Treatment of fibromyalgia

Abstract

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

Description

Technical Field

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

[0002] Fibromyalgia syndrome (FMS) is a highly prevalent (2 to 3% of the adult population) and complex syndrome, which is mainly characterized by the presence of chronic widespread pain, but also includes other widespread symptoms that adversely affect life function and quality, such as severe fatigue, cognitive dysfunction, and sleep disturbances ( et al., 2015). This impairs work ability, leading to decreased productivity and high healthcare costs (White et al., 2008). In patients with more severe diseases, the direct and indirect effects of FMS are higher (Chandran et al., 2012).

[0003] There are challenges surrounding the diagnosis of FMS. There is no confirmatory laboratory test, and thus, patients typically require >2 years to obtain a diagnosis, usually involving multiple consultations with different physicians. The lack of disease-specific biomarkers also hinders patient stratification and affects all research areas of FMS. Current clinical practice recommendations and guidelines for FMS include non-pharmacological and pharmacological strategies, with a focus on reducing symptoms and improving function. Pharmacological agents include tricyclic antidepressants, antiepileptic drugs, selective serotonin reuptake inhibitors, and norepinephrine / serotonin reuptake inhibitors. Although the US Food and Drug Administration has approved pregabalin, duloxetine, and milnacipran for the treatment of fibromyalgia in adults, the less-than-optimal efficacy of available therapies in many patients highlights the unmet clinical needs of this patient population. Patients with severe FMS are distinguished by their higher scores on pain and other scales, as well as a significant increase in disability and depression (Chandran et al., 2012). Due to limited available treatment options, patients with severe FMS have unmet needs.

[0004] The FcRn receptor rescues IgG from intracellular lysosomal degradation by recycling it from sorting endosomes back to the cell surface (Anderson et al., 2006). This is achieved through the binding of IgG to the FcRn receptor. Thus, in effect, FcRn rescues IgG from degradation and returns it to circulation. Albumin is also recycled similarly by FcRn, although through a different binding site on the FcRn molecule. It has been shown that knocking out or blocking FcRn eliminates this recycling, resulting in endosomal catabolism of IgG and a significant decrease in IgG concentration in both intravascular and extravascular (tissue) compartments. In fact, blocking of FcRn accelerates the removal of endogenous IgG. Summary of the Invention

[0005] 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 an anti-FcRn antibody or an FcRn-binding antibody fragment, which comprises:

[0006] (a) a heavy chain or heavy chain fragment having a variable region, wherein the variable region comprises three CDRs, and the three CDRs have the sequences of CDR H1 given in SEQ ID NO:4, the sequences of CDR H2 given in SEQ ID NO:5, and the sequences of CDR H3 given in SEQ ID NO:6, and

[0007] (b) a light chain or light chain fragment having a variable region, wherein the variable region comprises three CDRs, and the three CDRs have the sequences of CDR L1 given in SEQ ID NO:9, the sequences of CDR L2 given in SEQ ID NO:10, and the sequences of CDR L3 given in SEQ ID NO:11.

[0008] The FMS treated by the present invention is generally severe FMS. Severe FMS patients are distinguished by their higher scores on pain and other scales, for example, wherein the individual has a pain intensity 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 greater than or equal to 6. The patient may also have a Fibromyalgia Impact Questionnaire (FIQR) score greater than or equal to 64 and / or a fatigue numerical rating scale (fatigue NRS) score greater than or equal to 5.

[0009] The anti-FcRn antibody can be rozanolixizumab (sold under the trade name UDICAF ).

[0010] The dose of the anti-FcRn antibody or its FcRn-binding fragment is generally 1 mg / kg to 50 mg / kg, 4 mg / kg to 20 mg / kg, or 7 mg / kg to 10 mg / kg. The dose can be 420 mg, 560 mg, or 840 mg. In one embodiment, the dose is 560 mg.

[0011] For example, the anti-FcRn antibody or its FcRn-binding fragment can be 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.

[0012] The method may further comprise administering a therapeutically effective amount of a second agent for treating FMS, such as an analgesic, antidepressant, dopamine agonist, anti-epileptic, antihistamine, hypnotic, muscle relaxant, and antipsychotic. BRIEF DESCRIPTION OF THE DRAWINGS

[0013] Figure 1 Shown is that in the open field test, administration of IgG from FMS patients resulted in a statistically significant decrease in total activity, distance moved, and speed of the mice compared to mice receiving IgG from healthy controls. Treatment of mice that had received 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 moved, and speed compared to mice that had received isotype control antibody (UCB101.4 30 mg / kg) and IgG from FMS patients.

[0014] Figure 2 Shown is that in the cold allodynia test, compared to the baseline on day 0, all mice showed a decrease in latency after treatment with the antibody (UCB101.4 or UCB4470) and administration of IgG from HC or FMS pooled samples on day 3. This decrease was similar in all groups. In mice that had received IgG from FMS patients (groups FMA and FMB) treated with isotype control antibody (UCB101.4), the latency was generally decreased from day 3 until day 9 compared to mice receiving IgG from HC. This indicates that IgG from FMS patients makes the recipient mice hypersensitive to cold stimuli. When mice received IgG from the FMA pool, treatment with UCB4470 resulted in an inhibition of this trend towards hypersensitivity. However, when mice received IgG from the FMB pool, this trend was not observed with UCB4470.

[0015] Figure 3 is a schematic diagram of a Phase 2, multi-center, randomized, double-blind, placebo-controlled proof-of-concept study to evaluate the efficacy, safety, PK (pharmacokinetics), and PD (pharmacodynamics) of rozelixizumab in the treatment of severe FMS. The primary endpoint was the mean BPI-SF interference score after 12 weeks of double-blind treatment. EOS = end of study; QW = once weekly; sc = subcutaneous.

[0016] DETAILED DESCRIPTION

[0017] INTRODUCTION

[0018] Current FMS treatments, such as analgesics, focus on alleviating the specific symptoms of FMS, particularly pain, without treating the underlying cause of FMS. In contrast, the treatment of the present invention can treat the possible cause of FMS, namely serum IgG autoantibodies. The present invention inhibits the binding of IgG autoantibodies to the FcRn receptor, thereby inhibiting their rescue and accelerating their removal from the serum.

[0019] General Definitions

[0020] 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.

[0021] Generally, 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 a heavy chain sequence element, but the antibody may comprise further elements. In some embodiments of the present invention, the word "comprising" may be replaced with the phrase "consisting of". "Consisting of" is intended to be limiting.

[0022] In some embodiments of the present invention, the term "comprising" may be replaced with the phrase "consisting essentially of". "Consisting essentially of" means that specific further components may be present, namely those that do not significantly affect the basic characteristics of the subject matter.

[0023] For the purposes of the present invention, the term "fragment" refers to a continuous portion of a sequence. For example, a 50 - amino acid fragment of SEQ ID NO:1 refers to 50 consecutive amino acids of SEQ ID NO:1.

[0024] The term "about", when used in the context of describing a reduction in the IgG level of a subject, means that the reduction can be a defined percentage, plus or minus 10%, more specifically plus or minus 5%, or more specifically, plus or minus a single percentage point. For example, a reference to a "about" 70% reduction in the IgG level of a subject can refer to a reduction of 60 - 80%, more specifically 65 - 75%, or more specifically 69 - 71%.

[0025] Unless the context clearly dictates otherwise, the singular forms "a", "an", and "the" include plural referents. Thus, for example, a reference to "an amino acid" includes two or more instances or forms of such amino acid.

[0026] All publications, patents, and patent applications cited herein, whether supra or infra, are hereby incorporated by reference in their entirety.

[0027] Fibromyalgia Syndrome (FMS)

[0028] Fibromyalgia syndrome (FMS), also known as fibromyalgia, is a highly prevalent (2 to 3% of the adult population) and complex syndrome, which is mainly characterized by the presence of chronic widespread pain, but also includes a wide range of other symptoms that have an adverse impact on function and quality of life, such as severe fatigue, cognitive impairment, and sleep disturbances ( et al., 2015). This impairs work ability, resulting in decreased productivity and high healthcare costs (White et al., 2008). The direct and indirect costs associated with FMS are higher in patients with more severe disease (Chandran et al., 2012).

[0029] The symptoms of FMS include pain, aching, burning, stinging, hyperalgesia, allodynia, stiffness, muscle spasms, fatigue, reduced sleep quality, impaired memory, attention deficit, concentration deficit, speech disturbances, headache, migraine, constipation, diarrhea, dizziness, clumsiness, anxiety, and depression.

[0030] In one embodiment, treating FMS with the method according to the present invention includes reducing or eliminating one or more symptoms of FMS.

[0031] As used herein, "treating" and "treatment" refer to any reduction in the severity of FMS, and "preventing" or "prevention" refer to any reduction or delay in the appearance of FMS symptoms. Those of ordinary skill in the art will understand that any degree of protection or improvement of FMS or its related symptoms is beneficial to the subject, such as a human patient. The quality of life of the patient is improved by reducing the severity of the symptoms in the subject to any degree and / or delaying the appearance of the symptoms.

[0032] Thus, in one aspect, the method is carried out as soon as possible after determining that the subject has or is at risk of having FMS, particularly severe FMS.

[0033] In various aspects, an FcRn antagonist, such as an FcRn antibody or an FcRn-binding fragment thereof, is administered via an administration regimen that achieves an improvement in the BPI-SF score, FIQR score, pain NRS score, or fatigue NRS score compared to pre-treatment (baseline), where the improvement is a decrease in the relevant score compared to the baseline. The improvement in the score can be observed, for example, one week, two weeks, three weeks, four weeks, five weeks, six weeks, seven weeks, eight weeks, nine weeks, ten weeks, eleven weeks, or twelve weeks after the initial administration of the antagonist. In one example, an improvement in the score compared to the baseline is observed 10 weeks or 12 weeks or 24 weeks after the initial administration of the FcRn antagonist.

[0034] Alternatively or additionally, an FcRn antagonist, such as an FcRn antibody or an FcRn-binding fragment thereof, is administered via an administration regimen that achieves a reduction in IgG serum levels and / or the level of FMS-specific autoantibodies (such as antibodies that bind to cells in the dorsal root ganglia) compared to pre-treatment (baseline). A reduction in levels can be observed, for example, one week, two weeks, three weeks, four weeks, five weeks, six weeks, seven weeks, eight weeks, nine weeks, ten weeks, twelve weeks, or twenty-four weeks after the initial administration of the antibody or its antigen-binding fragment. In one example, a reduction in serum IgG levels is observed 10 weeks or 12 weeks or 24 weeks after the initial administration of the antibody or its FcRn-binding fragment. The IgG serum levels and / or the level of FMS-specific autoantibodies (such as antibodies that bind to cells in the dorsal root ganglia) can be reduced by at least 50%, at least 55%, at least 60%, at least 65%, or at least 70%, particularly compared to baseline.

[0035] Dose

[0036] The precise effective amount for treatment in human subjects will depend on the severity of the disease state, the overall health of the subject, age, weight, and gender, diet, time and frequency of administration, drug combination, sensitivity to treatment, and tolerance / response. Generally, an effective amount for treatment of an FcRn antagonist, such as an anti-FcRn antibody or a fragment thereof, is from 4 mg / kg to 50 mg / kg (such as from 4 mg / kg to 25 mg / kg, such as about 7 mg / kg, 10 mg / kg, 15 mg / kg, or 20 mg / kg). The composition can conveniently be presented in dosage forms containing a predetermined amount of the active FcRn antagonist of the present disclosure per dose.

[0037] The dosage ranges and regimens of any of the embodiments described herein include, but are not limited to, dosage ranges of 100 mg - 4000 mg doses (such as 280 mg, 420 mg, 560 mg, 840 mg, 1120 mg, or 1400 mg doses). The dose can be administered once every 1 - 10 weeks. In one embodiment, the dose is administered weekly. The dose can be administered by any route of administration, such as by subcutaneous administration or intravenous administration. For example, the dose can be administered by subcutaneous infusion. In one embodiment, a 560 mg dose is administered every 1 - 10 weeks.

[0038] Accordingly, the present invention provides a method for treating or preventing fibromyalgia syndrome (FMS) in a human in need thereof, the method 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.

[0039] In one aspect of the present invention, a dose of 560 mg 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, a dose of 560 mg is administered once a week.

[0040] In one embodiment of the present invention, a dose is administered once a week for a course of one, two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve weeks. More than one course may be administered. There may be an interval between one or more courses. For example, the first weekly dose of a subsequent course may start one, two, three, four, five, or six months after the last dose of a previous weekly course.

[0041] In one embodiment of the present invention, the method comprises administering to a human from 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. In one embodiment of the present invention, the method comprises administering to a human from 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. In one embodiment of the present invention, the method comprises administering to a human from 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.

[0042] In one embodiment of the present invention, the method comprises administering to a human a dose of an anti-FcRn antibody or an antigen-binding fragment thereof once a week for 12 or 24 weeks, wherein each dose is a 560 mg dose. In one embodiment of the present invention, the method comprises administering to a human a dose of an anti-FcRn antibody or an FcRn-binding fragment thereof once a week for at least 12 weeks, wherein each dose is a 560 mg dose. Administration can be subcutaneous.

[0043] 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 about 70%) reduction in the patient's serum IgG level. Alternatively, the dose can be selected to achieve a satisfactory improvement level 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 present 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 times, 1.5 times, 1.8 times, or 2.0 times the original dose; for example, the dose can be increased to 840 mg.

[0044] In one embodiment of the present invention, if the reduction in serum IgG level achieved by the dose is less than 70%, the dose can be increased. For example, the dose can be increased to 1.2 times, 1.5 times, 1.8 times, or 2.0 times the original dose. In one embodiment of the present invention, where the 560 mg dose achieves a reduction in serum IgG level of less than 70%, the dose can be increased to 840 mg.

[0045] In one embodiment of the present invention, if the reduction achieved by the dose is greater than 70%, the dose can be reduced. For example, the dose can be reduced to 0.75 times, 0.5 times, or 0.25 times the original dose. In one embodiment of the present invention, where the 560 mg dose achieves a reduction in IgG level of greater than 70%, the dose can be reduced to 420 mg.

[0046] In one example, the present invention also provides a method of treating or preventing fibromyalgia syndrome (FMS) in a human in need thereof, the method comprising administering to the human at least three doses, preferably at least six doses, of an anti - FcRn antibody or an antigen - binding fragment thereof, 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 optionally comprises a heavy chain and a light chain, the heavy chain comprising the sequence given in SEQ ID NO:1 and the light chain comprising the sequence given in SEQ ID NO:2. Similarly, the dose can be selected based on the patient's body weight.

[0047] In one example, a dose across body weight ranges (equivalent to approximately 7 mg / kg) can be used as follows:

[0048] · Body weight 40 to <49 kg: Dose to be administered is 280 mg

[0049] · Body weight 49 to <69 kg: Dose to be administered is 420 mg

[0050] · Body weight 69 to <89 kg: Dose to be administered is 560 mg

[0051] · Body weight 89 to <109 kg: Dose to be administered is 700 mg

[0052] · Body weight 109 to <129 kg: Dose to be administered is 840 mg

[0053] · Body weight 129 to <149 kg: Dose to be administered is 980 mg

[0054] · Body weight 149 to <169 kg: Dose to be administered is 1120 mg

[0055] · Body weight ≥169 kg: Dose to be administered is 1260 mg

[0056] These doses can be administered subcutaneously, for example, at intervals of once a week, for example, for 12 weeks.

[0057] In another example, a dose across body weight ranges (equivalent to approximately 10 mg / kg) can be used as follows:

[0058] · Body weight 40 to <49 kg: Dose to be administered is 420 mg

[0059] · Body weight 49 to <63 kg: Dose to be administered is 560 mg

[0060] · Body weight 63 to <77 kg: Dose to be administered is 700 mg

[0061] · Body weight 77 to <91 kg: Dose to be administered is 840 mg

[0062] · Body weight 91 to <105 kg: Dose to be administered is 980 mg

[0063] · Body weight 105 to <119 kg: Dose to be administered is 1120 mg

[0064] · Body weight 119 to <133 kg: Dose to be administered is 1260 mg

[0065] · Body weight 133 to <147 kg: Dose to be administered is 1400 mg

[0066] · Body weight 147 to <161 kg: The dose to be administered is 1540 mg

[0067] · Body weight ≥161 kg: The dose to be administered is 1680 mg

[0068] These doses can also be administered subcutaneously, for example, at weekly intervals, for example, for 12 weeks.

[0069] In one example, a dose equal to approximately 7 mg / kg is used. In one example, for a body weight between 40 and 49 kg, the dose is 280 mg. In one example, for a body weight equal to or greater than 49 kg but less than 69 kg, the dose is 420 mg. In one example, for a body weight equal to or greater than 69 kg but less than 89 kg, the dose is 560 mg. In one example, for a body weight equal to or greater than 89 kg but less than 109 kg, the dose is 700 mg. In one example, for a body weight equal to or greater than 109 kg but less than 129 kg, the dose is 840 mg. In one example, for a body weight equal to or greater than 129 kg but less than 149 kg, the dose is 980 mg. In one example, for a body weight equal to or greater than 149 kg but less than 169 kg, the dose is 1120 mg. In one example, for a body weight equal to or greater than 169 kg, the dose is 1260 mg.

[0070] Thus, in one example, the present invention also provides a method for treating or preventing fibromyalgia syndrome (FMS) in a person in need thereof, the method comprising administering to the person at least 3 doses, preferably at least 6 doses, more preferably at least 12 doses of an anti-FcRn antibody or FcRn-binding fragment, wherein for a body weight between 40 and 49 kg, the dose is 280 mg, for a body weight equal to or greater than 49 kg but less than 69 kg, the dose is 420 mg, for a body weight equal to or greater than 69 kg but less than 89 kg, the dose is 560 mg, for a body weight equal to or greater than 89 kg but less than 109 kg, the dose is 700 mg, for a body weight equal to or greater than 109 kg but less than 129 kg, the dose is 840 mg, for a body weight equal to or greater than 129 kg but less than 149 kg, the dose is 980 mg, for a body weight equal to or greater than 149 kg but less than 169 kg, the dose is 1120 mg, and for a body weight equal to or greater than 169 kg, the dose is 1260 mg.

[0071] Alternatively, one of the following doses across body weight ranges can be used:

[0072] · Body weight ≥35 to <70 kg: The dose to be administered is 420 mg;

[0073] · Body weight ≥ 70 kg: The dose to be administered is 560 mg; or

[0074] · Body weight ≥ 35 to < 70 kg: The dose to be administered is 420 mg

[0075] · Body weight ≥ 70 to < 100 kg: The dose to be administered is 560 mg

[0076] · Body weight ≥ 100 kg: The dose to be administered is 840 mg; or

[0077] · Body weight ≥ 35 to < 50 kg: The dose to be administered is 420 mg

[0078] · Body weight ≥ 50 to < 100 kg: The dose to be administered is 560 mg

[0079] · Body weight ≥ 100 kg: The dose to be administered is 840 mg; or

[0080] · Body weight < 50 kg: The dose to be administered is 420 mg

[0081] · Body weight 50 kg to < 100 kg: The dose to be administered is 560 mg

[0082] · Body weight 100 kg: The dose to be administered is 840 mg; or

[0083] · Body weight ≥ 35 to < 50 kg: The dose to be administered is 280 mg

[0084] · Body weight ≥ 50 to < 70 kg: The dose to be administered is 420 mg

[0085] · Body weight ≥ 70 to < 100 kg: The dose to be administered is 560 mg

[0086] · Body weight ≥ 100 kg: The dose to be administered is 840 mg

[0087] · Body weight ≥ 35 to < 50 kg: The dose to be administered is 420 mg

[0088] · Body weight ≥ 50 to < 70 kg: The dose to be administered is 560 mg

[0089] · Body weight ≥ 70 to < 100 kg: The dose to be administered is 840 mg

[0090] · Body weight ≥ 100 kg: The dose to be administered is 1120 mg

[0091] In one embodiment, a lower initial dose is given to the patient before a higher dose is subsequently administered. For example, the following doses across body weight ranges may be used:

[0092] · Body weight ≥ 35 to < 70 kg: The initial dose to be administered is 280 mg, and the subsequent dose is 420 mg;

[0093] · Body weight ≥ 70 kg: The initial dose to be administered is 420 mg; the subsequent dose is 560 mg.

[0094] In one embodiment, the patient is given a higher initial dose before being subsequently given a lower dose. For example, the following doses across weight ranges can be used:

[0095] · Body weight ≥ 35 to < 70 kg: The initial dose to be administered is 420 mg, and the subsequent dose is 280 mg;

[0096] · Body weight ≥ 70 kg: The initial dose to be administered is 560 mg; the subsequent dose is 420 mg.

[0097] Severe FMS

[0098] Pain throughout the body is generally considered the most debilitating symptom experienced by patients with fibromyalgia (Mease et al., 2011). Scales for measuring and monitoring pain levels vary and include the Visual Analogue Scale for pain (VAS), the McGill Pain Questionnaire, the Revised Fibromyalgia Impact Questionnaire pain item (FIQR), various Numerical Rating Scales (NRS) (usually recorded in a diary), and the Brief Pain Inventory-Short Form (BPI-SF).

[0099] These scales can be used to designate the patient population with severe FMS. Specifically, if an individual has an average daily pain score on the pain NRS of greater than or equal to 5 or 6 and less than 10, a BPI-SF interference score of greater than or equal to 6, a FIQR score of greater than or equal to 64, and / or a fatigue NRS score of greater than or equal to 5, then the individual can be classified as having severe FMS.

[0100] In one embodiment of the present invention, the FMS is severe FMS. In another embodiment, the pain intensity of the individual on the Pain NRS is greater than or equal to 5 or 6 and less than 10. In another embodiment, the individual has a Brief Pain Inventory - Short Form (BPI - SF) interference score of greater than or equal to 6 (up to 10). In another embodiment, the individual has a Revised Fibromyalgia Impact Questionnaire (FIQR) score of greater than or equal to 64 (up to 100). In another embodiment, the individual has a Fatigue Numerical Rating Scale (NRS) score of greater than or equal to 5 (up to 10). In another embodiment, the pain intensity of the individual on the Pain Numerical Rating Scale (NRS) is greater than or equal to 5 or 6 and less than 10, the Brief Pain Inventory - Short Form interference score is greater than or equal to 6 (up to 10), the Revised Fibromyalgia Impact Questionnaire (FIQR) score is greater than or equal to 64 (up to 100), and / or the Fatigue Numerical Rating Scale (NRS) score is greater than or equal to 5 (up to 10).

[0101] In one embodiment of the present invention, the method reduces the average interference score of the Brief Pain Inventory - Short Form (BPI - SF) of the individual. The method can reduce the BPI - SF score of the individual 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.

[0102] In another embodiment of the present invention, the method reduces the Revised Fibromyalgia Impact Questionnaire (FIQR) score of the individual. The method can reduce the FIQR score of the individual 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.

[0103] In another embodiment of the present invention, the method reduces the average daily pain score of the individual. The average daily pain score can be measured using the Pain NRS. The method can reduce the average daily pain score of the individual 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.

[0104] In another embodiment of the present invention, the method reduces the fatigue score of the individual. The fatigue score can be measured using the Fatigue NRS. The method can reduce the fatigue score of the individual 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.

[0105] Mild to moderate FMS

[0106] 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, such as where the individual has a pain intensity of less than 5 (e.g., 2 to 4) or less than 6 (e.g., 2 to 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 to 5); a Fibromyalgia Impact Questionnaire (FIQR) score of less than 64 (e.g., 10 to 63, 20 to 63, 30 to 63, 40 to 63, or 50 to 63); and / or a Fatigue Numerical Rating Scale (Fatigue NRS) score of less than 5 (e.g., 2 to 4).

[0107] Brief Pain Interference - Short Form (BPI - SF)

[0108] The Brief Pain Inventory - Short Form (BPI - SF) is a 9 - item self - administered questionnaire that is used to assess the severity of a patient's pain and the impact of this pain on the patient's daily functioning. The patient is asked to rate their worst pain, least pain, average pain, and current pain intensity, list current treatments and their perceived effectiveness, and rate on a 10 - point scale the degree to which pain interferes with general activities, mood, walking ability, normal work, relationships with others, sleep, and enjoyment of life.

[0109] The BPI - SF interference score measures the impact of pain on seven domains of daily life experience and is suitable for measuring the effectiveness of treatments that may improve the patient's pain experience and the functional interference experienced by the patient.

[0110] The 7 BPI - SF interference items include: general activities, mood, walking ability, normal work (including housework), relationships with others, sleep, and enjoyment of life. Each item is rated on a scale from 0 (no interference) to 10 (complete interference), with a recall period of 24 hours. The arithmetic mean of the 7 interference items can be used as a measure of pain interference.

[0111] Pain NRS

[0112] The Numerical Rating Scale is one of the most widely used pain scales in medicine. The NRS consists of a numerical version of the Visual Analogue Scale. The most common form of the NRS is a horizontal line with an 11 - point numerical range. It is marked from zero to ten, where zero is an example of a person with no pain and ten is the most severe possible pain. This type of scale can be administered orally. It can also be administered by physically completing it on paper.

[0113] Revised Fibromyalgia Impact Questionnaire (FIQR)

[0114] The Revised Fibromyalgia Impact Questionnaire (FIQR) is a self-report questionnaire that measures the functional ability and disease severity of patients with fibromyalgia. The FIQR is one of the most commonly used functional scoring tools in clinical practice and clinical trials to evaluate the treatment effectiveness of patients with fibromyalgia.

[0115] The FIQR consists of 21 individual questions in three related domains: function, overall impact, and symptoms. All questions refer to experiences in the past 7 days and are scored using an 11-point numeric rating scale (0 to 10, where 10 represents the most severe possible condition). The function domain contains nine questions about activities of daily living and accounts for 30% of the total FIQR score weight. The overall 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 contains 10 questions and assesses symptoms commonly reported by patients with fibromyalgia, such as tenderness, hyperalgesia, environmental sensitivity, balance disorders, and memory problems; it accounts for 50% of the total FIQR score. The total FIQR score (out of 100) is the sum of the scores of the three modified domain scores, namely: the sum of the function domain scores (range 0 to 90, divided by 3), the overall impact domain score (range 0 to 20), and the symptom domain score (range 0 to 100, divided by 2).

[0116] Fatigue NRS

[0117] The Fatigue NRS is a single-item 11-point level scale for patient management, anchored at 0 and 10, where 0 represents "no fatigue" and 10 represents "the worst you can imagine". Patients are asked to "please choose the number that describes your most severe fatigue level in the past 24 hours to rate your fatigue (tiredness, exhaustion)".

[0118] FcRn

[0119] FcRn is a non-covalent complex of the α-chain of the membrane protein FcRn and β2-microglobulin (β2M). In adult mammals, FcRn plays a key role in maintaining serum antibody levels by acting as a receptor that binds and rescues IgG isotype antibodies. IgG molecules are endocytosed by endothelial cells and, if they bind to FcRn, are recycled out into, for example, the circulation. In contrast, IgG molecules that do not bind to FcRn enter the cell and are targeted to the lysosomal pathway, where they are degraded. Variant 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).

[0120] FcRn antagonist

[0121] An FcRn antagonist can be a peptide, such as SYN1436.

[0122] The FcRn antagonist can be an Fc fragment, such as efgartigimod.

[0123] The FcRn antagonist can be an FcRn antibody or an FcRn-binding fragment thereof, such as rozelizumab, nipocalimab, orilanolimab, CSL730 / M230, ABY-039, or RVT-1401 (HL161).

[0124] Assays are described below that are suitable for assessing the ability of a test molecule, such as an FcRn antagonist, to block the activity of human FcRn and, in particular, the ability of human FcRn to recycle IgG.

[0125] Provided herein is an assay suitable for assessing the ability of a test molecule (such as an FcRn antagonist, such as an anti-FcRn antibody) to block the activity of human FcRn and, in particular, the ability of human FcRn to recycle IgG, wherein the assay comprises the steps of:

[0126] a) coating a surface with non-human mammalian cells recombinantly expressing the α-chain of human FcRn and human β2-microglobulin (β2M),

[0127] b) contacting the cells with the test molecule and IgG to be 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 IgG to bind to FcRn, optionally adding the test molecule prior to the IgG to be recycled, and incubating for a period of time sufficient to allow the test molecule to bind to FcRn,

[0128] c) washing with a slightly acidic buffer, and

[0129] d) detecting the amount of IgG internalized and / or recycled by the cells.

[0130] Provided herein is an assay suitable for assessing the ability of a test molecule (such as an FcRn antagonist, such as an anti-FcRn antibody) to block the activity of human FcRn and, in particular, the ability of human FcRn to recycle IgG, wherein the method comprises the steps of:

[0131] a) coating a surface with non-human mammalian cells recombinantly expressing the α-chain of human FcRn and human β2-microglobulin (β2M),

[0132] b) contacting the cells with a test antibody molecule and IgG to be recycled by the cells under mildly acidic conditions (e.g., about pH 5.9) for a period of time sufficient to allow both the test antibody molecule and IgG to bind to FcRn, optionally adding the test antibody molecule prior to the IgG to be recycled, and incubating for a period of time sufficient to allow the test antibody molecule to bind to FcRn,

[0133] c) washing with a slightly acidic buffer to remove unbound IgG and test antibody molecules, and

[0134] d) detecting the amount of IgG recycled by the cells.

[0135] Provided herein is an assay suitable for assessing the ability of a test molecule (e.g., an FcRn antagonist, such as an anti-FcRn antibody) to block the activity of human FcRn and in particular the ability of human FcRn to recycle IgG, wherein the method comprises the following steps:

[0136] a) coating non-human mammalian cells recombinantly expressing the α-chain of human FcRn and human β2-microglobulin (β2M) onto a surface,

[0137] b) contacting the cells with a test antibody molecule and IgG to be recycled by the cells under mildly acidic conditions (e.g., about pH 5.9) for a period of time sufficient to allow both the test antibody molecule and IgG to bind to FcRn, optionally adding the test antibody molecule prior to the IgG to be recycled, and incubating for a period of time sufficient to allow the test antibody molecule to bind to FcRn,

[0138] c) washing with a slightly acidic buffer to remove unbound IgG and test antibody molecules,

[0139] d) incubating the cells in a neutral buffer (e.g., about pH 7.2),

[0140] e) detecting the amount of IgG recycled by the cells by determining the amount of IgG released into the supernatant.

[0141] Suitable cells include Madin-Darby canine kidney (MDCK) II cells. Claypool et al., 2002 previously described the transfection of MDCK II cells with the alpha chain of human FcRn and human beta-2 microglobulin (β2M). The paper also described the recycling of IgG by these transfected cells. The medium used to support the cells during the test includes complete medium, which contains MEM (Gibco #21090-022), 1x non-essential amino acids (Gibco 11140-035), 1x sodium pyruvate (Gibco #11360-039), and L-glutamine (Gibco #25030-024). The acidic wash 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 (Sigma #A9647) can also be added. The neutral wash can be prepared by taking HBSS+ (PAA #H15-008) and adding 10M Hepes until a pH of 7.2 ± 0.5 is reached. Approximately 1% BSA (Sigma #A9647) can also be added. Washing the cells with the acidic buffer removes unbound test antibody and unbound IgG and allows further analysis to be performed. The acidic conditions used in step (b) promote the binding of IgG to FcRn and its internalization and recycling.

[0142] The amount of test FcRn antagonist (e.g., antibody or fragment) and IgG on the cell surface can be determined by washing the cells with the neutral wash and analyzing the supernatant / wash for the amount of test antibody or IgG. Importantly, no lysis buffer is used.

[0143] To determine the amount of IgG internalized by the cells, the FcRn antagonist (e.g., antibody) can first be removed from the cell surface with the neutral wash, then the cells can be lysed with the lysis buffer, and then the internal content can be analyzed. To determine the amount of IgG recycled by the cells, the cells are incubated for a suitable period of time under neutral conditions and the IgG content of the surrounding buffer is analyzed. If the surface and internal antibody content of the cells is required, the cells can be washed with the acidic wash to maintain the presence of the antibody on the cell surface, then the cells are lysed and the combined material is analyzed.

[0144] When it is desired to measure the internalization and recycling of IgG, run the samples in duplicate and perform the tests for internalization and recycling separately.

[0145] As described in the manufacturer's guidelines, a suitable lysis buffer for every 10 ml includes 150 mM NaCl, 20 mM Tris, pH 7.5, 1 mM EDTA, 1 mM EGTA, 1% Triton-X 100, and protease inhibitor / phosphatase inhibitor is added.

[0146] Typically, IgG to be recycled is labeled. In one example, biotinylated human IgG can be used. Then, for example, streptavidin sulfo-tag detection antibody (such as MSD #r32ad-5) of 25 mL of 0.2 μg / mL MSD blocking buffer can be used to detect IgG. The blocking buffer can contain 500 mM Tris, pH 7.5, 1.5 M NaCl, 0.2% Tween-20, and 1.5% BSA.

[0147] Alternatively, IgG can be pre-labeled with a fluorophore or similar label.

[0148] In one embodiment, a suitable surface is a plastic plate or well (such as a 96-well plate or the like), a glass slide, or a membrane. In one example, cells are coated onto the surface at a density that results in the formation of a monolayer.

[0149] In one embodiment, the assay described herein is not a measurement of transcytosis of an antibody across a membrane with a pH gradient from top to bottom, such as acidic conditions on one side of the membrane and neutral conditions on the bottom side of the membrane.

[0150] In one example, for instance, the test antibody or fragment and IgG are incubated with the cells in step (b) for about 1 hour at ambient temperature under acidic conditions to allow binding.

[0151] In one example, for instance, the test antibody or fragment is incubated with the cells in step (b) for about 1 hour at ambient temperature under acidic conditions to allow binding, and then the IgG to be recycled is added. Subsequently, for example, the IgG to be recycled by the cells is incubated with the cells in step (b) for about 1 hour at ambient temperature under acidic conditions to allow binding.

[0152] Neutral conditions facilitate the release of IgG into the supernatant.

[0153] In the IgG recycling assay as described above, the FcRn antagonist can have an EC 50 value of less than 100 nM, less than 50 nM, less than 25 nM, or less than 10 nM. For example, the FcRn antagonist can have an EC 50 value of 1 to 100 nM, 1 to 50 nM, 1 to 25 nM, or 1 to 10 nM.

[0154] Efgartigimod

[0155] Efgartigimod has been approved for generalized myasthenia gravis (MG). Efgartigimod is a monoclonal IgG1 Fc fragment that has been mutated at 5 residues to increase its affinity for FcRn at physiological pH and acidic pH. In a phase 2 randomized, placebo-controlled study in 24 MG patients, a maximum mean reduction of 70.7% in serum IgG from baseline was observed 1 week after the last infusion following 4 once-weekly (QW) intravenous (IV) administrations of 10 mg / kg efgartigimod (Peter et al., 2020).

[0156] Nicalizumab, onolizumab, and RVT-1401

[0157] Nicalizumab (M281), a high-affinity fully human monoclonal IgG1 anti-FcRn antibody designed to have no Fc effector potential (does not bind C1q and does not bind activated FcγR), and onolizumab (SYNT001), a humanized IgG4k mAb, are two other FcRn inhibitors with published first-in-human (FIH) data. Nicalizumab is currently in phase 2 trials for autoimmune hemolytic anemia, hemolytic disease of the fetus and newborn, and MG.

[0158] 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 has been completed in healthy volunteers. The SAD part of the study included weight-based and fixed intravenous and subcutaneous doses (fixed doses of 100 - 765 mg), while the MAD cohorts included weekly subcutaneous doses of 340 mg or 680 mg RVT-1401 or placebo for 4 weeks. IgG levels decreased by 47% after a single dose of 765 mg, with the trough reached 8 - 10 days after dosing. Weekly subcutaneous dosing with 680 mg reduced total IgG levels by 78%. An IgG reduction of ≥35% was maintained for more than 1 month after the last dose. A reversible dose-dependent decrease in albumin was observed (31% with 680 mg subcutaneous dosing) and was asymptomatic. Single and multiple doses of RVT-1401 were well tolerated, and no subject prematurely terminated the study due to an AE. The most common adverse events (AEs) in the phase 1 study were injection site erythema and swelling. None of the subjects in the MAD cohorts developed antidrug antibodies (Gable et al., 2020).

[0159] FcRn antagonist peptides

[0160] The FcRn antagonist for use in the present invention can be a peptide. Mezo et al., 2008 described a family of related peptides, all of which contain nine residues within a disulfide bond. The peptide may comprise a consensus sequence of Gly-His-Phe-Gly-Gly-X-Tyr, where X is preferably a hydrophobic amino acid. This consensus sequence has no homology with the Fc domain of IgG, and the cysteine disulfide bond can be in different positions relative to the consensus sequence.

[0161] SYN1436 is a 3.1 kDa peptide that binds to human FcRn (hFcRn) and inhibits the hFcRn-human IgG (hIgG) interaction. The core peptide sequence was discovered by screening a phage display peptide library and has 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.

[0162] IgG

[0163] 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 the IgG level of a subject. Administration of an FcRn antagonist can result in a ~70% reduction in the IgG level of a subject.

[0164] Autoantibodies responsible for FMS can bind to satellite glial cells (SGCs) in the dorsal root ganglia (DRGs). These anti-SGC IgG may contribute to FMS (Goebel et al., 2021; Krock et al., 2022).

[0165] In one embodiment of the present invention, patients with FMS have elevated serum levels of anti-SGC IgG. Patients can be selected for treatment according to the present invention based on the elevated serum levels of anti-SGC IgG. Patients with elevated serum levels of anti-SGC IgG generally have severe FMS. Suitable assays for determining anti-SGC IgG levels are described in Krock et al. and below.

[0166] Human DRGs can be harvested. DRG tissues can be fixed on slides, for example, with 4% PFA, blocked, for example, with PBS containing 3% normal donkey serum and 0.3% Triton X-100, and then incubated with 100 μg / ml unconjugated anti-human IgG Fab fragments (H+L, Jackson Immunoresearch). The slides can be incubated with fibromyalgia (FM) or healthy control (HC) serum diluted 1:500 in PBS containing 1% normal donkey serum and 0.1% Triton X-100. The slides can then be incubated with anti-human IgG antibody, incubated with antibodies against glial fibrillary acidic protein (GFAP) and neurofilament 200 (NF200), then incubated with appropriate secondary antibodies, counterstained with DAPI, and coverslipped with Prolong Gold mounting medium. Individual cells can be identified using the deep learning neural network Cellpose. Cellpose can be run using Python v3.7.9, and the region of interest for each cell can be imported into FIJI. The binding of human IgG to SGCs and neurons can then be evaluated in FIJI, and the percentage of cells with binding and the mean integrated density of IgG binding can be determined. Human DRG images can be analyzed using the drgquant pipeline. The experimenter can be blinded to the type of serum with which the cells or tissues are incubated.

[0167] Serum from patients with severe fibromyalgia can produce a higher percentage of IgG-bound SGCs compared to serum from healthy control patients. For example, serum from patients with severe fibromyalgia can result in at least 40%, at least 50%, at least 60%, or at least 65% of IgG-bound SGCs. For example, serum from patients with severe fibromyalgia can result in 55 - 80% or 60 - 75% of IgG-bound SGCs. For example, serum from healthy control patients can result in less than 40% of IgG-bound SGCs. For example, serum from healthy control patients can result in 20 to less than 55% of IgG-bound SGCs. For example, serum from patients with severe fibromyalgia can result in 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-bound SGCs compared to serum from healthy control patients. For example, serum from patients with severe fibromyalgia can result in 1.2 to 5-fold, 1.5 to 5-fold, 2 to 5-fold, or 3 to 5-fold higher percentage of IgG-bound SGCs compared to serum from healthy control patients.

[0168] Serum from patients with severe fibromyalgia can cause an increase in SGC binding strength compared to serum from healthy control patients. For example, serum from patients with severe fibromyalgia can give 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 can give a binding strength of 3 to 6. For example, serum from healthy control patients can give 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 can give a binding strength of 0 to 2.5. For example, serum from patients with severe fibromyalgia can give a binding strength that is at least 1.2 times, at least 1.5 times, at least 2 times, at least 3 times, at least 4 times, or at least 5 times higher than serum from healthy control patients. For example, serum from patients with severe fibromyalgia can give a binding strength that is 1.2 to 10 times, 1.5 to 10 times, 2 to 10 times, 3 to 10 times, 4 to 10 times, or 5 to 10 times higher than serum from healthy control patients.

[0169] In one aspect of the invention, administration of an FcRn antagonist results in a decrease in anti-SGC IgG levels in a subject of 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 decrease in anti-SGC IgG levels in a subject from 60% to 80%. Administration of an FcRn antagonist can result in a decrease in anti-SGC IgG levels in a subject of about 70%.

[0170] Dorsal root ganglion (DRG)

[0171] In humans, 31 pairs of right and left spinal nerves are formed by afferent sensory dorsal axons (dorsal roots) and motor ventral efferent axons (ventral roots). When the dorsal root emerges from the intervertebral neural foramen, it forms the dorsal root ganglion (DRG). The DRG is a group of cell bodies responsible for transmitting sensory information from receptors such as thermoreceptors, nociceptors, proprioceptors, and chemoreceptors to the CNS for response.

[0172] The DRG contains most of the sensory neurons of the body. These neurons transmit sensory nerve information from the periphery to the central nervous system (brain and spinal cord). Until recently, it was thought that DRG cell bodies only served as storage "helpers" in peripheral processes such as nociception. However, recent studies have shown that these cell bodies are not passive, but active participants in the signaling process; they sense specific molecules and produce the molecules required to regulate the process.

[0173] DRGs have important clinical applications, especially in their association with neuropathic pain. DRG neurons emerge from the dorsal roots of the spinal nerves and carry sensory information from various receptors, including those for pain and temperature, to the central nervous system for response.

[0174] In addition to neurons, DRGs also contain SGCs, which form thin cellular sheaths that cover the neurons. SGCs perform many functions associated with their close interaction with neurons, including regulating the microenvironment surrounding the neurons. SGCs express various receptors that regulate the levels of neurotransmitters in the neuronal microenvironment and thus affect neuronal excitability. The binding of IgG to SGCs may therefore affect nociception in DRGs.

[0175] Until recently, the dorsal root ganglion has been considered a passive organ that metabolically supports the functions and pathways between the peripheral nervous system (PNS) and the central nervous system (CNS). However, new research has shown that DRGs are active participants in peripheral processes, including the development of paroxysmal atrial fibrillation (PAF) injury, inflammation, and neuropathic pain. A correct understanding of the importance and functions of DRGs can help improve the diagnosis and treatment of neuropathic pain syndromes, such as fibromyalgia syndrome (FMS). (Ahimsadasan et al., Neuroanatomy, Dorsal Root Ganglion)

[0176] Antibody

[0177] As used herein, the term "antibody" generally refers to intact (whole) antibodies, i.e., elements containing two heavy chains and two light chains. Antibodies can contain further additional binding domains, such as the molecular DVD-Ig disclosed in WO 2007 / 024715, or the so-called (FabFv)2Fc described in WO2011 / 030107. Thus, antibodies as used herein include bivalent, trivalent, or tetravalent full-length antibodies.

[0178] Binding fragments of antibodies 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 (such as VH or VL or VHH), scFv, bivalent, trivalent or tetravalent antibodies, bis-scFv, bispecific antibodies, trisomes, trispecific antibodies, tetraspecific antibodies and epitope-binding fragments of any of the foregoing (see, e.g., Holliger and Hudson, 2005; Adair and Lawson, 2005). Methods for generating and manufacturing these antibody fragments are well known in the art (see, e.g., Verma et al., 1998). The Fab-Fv format was first disclosed in WO2009 / 040562, and its disulfide-stabilized version Fab-dsFv was first disclosed in WO2010 / 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 can contain multiple specificities such as bispecificity, or can be monovalent (see, e.g., WO 92 / 22583 and WO05 / 113605). One such example of the latter is the Tri-Fab (or TFM) described in WO92 / 22583.

[0179] A typical Fab' molecule comprises a heavy and a light chain pair, wherein the heavy chain comprises the variable region VH, the constant domain CH1 and a native or modified hinge region, while the light chain comprises the variable region VL and the constant domain CL.

[0180] In one embodiment, dimers of Fab' according to the present disclosure are provided to produce F(ab')2, for example dimerization can occur through the hinge.

[0181] In one embodiment, the antibody or its binding fragment comprises a binding domain. The binding domain generally comprises 6 CDRs, three from the heavy chain and three from the light chain. In one embodiment, the CDRs are located in frameworks and together form the variable region. Thus, in one embodiment, the antibody or binding fragment comprises a binding domain that specifically binds to an antigen, the binding domain comprising a light chain variable region and a heavy chain variable region.

[0182] It should be 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 (such as variable domains) provided by the present disclosure without significantly altering the ability of the antibody to bind FcRn. A person skilled in the art can readily test the effect of any amino acid substitution, addition and / or deletion, for example by using the methods described herein, particularly the methods in the examples, to determine FcRn.

[0183] One or more (e.g., 1, 2, 3, or 4) amino acid substitutions, additions, and / or deletions can be made to the framework regions employed in the antibodies or fragments provided by the present disclosure, and wherein the binding affinity to FcRn is maintained or increased.

[0184] Residues in the variable domains of antibodies are routinely numbered according to the system designed by Kabat et al. This system is described in Kabat et al., 1987, Sequences of Proteins of Immunological Interest, US Department of Health and Human Services, NIH, USA (hereinafter referred to as "Kabat et al. (see above)"). Unless otherwise indicated, this numbering system is used throughout this specification.

[0185] Kabat residue designations do not always directly correspond 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 or insertion of structural components of the underlying variable domain structure (whether framework or complementarity determining region (CDR)). The correct Kabat numbering of residues of a given antibody can be determined by aligning homologous residues in the antibody sequence with the "standard" Kabat numbering sequence.

[0186] According to the Kabat numbering system, 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). However, according to Chothia, 1987, the loop equivalent to CDR-H1 extends from residue 26 to residue 32. Thus, unless otherwise indicated, "CDR-H1" as used herein refers to residues 26 to 35, as described by the combination of the Kabat numbering system and the topological loop definition of Chothia.

[0187] According to the Kabat numbering system, 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).

[0188] The antibodies and fragments of the present disclosure block FcRn and thereby can prevent it from functioning in the recycling of IgG. As used herein, blocking refers to physical blocking, such as masking the receptor, but will also include situations where binding of the antibody or fragment to the epitope causes, for example, a conformational change such that the native ligand no longer binds to the receptor. The antibody molecules of the present disclosure bind to FcRn and thereby reduce or prevent (e.g., inhibit) the binding of FcRn to the constant region of IgG.

[0189] In one embodiment, the antibody or fragment thereof binds to FcRn competitively relative to IgG. In one instance, the antibody or binding fragment thereof functions as a competitive inhibitor of the binding of human FcRn to human IgG. In one instance, the antibody or binding fragment thereof binds to the IgG-binding site on FcRn. In one instance, the antibody or binding fragment thereof does not bind β2M.

[0190] Antibodies for use in the present disclosure can be obtained using any suitable method known in the art. FcRn polypeptides / proteins (including fusion proteins), cells that express the polypeptide (recombinantly or natively) (e.g., activated T cells) can be used to generate antibodies that specifically recognize FcRn. The polypeptide can be a "mature" polypeptide or a biologically active fragment or derivative thereof. The human protein is registered in Swiss-Prot under the accession number P55899. The extracellular domain of the alpha chain of human FcRn is provided in SEQ ID NO:21. The sequence of β2M is provided in SEQ ID NO:22.

[0191] In one embodiment, as described by Ober et al., 2001, the antigen is a mutant form of FcRn engineered to be presented on the cell surface such that there is little or no dynamic processing of FcRn being internalized within the cell, e.g., this can be achieved by generating a mutation in the cytoplasmic tail of the alpha chain of FcRn where di-leucine is mutated to di-alanine.

[0192] Polypeptides for immunizing a host can be prepared from genetically engineered host cells comprising an expression system by methods well known in the art, or they can be recovered from natural biological sources. In this application, the term "polypeptide" includes peptides, polypeptides, and proteins. Unless otherwise specified, these terms are used interchangeably. In some cases, the FcRn polypeptide can be part of a larger protein, such as a fusion protein, e.g., a fusion protein fused to an affinity tag or the like.

[0193] Antibodies generated against FcRn polypeptides can be obtained by administering the polypeptide to an animal, preferably a non-human animal, in cases where immunization of the animal is desired, using well-known and conventional protocols (see, e.g., Handbook of Experimental Immunology, D.M. Weir (ed.), Volume 4, Blackwell Scientific Publishers, Oxford, England, 1986). Many warm-blooded animals, such as rabbits, mice, rats, sheep, cows, camels, or pigs can be immunized. However, mice, rabbits, pigs, and rats are generally the most suitable.

[0194] Monoclonal antibodies can be prepared by any method known in the art, such as hybridoma technology (Kohler & Milstein, 1975), trihybridoma technology, human B-cell hybridoma technology (Kozbor et al., 1983), and EBV-hybridoma technology (Cole et al., 1985).

[0195] Antibodies for use in the present invention can also be generated using the single lymphocyte antibody method by cloning and expressing immunoglobulin variable region cDNAs derived from a single lymphocyte selected for production of a specific antibody, for example, by the methods described in Babcock, J. et al., 1996; WO92 / 02551; WO2004 / 051268, and International Patent Application No. WO2004 / 106377.

[0196] Assays can be used to screen for antibodies to measure binding to human FcRn and / or to measure the ability to block IgG binding to the receptor. An example of a binding assay is ELISA, particularly using a fusion protein of human FcRn and human Fc that is immobilized on a plate and detecting anti-FcRn antibodies that bind to the fusion protein using a secondary antibody. Examples of suitable antagonists and blocking assays are described in the examples herein.

[0197] Humanized antibodies, which include CDR-grafted antibodies, are antibody molecules having one or more complementarity determining regions (CDRs) from a non-human species and framework regions from human immunoglobulin molecules (see, for example, US 5,585,089; WO91 / 09967). It should be understood that it may only be necessary to transfer the specificity-determining residues of the CDRs rather than the entire CDRs (see, for example, Kashmiri et al., 2005). Humanized antibodies can optionally further comprise one or more framework residues derived from the non-human species from which the CDRs are derived. The latter are generally referred to as donor residues.

[0198] As used herein, specificity refers to an antibody that only recognizes the antigen it is specific for, or an antibody that has a significantly higher binding affinity when binding to its specific antigen compared to binding to antigens it is not specific for, for example, at least 5, 6, 7, 8, 9, 10 times higher binding affinity. As described below, binding affinity can be measured by techniques such as BIAcore. In one example, the antibodies of the present disclosure do not bind β2-microglobulin (β2M). In one example, the antibodies of the present disclosure bind cynomolgus monkey FcRn. In one example, the antibodies of the present disclosure do not bind rat or mouse FcRn.

[0199] 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 chain contains 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 murine monoclonal antibody) transplanted into the variable region framework of a recipient antibody (e.g., a human antibody). See Vaughan et al., 1998 for a review. In one embodiment, rather than transferring the entire CDR, one or more specificity-determining residues in any of the CDRs described above are transferred to the human antibody framework (see, e.g., Kashmiri et al., 2005). In one embodiment, only one or more specificity-determining residues in the CDRs described above are transferred to the human antibody framework. In another embodiment, only the specificity-determining residues in each of the CDRs described above are transferred to the human antibody framework.

[0200] When transplanting CDRs or specificity-determining residues, any suitable recipient variable region framework sequence (including murine, primate, and human framework regions) can be used depending on the class / type of the donor antibody from which the CDRs were derived.

[0201] Suitably, the humanized antibodies according to the present disclosure have variable domains comprising a human receptor framework region and one or more CDRs specifically provided herein. Thus, in one embodiment, there is provided a blocking humanized antibody that binds human FcRn, wherein the variable domain comprises a human receptor framework region and non-human donor CDRs.

[0202] 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., see above). 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 sequences can be obtained at: http: / / vbase.mrc- cpe.cam.ac.uk / Obtained.

[0203] In the humanized antibodies of the present disclosure, the recipient heavy and light chains do not necessarily need to be derived from the same antibody and, if desired, can contain composite chains having framework regions derived from different chains.

[0204] One such suitable framework region of the heavy chain of the humanized antibody of the present disclosure is derived from the human subgroup VH3 sequence 1-3 3-07 and JH4 (together with JH4) (SEQ ID NO:3).

[0205] Thus, in one instance, a humanized antibody is provided that comprises the sequence of CDRH1 given in SEQ ID NO:4, the sequence of CDR H2 given in SEQ ID NO:5, and the sequence of CDR H3 given in SEQ ID NO:6, wherein the heavy chain framework region is derived from human subgroup VH3 sequence 1-3 3-07 and JH4.

[0206] The sequence of human JH4 is as follows: (YFDY)WGQGTLVTVS (Seq ID No:7). The YFDY motif is part of CDR-H3 and not part of framework 4 (Ravetch, JV. et al., 1981, Cell, 27, 583-591).

[0207] In one instance, the heavy chain variable domain of the antibody comprises the sequence given in SEQ ID NO:1.

[0208] A suitable framework region of the light chain of the humanized antibody of the present disclosure is derived from the human germline subgroup VK1 sequence 2-1-(1)A30 and JK2 (SEQ ID NO:8).

[0209] Thus, in one instance, a humanized antibody is provided that comprises the sequence of CDRL1 given in SEQ ID NO:9, the sequence of CDR L2 given in SEQ ID NO:10, and the sequence of CDR L3 given in SEQ ID NO:11, wherein the light chain framework region is derived from human subgroup VK1 sequence 2-1-(1)A30 and JK2.

[0210] 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).

[0211] In one instance, the light chain variable domain of the antibody comprises the sequence given in SEQ ID NO:2.

[0212] In the humanized antibodies of the present disclosure, the framework regions need not have exactly the same sequence as the receptor antibody. For example, uncommon residues can be changed to residues that occur more frequently for that receptor chain class or type. Alternatively, selected residues in the receptor framework region can be changed such that they correspond to the residues found at the same positions in the donor antibody (see Reichmann et al., 1998). Such changes should be kept to a minimum required to restore the affinity of the donor antibody. A protocol for selecting residues in the receptor framework region that may need to be changed is set forth in WO91 / 09967.

[0213] Thus, in one embodiment, one, two, three, four, or five residues in the framework are replaced with alternative amino acid residues. Thus, in one example, a humanized antibody is provided, wherein the residues at positions 3, 24, 76, 93, and 94 (Kabat numbering) of at least the variable domain of the heavy chain are donor residues, see for example the sequence given in SEQ ID NO:1.

[0214] In one embodiment, residue 3 of the heavy chain variable domain is replaced with an alternative amino acid (such as glutamine).

[0215] In one embodiment, residue 24 of the heavy chain variable domain is replaced with an alternative amino acid (such as alanine).

[0216] In one embodiment, residue 76 of the heavy chain variable domain is replaced with an alternative amino acid (such as asparagine).

[0217] In one embodiment, residue 93 of the heavy chain is replaced with an alternative amino acid (such as alanine).

[0218] In one embodiment, residue 94 of the heavy chain is replaced with an alternative amino acid (such as arginine).

[0219] In one embodiment, in the 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.

[0220] Thus, in one example, a humanized antibody is provided, wherein the residues at positions 36, 37, and 58 (Kabat numbering) of at least the variable domain of the light chain are donor residues, see for example the sequence given in SEQ ID NO:2.

[0221] In one embodiment, residue 36 of the light chain variable domain is replaced with an alternative amino acid (such as tyrosine).

[0222] In one embodiment, residue 37 of the light chain variable domain is replaced with an alternative amino acid (such as glutamine).

[0223] In one embodiment, residue 58 of the light chain variable domain is replaced with an alternative amino acid (such as valine).

[0224] In one embodiment, in the humanized heavy chain variable region according to the present disclosure, residue 36 is tyrosine, residue 37 is glutamine and residue 58 is valine.

[0225] In one embodiment, the present disclosure provides antibody sequences that are 80% similar or identical to the sequences disclosed herein, such as 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% over part or all of the relevant sequences, such as variable domain sequences, CDR sequences, or variable domain sequences excluding CDRs. In one embodiment, the relevant sequence is SEQ ID NO:2. In one embodiment, the relevant sequence is SEQ ID NO:1.

[0226] In one embodiment, the present disclosure provides an antibody molecule that binds to human FcRn and comprises 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 given in SEQ ID NO:1.

[0227] In one embodiment, the present disclosure provides an antibody molecule that binds to human FcRn and comprises 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 given in SEQ ID NO:2.

[0228] In one embodiment, the present disclosure provides an antibody molecule that binds to human FcRn, wherein the antibody 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 given in SEQ ID NO:1, but wherein the antibody molecule has the sequence of CDR-H1 given in SEQ ID NO:4, the sequence of CDR-H2 given in SEQ ID NO:5, and the sequence of CDR-H3 given in SEQ ID NO:6.

[0229] In one embodiment, the present disclosure provides an antibody molecule that binds to human FcRn, wherein the antibody 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 given in SEQ ID NO:2, but wherein the antibody molecule has the sequence of CDR-L1 given in SEQ ID NO:9, the sequence of CDR-L2 given in SEQ ID NO:10, and the sequence of CDR-L3 given in SEQ ID NO:11.

[0230] In one embodiment, the present disclosure provides an antibody molecule that binds to human FcRn, wherein the antibody 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 given 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 given in SEQ ID NO:2, provided that the antibody molecule has the sequence of CDR-H1 given in SEQ ID NO:4, the sequence of CDR-H2 given in SEQ ID NO:5, the sequence of CDR-H3 given in SEQ ID NO:6, the sequence of CDR-L1 given in SEQ ID NO:9, the sequence of CDR-L2 given in SEQ ID NO:10, and the sequence of CDR-L3 given in SEQ ID NO:11.

[0231] As used herein, "identity" means that at any particular position in the aligned sequences, the amino acid residues are the same between the sequences. "Similarity" means that at any particular position in the aligned sequences, the amino acid residues are of a similar type between the sequences. For example, leucine can be replaced with isoleucine or valine. Other amino acids that are often replaced with each other include, but are not limited to:

[0232] - phenylalanine, tyrosine, and tryptophan (amino acids with aromatic side chains);

[0233] - lysine, arginine, and histidine (amino acids with basic side chains);

[0234] - aspartic acid and glutamic acid (amino acids with acidic side chains);

[0235] - asparagine and glutamine (amino acids with amide side chains); and

[0236] - cysteine and methionine (amino acids with sulfur-containing side chains).

[0237] The degree of identity and similarity can be easily calculated (Computational Molecular Biology, edited by Lesk, A.M., Oxford University Press, New York, 1988; Biocomputing. Informatics and Genome Projects, edited by Smith, D.W., Academic Press, New York, 1993; Computer Analysis of Sequence Data, Part 1, edited by Griffin, A.M. and Griffin, H.G., Humana Press, New Jersey, 1994; Sequence Analysis in Molecular Biology, von Heinje, G., Academic Press, 1987, Sequence Analysis Primer, edited by Gribskov, M. and Devereux, J., M Stockton Press, New York, 1991, BLAST software is available from NCBI TM (Altschul, S.F. et al., 1990, J. Mol. Biol. 215:403 - 410; Gish, W. & States, D.J. 1993, Nature Genet. 3:266 - 272. Madden, T.L. et al., 1996, Meth. Enzymol. 266:131 - 141; Altschul, S.F. et al., 1997, Nucleic Acids Res. 25:3389 - 3402; Zhang, J. & Madden, T.L. 1997, Genome Res. 7:649 - 656,).

[0238] The antibody molecules of the present disclosure can comprise intact antibody molecules with full-length heavy and light chains or fragments thereof, and can be, but are not limited to, Fab, modified Fab, Fab', modified Fab', F(ab')2, Fv, single-domain antibodies (such as VH or VL or VHH), scFv, bivalent, trivalent or tetravalent antibodies, bis-scFv, bispecific antibodies, trispecific antibodies or tetra-specific antibodies and epitope-binding fragments of any of the foregoing (see, e.g., Holliger and Hudson, 2005, Adair and Lawson, 2005). Methods for generating and manufacturing 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 can comprise multiple specificities, such as bispecificity, or can be monovalent (see, e.g., WO 92 / 22853, WO05 / 113605, WO2009 / 040562 and WO2(10 / 035012).

[0239] In one embodiment, the antibody molecule of the present disclosure is an antibody Fab fragment that comprises, for example, variable regions as shown in SEQ ID NO:2 and 1 for the light and heavy chains, respectively. In one embodiment, the antibody molecule has a light chain comprising the sequence given in SEQ ID NO:13 and a heavy chain comprising the sequence given in SEQ ID NO:14.

[0240] In one embodiment, the antibody molecule of the present disclosure is a full-length IgG1 antibody that comprises, for example, variable regions as shown in SEQ ID NO:2 and 1 for the light and heavy chains, respectively. In one embodiment, the antibody molecule has a light chain comprising the sequence given in SEQ ID NO:13 and a heavy chain comprising the sequence given in SEQ ID NO:15.

[0241] In one embodiment, the antibody molecule of the present disclosure is in the full-length IgG4 format that comprises, for example, variable regions as shown in SEQ ID NO:2 and 1 for the light and heavy chains, respectively. In one embodiment, the antibody molecule has a light chain comprising the sequence given in SEQ ID NO:13 and a heavy chain comprising the sequence given in SEQ ID NO:16.

[0242] In one embodiment, the antibody molecule of the present disclosure is in the full-length IgG4P format, which comprises variable regions as shown in SEQ ID NO: 2 and 1 for the light and heavy chains, respectively. In one embodiment, the antibody molecule has a light chain comprising the sequence given in SEQ ID NO: 13 and a heavy chain comprising the sequence given in SEQ ID NO: 17.

[0243] As used herein, IgG4P 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 described in Angal et al., 1993 which has been changed to proline.

[0244] In one embodiment, the antibody according to the present disclosure is provided in the form of an FcRn-binding antibody fusion protein, which comprises an immunoglobulin portion, such as a Fab or Fab' fragment, and one or two single-domain antibodies (dAbs) directly or indirectly linked thereto, such as those described in WO2009 / 040562, WO2010035012, WO2011 / 030107, WO2011 / 061492 and WO2011 / 086091 (all incorporated herein by reference).

[0245] In one embodiment, the fusion protein comprises two domain antibodies, such as paired as variable heavy (VH) and variable light (VL), optionally linked by a disulfide bond.

[0246] In one embodiment, the Fab or Fab' element of the fusion protein has the same or similar specificity as the single-domain antibody. In one embodiment, the Fab or Fab' has a different specificity from the single-domain antibody, that is, the fusion protein is multivalent. In one embodiment, the multivalent fusion protein according to the present disclosure has an albumin-binding site, such as where the VH / VL pair provides an albumin-binding site. In one such embodiment, the heavy chain comprises the sequence given in SEQ ID NO: 18 and the light chain comprises the sequence given in SEQ ID NO: 19 or SEQ ID NO: 20.

[0247] In one embodiment, the Fab or Fab' according to the present invention is conjugated to a PEG molecule or human serum albumin.

[0248] CA170_01519g57 and 1519 and 1519.g57 are used interchangeably herein and refer to a specific antibody variable region pair that can be used in a variety of different formats. These variable regions are the heavy chain sequence given in SEQ ID NO: 1 and the light chain sequence given in SEQ ID NO: 2.

[0249] If present, the constant region domain of an antibody molecule of the present disclosure can be selected according to the expected function of the antibody molecule, particularly the effector function that may be required. For example, the constant region domain can be a human IgA, IgD, IgE, IgG, or IgM domain. Specifically, human IgG constant region domains can be used, particularly the IgG1 and IgG3 isotypes when the antibody molecule is intended for therapeutic use and antibody effector function is required. Alternatively, the IgG2 and IgG4 isotypes can be used when the antibody molecule is intended for therapeutic purposes and antibody effector function is not required. It should be understood that sequence variants of these constant region domains can also be used. For example, the IgG4 molecule described by Angal et al., 1993, in which the serine at position 241 is changed to proline, can be used. Those skilled in the art will also understand that antibodies can undergo various post-translational modifications. The type and extent of such modifications generally depend on the host cell line used to express the antibody and the culture conditions. Such modifications can include variations in glycosylation, methionine oxidation, diketopiperazine formation, aspartic acid isomerization, and asparagine deamidation. A frequent modification is the loss of the carboxyl-terminal basic residue (e.g., lysine or arginine) due to the action of carboxypeptidase (as described in Harris, 1995). Thus, the C-terminal lysine of the antibody heavy chain may be absent.

[0250] In one embodiment, the antibody heavy chain comprises a CH1 domain and the antibody light chain comprises a CL domain, κ or λ.

[0251] In one embodiment, the light chain has the sequence given in SEQ ID NO:13 and the heavy chain has the sequence given in SEQ ID NO:17.

[0252] In one embodiment, the light chain has the sequence given in SEQ ID NO:13 and the heavy chain has the sequence given in SEQ ID NO:15.

[0253] In one embodiment, the C-terminal amino acid of the antibody molecule is cleaved during post-translational modification.

[0254] In one embodiment, the N-terminal amino acid of the antibody molecule is cleaved during post-translational modification.

[0255] The present disclosure also provides a specific region or epitope of human FcRn that is bound by an antibody provided by the present disclosure, particularly an antibody comprising the heavy chain sequence gH20 (SEQ ID NO:1) and / or the light chain sequence gL20 (SEQ ID NO:2).

[0256] 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 of the antibodies provided by the present disclosure. Examples of such methods include screening peptides of different lengths derived from FcRn that bind to the antibodies of the present disclosure, wherein the smallest fragment capable of binding to the antibody contains the sequence of the epitope recognized by the antibody. FcRn peptides can be produced synthetically or by protease digestion of the FcRn polypeptide. Peptides that bind 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 the antibodies of the present disclosure. Once identified, if desired, the epitope fragment that binds the antibody of the present disclosure can be used as an immunogen to obtain additional antibodies that bind the same epitope.

[0257] In one embodiment, the antibodies of the present disclosure bind to the extracellular sequence of the α-chain of human FcRn as shown below:

[0258] AESHLSLLYH LTAVSSPAPG TPAFWVSGWL GPQQYLSYNS LRGEAEPCGA WVWENQVSWYWEKETTDLRI KEKLFLEAFK ALGGKGP Y TL QGLLGCELGP DNTSVPTAKF ALNG EEF MNF DLKQGTWGGD WPEA LAISQR WQQQDKAANK ELTFLLFSCP HRLREHLERG RGNLEWKEPP SMRLKARPSS PGFSVLTCSAFSFYPPELQL RFLRNGLAAG TGQGDFGPNSDGSFHASSSL TVKSGDEHHY CCIVQHAGLA QPLRVELESPAKSS(SEQ ID NO:21).

[0259] The underlined residues are known to be crucial for the interaction of human FcRn with the Fc region of human IgG, and those residues highlighted in bold and italic are the residues involved in the interaction of FcRn with the 1519 antibody of the present disclosure comprising the heavy chain sequence gH20 (SEQ ID NO:1) and the light chain sequence gL20 (SEQ ID NO:2).

[0260] In one instance, the present disclosure provides an anti-FcRn antibody molecule that binds to an epitope of human FcRn, the epitope comprising at least one amino acid selected from residues V105, P106, T107, A108, and K109 of SEQ ID NO: 21 and at least one residue selected from P100, E115, E116, F117, M118, N119, F120, D121, L122, K123, Q124, G128, G129, D130, W131, P132, and E133 of SEQ ID NO: 94, such as at least 2, 3, 4, 5, 6, 7, 8, 9, or 10 residues.

[0261] In one instance, the epitope of the antibody molecule is determined by X-ray crystallography using the extracellular sequence of the α-chain of FcRn complexed with β2M (SEQ ID NO: 21).

[0262] In one instance, the present disclosure provides an anti-FcRn antibody molecule that binds to an epitope of human FcRn, the epitope comprising at least one amino acid selected from residues V105, P106, T107, A108, and K109 of SEQ ID NO: 21 and at least one residue selected from E115, E116, F117, M118, N119, F120, D121, L122, K123, and Q124 of SEQ ID NO: 21, such as at least 2, 3, 4, 5, 6, 7, 8, 9, or 10 residues.

[0263] In one instance, the present disclosure provides an anti-FcRn antibody molecule that binds to an epitope of human FcRn, the epitope comprising at least two, three, four, or five amino acids selected from residues V105, P106, T107, A108, and K109 of SEQ ID NO: 21 and at least one residue selected from E115, E116, F117, M118, N119, F120, D121, L122, K123, and Q124 of SEQ ID NO: 21.

[0264] In one instance, the present disclosure provides an anti-FcRn antibody molecule that binds to an epitope of human FcRn, the epitope comprising at least one amino acid selected from residues V105, P106, T107, A108, and K109 of SEQ ID NO: 21 and at least one residue selected from P100, E115, E116, F117, M118, N119, F120, D121, L122, K123, Q124, G128, G129, D130, W131, P132, and E133 of SEQ ID NO: 21.

[0265] In one instance, the present disclosure provides an anti-FcRn antibody molecule that binds to an epitope of human FcRn, the epitope comprising at least one amino acid selected from residues V105, P106, T107, A108, and K109 of SEQ ID NO: 21 and at least one residue selected from P100, M118, N119, F120, D121, L122, K123, Q124, and G128 of SEQ ID NO: 21.

[0266] In one instance, the present disclosure provides an anti-FcRn antibody molecule that binds to an epitope of human FcRn, the epitope comprising residues V105, P106, T107, A108, and K109 of SEQ ID NO: 21 and at least one residue selected from P100, M118, N119, F120, D121, L122, K123, Q124, and G128 of SEQ ID NO: 21.

[0267] In one instance, the present disclosure provides an anti-FcRn antibody molecule that binds to an epitope of human FcRn, the epitope comprising residues V105, P106, T107, A108, and K109 of SEQ ID NO: 21 and at least one residue selected from P100, E115, E116, F117, M118, N119, F120, D121, L122, K123, Q124, G128, G129, D130, W131, P132, and E133 of SEQ ID NO: 21.

[0268] In one instance, the present disclosure provides an anti-FcRn antibody molecule that binds to an epitope of human FcRn, the epitope comprising residues P100, V105, P106, T107, A108, and K109 of SEQ ID NO: 21 and at least one residue selected from E115, E116, F117, M118, N119, F120, D121, L122, K123, Q124, G128, G129, D130, W131, P132, and E133 of SEQ ID NO: 21. [[ID=!]]

[0269] In one instance, the "at least one residue" can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 residues.

[0270] In one instance, the present disclosure provides an anti-FcRn antibody molecule that binds to an epitope of human FcRn, the epitope comprising or consisting of residues 100, 105 - 109, 115 - 124, and 129 - 133 of SEQ ID NO: 21.

[0271] Antibodies that cross - block the binding of the antibody molecules according to the present disclosure, particularly antibody molecules comprising the heavy - chain sequence given in SEQ ID NO: 1 and the light - chain sequence given in SEQ ID NO: 2, can similarly be used to block FcRn activity. Accordingly, the present disclosure also provides an anti - FcRn antibody molecule that cross - blocks the binding of any of the antibody molecules described above herein to human FcRn and / or is cross - blocked by any of these antibodies from binding to human FcRn. In one embodiment, such an antibody binds to the same epitope as the antibodies described above herein. In another embodiment, the cross - blocking neutralizing antibody binds to an epitope adjacent and / or overlapping the epitope to which the antibodies described above herein bind.

[0272] Cross - blocking antibodies can be identified by any suitable method in the art, such as by using competitive ELISA or BIAcore assays, where the binding of the cross - blocking antibody to human FcRn prevents the binding of the antibodies of the present disclosure or vice versa. Such cross - blocking assays can use isolated native or recombinant FcRn or suitable fusion proteins / polypeptides. In one example, the extracellular domain of recombinant human FcRn (SEQ ID NO: 21) is used to measure binding and cross - blocking. In one example, the extracellular domain of the α - chain of recombinant human FcRn complexed with β2 - microglobulin (β2M) (SEQ ID NO: 22) is used.

[0273] In one embodiment, an anti - FcRn antibody molecule is provided that blocks the binding of FcRn to IgG and cross - blocks the binding of an antibody whose heavy chain comprises the sequence given in SEQ ID NO: 1 and whose light chain comprises the sequence given in SEQ ID NO: 2 to human FcRn. In one embodiment, the cross - blocking antibody provided by the present disclosure inhibits the binding of an antibody comprising the heavy - chain sequence given in SEQ ID NO: 1 and the light - chain sequence given in SEQ ID NO: 2 by more than 80%, such as more than 85%, such as more than 90%, particularly more than 95%.

[0274] Alternatively or additionally, anti-FcRn antibodies according to this aspect of the disclosure may be cross-blocked in their binding to human FcRn by an antibody comprising the heavy chain sequence given in SEQ ID NO: 1 and the light chain sequence given in SEQ ID NO: 2. Accordingly, there is also provided an anti-FcRn antibody molecule that blocks the binding of FcRn to IgG and is cross-blocked in its binding to human FcRn by an antibody comprising the heavy chain sequence given in SEQ ID NO: 1 and the light chain sequence given in SEQ ID NO: 2. In one embodiment, the anti-FcRn antibody provided by this aspect of the disclosure is inhibited in its binding to human FcRn by more than 80%, such as more than 85%, such as more than 90%, especially more than 95%, by an antibody comprising the heavy chain sequence given in SEQ ID NO: 1 and the light chain sequence given in SEQ ID NO: 2.

[0275] In one embodiment, the cross-blocking antibody provided by the disclosure is fully human. In one embodiment, the cross-blocking antibody provided by the disclosure is humanized. In one embodiment, the cross-blocking antibody provided by the disclosure has an affinity for human FcRn of 100 pM or less. In one embodiment, the cross-blocking antibody provided by the disclosure has an affinity for human FcRn of 50 pM or less. Affinity can be measured using the methods described hereinbelow.

[0276] Biomolecules (such as antibodies or fragments) contain acidic and / or basic functional groups, thereby conferring a net positive or negative charge on the molecule. The overall "observed" charge will depend 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 bears no net charge. In one example, the FcRn antibodies and fragments of the disclosure can be engineered to have an appropriate isoelectric point. This can result in antibodies and / or fragments with more robust properties, especially with suitable solubility and / or stability profiles and / or improved purification properties.

[0277] Accordingly, in one aspect, the disclosure provides humanized FcRn antibodies engineered to have an isoelectric point different from that of the originally identified antibody. For example, the antibody can be engineered by replacing amino acid residues, such as by replacing acidic amino acid residues with one or more basic amino acid residues. Alternatively, basic amino acid residues can be introduced or acidic amino acid residues can be removed. Or, if the molecule has an unacceptably high pI value, acidic residues can be introduced as needed to lower the pI. Importantly, care must be taken to maintain the desired activity of the antibody or fragment when manipulating the pI. Accordingly, in one embodiment, the engineered antibody or fragment has the same or substantially the same activity as the "unmodified" antibody or fragment.

[0278] 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.

[0279] The antibody molecules of the present disclosure suitably have a high binding affinity, particularly in the nanomolar range. Any suitable method known in the art (including BIAcore, as described in the examples herein, using isolated native or recombinant FcRn or a suitable fusion protein / polypeptide) can be used to measure the affinity. In one example, the affinity is measured using the extracellular domain of the α-chain of recombinant human FcRn (SEQ ID NO:21) binding to β2-microglobulin (β2M) (SEQ ID NO:22). Suitably, the antibody molecules of the present disclosure have a K D of about 1 nM or less for isolated human FcRn. In one embodiment, the antibody molecules of the present disclosure have a K D of about 500 pM or less (i.e., higher affinity). In one embodiment, the antibody molecules of the present disclosure have a K D of about 250 pM or less. In one embodiment, the antibody molecules of the present disclosure have a K D of about 200 pM or less. In one embodiment, the present disclosure provides an anti-FcRn antibody having a K D of about 100 pM or less. In one embodiment, the present disclosure provides a humanized anti-FcRn antibody having a K D of about 100 pM or less. In one embodiment, the present disclosure provides an anti-FcRn antibody having a K D of 50 pM or less.

[0280] Importantly, the antibodies of the present disclosure are able to bind human FcRn with comparable binding affinity at both pH 6 and pH 7.4. Thus, advantageously, the antibody is able to continue to bind FcRn even inside the endosome, thereby maximizing the blockade of the binding of FcRn to IgG.

[0281] In one embodiment, the present disclosure provides an anti-FcRn antibody having a K D of 100 pM or less when measured at pH 6 and pH 7.4.

[0282] The degree to which the antibodies or binding fragments of the present disclosure and a bound FcRn antagonist (e.g., an antibody) inhibit binding can be determined by those of ordinary skill 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. For surface plasmon resonance, the target molecule is immobilized on a solid phase and exposed to a ligand in a mobile phase that runs through a flow cell. If binding of the ligand to the immobilized target occurs, the local refractive index changes, resulting in a change in the SPR angle, which can be monitored in real time by detecting changes in the intensity of the reflected light. The rate of change of the SPR signal can be analyzed to yield the apparent rate constants for the association and dissociation phases of the binding reaction. The ratio of these values gives the apparent equilibrium constant (affinity) (see, e.g., Wolff et al., 1993).

[0283] In the present disclosure, SPR is generally used as follows to determine the affinity of a test antibody molecule. The test antibody molecule is captured on a solid phase, and the extracellular domain of the α-chain of human FcRn non-covalently complexed with β2M is run over the antibody captured in the mobile phase and the affinity of the test antibody molecule for human FcRn is determined. Any suitable method can be used to capture the test antibody molecule on the surface of a solid phase chip, such as using anti-Fc or anti-Fab' specific capture of the FcRn antagonist. In one example, the affinity is determined at pH 6. In one example, the affinity is determined at pH 7.4.

[0284] It should be understood that any suitable method known in the art can be used to alter the affinity of the antibodies provided by the present disclosure. 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 a variety of affinity maturation protocols, including mutating the CDRs (Yang et al., 1995), chain shuffling (Marks et al., 1992), using mutant strains of 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. (see above) discuss these affinity maturation methods.

[0285] In one embodiment, the antibody molecules of the present disclosure block human FcRn activity. Assays suitable for determining the ability of an antibody to block FcRn are described in the Examples herein. Assays suitable for determining whether an antibody blocks the interaction of FcRn with circulating IgG molecules are described in the Examples herein.

[0286] Pharmaceutical compositions

[0287] FcRn antagonists for use in the present invention, such as FcRn antibodies or FcRn-binding fragments thereof, can be provided as such a pharmaceutical or diagnostic composition that comprises a combination of an antagonist molecule of the present disclosure with one or more pharmaceutically acceptable excipients, diluents or carriers. The composition is typically supplied as part of a sterile pharmaceutical composition, which will generally include a pharmaceutically acceptable carrier. The pharmaceutical compositions of the present invention may also contain pharmaceutically acceptable excipients.

[0288] The present disclosure also provides a method for preparing a pharmaceutical or diagnostic composition, the method comprising adding and mixing an antibody molecule of the present invention with one or more pharmaceutically acceptable excipients, diluents or carriers.

[0289] FcRn antagonists, such as FcRn antibodies or FcRn-binding fragments thereof, can be the sole active ingredient in a pharmaceutical or diagnostic composition, or can be accompanied by other active ingredients, which include other antibody components or non-antibody components, such as steroids or other drug molecules, which in one instance are drug molecules whose half-life is independent of FcRn binding.

[0290] The pharmaceutical composition can conveniently be presented in a dosage form containing a predetermined amount of the active agent of the present invention per dose.

[0291] The therapeutic dose of an antibody according to the present disclosure shows no significant toxicological effects in vivo.

[0292] A pharmaceutically acceptable carrier should not itself induce the production of antibodies harmful to the individual receiving the composition and should not be toxic.

[0293] Suitable carriers can be large, slowly metabolized macromolecules such as proteins, polypeptides, liposomes, polysaccharides, polylactic acid, polyglycolic acid, polymeric amino acids, amino acid copolymers and inactivated virus particles.

[0294] Pharmaceutically acceptable salts can be used, such as mineral acid salts, such as hydrochloride, hydrobromide, phosphate and sulfate salts, or salts of organic acids, such as acetate, propionate, malate and benzoate salts.

[0295] The pharmaceutically acceptable carrier in the pharmaceutical composition may also contain liquids such as water, saline, glycerol and ethanol. In addition, auxiliary substances such as wetting agents or emulsifying agents or pH buffering substances may be present in such a composition. Such carriers enable the pharmaceutical composition to be formulated into tablets, pills, dragees, capsules, liquids, gels, syrups, slurries and suspensions for administration to a patient.

[0296] Suitable administration forms include forms suitable for parenteral administration, such as by injection or infusion, such as by bolus or continuous infusion. When the product is for injection or infusion, it can take the form of a suspension, solution or emulsion in an oily or aqueous vehicle, and it can contain formulatory agents such as suspending agents, preservatives, stabilizers and / or dispersing agents.

[0297] Alternatively, the FcRn antagonist, such as an FcRn antibody or an FcRn-binding fragment thereof, can be in a dry form for reconstitution with a suitable sterile liquid before use.

[0298] Once formulated, the compositions of the 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 suitable for administration to human subjects.

[0299] Suitably, in the formulations according to the present disclosure, the pH of the final formulation is not similar to the value of 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 suitable.

[0300] Although not wishing to be bound by theory, it is believed that this may ultimately provide a final formulation with improved stability, such as the antibody or fragment remaining in solution.

[0301] The pharmaceutical compositions of the invention can be administered by any number of routes, including but not limited to oral, intravenous, intramuscular, intraarterial, intramedullary, intraventricular, intracisternal, transdermal, percutaneous (e.g., see WO98 / 20734), subcutaneous, intraperitoneal, intranasal, enteral, topical, sublingual, intravaginal or rectal routes. The pharmaceutical compositions of the invention can also be administered using a hypospray. Generally, the therapeutic composition can be prepared as an injectable, either as a liquid solution or a suspension. Solid forms suitable for solution or suspension in a liquid vehicle before injection can also be prepared.

[0302] Direct delivery of the composition is typically accomplished by injection, subcutaneously, intraperitoneally, intravenously or intramuscularly, or delivery into the interstitial space of a tissue. The dosing regimen can be a single-dose or multi-dose regimen. Preferably, the delivery is subcutaneous. In one example, the delivery is by subcutaneous infusion. In one example, the delivery is not intravenous.

[0303] It should be understood that the active ingredient in the composition can be an antibody molecule. Thus, it will be readily degraded in the gastrointestinal tract. Therefore, if the composition is to be administered by a route using the gastrointestinal tract, the composition will need to contain an agent that protects the antibody from degradation but releases the antibody after its absorption from the gastrointestinal tract.

[0304] A detailed discussion of pharmaceutically acceptable carriers can be found in Remington's Pharmaceutical Sciences (Mack Publishing Company, NJ, 1991).

[0305] The FcRn antagonists of the present invention can be delivered dispersed in a solvent, for example, in the form of a solution or a suspension. It can be suspended in a suitable physiological solution, such as saline or other pharmaceutically acceptable solvents or buffer solutions. The suspension can employ, for example, freeze-dried antibodies.

[0306] Therapeutic suspension or solution formulations can also contain one or more excipients. Excipients are well known in the art and include buffers (such as citrate buffers, phosphate buffers, acetate buffers, and bicarbonate buffers), amino acids, urea, alcohols, ascorbic acid, phospholipids, proteins (such as serum albumin), EDTA, sodium chloride, liposomes, mannitol, sorbitol, and glycerol. The solution or suspension can be encapsulated in liposomes or biodegradable microspheres. The formulation will generally be provided in a substantially sterile form using aseptic manufacturing processes.

[0307] This can include the production and sterilization of the buffer solvent / solution used for formulation by filtration, the aseptic suspension of the FcRn antagonist in the sterile buffer solvent solution, and the dispensing of the formulation into sterile containers by methods familiar to those of ordinary skill in the art.

[0308] Once formulated, the compositions of the present disclosure can be administered directly to human subjects, but the present disclosure also contemplates that the method can be used on non-human subjects.

[0309] Therapeutically effective amount

[0310] The composition preferably contains a therapeutically effective amount of an FcRn antagonist, such as an FcRn antibody (or an antigen-binding fragment thereof). As used herein, the term "therapeutically effective amount" refers to the amount of the therapeutic FcRn antagonist required to treat, alleviate, or prevent a targeted disease or condition or to exhibit a detectable therapeutic or prophylactic effect.

[0311] Combination therapy

[0312] The composition can be administered to a patient alone or can be administered in combination with other agents, drugs, or hormones (e.g., simultaneously, sequentially, or separately). In one embodiment, an FcRn antagonist according to the present disclosure, such as an FcRn antibody or an FcRn-binding fragment thereof, is used with a second agent. In some embodiments, the second agent is an analgesic, an antidepressant, a dopamine agonist such as pramipexole, an antiepileptic drug, an antihistamine, a hypnotic, a muscle relaxant, and an antipsychotic.

[0313] In some embodiments, the analgesic is selected from acetaminophen, ibuprofen, and opioid drugs such as codeine, tramadol, morphine, and oxycodone.

[0314] In some embodiments, the antidepressant is selected from tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors (SNRIs), and selective serotonin reuptake inhibitors (SSRIs).

[0315] In some embodiments, the tricyclic antidepressants are selected from amitriptyline, desipramine, clomipramine, protriptyline, doxepin, imipramine, amoxapine, trazodone, nortriptyline, and trimipramine.

[0316] In some embodiments, the SNRIs are selected from venlafaxine, duloxetine, desvenlafaxine, levomilnacipran, and milnacipran.

[0317] In some embodiments, the SSRIs are selected from citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline.

[0318] In some embodiments, the antiepileptic drugs are selected from gabapentin and pregabalin.

[0319] In some embodiments, the hypnotic is a benzodiazepine class or a non-benzodiazepine class.

[0320] In some embodiments, the benzodiazepine class is selected from lorazepam, clonazepam, diazepam, and alprazolam.

[0321] In some embodiments, the non-benzodiazepine class is selected from zolpidem, zaleplon, and eszopiclone.

[0322] In some embodiments, the muscle relaxants are selected from cyclobenzaprine, flexeril, orphenadrine citrate, tizanidine, and carisoprodol.

[0323] In some embodiments, the antipsychotic is quetiapine.

[0324] Example 1

[0325] Introduction

[0326] Transfer of serum IgG from patients with severe FMS to rodents produced the typical features of clinical FMS in rodents, including mechanical allodynia, thermal hyperalgesia, reduced grip strength, and small fiber pathology (Goebel et al., 2021), compared to transfer of serum IgG from healthy volunteers. Fibromyalgia patients with high levels of anti-satellite glial cell IgG antibodies had more severe symptoms (Krock et al., 2022).

[0327] As detailed below, the following experiments were conducted to evaluate the in vivo efficacy of an anti-mouse FcRn antibody (UCB4470) in a murine model of FMS IgG transfer.

[0328] Methods

[0329] Mice were administered healthy control (HC) IgG (pooled from 4 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 on the Visual Analogue Scale (VAS) > 60). Each pool consisted of IgG from 4 FMS patients.

[0330] All IgG pools were administered i.p. at 8 mg to each group of n = 6 mice on 2 consecutive days (day 0 and day 1). The groups are described below.

[0331] Mice were treated with an anti-mouse FcRn antibody (antibody UCB4470, Smith et al., 2019) or isotype control antibody (UCB101.4) at 30 mg / kg by intravenous injection starting 1 day before (-1 day) administration of the HC or FMS IgG pools (FMA and FMB). Then UCB4470 and UCB101.4 were administered i.p. on days 2, 6, 10, and 14.

[0332] In Vivo Groups

[0333] Group 1 - 8 mg IgG HC pool + isotype control antibody, UCB101.4 at 30 mg / kg (n = 6 mice)

[0334] 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 at 30 mg / kg.

[0335] Group 3 - 8 mg IgG FMS pool A (FMA, n = 6 mice) or FMS pool B (FMB, n = 6 mice) + antibody UCB4470 at 30 mg / kg.

[0336] Behavioral Assessments

[0337] After administration of HC or FMSIgG, behavioral changes in the mice of each group were evaluated. On day 4, the open field test and video tracking software Ethovision XT 17 (Noldus) were used to evaluate changes in activity and locomotion. The mice were placed in the open field arena, and their behavior was recorded for a 30-minute period. Then, the total activity, locomotion distance, and speed of each mouse were calculated ( Figure 1 ). One-Way ANOVA was used to analyze the data to determine statistical significance, p<0.05* and p<0.01**.

[0338] The cold allodynia was evaluated using the popsicle test, and the latency for the mice to withdraw their paws from the cold stimulus was recorded in seconds ( Figure 2 ). The mice were acclimated to the popsicle test 2 weeks before the start of the study. Then, measurements were taken at baseline (day 0) and on days 3, 6, 9, and 14.

[0339] Injections of UCB101.4 and UCB4470 were performed between 9 - 10 am, and behavioral evaluations were conducted between 2 - 5 pm.

[0340] Results

[0341] In the open field test, administration of IgG from FMS patients to the mice (FMA and FMB pools) resulted in a statistically significant decrease in the total activity, locomotion distance, and speed of the mice compared to the mice administered IgG from healthy controls ( Figure 1 ). This decrease in total activity indicates that IgG from FMS patients is having an effect in the mice, making them less willing to move compared to the mice administered HC IgG. Treatment of the mice administered IgG from FMS patients with 30 mg / kg of the anti-mouse FcRn antibody (UCB4470) resulted in a statistically significant increase in the total activity, locomotion distance, and speed compared to the mice that had received the isotype control antibody (UCB101.4 30 mg / kg) and IgG from FMS patients ( Figure 1 ). Thus, blocking FcRn with UCB4470 restored normal activity in the mice.

[0342] In the cold allodynia test, compared to the baseline on day 0, all mice showed a decrease in latency after treatment with the antibody (UCB101.4 or UCB4470) and administration of IgG from the HC or FMS pooled samples on day 3. This decrease was similar in all groups. In the mice administered IgG from FMS patients (FMA and FMB) treated with the isotype control antibody (UCB101.4), the latency generally decreased from day 3 until day 9 compared to the mice that received IgG from HC ( Figure 2) This indicates that IgG from FMS patients renders recipient mice hypersensitive to cold stimuli. When mice received IgG from the FMA pool, treatment with UCB4470 resulted in inhibition of this hypersensitive tendency. However, when mice received IgG from the FMB pool, this tendency was not observed with UCB4470.

[0343] Conclusion

[0344] Overall, these data indicate that transfer of IgG from FMS patients leads to behavioral differences and hypersensitivity to cold stimuli in recipient mice compared to transfer of IgG from HC. The data also indicate that treatment with an anti-FcRn antibody can restore normal activity in mice and has a tendency to protect against hypersensitivity to cold stimuli from one of the two IgG pools from FMS patients. Thus, reducing IgG by blocking FcRn may have a therapeutic effect in FMS patients with high pain intensity.

[0345] Example 2

[0346] We are conducting a Phase 2, multi-center, randomized, double-blind, placebo-controlled proof-of-concept study to evaluate the efficacy, safety, PK, and PD of rozelixizumab in the treatment of severe FMS. Rozelixizumab is an anti-FcRn antibody that inhibits the binding of IgG to FcRn. The primary endpoint is the mean BPI-SF interference score after 12 weeks of double-blind treatment.

[0347] The study includes a screening period of up to 28 days, a 2-week single-blind lead-in period, two subsequent 12-week double-blind treatment periods, followed by a 2-week single-blind washout period and a 5-week safety follow-up (SFU) period.

[0348] Study participants were selected based on previously diagnosed fibromyalgia (as defined by the 2016 revision of the 2010 / 2011 fibromyalgia diagnostic criteria (American College of Rheumatology Preliminary Diagnostic Criteria)) plus the following characteristics during the screening period:

[0349] a. BPI-SF interference ≥ 6;

[0350] b. Study participants had been diagnosed with FMS for at least 6 months;

[0351] c. Study participants had had FMS symptoms for at least 2 years prior to enrollment.

[0352] Before randomization, participants had to have confirmed:

[0353] a. The average daily pain intensity for 24 hours is ≥6 and <10, as evaluated by the NRS for pain. This will be evaluated during a 10-day period within the screening period. The study participants are required to have at least 7 out of 10 evaluations during this 10-day period within the screening period.

[0354] b. The NRS score for pain should be ≥4 in all completed evaluations during this 10-day period.

[0355] The study participants will be randomly assigned to one of 3 sequences in a 1:1:1 ratio. The study participants in each sequence will receive the following treatment regimens during the double-blind treatment period (see Figure 3 ):

[0356] · Sequence 1: Rozelizumab 560 mg subcutaneous (sc) once weekly (QW) for 24 weeks (12 + 12-week treatment period) (N = 20, Group 1)

[0357] · Sequence 2: Placebo sc QW for 12 weeks, then Rozelizumab 560 mg sc QW for 12 weeks (N = 20, Group 2)

[0358] · Sequence 3: Placebo sc QW for 24 weeks (N = 20, Group 3)

[0359] The initial 2-week lead-in period and the final 2-week washout period are unknown to the study participants, and the study participants are not informed that they are receiving a placebo to limit the influence of any start-of-study or end-of-study induced placebo effects. The two 12-week treatment periods are unknown to the study participants, the investigators, and the sponsor. Importantly, the study participants do not know when their treatment changes, whether from the lead-in period to Phase 1, or from Phase 1 to Phase 2, or from Phase 2 to the washout period.

[0360] A mid-term analysis may be conducted after approximately 30 study participants have been randomly assigned and these study participants have completed their 2 double-blind treatment periods, with the possibility of stopping due to efficacy or futility.

[0361] The Safety Monitoring Committee (SMC) will regularly review the available blinded safety data (approximately every 3 months, with the option to adjust the frequency based on the recruitment rate).

[0362] The outcomes will be evaluated using the Brief Pain Inventory-Short Form (BPI-SF), the Numerical Rating Scale for Pain (NRS for pain), the Revised Fibromyalgia Impact Questionnaire (FIQR), and the Numerical Rating Scale for Fatigue (NRS for fatigue).

[0363] Brief Pain Inventory-Short Form (BPI-SF)

[0364] The BPI-SF was designed to measure multiple clinically relevant aspects of pain in cancer populations, such as pain intensity and interference from pain. There are two versions; the short form is the most commonly used version and is often included in the context of clinical trials (Williams and Arnold, 2011). The short form of the BPI is a self-administered questionnaire used to assess the pain severity of study participants and the impact of this pain on the daily functioning of study participants. The BPI-SF assesses the location of pain, pain intensity, and functional interference from pain. Study participants should complete the BPI-SF in a quiet place before each visit (including the dosing day), prior to other patient-reported outcomes (PRO) or protocol-specified assessments.

[0365] The 4 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 scored on a scale from 0 (no pain) to 10 (the worst pain you can imagine), with a recall period of 24 hours.

[0366] The 7 BPI-SF interference items include: general activity, mood, walking ability, normal work (including housework), relationships with others, sleep, and enjoyment of life. Each item is scored on a scale from 0 (not interfering) to 10 (completely interfering), with a recall period of 24 hours. The arithmetic mean of the 7 interference items can be used as a measure of pain interference.

[0367] Pain Numerical Rating Scale (Pain NRS)

[0368] The Pain NRS is a numerical version of the VAS (Visual Analogue Scale), where the responder selects the integer that best describes "How much pain have you experienced on average in the past 24 hours?". The 11-point Pain NRS ranges from 0 (no pain) to 10 (the worst pain you can imagine).

[0369] The daily average pain for the past 24 hours is captured using the Pain NRS in a diary over a 10-day period during the screening period. Study participants need to have at least 7 out of 10 daily Pain NRS assessments during this 10-day period to be eligible for randomization. All Pain NRS scores recorded during the 10-day period within the screening period are used to calculate the average daily average 24-hour pain intensity ≥6 and <10 for inclusion (e.g., if 10 daily scores are available, the average of 10 days is taken; if 9 daily scores are available, the average of 9 days is taken, etc.).

[0370] During the lead-in period and at the end of the treatment period, the Pain NRS is collected daily for 7 consecutive days after the assessment visit. For all other visits, only the average pain for the 24 hours prior to the visit is captured using the Pain NRS.

[0371] Revised Fibromyalgia Impact Questionnaire (FIQR)

[0372] The FIQR is a 21-item questionnaire with a 7-day recall period. The FIQR consists of 3 domains: Function, Overall Impact, and Symptoms. Each item is based on an 11-point numeric rating scale. The FIQR is completed by participants during the study visit.

[0373] Fatigue Numeric Rating Scale (Fatigue NRS)

[0374] The Fatigue NRS is a numeric version of the VAS, in which responders select the integer that best describes "How much fatigue have you experienced, on average, in the past 24 hours?" The range of the 11-point Fatigue NRS is from 0 (no fatigue) to 10 (the most severe fatigue you can imagine). The Fatigue NRS will be completed by participants at home / during the study visit.

[0375] Sequence

[0376]

[0377]

[0378]

[0379]

[0380]

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[0429] Aspects of the present disclosure

[0430] 1. A method of 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 inhibits the binding of IgG to the FcRn receptor.

[0431] 2. The method of aspect 1, wherein the FMS is severe FMS.

[0432] 3. The method of aspect 1 or 2, wherein the pain intensity of the individual's Numerical Rating Scale for Pain (Pain NRS) is greater than 5 and less than 10 (i.e., equal to or greater than 6 and less than 10).

[0433] 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 greater than or equal to 6.

[0434] 5. The method of any one of aspects 1 - 4, wherein the individual has a Fibromyalgia Impact Questionnaire (FIQR) score of greater than or equal to 64.

[0435] 6. The method of any one of aspects 1 - 5, wherein the individual has a Numerical Rating Scale for Fatigue (Fatigue NRS) score of greater than or equal to 5.

[0436] 7. The method of any one of aspects 1 - 6, wherein the pain intensity of the individual's Numerical Rating Scale for Pain (Pain NRS) is greater than 5 and less than 10 (i.e., equal to or greater than 6 and less than 10), the Brief Pain Inventory - Short Form (BPI - SF) interference score is greater than or equal to 6, the Fibromyalgia Impact Questionnaire (FIQR) score is greater than or equal to 64, and the Numerical Rating Scale for Fatigue (Fatigue NRS) score is greater than or equal to 5.

[0437] 8. The method of any one of aspects 1 - 7, wherein treating FMS comprises reducing or eliminating one or more symptoms of FMS.

[0438] 9. The method of aspect 8, wherein one or more symptoms of FMS are selected from: pain, soreness, burning sensation, stabbing pain, hyperalgesia, allodynia, stiffness, muscle spasm, fatigue, reduced sleep quality, impaired memory, attention deficit, concentration deficit, speech disorder, headache, migraine, constipation, diarrhea, dizziness, clumsiness, anxiety, and depression.

[0439] 10. The method of any one of aspects 1 - 9, wherein the method reduces the average interference score of the individual's Brief Pain Inventory - Short Form (BPI - SF).

[0440] 11. The method of aspect 10, wherein the method reduces the BPI-SF score of the individual 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.

[0441] 12. The method of any one of aspects 1-11, wherein the method reduces the Fibromyalgia Impact Questionnaire (FIQR) score of the individual.

[0442] 13. The method of aspect 12, wherein the method reduces the FIQR score of the individual 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.

[0443] 14. The method of any one of aspects 1-13, wherein the method reduces the average daily pain score of the individual.

[0444] 15. The method of aspect 14, wherein the average daily pain score is measured using a Pain Numerical Rating Scale (NRS).

[0445] 16. The method of aspect 15, wherein the method reduces the average daily pain score of the individual 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.

[0446] 17. The method of any one of aspects 1-16, wherein the method reduces the fatigue score of the individual.

[0447] 18. The method of aspect 17, wherein the fatigue score is measured using a Fatigue Numerical Rating Scale (NRS).

[0448] 19. The method of aspect 18, wherein the method reduces the 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.

[0449] 20. The method of any one of aspects 1-19, wherein administration of an FcRn antagonist results in a reduction in serum IgG of 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%.

[0450] 21. The method of any one of aspects 1-20, wherein administration of an FcRn antagonist results in a 60% to 80% reduction in serum IgG level.

[0451] 22. The method of any one of aspects 1-21, wherein administration of an FcRn antagonist results in a reduction in serum IgG level of approximately 70%.

[0452] 23. The method of any one of aspects 1-22, wherein the serum from the individual produces a higher percentage of IgG binding to satellite glial cells (SGCs) or an increased SGC binding intensity compared to the serum from healthy control patients.

[0453] 24. The method of any one of aspects 1-23, wherein administration of an FcRn antagonist results in a reduction of 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% in the anti-SGC IgG level in the individual.

[0454] 25. The method of any one of aspects 1-24, wherein the FcRn antagonist is an Fc fragment that binds to the FcRn receptor.

[0455] 26. The method of aspect 25, wherein the Fc fragment is efgartigimod.

[0456] 27. The method of any one of aspects 1-26, wherein the FcRn antagonist is a peptide that blocks the binding of IgG to the FcRn receptor.

[0457] 28. The method of aspect 27, wherein the peptide is SYN1436.

[0458] 29. The method of any one of aspects 1-24, wherein the FcRn antagonist is an anti-FcRn antibody or an FcRn-binding fragment thereof.

[0459] 30. The method of aspect 29, wherein the anti-FcRn antibody or FcRn-binding fragment is selected from rozelixizumab, nicalizumab, onolizumab, CSL730 / M230, ABY-039 and RVT-1401 (HL161).

[0460] 31. The method of aspect 29 or aspect 30, wherein the anti-FcRn antibody or an FcRn-binding fragment thereof is rozelixizumab.

[0461] 32. The method of any one of aspects 29-31, wherein the anti-FcRn antibody or an FcRn-binding fragment thereof comprises:

[0462] (a) a heavy chain or a heavy chain fragment having a variable region, wherein the variable region comprises three CDRs, and the three CDRs have the sequences of CDR H1 given in SEQ ID NO:4, the sequence of CDR H2 given in SEQ ID NO:5, and the sequence of CDR H3 given in SEQ ID NO:6, and

[0463] (b) A light chain or light chain fragment having a variable region, wherein the variable region comprises three CDRs having the sequences of CDR L1 given in SEQ ID NO:9, the sequence of CDR L2 given in SEQ ID NO:10, and the sequence of CDR L3 given in SEQ ID NO:11.

[0464] 33. The method of any one of aspects 29 - 32, wherein the anti - FcRn antibody or its FcRn - binding fragment comprises a heavy - chain variable region having the sequence given in SEQ ID NO:1 and a light - chain variable region having the sequence given in SEQ ID NO:2.

[0465] 34. The method of any one of aspects 29 - 33, wherein the anti - FcRn antibody or its FcRn - binding fragment is a scFv, Fv, Fab or Fab' fragment.

[0466] 35. The method of aspect 34, wherein the Fab fragment comprises a heavy chain having the sequence given in SEQ ID NO:14 and a light chain having the sequence given in SEQ ID NO:13.

[0467] 36. The method of any one of aspects 29 - 35, wherein the anti - FcRn antibody comprises a heavy chain having the sequence given in SEQ ID NO:17 and a light chain having the sequence given in SEQ ID NO:13.

[0468] 37. The method of any one of aspects 29 - 36, wherein the anti - FcRn antibody or its FcRn - binding fragment is administered at a dose of 1 mg / kg to 50 mg / kg.

[0469] 38. The method of any one of aspects 29 - 37, wherein the anti - FcRn antibody or its FcRn - binding fragment is administered at a dose of 4 mg / kg to 20 mg / kg.

[0470] 39. The method of any one of aspects 29 - 38, wherein the anti - FcRn antibody or its FcRn - binding fragment is administered at a dose of 7 mg / kg to 10 mg / kg.

[0471] 40. The method of any one of aspects 29 - 39, wherein the anti - FcRn antibody or its FcRn - binding fragment is administered at a dose of 560 mg.

[0472] 41. The method of any one of aspects 29 - 40, wherein the anti - FcRn antibody or its FcRn - binding fragment is administered subcutaneously.

[0473] 42. The method according to any one of aspects 29 - 41, wherein the anti - FcRn antibody or its FcRn - binding fragment 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.

[0474] 43. The method according to any one of aspects 29 - 42, wherein the anti - FcRn antibody or its FcRn - binding fragment is administered once a week.

[0475] 44. The method according to any one of aspects 1 - 43, wherein the method further comprises administering a therapeutically effective amount of a second agent for treating FMS.

[0476] 45. The method according to aspect 44, wherein the second agent is selected from analgesics, antidepressants, dopamine agonists, anti - epileptic drugs, antihistamines, hypnotics, muscle relaxants, and antipsychotics.

[0477] 46. The method according to aspect 45, wherein the analgesics are selected from acetaminophen (paracetamol), ibuprofen, and opioid drugs such as codeine, tramadol, morphine, and oxycodone.

[0478] 47. The method according to aspect 45, wherein the antidepressants are selected from tricyclic antidepressants, serotonin - norepinephrine reuptake inhibitors (SNRI), and selective serotonin reuptake inhibitors (SSRI).

[0479] 48. The method according to aspect 47, wherein the tricyclic antidepressants are selected from amitriptyline, desipramine, clomipramine, protriptyline, doxepin, imipramine, amoxapine, trazodone, nortriptyline, and trimipramine.

[0480] 49. The method according to aspect 47, wherein the SNRI are selected from venlafaxine, duloxetine, desvenlafaxine, levomilnacipran, and milnacipran.

[0481] 50. The method according to aspect 47, wherein the SSRI are selected from citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline.

[0482] 51. The method according to aspect 45, wherein the anti - epileptic drugs are selected from gabapentin and pregabalin.

[0483] 52. The method according to aspect 45, wherein the hypnotic is a benzodiazepine or non - benzodiazepine class.

[0484] 53. The method according to aspect 52, wherein the benzodiazepines are selected from lorazepam, clonazepam, diazepam, and alprazolam.

[0485] 54. The method of aspect 52, wherein the non-benzodiazepines are selected from zolpidem, zaleplon, and eszopiclone.

[0486] 55. The method of aspect 45, wherein the muscle relaxant is selected from cyclobenzaprine, flexeril, orphenadrine citrate, tizanidine, and carisoprodol.

[0487] 56. The method of aspect 45, wherein the antipsychotic is quetiapine.

[0488] 57. An FcRn antagonist in a method for treating or preventing fibromyalgia syndrome (FMS) in an individual, wherein the FcRn antagonist inhibits the binding of IgG to the FcRn receptor.

[0489] 58. Use of an FcRn antagonist in the preparation 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. A method of 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 an anti-FcRn antibody or an FcRn-binding antibody fragment, which comprises: (a) a heavy chain or heavy chain fragment having a variable region, wherein the variable region comprises three CDRs having the sequences of CDR H1 given in SEQ ID NO:4, the sequence of CDR H2 given in SEQ ID NO:5, and the sequence of CDR H3 given in SEQ ID NO:6, and (b) a light chain or light chain fragment having a variable region, wherein the variable region comprises three CDRs having the sequences of CDR L1 given in SEQ ID NO:9, the sequence of CDR L2 given in SEQ ID NO:10, and the sequence of CDR L3 given in SEQ ID NO:

11.

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

2.

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

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

13.

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

13.

6. The method according to claim 1, 2 or 5, wherein the anti-FcRn antibody is rozelixizumab.

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

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

9. The method according to any one of claims 1-7, wherein the pain intensity of the individual on the Pain Numerical Rating Scale (Pain NRS) is equal to or greater than 6 and less than 10.

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

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

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

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

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

15. The method according to claim 14, wherein one or more symptoms of FMS are selected from pain, soreness, burning sensation, stabbing pain, hyperalgesia, allodynia, stiffness, muscle spasm, fatigue, reduced sleep quality, impaired memory, attention deficit, concentration deficit, speech disorder, headache, migraine, constipation, diarrhea, dizziness, clumsiness, anxiety, and depression.

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

17. The method according to claim 16, wherein the method reduces the BPI-SF score of the individual 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. The method according to any one of claims 1-17, wherein the method reduces the Fibromyalgia Impact Questionnaire (FIQR) score of the individual.

19. The method according to claim 18, wherein the method reduces the FIQR score of the individual 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. The method according to any one of claims 1-19, wherein the method reduces the average daily pain score of the individual.

21. The method according to claim 20, wherein the average daily pain score is measured using a numerical rating scale for pain (NRS).

22. The method according to claim 21, wherein the method reduces the average daily pain score of the individual 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. The method according to any one of claims 1-22, wherein the method reduces the fatigue score of the individual.

24. The method according to claim 23, wherein the fatigue score is measured using a fatigue numerical rating scale (NRS).

25. The method according to claim 24, wherein the method reduces the 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.

26. The method according to any one of claims 1-25, wherein administering an 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 an 80%, or at least a 90% reduction in serum IgG of an individual.

27. The method according to any one of claims 1-26, wherein administering an FcRn antagonist results in a 60-80% reduction in serum IgG level.

28. The method according to any one of claims 1-27, wherein administering an FcRn antagonist results in a reduction in serum IgG level of about 70%.

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

30. The method according to any one of claims 1-29, wherein administering an 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 an 80%, or at least a 90% reduction in anti-SGC IgG level in an individual.

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

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

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

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

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

36. The method according to any one of claims 1-35, wherein an anti-FcRn antibody or its FcRn-binding fragment 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 according to any one of claims 1-36, wherein an anti-FcRn antibody or its FcRn-binding fragment is administered once a week.

38. The method according to any one of claims 1-37, wherein the method further comprises administering a therapeutically effective amount of a second agent for treating FMS.

39. The method according to claim 38, wherein the second agent is selected from analgesics, antidepressants, dopamine agonists, antiepileptic drugs, antihistamines, hypnotics, muscle relaxants, and antipsychotics.

40. The method according to claim 39, wherein the analgesic is selected from paracetamol (acetaminophen), ibuprofen, and opioid drugs such as codeine, tramadol, morphine, and oxycodone.

41. The method according to claim 39, wherein the antidepressant is selected from tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors (SNRIs), and selective serotonin reuptake inhibitors (SSRIs).

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

43. The method according to claim 41, wherein the SNRI is selected from venlafaxine, duloxetine, desvenlafaxine, levomilnacipran, and milnacipran.

44. The method according to claim 41, wherein the SSRI is selected from citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline.

45. The method according to claim 39, wherein the antiepileptic drug is selected from gabapentin and pregabalin.

46. The method according to claim 39, wherein the hypnotic is a benzodiazepine class or a non-benzodiazepine class.

47. The method according to claim 46, wherein the benzodiazepines are selected from lorazepam, clonazepam, diazepam and alprazolam.

48. The method according to claim 46, wherein the non-benzodiazepine is selected from zolpidem, zaleplon, and eszopiclone.

49. The method according to claim 39, wherein the muscle relaxant is selected from cyclobenzaprine, flexeril, orphenadrine citrate, tizanidine, and carisoprodol.

50. The method according to claim 39, wherein the antipsychotic drug is quetiapine.

51. An FcRn antagonist in a method 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, wherein the variable region comprises three CDRs having the sequences of CDR H1 given in SEQ ID NO:4, the sequence of CDR H2 given in SEQ ID NO:5, and the sequence of CDR H3 given in SEQ ID NO:6, and (b) a light chain or light chain fragment having a variable region, wherein the variable region comprises three CDRs having the sequences of CDR L1 given in SEQ ID NO:9, the sequence of CDR L2 given in SEQ ID NO:10, and the sequence of CDR L3 given in SEQ ID NO:

11.

52. Use of an FcRn antagonist in the preparation 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, wherein the variable region comprises three CDRs having the sequences of CDR H1 given in SEQ ID NO:4, the sequence of CDR H2 given in SEQ ID NO:5, and the sequence of CDR H3 given in SEQ ID NO:6, and (b) A light chain or light chain fragment having a variable region, wherein the variable region comprises three CDRs having the sequences of CDR L1 given in SEQ ID NO:9, the sequence of CDR L2 given in SEQ ID NO:10, and the sequence of CDR L3 given in SEQ ID NO:11.

Images