (Mease et al., 2011). Scales used to measure and monitor pain levels vary, including the visual analog scale (VAS), the McGill Pain Questionnaire, the Fibromyalgia Questionnaire-Pain Item-Revised (FIQR), various numeric rating scales (NRS) (often recorded in a diary), and the Brief Pain Inventory-Short Form (BPI-SF).

[0048] These scales can be used to identify patient populations with severe FMS. In particular, individuals can be classified as having severe FMS if they have an average daily pain score of 5 or 6 or greater and less than 10 on the Pain NRS, a BPI-SF interference score of 6 or greater, an FIQR score of 64 or greater, and / or a fatigue NRS score of 5 or greater.

[0049] In one embodiment of the invention, the FMS is severe FMS. In another embodiment, the individual has a pain intensity of 5 or 6 or more and less than 10 on the Pain NRS. In another embodiment, the individual has a Brief Pain Inventory-Short Form (BPI-SF) interference score of 6 or more (up to a maximum of 10). In another embodiment, the individual has a Revised Fibromyalgia Questionnaire (FIQR) score of 64 or more (up to a maximum of 100). In another embodiment, the individual has a Fatigue Numeric Rating Scale (NRS) score of 5 or more (up to a maximum of 10). In another embodiment, the individual has a pain intensity of 5 or more and less than 10 on the Pain Numeric Rating Scale (NRS), a Brief Pain Inventory-Short Interference score of 6 or more (up to a maximum of 10), a Revised Fibromyalgia Questionnaire (FIQR) score of 64 or more (up to a maximum of 100), and / or a Fatigue Numeric Rating Scale (NRS) score of 5 or more (up to a maximum of 10).

[0050] In one aspect of the invention, the method reduces the individual's Brief Pain Inventory-Short Form (BPI-SF) mean interference score. The method may reduce the individual's BPI-SF score 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, or at least 9.

[0051] In another aspect of the invention, the method reduces an individual's Fibromyalgia Questionnaire-Revised (FIQR) score. The method may reduce the individual's FIQR 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, 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, or at least 95.

[0052] In another aspect of the invention, the method reduces an individual's average daily pain score. The average daily pain score can be measured using the Pain NRS. The method can reduce an individual's average daily pain score 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, or at least 9.

[0053] In another aspect of the invention, the method reduces an individual's fatigue score. The fatigue score can be measured using the Fatigue NRS. The method can reduce the individual's fatigue score 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, or at least 9.

[0054] Mild to moderate FMS The FMS treated by the present invention can be mild or moderate FMS. Patients with mild or moderate FMS are distinguished by their lower scores on pain and other scales, for example, individuals with a pain intensity of less than 5 (e.g., 2-4) or less than 6 (e.g., 2-5) on the Pain Numerical Rating Scale (Pain NRS), a Brief Pain Inventory-Short Form (BPI-SF) interference score of less than 6 (e.g., 2-5), a Fibromyalgia Questionnaire (FIQR) score of less than 64 (e.g., 10-63, 20-63, 30-63, 40-63, or 50-63), and / or a Fatigue Numerical Rating Scale (Fatigue NRS) score of less than 5 (e.g., 2-4).

[0055] Brief Pain Intervention Measure-Short Form (BPI-SF) The Brief Pain Inventory-Short Form (BPI-SF) is a 9-item self-administered questionnaire used to assess a patient's pain severity and the impact of this pain on their daily functioning. Patients are asked to rate their worst, least, average, and current pain intensity, list current treatments and their perceived effectiveness, and rate on a 10-point scale the extent to which pain interferes with general activities, mood, ability to walk, usual tasks, relationships with others, sleep, and enjoyment of life.

[0056] The BPI-SF interference score measures the impact of pain across seven domains of daily life experience and is suitable for measuring the effect of treatments that may improve the experience of pain and the functional interference experienced by patients.

[0057] The seven BPI-SF interference items include general activities, mood, walking ability, usual tasks (including housework), relationships with others, sleep, and enjoyment of life. Each item is rated on a scale of 0 (not interfering) to 10 (completely interfering), with a 24-hour recall period. The arithmetic mean of the seven interference items can be used as a measure of pain interference.

[0058] pain NRS The Numerical Rating Scale is one of the most commonly used pain scales in medicine. The NRS consists of a numerical version of the visual analog scale. The most common form of the NRS is a horizontal line with an 11-point numerical range. It is displayed on a scale of 0 to 10, with 0 being an example of no pain and 10 being the worst possible pain. This type of scale can be administered verbally or by paper, which must be completed physically.

[0059] Fibromyalgia Questionnaire-Revised (FIQR) The Fibromyalgia Questionnaire-Revised (FIQR) is a self-report questionnaire that measures functional ability and disease severity in patients with fibromyalgia. The FIQR is one of the most used functional assessment instruments in clinical practice and clinical trials for the evaluation of treatment effectiveness in patients with fibromyalgia.

[0060] The FIQR consists of 21 individual questions across three related domains: function, global impact, and symptoms. All questions relate to experiences over the past seven days and are scored using an 11-point numerical rating scale (0–10, with 10 indicating the worst possible state). The function domain includes nine questions addressing activities of daily living and contributes 30% of the total FIQR score weighting. The global impact domain consists of two questions regarding the overall impact of fibromyalgia on function and the overall impact of symptom severity. 20% of the total FIQR score is attributed to this domain. The symptom domain includes 10 questions and assesses symptoms commonly reported by fibromyalgia patients, such as tenderness, hyperalgesia, environmental sensitivity, balance problems, and memory problems. This accounts for 50% of the total FIQR score. The total FIQR score (out of 100) is the sum of the three modified domain scores: the total score for the functioning domain (range 0–90 divided by 3), the score for the global impact domain (range 0–20), and the score for the symptoms domain (range 0–100 divided by 2).

[0061] Fatigue NRS The Fatigue NRS is a single-item, 11-point horizontal scale administered by the patient, anchored between 0 and 10, where 0 represents "no fatigue" and 10 represents "worst imaginable." Patients are asked to "rate your fatigue (feeling weak, tired) by selecting the number that describes the worst level of fatigue you have experienced in the past 24 hours."

[0062] FcRn FcRn is a noncovalent complex of the membrane protein FcRnα chain and β2-microglobulin (β2M). In adult mammals, FcRn plays an important role in maintaining serum antibody levels by acting as a receptor that binds and salvages antibodies of the IgG isotype. IgG molecules are internalized by endothelial cells, and upon binding to FcRn, they are recycled back into the circulation. In contrast, IgG molecules that do not bind to FcRn enter cells and are targeted to the lysosomal pathway, where they are degraded. A mutant IgG1 in which His435 is mutated to alanine results in selective loss of FcRn binding and a significantly reduced serum half-life (Firan et al., 2001).

[0063] FcRn antagonists The FcRn antagonist can be a peptide such as SYN1436.

[0064] The FcRn antagonist can be an Fc fragment, such as efgartigimod.

[0065] The FcRn antagonist can be an FcRn antibody or an FcRn-binding fragment thereof, such as rozanolixizumab, nipocalimab, orilanolimab, CSL730 / M230, ABY-039, or RVT-1401 (HL161).

[0066] Suitable assays for assessing the ability of a test molecule, such as an FcRn antagonist, to block human FcRn activity, particularly the ability of human FcRn to recycle IgG, are described below.

[0067] 1. An assay suitable for assessing the ability of a test molecule, such as an FcRn antagonist, such as an anti-FcRn antibody, to block human FcRn activity, in particular the ability of human FcRn to recycle IgG, comprising: a) coating a surface of non-human mammalian cells recombinantly expressing human FcRn alpha chain and human β2 microglobulin (β2M); b) contacting the cells with the test molecule and IgG recycled by the cells under mildly acidic conditions, such as about pH 5.9, for a period of time sufficient to allow both the test molecule and the IgG to bind to FcRn, optionally adding the test molecule before the IgG is recycled, and incubating for a period of time sufficient to allow the test molecule to bind to FcRn; c) washing with a slightly acidic buffer solution; and d) detecting the amount of IgG internalized and / or recycled by the cells Provided herein are assays comprising:

[0068] 1. An assay suitable for assessing the ability of a test molecule, such as an FcRn antagonist, such as an anti-FcRn antibody, to block human FcRn activity, in particular the ability of human FcRn to recycle IgG, the method comprising: a) coating a surface of non-human mammalian cells recombinantly expressing human FcRn alpha chain and human β2 microglobulin (β2M); b) contacting the cells with the test antibody molecule and the IgG recycled by the cells under mildly acidic conditions, such as about pH 5.9, for a period of time sufficient to allow both the test antibody molecule and the IgG to bind to FcRn, optionally adding the test antibody molecule before the IgG is recycled, and incubating for a period of time sufficient to allow the test antibody molecule to bind to FcRn; c) washing with a slightly acidic buffer to remove unbound IgG and test antibody molecules; and d) detecting the amount of IgG recycled by the cells Provided herein are assays comprising:

[0069] 1. An assay suitable for assessing the ability of a test molecule, such as an FcRn antagonist, such as an anti-FcRn antibody, to block human FcRn activity, in particular the ability of human FcRn to recycle IgG, the method comprising: a) coating a surface of non-human mammalian cells recombinantly expressing human FcRn alpha chain and human β2 microglobulin (β2M); b) contacting the cells with the test antibody molecule and the IgG recycled by the cells under mildly acidic conditions, such as about pH 5.9, for a period of time sufficient to allow both the test antibody molecule and the IgG to bind to FcRn, optionally adding the test antibody molecule before the IgG is recycled, and incubating for a period of time sufficient to allow the test antibody molecule to bind to FcRn; c) washing with a slightly acidic buffer to remove unbound IgG and test antibody molecules; d) incubating the cells in a neutral buffer, such as at about pH 7.2 e) detecting the amount of IgG recycled by the cells by determining the amount of IgG released into the supernatant Provided herein are assays comprising:

[0070] Suitable cells include Madin-Darby canine kidney (MDCK) II cells. Transfection of MDCK II cells with human FcRn alpha chain and human β2 microglobulin (β2M) was previously described by Claypool et al., 2002. This paper also describes IgG recycling by these transfected cells. Media for supporting cells during testing include complete media containing MEM (Gibco #21090-022), 1x non-essential amino acids (Gibco #11140-035), 1x sodium pyruvate (Gibco #11360-039), and L-glutamine (Gibco #25030-024). Acidic wash solution can be prepared by taking HBSS+ (PAA #H15-008) and adding 1M MES until a pH of 5.9 + / - 0.5 is reached. Approximately 1% BSA may be added (Sigma #A9647). A neutral wash solution can be prepared by taking HBSS+ (PAA #H15-008) and adding 10 M Hepes to reach a pH of 7.2 + / - 0.5. Approximately 1% BSA may be added (Sigma #A9647). Washing the cells with an acidic buffer removes unbound test antibody and unbound IgG, allowing further analysis. The acidic conditions used in step (b) promote the binding of IgG to FcRn and its internalization and recycling.

[0071] The amount of test FcRn antagonist, such as antibody or fragment and IgG, on the surface of the cells can be determined by washing the cells with a neutral wash solution and analyzing the supernatant / wash solution to detect the amount of test antibody or IgG. Importantly, no lysis buffer is used.

[0072] To determine the amount of IgG internalized by cells, FcRn antagonists such as antibodies can be first removed from the cell surface with a neutral wash, the cells lysed with a lysis buffer, and then the internal contents analyzed. To determine the amount of IgG recycled by cells, the cells are incubated under neutral conditions for an appropriate period of time, and the surrounding buffer is analyzed for IgG content. If the antibody content on the cell surface and inside the cell is required, the cells can be washed with an acid wash to maintain the presence of antibody on the cell surface, followed by cell lysis and analysis of the combined material.

[0073] If it is desired to measure both internalization and recycling of an IgG sample, duplicates are run and internalization and recycling tests are performed separately.

[0074] A suitable lysis buffer contains 150 mM NaCl, 20 mM Tris, pH 7.5, 1 mM EDTA, 1 mM EGTA, 1% Triton-X100, and for every 10 ml, add protease inhibitors / phosphate inhibitors as specified in the manufacturer's guidelines.

[0075] Typically, the recycled IgG is labeled. In one example, biotinylated human IgG can be used. The IgG can then be detected using, for example, 25 mL of 0.2 μg / mL streptavidin sulfo-tag detection antibody (such as MSD #r32ad-5) in MSD blocking buffer. The blocking buffer can include 500 mM Tris, pH 7.5, 1.5 M NaCl, 0.2% Tween-20, and 1.5% BSA.

[0076] Alternatively, the IgG may be pre-labeled with a fluorophore or similar label.

[0077] In one embodiment, a suitable surface is a plastic plate or well, such as a 96-well plate, a glass slide, or a membrane. In one example, the cells are coated onto the surface at a density that results in the formation of a monolayer.

[0078] In one aspect, the assays described herein are not measurements of transcytosis of antibodies from top to bottom across a membrane that involves a pH gradient across the membrane, e.g., acidic conditions on one side of the membrane and neutral conditions on the bottom side of the membrane.

[0079] In one example, the test antibody or fragment and IgG may be incubated with the cells in step (b), for example, for about 1 hour at ambient temperature under acidic conditions to allow binding.

[0080] In one example, the test antibody or fragment may be incubated with the cells in step (b) for about 1 hour, e.g., at ambient temperature under acidic conditions, to allow binding before the addition of the recycled IgG, which may then be incubated with the cells in step (b) for about 1 hour, e.g., at ambient temperature under acidic conditions, to allow binding.

[0081] Neutral conditions promote the release of IgG into the supernatant.

[0082] In the above IgG recycling assay, the FcRn antagonist may have an EC50 value of less than 100 nM, less than 50 nM, less than 25 nM, or less than 10 nM. For example, the FcRn antagonist may have an EC50 value of 1 to 100 nM, 1 to 50 nM, 1 to 25 nM, or 1 to 10 nM.

[0083] Efgarchigimod Efgartigimod is approved for generalized myasthenia gravis (MG). Efgartigimod is a monoclonal IgG1 Fc fragment mutated at five residues to increase affinity for FcRn at both physiological and acidic pH. In a phase 2, randomized, placebo-controlled study in 24 patients with MG after four once-weekly (QW) intravenous (IV) doses of 10 mg / kg efgartigimod, a mean maximum reduction in serum IgG from baseline of 70.7% was observed 1 week after the final infusion (Peter et al., 2020).

[0084] Nipocalimab, orilanolimab and RVT-1401 Nipocalimab (M281), a high-affinity, fully human monoclonal IgG1 anti-FcRn antibody engineered to have no Fc effector capacity (no C1q binding and no binding to activating FcgRs), and orilanolimab (SYNT001), a humanized IgG4k mAb, are two additional FcRn inhibitors with published first-in-human (FIH) data. Nipocalimab is currently in phase 2 trials for autoimmune hemolytic anemia, hemolytic disease of the fetus and newborn, and MG.

[0085] RVT-1401 is a fully human monoclonal antibody formulated for intravenous or subcutaneous injection. A Phase 1 single ascending dose / multiple ascending dose (SAD / MAD) study in healthy volunteers has been completed. The SAD portion of the study included fixed, weight-based intravenous and subcutaneous doses (fixed doses 100-765 mg), while the MAD cohort included weekly subcutaneous doses of 340 or 680 mg RVT-1401 or placebo for 4 weeks. IgG levels were reduced by 47% after a single 765 mg dose, reaching a nadir 8-10 days after administration. Weekly subcutaneous administration of 680 mg reduced total IgG levels by 78%. ≥35% IgG reduction was maintained for more than 1 month after the last dose. A reversible, dose-dependent reduction in albumin was observed (31% with the 680 mg subcutaneous dose) and was asymptomatic. Single and multiple doses of RVT-1401 were well tolerated, with no subjects prematurely discontinuing the study due to AEs. The most common adverse events (AEs) in the Phase 1 study were injection site erythema and swelling. No subjects in the MAD cohort developed anti-drug antibodies (Gable et al., 2020).

[0086] FcRn antagonist peptides The FcRn antagonist for use in the present invention may be a peptide. Mezo et al., 2008, described a family of related peptides, all of which contained nine residues in disulfide bonds. The peptide may contain the consensus sequence Gly-His-Phe-Gly-Gly-X-Tyr, where X is preferably a hydrophobic amino acid. The consensus sequence does not share homology with the Fc domain of IgG, and the cysteine ​​disulfide bond may be at various positions relative to the consensus sequence.

[0087] SYN1436 is a 3.1 kDa peptide that binds to human FcRn (hFcRn) and inhibits hFcRn-human IgG (hIgG) interactions. The core peptide sequence was discovered using phage display peptide library screening and shares no homology with the Fc domain of IgG. The peptide was chemically optimized to enhance its in vivo stability and binding properties to hFcRn. SYN1436 modulates IgG levels in hFcRn transgenic mice and cynomolgus monkeys.

[0088] IgG In one aspect of the present invention, administration of an FcRn antagonist results in a reduction of serum IgG in an individual 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%, or at least 90%. Administration of an FcRn antagonist can result in a 60% to 80% reduction in a subject's IgG levels. Administration of an FcRn antagonist can result in an approximately 70% reduction in a subject's IgG levels.

[0089] Autoantibodies responsible for FMS can bind to satellite glial cells (SGCs) in the dorsal root ganglion (DRG), and these anti-SGC IgGs may contribute to FMS (Goebel et al., 2021; Krock et al., 2022).

[0090] In one embodiment of the present invention, FMS patients have elevated serum levels of anti-SGC IgG. Patients can be selected for treatment according to the present invention based on elevated serum levels of anti-SGC IgG. Patients with elevated serum levels of anti-SGC IgG typically have severe FMS. Suitable assays for determining anti-SGC IgG levels are described in Krock et al. and below.

[0091] Human DRGs may be collected. DRG tissue may be fixed to slides using, for example, 4% PFA, blocked using, for example, 3% normal donkey serum and 0.3% Triton X-100 in PBS, and then incubated with 100 μg / ml of unconjugated anti-human IgG Fab fragments (H+L, Jackson Immunoresearch). Slides may also be incubated with fibromyalgia (FM) or healthy control (HC) serum diluted 1:500 in 1% normal donkey serum and 0.1% Triton X-100 in PBS. Slides may then be incubated with anti-human IgG antibodies, antibodies against glial fibrillary acidic protein (GFAP) and neurofilament 200 (NF200), and then appropriate secondary antibodies, counterstained with DAPI, and mounted using Prolong Gold mounting medium. Individual cells may be identified using Cellpose, a deep learning neural network. Cellpose can be run in Python v3.7.9, and regions of interest for each cell can be imported into FIJI. Human IgG binding to SGCs and neurons can then be assessed in FIJI to determine the percentage of bound cells and the average integrated density of IgG binding. Human DRG images can be analyzed using the drgquant pipeline. Experimenters can be blinded to the type of serum with which the cells or tissues were incubated.

[0092] Serum from patients with severe fibromyalgia may produce a higher percentage of IgG-binding SGCs compared to serum from healthy control patients. For example, serum from patients with severe fibromyalgia may produce at least 40%, at least 50%, at least 60%, or at least 65% IgG-binding SGCs. For example, serum from patients with severe fibromyalgia may produce 55-80% or 60-75% IgG-binding SGCs. For example, serum from healthy control patients may produce less than 40% IgG-binding SGCs. For example, serum from healthy control patients may produce less than 20-55% IgG-binding SGCs. For example, serum from patients with severe fibromyalgia may produce at least 1.2-fold, at least 1.5-fold, at least 2-fold, at least 3-fold, or at least 4-fold higher percentage of IgG-binding SGCs than serum from healthy control patients. For example, serum from a patient with severe fibromyalgia may yield a 1.2-5 fold, 1.5-5 fold, 2-5 fold, or 3-5 fold higher percentage of IgG-binding SGCs than serum from a healthy control patient.

[0093] Serum from patients with severe fibromyalgia may provide increased SGC binding strength compared to serum from healthy control patients. For example, serum from patients with severe fibromyalgia may provide a binding strength of at least 2.5, at least 3, at least 3.5, at least 4, at least 4.5, or at least 5. For example, serum from patients with severe fibromyalgia may provide a binding strength of 3 to 6. For example, serum from healthy control patients may provide a binding strength of less than 2.5, less than 2, less than 1.5, or less than 1. For example, serum from healthy control patients may provide a binding strength of 0 to 2.5. For example, serum from patients with severe fibromyalgia may provide a binding strength that is at least 1.2-fold, at least 1.5-fold, at least 2-fold, at least 3-fold, at least 4-fold, or at least 5-fold higher than serum from healthy control patients. For example, serum from a patient with severe fibromyalgia may yield binding strength that is 1.2-10 fold, 1.5-10 fold, 2-10 fold, 3-10 fold, 4-10 fold, or 5-10 fold higher than serum from a healthy control patient.

[0094] In one aspect of the present invention, administration of an FcRn antagonist results in a reduction in a subject's anti-SGC IgG levels 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%, or at least 90%. Administration of an FcRn antagonist can result in a 60% to 80% reduction in a subject's anti-SGC IgG levels. Administration of an FcRn antagonist can result in a reduction in a subject's anti-SGC IgG (ant-SGC IgG) levels by about 70%.

[0095] Dorsal root ganglion (DRG) In humans, the 31 pairs of left and right spinal nerves are formed from afferent sensory dorsal axons (dorsal roots) and motor efferent ventral axons (ventral roots). As the dorsal roots emerge from the intervertebral foramina, they form the dorsal root ganglion (DRG). The DRG is a collection of cell bodies responsible for transmitting sensory information from receptors, such as thermoreceptors, nociceptors, proprioceptors, and chemoreceptors, to the CNS for response.

[0096] The DRG contains the majority of the body's sensory neurons. These neurons relay sensory neural information from the periphery to the central nervous system (brain and spinal cord). Until recently, DRG cell bodies were thought to act only as storage "auxiliaries" in peripheral processes such as nociception. However, recent studies have shown that these cell bodies are active, rather than passive, participants in signaling processes. They sense specific molecules and produce the molecules necessary to regulate the process.

[0097] The DRG has important clinical uses, particularly in relation to neuropathic pain. DRG neurons emerge from the dorsal roots of spinal nerves and carry sensory information from a variety of receptors, including those related to pain and temperature, to the central nervous system for response.

[0098] In addition to neurons, DRGs also contain SGCs, which form a thin cell sheath that surrounds neurons. SGCs play several roles related to their close interaction with neurons, including regulating the microenvironment surrounding neurons. SGCs express various receptors that regulate neurotransmitter levels in the neuronal microenvironment, thereby affecting neuronal excitability. Therefore, IgG binding to SGCs can affect nociception in DRGs.

[0099] Until recently, the dorsal root ganglion was considered a passive organ, metabolically supporting functions and pathways between the peripheral nervous system (PNS) and the central nervous system (CNS). However, new research suggests that the DRG is an active participant in peripheral processes, including paroxysmal atrial fibrillation (PAF), injury, inflammation, and the development of neuropathic pain. A proper understanding of the importance and function of the DRG may help improve the diagnosis and treatment of neuropathic pain syndromes, such as fibromyalgia syndrome (FMS). (Ahimsadasan et al., Neuroanatomy, Dorsal Root Ganglion)

[0100] antibody The term "antibody" as used herein generally relates to an intact (whole) antibody, i.e., an antibody comprising two heavy and two light chain components. Antibodies may comprise further additional binding domains, for example according to the molecule DVD-Ig disclosed in WO2007 / 024715, or the so-called (FabFv)2Fc described in WO2011 / 030107. Thus, antibodies as used herein include bivalent, trivalent, or tetravalent full-length antibodies.

[0101] Antibody binding fragments include single-chain antibodies (i.e., full-length heavy and light chains); Fab, modified Fab, Fab', modified Fab', F(ab')2, Fv, Fab-Fv, Fab-dsFv, single-domain antibodies (e.g., VH or VL or VHH), scFv, bivalent, trivalent, or tetravalent antibodies, Bis-scFv, diabodies, tribodies, triabodies, tetrabodies, and epitope-binding fragments of any of the above (see, e.g., Holliger and Hudson, 2005; Adair and Lawson, 2005). Methods for generating and producing these antibody fragments are well known in the art (see, e.g., Verma et al., 1998). The Fab-Fv format was first disclosed in WO 2009 / 040562, and its disulfide-stabilized version, Fab-dsFv, was first disclosed in WO 2010 / 035012. Other antibody fragments for use in the present invention include the Fab and Fab' fragments described in International Patent Applications WO2005 / 003169, WO2005 / 003170, and WO2005 / 003171. Multivalent antibodies may comprise multiple specificities, e.g., bispecific, or may be monospecific (see, e.g., WO92 / 22583 and WO05 / 113605). One such example of the latter is Tri-Fab (or TFM), described in WO92 / 22583.

[0102] A typical Fab' molecule comprises a pair of heavy and light chains, the heavy chain comprising a variable domain VH, a constant domain CH1 and a native or modified hinge region, and the light chain comprising a variable domain VL and a constant domain CL.

[0103] In one aspect, there is provided a dimer of a Fab' according to the present disclosure to form a F(ab')2, where dimerization can be via a hinge, for example.

[0104] In one embodiment, the antibody or binding fragment thereof comprises a binding domain. The binding domain generally comprises six CDRs, three from the heavy chain and three from the light chain. In one embodiment, the CDRs are within a framework and together form a variable region. Thus, in one embodiment, the antibody or binding fragment comprises a binding domain specific for an antigen comprising a light chain variable region and a heavy chain variable region.

[0105] It is understood that one or more (e.g., 1, 2, 3, or 4) amino acid substitutions, additions, and / or deletions can be made to the CDRs or other sequences (e.g., variable domains) provided by the present disclosure without significantly altering the ability of the antibody to bind to FcRn. The effect of any amino acid substitution, addition, and / or deletion can be readily tested by one of skill in the art, for example, by using the methods described herein, particularly in the examples, for determining FcRn.

[0106] One or more (e.g., 1, 2, 3, or 4) amino acid substitutions, additions, and / or deletions may be made to the framework regions utilized in the antibodies or fragments provided by the present disclosure, wherein binding affinity to FcRn is maintained or increased.

[0107] Residues in antibody variable domains are conventionally numbered according to the system devised by Kabat et al., as described in Sequences of Proteins of Immunological Interest, US Department of Health and Human Services, NIH, USA, Kabat et al., 1987 (hereinafter "Kabat et al., supra"). This numbering system is used herein unless otherwise indicated.

[0108] The Kabat residue designations do not necessarily correspond directly to the linear numbering of amino acid residues. The actual linear amino acid sequence may contain fewer or additional amino acids than the strict Kabat numbering, corresponding to shortening of, or insertion into, structural elements of the basic variable domain structure, whether framework or complementarity-determining region (CDR). For a given antibody, the correct Kabat numbering of residues can be determined by aligning homologous residues in the sequence of the antibody with the "standard" Kabat numbering sequence.

[0109] The CDRs of the heavy chain variable domain are located at residues 31-35 (CDR-H1), residues 50-65 (CDR-H2), and residues 95-102 (CDR-H3) according to the Kabat numbering system. However, according to Chothia, 1987, the loop corresponding to CDR-H1 extends from residue 26 to residue 32. Therefore, unless otherwise indicated, "CDR-H1" as used herein is intended to refer to residues 26 to 35 as described by a combination of the Kabat numbering system and Chothia's topological loop definition.

[0110] The CDRs of the light chain variable domain are located at residues 24-34 (CDR-L1), residues 50-56 (CDR-L2) and residues 89-97 (CDR-L3) according to the Kabat numbering system.

[0111] The antibodies and fragments of the present disclosure can block FcRn, thereby preventing it from functioning in IgG recycling. Blocking, as used herein, refers to physical blocking, such as occluding the receptor, but also includes cases in which the antibody or fragment binds to an epitope, thereby causing, for example, a conformational change such that the natural ligand for the receptor no longer binds. The antibody molecules of the present disclosure bind to FcRn, thereby reducing or preventing (e.g., inhibiting) FcRn binding to the IgG constant region.

[0112] In one embodiment, the antibody or fragment thereof binds to FcRn competitively with IgG. In one example, the antibody or binding fragment thereof functions as a competitive inhibitor of human FcRn binding to human IgG. In one example, the antibody or binding fragment thereof binds to the IgG-binding site of FcRn. In one example, the antibody or binding fragment thereof does not bind to β2M.

[0113] Antibodies for use in the present disclosure can be obtained using any suitable method known in the art. FcRn polypeptides / proteins, including fusion proteins, and cells (recombinantly or naturally) expressing the polypeptides (such as activated T cells) can be used to produce antibodies that specifically recognize FcRn. The polypeptides may be "mature" polypeptides or biologically active fragments or derivatives thereof. The human protein is registered in Swiss-Prot under the number P55899. The extracellular domain of the human FcRn alpha chain is provided in SEQ ID NO: 21. The sequence of β2M is provided in SEQ ID NO: 22.

[0114] In one embodiment, the antigen is a mutant form of FcRn that has been engineered to present FcRn on the surface of cells with little or no dynamic processing as the FcRn is internalized into the cell; for example, this can be achieved by making a mutation in the cytoplasmic tail of the FcRn alpha chain, where a di-leucine is mutated to a di-alanine, as described in Ober et al. 2001.

[0115] The polypeptides used to immunize a host can be prepared by processes well known in the art from genetically engineered host cells containing expression systems, or can be recovered from natural biological sources. In this application, the term "polypeptide" includes peptides, polypeptides, and proteins, which are used interchangeably unless otherwise specified. In some instances, the FcRn polypeptide can be part of a larger protein, such as a fusion protein fused to an affinity tag or the like.

[0116] Antibodies raised against FcRn polypeptides can be obtained by administering the polypeptide to animals, preferably non-human animals, using well-known conventional protocols if immunization of animals is required (see, for example, Handbook of Experimental Immunology, D.M. Weir (ed.), Vol. 4, Blackwell Scientific Publishers, Oxford, England, 1986). Many warm-blooded animals can be immunized, such as rabbits, mice, rats, sheep, cattle, camels, or pigs. However, mice, rabbits, pigs, and rats are generally most suitable.

[0117] Monoclonal antibodies can be prepared by any method known in the art, such as the hybridoma technique (Kohler & Milstein, 1975), trioma technique, human B-cell hybridoma technique (Kozbor et al., 1983), and EBV-hybridoma technique (Cole et al., 1985).

[0118] Antibodies for use in the present invention can also be produced using single lymphocyte antibody techniques by cloning and expressing immunoglobulin variable region cDNA generated from a single lymphocyte selected to produce a particular antibody, for example, by methods described by Babcook, J. et al., 1996, WO92 / 02551, WO2004 / 051268 and International Patent Application No. WO2004 / 106377.

[0119] Antibodies can be screened using assays that measure binding to human FcRn and / or assays that measure the ability to block IgG binding to the receptor. An example of a binding assay is ELISA, which uses a fusion protein of human FcRn and human Fc immobilized on a plate and utilizes a secondary antibody to detect anti-FcRn antibodies bound to the fusion protein. Examples of suitable competition and blocking assays are described in the Examples section of this specification.

[0120] Humanized antibodies (including CDR-grafted antibodies) are antibody molecules having one or more complementarity-determining regions (CDRs) from a non-human species and framework regions from a human immunoglobulin molecule (see, e.g., US Pat. No. 5,585,089, WO 91 / 09967). It is understood that only the specificity-determining residues of the CDRs need to be transferred, rather than the entire CDR (see, e.g., Kashmiri et al., 2005). Humanized antibodies may optionally further comprise one or more framework residues derived from the non-human species from which the CDRs are derived. The latter are often referred to as donor residues.

[0121] As used herein, specific is intended to refer to an antibody that recognizes only the antigen for which it is specific, or an antibody that has a significantly higher binding affinity, e.g., at least 5, 6, 7, 8, 9, or 10 times higher, for the antigen for which it is specific compared to binding to an antigen for which it is nonspecific. Binding affinity can be measured by techniques such as BIAcore, described herein below. In one example, an antibody of the present disclosure does not bind to β2 microglobulin (β2M). In one example, an antibody of the present disclosure binds to cynomolgus monkey FcRn. In one example, an antibody of the present disclosure does not bind to rat or mouse FcRn.

[0122] In one embodiment, the antibody or fragment according to the present disclosure is humanized. As used herein, the term "humanized antibody molecule" refers to an antibody molecule in which the heavy and / or light chains comprise one or more CDRs (including one or more modified CDRs, if desired) from a donor antibody (e.g., a non-human antibody such as a mouse monoclonal antibody) grafted onto the heavy and / or light chain variable region framework of an acceptor antibody (e.g., a human antibody). For a review, see Vaughan et al., 1998. In one embodiment, rather than transferring the entire CDR, only one or more specificity-determining residues from any one of the CDRs described hereinabove are transferred into the human antibody framework (see, e.g., Kashmiri et al., 2005). In one embodiment, only the specificity-determining residues from one or more of the CDRs described hereinabove are transferred into the human antibody framework. In another embodiment, only the specificity-determining residues from each of the above CDRs are transferred into the human antibody framework.

[0123] When CDRs or specificity-determining residues are grafted, any suitable acceptor variable region framework sequence can be used, taking into account the class / type of donor antibody from which the CDRs are derived, including murine, primate and human framework regions.

[0124] Suitably, humanized antibodies according to the present disclosure have variable domains comprising human acceptor framework regions and one or more of the CDRs specifically provided herein. Thus, in one aspect, blocking humanized antibodies that bind to human FcRn are provided, wherein the variable domains comprise human acceptor framework regions and non-human donor CDRs.

[0125] Examples of human frameworks that can be used in the present invention are KOL, NEWM, REI, EU, TUR, TEI, LAY, and POM (Kabat et al., supra). For example, KOL and NEWM can be used for the heavy chain, REI can be used for the light chain, and EU, LAY, and POM can be used for both the heavy and light chains. Alternatively, human germline sequences can be used. These include: http: / / vbase.mrc-cpe.cam.ac.uk / It is available at.

[0126] In the humanized antibodies of the present disclosure, the acceptor heavy and light chains do not necessarily have to be derived from the same antibody, but can, if desired, comprise composite chains having framework regions derived from different chains.

[0127] One suitable framework region for the heavy chain of a humanized antibody of the present disclosure is derived from the human subgroup VH3 sequence 1-3 3-07 (SEQ ID NO: 3) together with JH4.

[0128] Thus, in one example, a humanized antibody is provided that comprises the sequence set forth in SEQ ID NO: 4 for CDR-H1, the sequence set forth in SEQ ID NO: 5 for CDR-H2, and the sequence set forth in SEQ ID NO: 6 for CDRH3, wherein the heavy chain framework regions are derived from human subgroup VH3 sequence 1-3 3-07 together with JH4.

[0129] The sequence of human JH4 is as follows: (YFDY)WGQGTLVTVS (SEQ ID NO: 7). The YFDY motif is part of CDR-H3, but not part of framework 4 (Ravetch, JV et al., 1981, Cell, 27, 583-591).

[0130] In one example, the heavy chain variable domain of the antibody comprises the sequence shown in SEQ ID NO:1.

[0131] Suitable framework regions for the light chain of the humanized antibodies of this disclosure are derived from the human germline subgroup VK1 sequence 2-1-(1)A30 together with JK2 (SEQ ID NO: 8).

[0132] Thus, in one example, a humanized antibody is provided that comprises the sequence set forth in SEQ ID NO: 9 for CDR-L1, the sequence set forth in SEQ ID NO: 10 for CDR-L2, and the sequence set forth in SEQ ID NO: 11 for CDRL3, wherein the light chain framework regions are derived from the human subgroup VK1 sequence 2-1-(1)A30 together with JK2.

[0133] The JK2 sequence is as follows: (YT)FGQGTKLEIK (SEQ ID NO: 12). The YT motif is part of CDR-L3 and not part of framework 4 (Hieter, PA., et al., 1982).

[0134] In one example, the light chain variable domain of the antibody comprises the sequence shown in SEQ ID NO:2.

[0135] In the humanized antibodies of the present disclosure, the framework regions need not have exactly the same sequence as those of the acceptor antibody. For example, unusual residues may be changed to residues occurring more frequently for that class or type of acceptor chain. Alternatively, selected residues in the acceptor framework regions may be changed so that they correspond to residues found at the same position in the donor antibody (see Reichmann et al., 1998). Such changes should be kept to the minimum necessary to restore the affinity of the donor antibody. Protocols for selecting residues in acceptor framework regions that may need to be changed are described in WO 91 / 09967.

[0136] Thus, in one aspect, 1, 2, 3, 4, or 5 residues in the framework are replaced with alternative amino acid residues. Thus, in one example, a humanized antibody is provided in which at least each of residues at positions 3, 24, 76, 93, and 94 (Kabat numbering) of the heavy chain variable domain are donor residues; see, e.g., the sequence set forth in SEQ ID NO:1.

[0137] In one embodiment, residue 3 of the heavy chain variable domain is replaced with an alternative amino acid, for example glutamine.

[0138] In one embodiment, residue 24 of the heavy chain variable domain is replaced with an alternative amino acid, eg, alanine.

[0139] In one embodiment, residue 76 of the heavy chain variable domain is replaced with an alternative amino acid, eg, asparagine.

[0140] In one embodiment, residue 93 of the heavy chain is replaced with an alternative amino acid, for example, alanine.

[0141] In one embodiment, residue 94 of the heavy chain is replaced with an alternative amino acid, eg, arginine.

[0142] In one embodiment, in a humanized heavy chain variable region according to the present disclosure, residue 3 is glutamine, residue 24 is alanine, residue 76 is asparagine, residue 93 is alanine, and residue 94 is arginine.

[0143] Thus, in one example, a humanized antibody is provided in which at least each of residues 36, 37 and 58 (Kabat numbering) of the light chain variable domain are donor residues, see for example the sequence shown in SEQ ID NO:2.

[0144] In one embodiment, residue 36 of the light chain variable domain is replaced with an alternative amino acid, eg, tyrosine.

[0145] In one embodiment, residue 37 of the light chain variable domain is replaced with an alternative amino acid, for example glutamine.

[0146] In one embodiment, residue 58 of the light chain variable domain is replaced with an alternative amino acid, for example, valine.

[0147] In one embodiment, in a humanized heavy chain variable region according to the present disclosure, residue 36 is a tyrosine, residue 37 is a glutamine, and residue 58 is a valine.

[0148] In one aspect, the disclosure provides antibody sequences that are 80% similar or identical to a sequence disclosed herein, e.g., 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% similar or identical over part or all of a related sequence, e.g., a variable domain sequence, a CDR sequence, or a variable domain sequence excluding the CDRs. In one aspect, the related sequence is SEQ ID NO: 2. In one aspect, the related sequence is SEQ ID NO: 1.

[0149] In one aspect, the present disclosure provides an antibody molecule that binds to human FcRn, comprising a heavy chain, wherein the variable domain of the heavy chain comprises a sequence having at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity or similarity to the sequence set forth in SEQ ID NO:1.

[0150] In one aspect, the present disclosure provides an antibody molecule that binds to human FcRn, comprising a light chain, wherein the variable domain of the light chain comprises a sequence having at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity or similarity to the sequence set forth in SEQ ID NO:2.

[0151] In one aspect, the present disclosure provides an antibody molecule that binds to human FcRn, having a heavy chain variable domain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% similar or identical to the sequence set forth in SEQ ID NO: 1, wherein CDR-H1 has the sequence set forth in SEQ ID NO: 4, CDR-H2 has the sequence set forth in SEQ ID NO: 5, and CDR-H3 has the sequence set forth in SEQ ID NO: 6.

[0152] In one aspect, the present disclosure provides an antibody molecule that binds to human FcRn, wherein the antibody molecule has a light chain variable domain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% similar or identical to the sequence set forth in SEQ ID NO: 2, but with CDR-L1 having the sequence set forth in SEQ ID NO: 9, CDR-L2 having the sequence set forth in SEQ ID NO: 10, and CDR-L3 having the sequence set forth in SEQ ID NO: 11.

[0153] In one aspect, the present disclosure provides an antibody molecule that binds to human FcRn, wherein the antibody molecule has a heavy chain variable domain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% similar or identical to the sequence set forth in SEQ ID NO: 1, and a light chain variable domain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% similar or identical to the sequence set forth in SEQ ID NO: 2, wherein for CDR-H1 the sequence set forth in SEQ ID NO: 4, for CDR-H2 the sequence set forth in SEQ ID NO: 5, for CDR-H3 the sequence set forth in SEQ ID NO: 6, for CDR-L1 the sequence set forth in SEQ ID NO: 9, for CDR-L2 the sequence set forth in SEQ ID NO: 10, and for CDR-L3 the sequence set forth in SEQ ID NO: 11.

[0154] As used herein, "identity" indicates that at any particular position in the aligned sequences, the amino acid residue is the same between the sequences. As used herein, "similarity" indicates that at any particular position in the aligned sequences, the amino acid residue is of a similar type between the sequences. For example, leucine may be substituted for isoleucine or valine. Other amino acids that can often be substituted for one another include, but are not limited to, the following: phenylalanine, tyrosine and tryptophan (amino acids with aromatic side chains), lysine, arginine and histidine (amino acids with basic side chains); - aspartic acid and glutamic acid (amino acids with acidic side chains), asparagine and glutamine (amino acids with amide side chains), and - Cysteine ​​and methionine (amino acids with sulfur-containing side chains).

[0155] The degree of identity and similarity can be easily calculated (Computational Molecular Biology, Lesk, AM, ed., Oxford University Press, New York, 1988; Biocomputing, Informatics and Genome Projects, Smith, DW, ed., Academic Press, New York, 1993; Computer Analysis of Sequence Data, Part 1, Griffin, AM, and Griffin, HG, eds., Humana Press, New Jersey, 1994; Sequence Analysis in Molecular Biology, von Heinje, G., Academic Press, 1987; Sequence Analysis Primer, Gribskov, M. and Devereux, J., eds., Stockton Press, New York, 1991; BLAST™ software available from NCBI (Altschul, S., et al.). al.,1990, J.Mol.Biol.215:403-410, Gish,W.&States,DJ1993,Nature Genet.3:266-272.Madden,TLet al.,1996,Meth.Enzymol.266:131-141, Altschul,SFet al.,1997,Nucleic Acids Res.25:3389-3402, Zhang, J. & Madden, TL1997, Genome Res.7:649-656,).

[0156] Antibody molecules of the present disclosure may include intact antibody molecules having full-length heavy and light chains or fragments thereof, including, but not limited to, Fab, modified Fab, Fab', modified Fab', F(ab'), Fv, single-domain antibodies (e.g., VH or VL or VHH), scFv, bivalent, trivalent or tetravalent antibodies, Bis-scFv, diabodies, triabodies, tetrabodies, and epitope-binding fragments of any of the above (see, e.g., Holliger and Hudson, 2005; Adair and Lawson, 2005). Methods for generating and producing these antibody fragments are well known in the art (see, e.g., Verma et al., 1998). Other antibody fragments for use in the present disclosure include the Fab and Fab' fragments described in International Patent Applications WO2005 / 003169, WO2005 / 003170, and WO2005 / 003171. Multivalent antibodies may comprise multiple specificities, e.g., bispecific, or may be monospecific (see, e.g., WO92 / 22853, WO05 / 113605, WO2009 / 040562, and WO2010 / 035012).

[0157] In one embodiment, an antibody molecule of the disclosure is an antibody Fab fragment, e.g., comprising the variable regions set forth in SEQ ID NOs: 2 and 1 for the light and heavy chains, respectively. In one embodiment, the antibody molecule has a light chain comprising the sequence set forth in SEQ ID NO: 13 and a heavy chain comprising the sequence set forth in SEQ ID NO: 14.

[0158] In one embodiment, an antibody molecule of the disclosure is a full-length IgG1 antibody, e.g., comprising the variable regions set forth in SEQ ID NOs: 2 and 1 for the light and heavy chain, respectively. In one embodiment, the antibody molecule has a light chain comprising the sequence set forth in SEQ ID NO: 13 and a heavy chain comprising the sequence set forth in SEQ ID NO: 15.

[0159] In one embodiment, the antibody molecule of the disclosure is in a full-length IgG4 format, e.g., comprising the variable regions set forth in SEQ ID NOs: 2 and 1 for the light and heavy chain, respectively. In one embodiment, the antibody molecule has a light chain comprising the sequence set forth in SEQ ID NO: 13 and a heavy chain comprising the sequence set forth in SEQ ID NO: 16.

[0160] In one aspect, the antibody molecule of the disclosure is in a full-length IgG4P format, e.g., comprising the variable regions set forth in SEQ ID NOs: 2 and 1 for the light and heavy chain, respectively. In one aspect, the antibody molecule has a light chain comprising the sequence set forth in SEQ ID NO: 13, and a heavy chain comprising the sequence set forth in SEQ ID NO: 17.

[0161] IgG4P, as used herein, is a mutant of the wild-type IgG4 isotype in which amino acid 241 is replaced by proline, see for example the serine at position 241 changed to proline as described in Angal et al., 1993.

[0162] In one aspect, an antibody according to the present disclosure is provided as an FcRn-binding antibody fusion protein comprising an immunoglobulin portion, such as a Fab or Fab' fragment, and one or two single domain antibodies (dAbs) linked directly or indirectly thereto, as described, for example, in WO2009 / 040562, WO2010035012, WO2011 / 030107, WO2011 / 061492, and WO2011 / 086091, all of which are incorporated herein by reference.

[0163] In one embodiment, the fusion protein comprises two domain antibodies, for example as a pairing of a variable heavy chain (VH) and a variable light chain (VL), optionally linked by a disulfide bond.

[0164] In one embodiment, the Fab or Fab' components of the fusion protein have the same or similar specificity as one or more single domain antibodies. In one embodiment, the Fab or Fab' have a different specificity to one or more single domain antibodies, i.e., the fusion protein is multivalent. In one embodiment, a multivalent fusion protein according to the present disclosure comprises an albumin binding site, e.g., a VH / VL pair therein provides an albumin binding site. In one such embodiment, the heavy chain comprises the sequence set forth in SEQ ID NO: 18 and the light chain comprises the sequence set forth in SEQ ID NO: 19 or SEQ ID NO: 20.

[0165] In one aspect, a Fab or Fab' according to the present disclosure is conjugated to a PEG molecule or human serum albumin.

[0166] CA170_01519g57 and 1519 and 1519.g57 are used interchangeably herein to refer to a particular pair of antibody variable regions that can be used in several different formats. These variable regions are the heavy chain sequence shown in SEQ ID NO: 1 and the light chain sequence shown in SEQ ID NO: 2.

[0167] The constant region domains of the antibody molecules of the present disclosure, if present, can be selected taking into consideration the proposed function of the antibody molecule, particularly any effector functions that may be required. For example, the constant region domains can be human IgA, IgD, IgE, IgG, or IgM domains. In particular, when the antibody molecule is intended for therapeutic use and antibody effector functions are required, human IgG constant region domains, particularly those of the IgG1 and IgG3 isotypes, can be used. Alternatively, when the antibody molecule is intended for therapeutic purposes and antibody effector functions are not required, IgG2 and IgG4 isotypes may be used. It is understood that sequence variants of these constant region domains can also be used. For example, an IgG4 molecule in which serine at position 241 is changed to proline, as described in Angal et al., 1993, may be used. It is also understood by those skilled in the art that antibodies can undergo various post-translational modifications. The type and extent of these modifications often depend on the host cell line and culture conditions used to express the antibody. Such modifications may include altered glycosylation, methionine oxidation, diketopiperazine formation, aspartic acid isomerization, and asparagine deamidation. A frequent modification is the loss of a carboxy-terminal basic residue (such as lysine or arginine) by the action of carboxypeptidases (as described in Harris, 1995). Thus, the C-terminal lysine of the antibody heavy chain may be absent.

[0168] In one embodiment, the antibody heavy chain comprises a CH1 domain and the antibody light chain comprises a CL domain, either kappa or lambda.

[0169] In one embodiment, the light chain has the sequence set forth in SEQ ID NO:13 and the heavy chain has the sequence set forth in SEQ ID NO:17.

[0170] In one embodiment, the light chain has the sequence set forth in SEQ ID NO:13 and the heavy chain has the sequence set forth in SEQ ID NO:15.

[0171] In one embodiment, the C-terminal amino acid from the antibody molecule is cleaved during post-translational modification.

[0172] In one embodiment, the N-terminal amino acid from the antibody molecule is cleaved during post-translational modification.

[0173] Also provided by the present disclosure are specific regions or epitopes of human FcRn bound by the antibodies provided by the present disclosure, particularly antibodies comprising the heavy chain sequence gH20 (SEQ ID NO: 1) and / or the light chain sequence gL20 (SEQ ID NO: 2).

[0174] This specific region or epitope of the human FcRn polypeptide can be identified by any suitable epitope mapping method known in the art in combination with any one of the antibodies provided by the present disclosure. An example of such a method includes screening peptides of various lengths derived from FcRn for binding to an antibody of the present disclosure using the smallest fragment capable of specifically binding to the antibody that contains the sequence of the epitope recognized by the antibody. FcRn peptides can be produced synthetically or by proteolytic digestion of the FcRn polypeptide. Peptides that bind to the antibody can be identified, for example, by mass spectrometry. In another example, NMR spectroscopy or X-ray crystallography can be used to identify the epitope bound by an antibody of the present disclosure. Once identified, the epitope fragment that binds to an antibody of the present disclosure can be used as an immunogen to obtain additional antibodies that bind to the same epitope, if necessary.

[0175] In one embodiment, an antibody of the disclosure binds to the human FcRn alpha chain extracellular sequence shown below (SEQ ID NO: 21): JPEG2025539866000002.jpg47159

[0176] The underlined residues are those known to be important for the interaction between human FcRn and the Fc region of human IgG, and the bold and italicized residues are those involved in the interaction between FcRn and the 1519 antibody of the present disclosure, which comprises the heavy chain sequence gH20 (SEQ ID NO: 1) and the light chain sequence gL20 (SEQ ID NO: 2).

[0177] In one example, the present disclosure provides an anti-FcRn antibody molecule that binds to an epitope of human FcRn, comprising at least one residue, e.g., at least one amino acid selected from the group consisting of at least 2, 3, 4, 5, 6, 7, 8, 9, or 10 residues, selected from the group consisting of residues V105, P106, T107, A108, and K109 of SEQ ID NO: 21, and P100, E115, E116, F117, M118, N119, F120, D121, L122, K123, Q124, G128, G129, D130, W131, P132, and E133 of SEQ ID NO: 94.

[0178] In one example, the epitope of the antibody molecule is determined by X-ray crystallography using the FcRn alpha chain extracellular sequence (SEQ ID NO: 21) in complex with β2M.

[0179] In one example, the present disclosure provides an anti-FcRn antibody molecule that binds to an epitope of human FcRn, comprising at least one residue selected from the group consisting of residues V105, P106, T107, A108, and K109 of SEQ ID NO: 21, and E115, E116, F117, M118, N119, F120, D121, L122, K123, and Q124 of SEQ ID NO: 21, e.g., at least one amino acid selected from the group consisting of at least 2, 3, 4, 5, 6, 7, 8, 9, or 10 residues.

[0180] In one example, the present disclosure provides an anti-FcRn antibody molecule that binds to an epitope of human FcRn comprising at least 2, 3, 4, or 5 amino acids selected from the group consisting of residues V105, P106, T107, A108, and K109 of SEQ ID NO: 21, and at least one residue selected from the group consisting of E115, E116, F117, M118, N119, F120, D121, L122, K123, and Q124 of SEQ ID NO: 21.

[0181] In one example, the present disclosure provides an anti-FcRn antibody molecule that binds to an epitope of human FcRn comprising at least one amino acid selected from the group consisting of residues V105, P106, T107, A108, and K109 of SEQ ID NO: 21, and at least one residue selected from the group consisting of P100, E115, E116, F117, M118, N119, F120, D121, L122, K123, Q124, G128, G129, D130, W131, P132, and E133 of SEQ ID NO: 21.

[0182] In one example, the present disclosure provides an anti-FcRn antibody molecule that binds to an epitope of human FcRn comprising at least one amino acid selected from the group consisting of residues V105, P106, T107, A108, and K109 of SEQ ID NO: 21, and at least one residue selected from the group consisting of P100, M118, N119, F120, D121, L122, K123, Q124, and G128 of SEQ ID NO: 21.

[0183] In one example, the present disclosure provides an anti-FcRn antibody molecule that binds to an epitope of human FcRn comprising at least one residue selected from the group consisting of residues V105, P106, T107, A108, and K109 of SEQ ID NO: 21, and P100, M118, N119, F120, D121, L122, K123, Q124, and G128 of SEQ ID NO: 21.

[0184] In one example, the present disclosure provides an anti-FcRn antibody molecule that binds to an epitope of human FcRn comprising at least one residue selected from the group consisting of residues V105, P106, T107, A108, and K109 of SEQ ID NO: 21, and P100, E115, E116, F117, M118, N119, F120, D121, L122, K123, Q124, G128, G129, D130, W131, P132, and E133 of SEQ ID NO: 21.

[0185] In one example, the present disclosure provides an anti-FcRn antibody molecule that binds to an epitope of human FcRn comprising at least one residue selected from the group consisting of residues P100, V105, P106, T107, A108, and K109 of SEQ ID NO: 21, and E115, E116, F117, M118, N119, F120, D121, L122, K123, Q124, G128, G129, D130, W131, P132, and E133 of SEQ ID NO: 21.

[0186] In one example, "at least one residue" can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 residues.

[0187] In one example, the present disclosure provides an anti-FcRn antibody molecule that binds to an epitope of human FcRn comprising or consisting of residues 100, 105-109, 115-124, and 129-133 of SEQ ID NO:21.

[0188] Antibodies that cross-block the binding of antibody molecules according to the present disclosure, particularly antibody molecules comprising the heavy chain sequence shown in SEQ ID NO: 1 and the light chain sequence shown in SEQ ID NO: 2, may similarly be useful in blocking FcRn activity. Thus, the present disclosure also provides anti-FcRn antibody molecules that cross-block the binding of any one of the antibody molecules described hereinabove to human FcRn and / or are cross-blocked from binding to human FcRn by any one of those antibodies. In one embodiment, such antibodies bind to the same epitope as the antibodies described hereinabove. In another embodiment, cross-blocking neutralizing antibodies bind to an epitope adjacent to and / or overlapping with the epitope bound by the antibodies described hereinabove.

[0189] Cross-blocking antibodies can be identified using any suitable method in the art, for example, by using a competitive ELISA or BIAcore assay in which binding of the cross-blocking antibody to human FcRn prevents binding of an antibody of the present disclosure, or vice versa. Such cross-blocking assays may use isolated native or recombinant FcRn or suitable fusion proteins / polypeptides. In one example, binding and cross-blocking are measured using recombinant human FcRn extracellular domain (SEQ ID NO: 21). In one example, recombinant human FcRn alpha chain extracellular domain is used in complex with β2-microglobulin (β2M) (SEQ ID NO: 22).

[0190] In one aspect, an anti-FcRn antibody molecule is provided that blocks FcRn binding to IgG and cross-blocks the binding to human FcRn of an antibody whose heavy chain comprises the sequence set forth in SEQ ID NO: 1 and whose light chain comprises the sequence set forth in SEQ ID NO: 2. In one aspect, the cross-blocking antibody provided by the present disclosure inhibits binding of an antibody comprising the heavy chain sequence set forth in SEQ ID NO: 1 and the light chain sequence set forth in SEQ ID NO: 2 by more than 80%, for example, more than 85%, for example, more than 90%, particularly more than 95%.

[0191] Alternatively or additionally, an anti-FcRn antibody according to this aspect of the disclosure may be cross-blocked from binding to human FcRn by an antibody comprising the heavy chain sequence shown in SEQ ID NO: 1 and the light chain sequence shown in SEQ ID NO: 2. Thus, also provided is an anti-FcRn antibody molecule that blocks FcRn binding to IgG and is cross-blocked from binding to human FcRn by an antibody comprising the heavy chain sequence shown in SEQ ID NO: 1 and the light chain sequence shown in SEQ ID NO: 2. In one embodiment, the anti-FcRn antibody provided by this aspect of the disclosure is inhibited from binding to human FcRn by more than 80%, for example more than 85%, for example more than 90%, particularly more than 95%, by an antibody comprising the heavy chain sequence shown in SEQ ID NO: 1 and the light chain sequence shown in SEQ ID NO: 2.

[0192] In one embodiment, the cross-blocking antibodies provided by the present disclosure are fully human. In one embodiment, the cross-blocking antibodies provided by the present disclosure are humanized. In one embodiment, the cross-blocking antibodies provided by the present disclosure have an affinity for human FcRn of 100 pM or less. In one embodiment, the cross-blocking antibodies provided by the present disclosure have an affinity for human FcRn of 50 pM or less. Affinity can be measured using the methods described herein below.

[0193] Biological molecules, such as antibodies or fragments, contain acidic and / or basic functional groups, thereby conferring a net positive or negative charge to the molecule. The amount of overall "observed" charge depends on the absolute amino acid sequence of the entity, the local environment of the charged groups in the 3D structure, and the environmental conditions of the molecule. The isoelectric point (pI) is the pH at which a particular molecule or its solvent-accessible surface has no net charge. In one example, the FcRn antibodies and fragments of the present disclosure can be engineered to have an appropriate isoelectric point. This can result in antibodies and / or fragments with more robust properties, particularly favorable solubility and / or stability profiles and / or improved purification characteristics.

[0194] Thus, in one aspect, the present disclosure provides a humanized FcRn antibody engineered to have an isoelectric point different from that of the initially identified antibody. The antibody can be engineered by replacing amino acid residues, for example, by replacing an acidic amino acid residue with one or more basic amino acid residues. Alternatively, basic amino acid residues can be introduced, or acidic amino acid residues can be removed. Alternatively, if the molecule has an unacceptably high pI, acidic residues can be introduced, as needed, to lower the pI. It is important to note that when engineering the pI, care must be taken to retain the desired activity of the antibody or fragment. Thus, in one aspect, the engineered antibody or fragment has the same or substantially the same activity as the "unmodified" antibody or fragment.

[0195] Programs such as ExPASY http: / / www.expasy.ch / tools / pi_tool.html, and http: / / www.iut-arles.up.univ-mrs.fr / w3bb / d_abim / compo-p.html can be used to predict the isoelectric point of an antibody or fragment.

[0196] The antibody molecules of the present disclosure preferably have high binding affinities, particularly in the nanomolar range. Affinity can be measured using any suitable method known in the art, including BIAcore as described in the examples herein, using isolated native or recombinant FcRn or suitable fusion proteins / polypeptides. In one example, affinity is measured using recombinant human FcRn alpha chain extracellular domain (SEQ ID NO: 21) related to β2 microglobulin (β2M) (SEQ ID NO: 22). Preferably, the antibody molecules of the present disclosure have a K for isolated human FcRn of about 1 nM or less. D In one embodiment, the antibody molecule of the present disclosure has a K of about 500 pM or less. D In one aspect, the antibody molecules of the present disclosure have a K of about 250 pM or less. D In one embodiment, the antibody molecule of the present disclosure has a K of about 200 pM or less. DIn one aspect, the present disclosure provides a compound having a K of about 100 pM or less. D In one aspect, the present disclosure provides an anti-FcRn antibody having a K of about 100 pM or less. D In one aspect, the present disclosure provides a humanized anti-FcRn antibody having a K D The present invention provides an anti-FcRn antibody having the formula:

[0197] Importantly, the antibodies of the present disclosure can bind to human FcRn with comparable binding affinity at both pH 6 and pH 7.4. Thus, advantageously, the antibodies can remain bound to FcRn even within endosomes, thereby maximizing blockade of FcRn binding to IgG.

[0198] In one aspect, the present disclosure provides a soluble ... D The present invention provides an anti-FcRn antibody having the formula:

[0199] The affinity of the antibodies or binding fragments of the present disclosure, as well as the degree to which a binding FcRn antagonist (such as an antibody) inhibits binding, can be determined by those skilled in the art using conventional techniques, such as those described by Scatchard et al., 1949, or by surface plasmon resonance (SPR) using a system such as BIAcore. In surface plasmon resonance, a target molecule is immobilized on a solid phase and exposed to a ligand in a mobile phase that moves along a flow cell. Binding of the ligand to the immobilized target changes the local refractive index, resulting in a change in the SPR angle, which can be monitored in real time by detecting changes in the intensity of reflected light. The rate of change in the SPR signal can be analyzed to obtain the apparent rate constants for the association and dissociation phases of the binding reaction. The ratio of these values ​​provides the apparent equilibrium constant (affinity) (see, for example, Wolff et al., 1993).

[0200] In the present disclosure, the affinity of a test antibody molecule is typically determined using SPR as follows: the test antibody molecule is captured on a solid phase, and the human FcRn alpha chain extracellular domain in a non-covalent complex with β2M is flowed over the captured antibody in a mobile phase to determine the affinity of the test antibody molecule for human FcRn. The test antibody molecule can be captured on a solid phase chip surface using any suitable method, for example, using an anti-Fc or anti-Fab' specific capture FcRn antagonist. In one example, the affinity is determined at pH 6. In one example, the affinity is determined at pH 7.4.

[0201] It is understood that the affinity of antibodies provided by the present disclosure can be altered using any suitable method known in the art. Accordingly, the present disclosure also relates to variants of the antibody molecules of the present disclosure that have improved affinity for FcRn. Such variants can be obtained by several affinity maturation protocols, including CDR mutation (Yang et al., 1995), chain shuffling (Marks et al., 1992), the use of mutagenized strains of Escherichia coli (E. coli) (Low et al., 1996), DNA shuffling (Patten et al., 1997), phage display (Thompson et al., 1996), and sexual PCR (Crameri et al., Nature, 1998). Vaughan et al. (supra) discuss these affinity maturation methods.

[0202] In one embodiment, the antibody molecule of the present disclosure blocks human FcRn activity. Suitable assays for determining the ability of an antibody to block FcRn are described in the examples herein. Suitable assays for determining whether an antibody blocks FcRn interaction with circulating IgG molecules are described in the examples herein.

[0203] Pharmaceutical Composition FcRn antagonists for use in the present invention, such as FcRn antibodies or FcRn-binding fragments thereof, can be provided as pharmaceutical or diagnostic compositions comprising the antagonist molecules of the present disclosure in combination with one or more pharmaceutically acceptable excipients, diluents, or carriers. The compositions are generally supplied as part of a sterile pharmaceutical composition that usually includes a pharmaceutically acceptable carrier. The pharmaceutical compositions of the present invention can further comprise a pharmaceutically acceptable excipient.

[0204] The present disclosure also provides methods for preparing a pharmaceutical or diagnostic composition comprising adding and mixing an antibody molecule of the invention together with one or more pharmaceutically acceptable excipients, diluents or carriers.

[0205] The FcRn antagonist, such as an FcRn antibody or an FcRn-binding fragment thereof, may be the only active ingredient in a pharmaceutical or diagnostic composition, or may be accompanied by other active ingredients, including other antibody components or non-antibody components such as steroids or other drug molecules, in one example of which the half-life is unrelated to FcRn binding.

[0206] Pharmaceutical compositions may conveniently be presented in dosage forms containing a predetermined amount of an active agent of the invention per dose.

[0207] Therapeutic doses of antibodies according to the present disclosure do not show obvious toxic effects in vivo.

[0208] A pharmaceutically acceptable carrier should not itself induce the production of antibodies harmful to the individual receiving the composition and should not be toxic.

[0209] Suitable carriers can be large, slowly metabolized macromolecules such as proteins, polypeptides, liposomes, polysaccharides, polylactic acids, polyglycolic acids, polymeric amino acids, amino acid copolymers, and inactive virus particles.

[0210] Pharmaceutically acceptable salts can be used, for example, mineral acid salts such as hydrochlorides, hydrobromides, phosphates and sulfates, or salts of organic acids such as acetates, propionates, malonates and benzoates.

[0211] Pharmaceutically acceptable carriers in therapeutic compositions may further contain liquids such as water, saline, glycerol, and ethanol. Additionally, auxiliary substances, such as wetting or emulsifying agents or pH buffering substances, may be present in such compositions. Such carriers enable the pharmaceutical compositions to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, and suspensions for ingestion by the patient.

[0212] Forms suitable for administration include forms suitable for parenteral administration, for example by injection or infusion, for example by bolus injection or continuous infusion. When the product is intended for injection or infusion, it may take the form of a suspension, solution or emulsion in an oily or aqueous vehicle and may contain formulatory agents such as suspending agents, preservatives, stabilizing agents and / or dispersing agents.

[0213] Alternatively, the FcRn antagonist, such as an FcRn antibody or an FcRn-binding fragment thereof, may be in a dried form for reconstitution prior to use in an appropriate sterile solution.

[0214] Once formulated, the compositions of the present invention can be administered directly to a subject. The subject to be treated can be an animal. However, in one or more embodiments, the compositions are adapted for administration to a human subject.

[0215] Preferably, in formulations according to the present disclosure, the pH of the final formulation is not similar to the isoelectric point of the antibody or fragment; for example, if the pi of the protein is in the range of 8-9 or higher, a formulation pH of 7 may be appropriate.

[0216] Without wishing to be bound by theory, it is believed that this may ultimately provide a final formulation with improved stability, eg, the antibody or fragment remains in solution.

[0217] The pharmaceutical compositions of the present invention can be administered by any number of routes, including, but not limited to, oral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracerebroventricular, transdermal (see, e.g., WO 98 / 20734), subcutaneous, intraperitoneal, intranasal, enteral, topical, sublingual, vaginal, or rectal routes. Hypodermic sprays can also be used to administer the pharmaceutical compositions of the present invention. Typically, therapeutic compositions can be prepared as injectables, either as liquid solutions or suspensions. Solid forms suitable for dissolution or suspension in a liquid vehicle prior to injection can also be prepared.

[0218] Direct delivery of the composition is generally achieved by subcutaneous, intraperitoneal, intravenous or intramuscular injection, or delivered to the interstitial space of a tissue. The dosage regimen can be a single dose schedule or a multiple dose schedule. Preferably, delivery is subcutaneous. In one example, delivery is by subcutaneous injection. In one example, delivery is not intravenous.

[0219] It is understood that the active ingredient in the composition can be antibody molecule.Therefore, it is easily degraded in the digestive tract.Therefore, when the composition is administered by the route that uses the digestive tract, the composition must contain the agent that protects antibody from degradation, but releases antibody after absorption from the digestive tract.

[0220] A complete discussion of pharmaceutically acceptable carriers is available in Remington's Pharmaceutical Sciences (Mack Publishing Company, NJ. 1991).

[0221] The FcRn antagonist of the present invention can be dispersed in a solvent and delivered in the form of, for example, a solution or suspension. It can be suspended in an appropriate physiological solution, such as physiological saline or other pharmacologically acceptable solvent or buffer solution. A suspension can utilize, for example, a lyophilized antibody.

[0222] Therapeutic suspension or solution formulations may also contain one or more excipients. Excipients are well known in the art and include buffers (e.g., citrate buffer, phosphate buffer, acetate buffer, and bicarbonate buffer), amino acids, urea, alcohol, ascorbic acid, phospholipids, proteins (e.g., serum albumin), EDTA, sodium chloride, liposomes, mannitol, sorbitol, and glycerol. The solution or suspension can be encapsulated in liposomes or biodegradable microspheres. The formulations are generally provided in a substantially sterile form using a sterile manufacturing process.

[0223] This may involve producing and sterilizing by filtration the buffer solvent / solution used in the formulation, aseptically suspending the FcRn antagonist in a sterile buffer solvent solution, and dispensing the formulation into sterile containers by methods well known to those skilled in the art.

[0224] Once formulated, the compositions of the present disclosure can be administered directly to human subjects, although the present disclosure also contemplates that the methods can be utilized with non-human subjects.

[0225] Therapeutically effective dose The composition preferably comprises a therapeutically effective amount of an FcRn antagonist, e.g., an FcRn antibody (or an antigen-binding fragment thereof). As used herein, the term "therapeutically effective amount" refers to the amount of a therapeutic FcRn antagonist required to treat, ameliorate, or prevent a target disease or condition, or to exhibit a detectable therapeutic or prophylactic effect.

[0226] Combination therapy The compositions may be administered to a patient individually or in combination (e.g., simultaneously, sequentially, or separately) with other agents, drugs, or hormones. In one embodiment, an FcRn antagonist according to the present disclosure, such as an FcRn antibody or an FcRn-binding fragment thereof, is utilized in conjunction with a second agent. In some embodiments, the second agent is an analgesic, an antidepressant, a dopamine agonist such as pramipexole, an antiseizure agent, an antihistamine, a hypnotic, a muscle relaxant, and an antipsychotic.

[0227] In some embodiments, the analgesic is selected from the group consisting of paracetamol (acetaminophen), ibuprofen, and opiates such as codeine, tramadol, morphine, and oxycodone.

[0228] In some embodiments, the antidepressant is selected from the group consisting of a tricyclic antidepressant, a serotonin-noradrenaline reuptake inhibitor (SNRI), and a selective serotonin reuptake inhibitor (SSRI).

[0229] In some embodiments, the tricyclic antidepressant is selected from the group consisting of amitriptyline, desipramine, clomipramine, protriptyline, doxepin, imipramine, amoxapine, trazodone, nortriptyline, and trimipramine.

[0230] In some embodiments, the SNRI is selected from the group consisting of venlafaxine, duloxetine, desvenlafaxine, levomilnacipran, and milnacipran.

[0231] In some embodiments, the SSRI is selected from the group consisting of citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline.

[0232] In some embodiments, the anti-seizure drug is selected from the group consisting of gabapentin and pregabalin.

[0233] In some embodiments, the hypnotic agent is a benzodiazepine or a non-benzodiazepine.

[0234] In some embodiments, the benzodiazepine is selected from the group consisting of lorazepam, clonazepam, diazepam, and alprazolam.

[0235] In some embodiments, the non-benzodiazepine is selected from the group consisting of zolpidem, zaleplon, and eszopiclone.

[0236] In some embodiments, the muscle relaxant is selected from the group consisting of cyclobenzaprine, flexeril, orphenadrine citrate, tizanidine, and carisoprodol.

[0237] In some embodiments, the antipsychotic is quetiapine.

[0238] Example 1 Introduction Transfer of serum IgG from human patients with severe FMS to rodents resulted in typical features of clinical FMS in rodents, including allodynia, heat hypersensitivity, reduced grip strength, and small fiber lesions, when compared with transfer of serum IgG from healthy volunteers (Goebel et al., 2021). Fibromyalgia patients with high levels of anti-satellite glial cell IgG antibodies exhibit more severe symptoms (Krock et al., 2022).

[0239] As described in detail below, the following experiment was performed to evaluate the efficacy of an anti-mouse FcRn antibody (UCB4470) in vivo in an FMS patient IgG transfer model.

[0240] method Mice were administered either healthy control (HC) IgG (pooled from four HC donors) or FMS patient IgG. FMS patient IgG consisted of two pools (FMA and FMB) derived from patients with high pain intensity (FIQ >65 and mean pain >60 on the visual analog scale (VAS)). Each pool consisted of IgG from four FMS patients.

[0241] All IgG pools were administered intraperitoneally (ip) at 8 mg on two consecutive days (days 0 and 1) to n=6 mice per group. Groups are outlined below.

[0242] Mice were treated with either an anti-mouse FcRn antibody (antibody UCB4470, Smith et al., 2019) or an isotype control antibody (UCB101.4) at 30 mg / kg, starting 1 day (day -1) before administration of either the HC or FMS IgG pools (FMA and FMB) by intravenous injection. UCB4470 and UCB101.4 were administered i.p. on days 2, 6, 10, and 14.

[0243] In vivo group Group 1 - 8 mg of IgG HC pool + isotype control antibody, UCB101.4 30 mg / kg (n=6 mice)

[0244] Group 2 - 8 mg IgG FMS Pool A (FMA, n=6 mice) or FMS Pool B (FMB, n=6 mice) + isotype control antibody, UCB101.4 30 mg / kg.

[0245] Group 3 - 8 mg IgG FMS Pool A (FMA, n=6 mice) or FMS Pool B (FMB, n=6 mice) + antibody UCB4470 30 mg / kg.

[0246] Behavioral assessment Mice from each group were evaluated for behavioral changes after administration of either HC or FMS IgG. On day 4, changes in activity and movement were assessed using an open field test with video tracking software EthovisionXT 17 (Noldus). Mice were placed in the open field area, and their behavior was recorded for 30 minutes. Total activity, distance traveled, and speed were then calculated for each mouse (Figure 1). Data were analyzed using one-way ANOVA, with statistical significance determined at p<0.05* and p<0.01**.

[0247] Cold allodynia was assessed using the ice stick test, and the latency (in seconds) for mice to withdraw their paw from the cold stimulus was recorded (Figure 2). Mice were acclimated to the ice stick test 2 weeks before the start of the study. Measurements were then taken at baseline (day 0) and days 3, 6, 9, and 14.

[0248] Injections of UCB101.4 and UCB4470 were performed between 9:00 AM and 10:00 AM, and behavioral assessments were performed between 2:00 PM and 5:00 PM.

[0249] result In the open field test, administration of IgG from FMS patients (FMA and FMB pools) to mice resulted in a statistically significant decrease in total activity, distance traveled, and speed compared to mice administered IgG from healthy controls (Figure 1). This reduction in overall activity indicates that IgG from FMS patients has an effect on mice, making them less mobile than mice administered HC IgG. Treatment of mice receiving IgG from FMS patients with 30 mg / kg of an anti-mouse FcRn antibody (UCB4470) resulted in a statistically significant increase in total activity, distance traveled, and speed compared to mice receiving an isotype control antibody (UCB101.4 30 mg / kg) and IgG from FMS patients (Figure 1). Thus, blockade of FcRn with UCB4470 restores normal activity in mice.

[0250] In the cold allodynia test, all mice showed a reduction in latency after treatment with antibody (UCB101.4 or UCB4470) and administration of IgG from HC or FMS pool samples on day 3 compared to baseline on day 0. This reduction was similar across all groups. Mice receiving IgG from FMS patients (FMA and FMB) treated with an isotype control antibody (UCB101.4) showed an overall reduction in latency from day 3 to day 9 compared to mice receiving IgG from HC (Figure 2). This suggests that IgG from FMS patients sensitizes recipient mice to cold stimuli. Treatment with UCB4470 tended to inhibit this hypersensitivity when mice received IgG from the FMA pool. However, this trend was not observed with UCB4470 when mice received IgG from the FMB pool.

[0251] conclusion Overall, these data indicate that transfer of IgG from FMS patients results in behavioral differences and hypersensitivity to cold stimuli in recipient mice compared with transfer of IgG from HCs. The data also show that treatment with anti-FcRn antibodies can restore normal activity in mice and tends to protect against hypersensitivity to cold stimuli in one of the two pools of IgG from FMS patients tested. Therefore, reducing IgG by blocking FcRn may have a therapeutic effect in FMS patients with high pain intensity.

[0252] Example 2 We will conduct a phase 2, multicenter, randomized, double-blind, placebo-controlled, proof-of-concept study to evaluate the efficacy, safety, PK, and PD of rozanolixizumab for the treatment of severe FMS. Rozanolixizumab is an anti-FcRn antibody that inhibits IgG binding to FcRn. The primary endpoint is the mean BPI-SF interference score after 12 weeks of double-blind treatment.

[0253] The study consists of a screening period of up to 28 days, a 2-week single-blind run-in period, followed by two 12-week double-blind treatment periods, followed by a 2-week single-blind run-out period and a 5-week safety follow-up (SFU) period.

[0254] Study participants will be selected based on a previously confirmed diagnosis of fibromyalgia as defined by the 2016 revisions to the 2010 / 2011 fibromyalgia diagnostic criteria (American College of Rheumatology Preliminary Diagnostic Criteria) and the following characteristics during the screening period: a.BPI-SF interference ≥ 6; b. Study participants have been diagnosed with FMS for at least 6 months; c. Study participants had FMS symptoms for at least 2 years prior to enrollment.

[0255] Before randomization, participants must confirm the following: Average daily average 24-hour pain intensity ≥ 6 and < 10 as assessed by the Pain NRS, which will be assessed over a 10-day period within the screening period. Study participants will need a minimum of 7 out of 10 ratings over this 10-day period within the screening period. b. Pain NRS scores must be ≧4 on all completed assessments within this 10-day period.

[0256] Study participants will be randomized in a 1:1:1 ratio to one of three sequences. Study participants in each sequence will receive the following treatment regimen during the double-blind treatment period (see Figure 3): Sequence 1: Rozanolixizumab 560 mg subcutaneously (sc) once weekly (QW) for 24 weeks (12 + 12 weeks treatment period) (N=20, Group 1) Sequence 2: Placebo sc QW for 12 weeks followed by rozanolixizumab 560 mg sc QW for 12 weeks (N=20, Group 2) Sequence 3: Placebo sc QW for 24 weeks (N=20, Group 3)

[0257] The first 2-week run-in period and the final 2-week run-out period are participant-blinded; participants are unaware that they are receiving a placebo, limiting the impact of placebo effects induced at the beginning or end of the study. The two 12-week treatment periods are participant-, investigator-, and sponsor-blinded. It is important that participants do not know when their treatment will change, whether they will proceed from run-in to Period 1, Period 1 to Period 2, or Period 2 to run-out.

[0258] Approximately 30 study participants will be randomized, and an interim analysis can be performed after study participants have completed two double-blind treatment periods, with the possibility of discontinuing for efficacy or futility.

[0259] A Safety Monitoring Committee (SMC) will review available blinded safety data periodically (approximately every 3 months with the option to adapt the frequency based on recruitment rate).

[0260] Outcomes will be assessed using the Brief Pain Inventory-Short Form (BPI-SF), Pain Numeric Rating Scale (Pain NRS), Fibromyalgia Questionnaire-Revised (FIQR) and Fatigue Numeric Rating Scale (Fatigue NRS).

[0261] Brief Pain Inventory-Short Form (BPI-SF) The BPI-SF was designed to measure multiple clinically relevant aspects of pain, such as pain intensity and interference from pain, in cancer populations. Two versions are available. The short version is the most commonly used and is often included in clinical trial contexts (Williams and Arnold, 2011). The short version of the BPI is a self-administered questionnaire used to assess a study participant's pain severity and the impact of this pain on their daily functioning. The BPI-SF assesses pain location, pain intensity, and functional interference from pain. The BPI-SF should be completed by study participants in a quiet location at each visit, including on dosing days, before any other patient-reported outcomes (PROs) or protocol-specified assessments.

[0262] The four BPI-SF severity items include worst pain in the past 24 hours, least pain in the past 24 hours, average pain, and current pain. Each item is rated on a scale of 0 (no pain) to 10 (worst pain imaginable), with a 24-hour recall period.

[0263] The seven BPI-SF interference items include general activities, mood, walking ability, usual tasks (including housework), relationships with others, sleep, and enjoyment of life. Each item is rated on a scale of 0 (not interfering) to 10 (completely interfering), with a 24-hour recall period. The arithmetic mean of the seven interference items can be used as a measure of pain interference.

[0264] Numerical Pain Rating Scale (Pain NRS) The Pain NRS is a numeric version of the VAS (visual analog scale) in which respondents select the whole number that best describes "On average, how much pain have you experienced over the past 24 hours?" The 11-point Pain NRS ranges from 0 (no pain) to 10 (worst pain imaginable).

[0265] Average daily pain over the past 24 hours is recorded using the pain NRS through a diary over a 10-day period within the screening period. Study participants are required to have a minimum of 7 of 10 daily pain NRS assessments over this 10-day period to be eligible for randomization. All pain NRS scores recorded over the 10-day period within the screening period are used to calculate the average daily average 24-hour pain intensity for inclusion: ≥ 6 and < 10 (e.g., if 10 daily scores are available, take the average over 10 days; if 9 daily scores are available, take the average over 9 days, etc.).

[0266] During the run-in period and at the end of the treatment period, the pain NRS is collected daily for 7 consecutive days after the assessment visit. At all other visits, the average pain in the preceding 24 hours before the visit is recorded by the pain NRS for that day only.

[0267] Fibromyalgia Questionnaire-Revised (FIQR) The FIQR is a 21-item questionnaire with a 7-day recall period. The FIQR includes three domains: functioning, global impact, and symptoms. Each item is based on an 11-point numeric rating scale. The FIQR is completed by participants during study visits.

[0268] Fatigue Numerical Rating Scale (Fatigue NRS) The Fatigue NRS is a numeric version of the VAS in which respondents select the whole number that best describes "On average, how fatigued have you experienced over the past 24 hours?" The 11-point Fatigue NRS ranges from 0 (no fatigue) to 10 (worst fatigue imaginable). The Fatigue NRS is completed by participants at home / during study visits.

[0269] Table 1-1 Table 1-2 Table 1-3 Table 1-4 Table 1-5 Table 1-6

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[0271] Aspects of the Disclosure 1. A method for treating or preventing fibromyalgia syndrome (FMS) in an individual, comprising administering to the individual a therapeutically effective amount of an FcRn antagonist, wherein the FcRn antagonist inhibits the binding of IgG to the FcRn receptor.

[0272] 2. The method of aspect 1, wherein the FMS is severe FMS.

[0273] 3. The method of aspect 1 or 2, wherein the individual has a pain intensity of greater than 5 and less than 10 (i.e., 6 or greater and less than 10) on the Pain Numerical Rating Scale (Pain NRS).

[0274] 4. The method of any one of aspects 1-3, wherein the individual has a Brief Pain Inventory-Short Form (BPI-SF) interference score of 6 or greater.

[0275] 5. The method of any one of aspects 1-4, wherein the individual has a Fibromyalgia Questionnaire (FIQR) score of 64 or greater.

[0276] 6. The method of any one of aspects 1-5, wherein the individual has a Fatigue Numeric Rating Scale (Fatigue NRS) score of 5 or greater.

[0277] 7. The method of any one of aspects 1-6, wherein the individual has a pain intensity of greater than 5 and less than 10 (i.e., 6 or greater and less than 10) on the Pain Numerical Rating Scale (Pain NRS), a Brief Pain Inventory-Short Form (BPI-SF) interference score of 6 or greater, a Fibromyalgia Questionnaire (FIQR) score of 64 or greater, and a Fatigue Numerical Rating Scale (Fatigue NRS) score of 5 or greater.

[0278] 8. The method of any one of aspects 1-7, wherein treating FMS comprises reducing or eliminating one or more symptoms of FMS.

[0279] 9. The method of aspect 8, wherein the one or more symptoms of FMS are selected from the group consisting of pain, tingling, burning, stabbing, hyperalgesia, allodynia, stiffness, muscle spasms, fatigue, reduced sleep quality, memory impairment, attention deficit, concentration deficit, speech disorder, headache, migraine, constipation, diarrhea, dizziness, clumsiness, anxiety, and depression.

[0280] 10. The method of any one of aspects 1-9, wherein the method reduces the individual's Brief Pain Inventory-Short Form (BPI-SF) mean interference score.

[0281] 11. The method of aspect 10, wherein the individual's BPI-SF score is reduced 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, or at least 9.

[0282] 12. The method of any one of aspects 1-11, wherein the method reduces the individual's Fibromyalgia Questionnaire (FIQR) score.

[0283] 13. The method of aspect 12, wherein the FIQR score of the individual is reduced 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, 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, or at least 95.

[0284] 14. The method of any one of aspects 1-13, wherein the method reduces the individual's mean daily pain score.

[0285] 15. The method of aspect 14, wherein the mean daily pain score is measured using a pain numeric rating scale (NRS).

[0286] 16. The method of aspect 15, wherein the individual's mean daily pain score is reduced 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, or at least 9.

[0287] 17. The method of any one of aspects 1-16, wherein the fatigue score of the individual is reduced.

[0288] 18. The method of aspect 17, wherein the fatigue score is measured using a fatigue numeric rating scale (NRS).

[0289] 19. The method of aspect 18, wherein the fatigue score is reduced 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, or at least 9.

[0290] 20. The method of any one of aspects 1-19, wherein administration of the FcRn antagonist results in at least a 10%, at least a 20%, at least a 30%, at least a 40%, at least a 50%, at least a 60%, at least a 70%, at least a 80%, or at least a 90% reduction in serum IgG in the individual.

[0291] 21. The method of any one of aspects 1 to 20, wherein administration of the FcRn antagonist results in a reduction of serum IgG levels by 60-80%.

[0292] 22. The method of any one of aspects 1-21, wherein administration of the FcRn antagonist results in a reduction of serum IgG levels by about 70%.

[0293] 23. The method of any one of aspects 1 to 22, wherein serum from the individual results in a higher percentage of IgG-binding satellite glial cells (SGCs) or increased SGC binding intensity compared to serum from a healthy control patient.

[0294] 24. The method of any one of aspects 1-23, wherein administration of the FcRn antagonist results in at least a 10%, at least a 20%, at least a 30%, at least a 40%, at least a 50%, at least a 60%, at least a 70%, at least a 80%, or at least a 90% reduction in the level of anti-SGC IgG in the individual.

[0295] 25. The method of any one of aspects 1 to 24, wherein the FcRn antagonist is an Fc fragment that binds to the FcRn receptor.

[0296] 26. The method of aspect 25, wherein the Fc fragment is efgartigimod.

[0297] 27. The method of any one of aspects 1 to 26, wherein the FcRn antagonist is a peptide that blocks binding of IgG to the FcRn receptor.

[0298] 28. The method of aspect 27, wherein the peptide is SYN1436.

[0299] 29. The method of any one of aspects 1 to 24, wherein the FcRn antagonist is an anti-FcRn antibody or an FcRn-binding fragment thereof.

[0300] 30. The method of aspect 29, wherein the anti-FcRn antibody or FcRn-binding fragment is selected from the list consisting of rozanolixizumab, nipocalimab, orilanolimab, CSL730 / M230, ABY-039, and RVT-1401 (HL161).

[0301] 31. The method of aspect 29 or aspect 30, wherein the anti-FcRn antibody or FcRn-binding fragment thereof is rozanolixizumab.

[0302] 32. The anti-FcRn antibody or FcRn-binding fragment thereof is (a) a heavy chain or heavy chain fragment having a variable region, the variable region comprising three CDRs having the sequences shown in SEQ ID NO: 4 for CDR H1, SEQ ID NO: 5 for CDR H2, and SEQ ID NO: 6 for CDR H3; (b) a light chain or light chain fragment having a variable region, the variable region comprising three CDRs having the sequences shown in SEQ ID NO: 9 for CDR L1, SEQ ID NO: 10 for CDR L2, and SEQ ID NO: 11 for CDR L3; 32. The method of any one of aspects 29 to 31, comprising:

[0303] 33. The method of any one of aspects 29 to 32, wherein the anti-FcRn antibody or FcRn-binding fragment thereof comprises a heavy chain variable region having the sequence shown in SEQ ID NO: 1 and a light chain variable region having the sequence shown in SEQ ID NO: 2.

[0304] 34. The method of any one of aspects 29 to 33, wherein the anti-FcRn antibody or FcRn-binding fragment is an scFv, Fv, Fab, or Fab' fragment.

[0305] 35. The method of aspect 34, wherein the Fab fragment comprises a heavy chain having the sequence set forth in SEQ ID NO: 14 and a light chain having the sequence set forth in SEQ ID NO: 13.

[0306] 36. The method of any one of aspects 29 to 35, wherein the anti-FcRn antibody comprises a heavy chain having the sequence shown in SEQ ID NO: 17 and a light chain having the sequence shown in SEQ ID NO: 13.

[0307] 37. The method of any one of aspects 29 to 36, wherein the anti-FcRn antibody or FcRn-binding fragment thereof is administered at a dose of 1 mg / kg to 50 mg / kg.

[0308] 38. The method of any one of aspects 29 to 27, wherein the anti-FcRn antibody or FcRn-binding fragment thereof is administered at a dose of 4 mg / kg to 20 mg / kg.

[0309] 39. The method of any one of aspects 29 to 38, wherein the anti-FcRn antibody or FcRn-binding fragment thereof is administered at a dose of 7 mg / kg to 10 mg / kg.

[0310] 40. The method of any one of aspects 29 to 39, wherein the anti-FcRn antibody or FcRn-binding fragment thereof is administered at a dose of 560 mg.

[0311] 41. The method of any one of aspects 29 to 40, wherein the anti-FcRn antibody or FcRn-binding fragment thereof is administered subcutaneously.

[0312] 42. The method of any one of aspects 29 to 41, wherein the anti-FcRn antibody or FcRn-binding fragment thereof is administered once a day, three times a week, twice a week, once a week, once every two weeks, once every three weeks, once a month, once every six weeks, once every two months, once every three months, once every four months, once every five months, or once every six months.

[0313] 43. The method of any one of aspects 29 to 42, wherein the anti-FcRn antibody or FcRn-binding fragment thereof is administered once a week.

[0314] 44. The method of any one of aspects 1-43, further comprising administering a therapeutically effective amount of a second agent for treating FMS.

[0315] 45. The method of aspect 44, wherein the second agent is selected from the group consisting of an analgesic, an antidepressant, a dopamine agonist, an antiseizure agent, an antihistamine, a hypnotic, a muscle relaxant, and an antipsychotic.

[0316] 46. ​​The method of aspect 45, wherein the analgesic is selected from the group consisting of paracetamol (acetaminophen), ibuprofen, and opiates such as codeine, tramadol, morphine, and oxycodone.

[0317] 47. The method of aspect 45, wherein the antidepressant is selected from the group consisting of a tricyclic antidepressant, a serotonin-noradrenaline reuptake inhibitor (SNRI), and a selective serotonin reuptake inhibitor (SSRI).

[0318] 48. The method of aspect 47, wherein the tricyclic antidepressant is selected from the group consisting of amitriptyline, desipramine, clomipramine, protriptyline, doxepin, imipramine, amoxapine, trazodone, nortriptyline, and trimipramine.

[0319] 49. The method of aspect 47, wherein the SNRI is selected from the group consisting of venlafaxine, duloxetine, desvenlafaxine, levomilnacipran, and milnacipran.

[0320] 50. The method of aspect 47, wherein the SSRI is selected from the group consisting of citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline.

[0321] 51. The method of aspect 45, wherein the anti-seizure drug is selected from the group consisting of gabapentin and pregabalin.

[0322] 52. The method of aspect 45, wherein the hypnotic agent is a benzodiazepine or a non-benzodiazopine.

[0323] 53. The method of aspect 52, wherein the benzodiazepine is selected from the group consisting of lorazepam, clonazepam, diazepam, and alprazolam.

[0324] 54. The method of aspect 52, wherein the non-benzodiazepine is selected from the group consisting of zolpidem, zaleplon, and eszopiclone.

[0325] 55. The method of aspect 45, wherein the muscle relaxant is selected from the group consisting of cyclobenzaprine, flexeril, orphenadrine citrate, tizanidine, and carisoprodol.

[0326] 56. The method of aspect 45, wherein the antipsychotic is quetiapine.

[0327] 57. An FcRn antagonist for use in a method for treating or preventing fibromyalgia syndrome (FMS) in an individual, wherein the FcRn antagonist inhibits binding of IgG to the FcRn receptor.

[0328] 58. Use of an FcRn antagonist for the manufacture of a medicament for treating or preventing fibromyalgia syndrome (FMS) in an individual, wherein the FcRn antagonist inhibits the binding of IgG to the FcRn receptor.

Claims

1. 1. A method of treating or preventing fibromyalgia syndrome (FMS) in an individual, comprising administering to said individual a therapeutically effective amount of an FcRn antagonist; The method, wherein the FcRn antagonist is an anti-FcRn antibody or an FcRn-binding antibody fragment, comprises the following (a) and (b): (a) a heavy chain or heavy chain fragment having a variable region, the variable region comprising three CDRs having the sequences shown in SEQ ID NO: 4 for CDR H1, SEQ ID NO: 5 for CDR H2, and SEQ ID NO: 6 for CDR H3; (b) A light chain or light chain fragment having a variable region, wherein the variable region comprises three CDRs having the sequences shown in SEQ ID NO: 9 for CDR L1, SEQ ID NO: 10 for CDR L2, and SEQ ID NO: 11 for CDR L3.

2. The method of claim 1, wherein the anti-FcRn antibody or FcRn-binding fragment thereof comprises a heavy chain variable region having the sequence shown in SEQ ID NO: 1 and a light chain variable region having the sequence shown in SEQ ID NO:

2.

3. The method of claim 1 or claim 2, wherein the FcRn-binding fragment is an scFv, Fv, Fab or Fab' fragment.

4. 4. The method of claim 3, wherein the Fab fragment comprises a heavy chain having the sequence shown in SEQ ID NO: 14 and a light chain having the sequence shown in SEQ ID NO:

13.

5. The method of claim 1 or claim 2, wherein the anti-FcRn antibody comprises a heavy chain having the sequence set forth in SEQ ID NO: 17 and a light chain having the sequence set forth in SEQ ID NO:

13.

6. The method of claim 1, 2, or 5, wherein the anti-FcRn antibody is rozanolixizumab.

7. The method of any one of claims 1 to 6, wherein the FMS is severe FMS.

8. 8. The method of any one of claims 1 to 7, wherein the individual has a pain intensity of greater than 5 and less than 10 on the Pain Numeric Rating Scale (Pain NRS).

9. 8. The method of any one of claims 1 to 7, wherein the individual has a pain intensity of 6 or more and less than 10 on the Pain Numeric Rating Scale (Pain NRS).

10. 10. The method of any one of claims 1 to 9, wherein the individual has a Brief Pain Inventory-Short Form (BPI-SF) interference score of 6 or greater.

11. 11. The method of any one of claims 1 to 10, wherein the individual has a Fibromyalgia Questionnaire (FIQR) score of 64 or greater.

12. 12. The method of any one of claims 1 to 11, wherein the individual has a Fatigue Numeric Rating Scale (Fatigue NRS) score of 5 or greater.

13. 13. The method of any one of claims 1 to 12, wherein the individual has a pain intensity of greater than 5 and less than 10 (i.e., 6 or greater and less than 10) on the Pain Numerical Rating Scale (Pain NRS), a Brief Pain Inventory-Short Form (BPI-SF) interference score of 6 or greater, a Fibromyalgia Questionnaire (FIQR) score of 64 or greater, and a Fatigue Numerical Rating Scale (Fatigue NRS) score of 5 or greater.

14. 14. The method of any one of claims 1 to 13, wherein treating FMS comprises reducing or eliminating one or more of the symptoms of FMS.

15. 15. The method of claim 14, wherein the one or more symptoms of FMS are selected from the group consisting of pain, tingling, burning, stabbing, hyperalgesia, allodynia, stiffness, muscle spasms, fatigue, reduced sleep quality, memory impairment, attention deficit, concentration deficit, speech disorder, headache, migraine, constipation, diarrhea, dizziness, clumsiness, anxiety, and depression.

16. 16. The method of any one of claims 1 to 15, wherein the method reduces the individual's Brief Pain Inventory-Short Form (BPI-SF) mean interference score.

17. 17. The method of claim 16, wherein the BPI-SF score of the individual is reduced 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, or at least 9.

18. 18. The method of any one of claims 1 to 17, which reduces the Fibromyalgia Questionnaire (FIQR) score of the individual.

19. 20. The method of claim 18, wherein the FIQR score of the individual is reduced 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, 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, or at least 95.

20. 20. The method of any one of claims 1 to 19, wherein the method reduces the individual's average daily pain score.

21. 21. The method of claim 20, wherein the average daily pain score is measured using the Numerical Rating Scale (NRS).

22. 22. The method of claim 21, wherein the individual's average daily pain score is reduced 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, or at least 9.

23. 23. The method of any one of claims 1 to 22, wherein the fatigue score of the individual is reduced.

24. 24. The method of claim 23, wherein the fatigue score is measured using the Numerical Rating Scale for Fatigue (NRS).

25. 25. The method of claim 24, wherein the fatigue score is reduced 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, or at least 9.

26. 26. The method of any one of claims 1-25, wherein administration of the FcRn antagonist results in a reduction of serum IgG in the individual 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%, or at least 90%.

27. 27. The method of any one of claims 1 to 26, wherein administration of the FcRn antagonist results in a reduction of serum IgG levels of 60-80%.

28. 28. The method of any one of claims 1 to 27, wherein administration of the FcRn antagonist results in a reduction of serum IgG levels by about 70%.

29. 29. The method of any one of claims 1 to 28, wherein serum from the individual results in a higher percentage of IgG-binding satellite glial cells (SGCs) or increased SGC binding strength compared to serum from a healthy control patient.

30. 30. The method of any one of claims 1 to 29, wherein administration of the FcRn antagonist results in a reduction in the level of anti-SGC IgG in the individual 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%, or at least 90%.

31. The method of any one of claims 1 to 30, wherein the anti-FcRn antibody or FcRn-binding fragment thereof is administered at a dose of 1 mg / kg to 50 mg / kg.

32. 32. The method of any one of claims 1 to 31, wherein the anti-FcRn antibody or FcRn-binding fragment thereof is administered at a dose of 4 mg / kg to 20 mg / kg.

33. 33. The method of any one of claims 1 to 32, wherein the anti-FcRn antibody or FcRn-binding fragment thereof is administered at a dose of 7 mg / kg to 10 mg / kg.

34. 34. The method of any one of claims 1 to 33, wherein the anti-FcRn antibody or FcRn-binding fragment thereof is administered at a dose of 560 mg.

35. The method of any one of claims 1 to 34, wherein the anti-FcRn antibody or FcRn-binding fragment thereof is administered subcutaneously.

36. The method of any one of claims 1 to 35, wherein the anti-FcRn antibody or FcRn-binding fragment thereof is administered once a day, three times a week, twice a week, once a week, once every two weeks, once every three weeks, once a month, once every six weeks, once every two months, once every three months, once every four months, once every five months, or once every six months.

37. The method of any one of claims 1 to 36, wherein the anti-FcRn antibody or FcRn-binding fragment thereof is administered once a week.

38. 38. The method of any one of claims 1 to 37, further comprising administering a therapeutically effective amount of a second agent for treating FMS.

39. 39. The method of claim 38, wherein the second agent is selected from the group consisting of analgesics, antidepressants, dopaminergic agents, antiseizure agents, antihistamines, hypnotics, muscle relaxants, and antipsychotics.

40. 40. The method of claim 39, wherein the analgesic is selected from the group consisting of paracetamol (acetaminophen), ibuprofen, and opiates such as codeine, tramadol, morphine, and oxycodone.

41. 40. The method of claim 39, wherein the antidepressant is selected from the group consisting of a tricyclic antidepressant, a serotonin-noradrenaline reuptake inhibitor (SNRI), and a selective serotonin reuptake inhibitor (SSRI).

42. 42. The method of claim 41, wherein the tricyclic antidepressant is selected from the group consisting of amitriptyline, desipramine, clomipramine, protriptyline, doxepin, imipramine, amoxapine, trazodone, nortriptyline, and trimipramine.

43. 42. The method of claim 41, wherein the SNRI is selected from the group consisting of venlafaxine, duloxetine, desvenlafaxine, levomilnacipran, and milnacipran.

44. 42. The method of claim 41, wherein the SSRI is selected from the group consisting of citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline.

45. 40. The method of claim 39, wherein the anti-seizure drug is selected from the group consisting of gabapentin and pregabalin.

46. 40. The method of claim 39, wherein the hypnotic is a benzodiazepine or a non-benzodiazopine.

47. 47. The method of claim 46, wherein the benzodiazepine is selected from the group consisting of lorazepam, clonazepam, diazepam, and alprazolam.

48. 47. The method of claim 46, wherein the non-benzodiazepine is selected from the group consisting of zolpidem, zaleplon, and eszopiclone.

49. 40. The method of claim 39, wherein the muscle relaxant is selected from the group consisting of cyclobenzaprine, flexeril, orphenadrine citrate, tizanidine, and carisoprodol.

50. 40. The method of claim 39, wherein the antipsychotic is quetiapine.

51. 1. An FcRn antagonist for use in a method for treating or preventing fibromyalgia syndrome (FMS) in an individual, comprising: (a) a heavy chain or heavy chain fragment having a variable region, the variable region comprising three CDRs having the sequences set forth in SEQ ID NO: 4 for CDR H1, SEQ ID NO: 5 for CDR H2, and SEQ ID NO: 6 for CDR H3; and (b) a light chain or light chain fragment having a variable region, the variable region comprising three CDRs having the sequences shown in SEQ ID NO: 9 for CDR L1, SEQ ID NO: 10 for CDR L2, and SEQ ID NO: 11 for CDR L3. An FcRn antagonist, which is an anti-FcRn antibody or an FcRn-binding antibody fragment comprising:

52. 1. Use of an FcRn antagonist for the manufacture of a medicament for treating or preventing fibromyalgia syndrome (FMS) in an individual, wherein the FcRn antagonist is an anti-FcRn antibody or an FcRn-binding antibody fragment comprising: (a) a heavy chain or heavy chain fragment having a variable region, the variable region comprising three CDRs having the sequences set forth in SEQ ID NO: 4 for CDR H1, SEQ ID NO: 5 for CDR H2, and SEQ ID NO: 6 for CDR H3; and (b) A light chain or light chain fragment having a variable region, wherein the variable region comprises three CDRs having the sequences shown in SEQ ID NO: 9 for CDR L1, SEQ ID NO: 10 for CDR L2, and SEQ ID NO: 11 for CDR L3.

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