Dosage and administration regimens for the treatment or prevention of Guillain-Barre syndrome with the use of the anti-C5 antibody clovalimab

Abstract

The present invention relates to dosages and administration regimens of anti-C5 antibodies, particularly the anti-C5 antibody clovalimab, for use in a method of treating or preventing GBS in a subject. The dosages and treatment regimens of the present invention comprise administering a loading dose of an anti-C5 antibody, preferably the anti-C5 antibody clovalimab, followed by administration of (a) a maintenance dose of the anti-C5 antibody to the subject, where the initial loading dose is given intravenously to the subject and the maintenance dose is administered subcutaneously at a dose lower than the intravenous loading dose.

Description

[Technical field]

[0001] The present invention relates to dosages and administration regimens of anti-C5 antibodies, particularly the anti-C5 antibody clovalimab, for use in methods of treating or preventing Guillain-Barre Syndrome (GBS). The dosages and treatment regimens of the present invention include administering a loading dose of an anti-C5 antibody, preferably the anti-C5 antibody clovalimab, to a subject, followed by a maintenance dose of the anti-C5 antibody, where an initial loading dose is given to the subject intravenously and doses are administered subcutaneously at a lower dose than the intravenous loading dose. [Background technology]

[0002] The classical pathway is usually activated by the formation of antigen-antibody complexes. Independently, the first step in the activation of the lectin pathway is the binding of specific lectins such as mannan-binding lectin (MBL), H-ficolin, M-ficolin, L-ficolin, and the C-type lectin CL-11. In contrast, the alternative pathway spontaneously undergoes low-level turnover activation, which can be easily amplified on foreign or other abnormal surfaces (bacteria, yeast, virus-infected cells, or damaged tissues). These pathways converge at the point where complement component C3 is cleaved by active proteases to generate C3a and C3b.

[0003] Guillain-Barré syndrome (GBS) is a rare but potentially fatal disease of the peripheral nerves and nerve roots, usually caused by infection. GBS is an acute, heterogeneous, paralytic inflammatory peripheral neuropathy characterized by rapidly progressive, symmetric limb weakness, leading to reduced or absent muscle response to stimuli [1].

[0004] The prognosis of GBS is determined by the extent of axonal loss during the acute phase, and if axonal damage is minimized by effective early treatment during the acute phase, sufficient nerve regeneration and concomitant sprouting from surviving motor axons can be expected several months after the disease peak. Intravenous immunoglobulin (IVIg) (400 mg / kg body weight daily for 5 days) and plasma exchange (PE) (50 mL plasma / kg body weight in 5 sessions over 1–2 weeks), both introduced in the 1980s, are established treatments for GBS and are considered equally effective as first-line treatments. PE and IVIg have been shown to accelerate recovery in the acute and subacute phases of the disease starting within 2 weeks of the onset of weakness [2, 3, 4]. Beyond these periods, evidence regarding efficacy is lacking, and it remains unclear whether these treatments will sufficiently improve the long-term outcome of patients with Guillain-Barré syndrome [3, 4]. IVIg is usually the treatment of choice, as it is easier to administer than plasma exchange and is generally widely available. Complement inhibition is a novel approach to treat GBS, and complement activation appears to contribute to neurodegeneration in GBS. Early acute treatment may prevent complement-mediated long-term neurological damage. Complement activation is thought to play a key role in the pathogenesis of all GBS variants [5]. Human proof-of-concept data supporting the use of a C5 complement inhibitor (eculizumab) is available from the phase 2 JET study in patients with severe GBS [6]. The study was a 24-week, multicenter, double-blind, placebo-controlled, randomized phase 2 trial conducted in Japan. In this study, the proportion of patients regaining walking ability by week 4, the primary endpoint, did not exceed the predefined response threshold (50%) in the eculizumab group. However, eculizumab showed potential evidence of improvement in motor function in secondary endpoints [6]. Clovalimab is a novel humanized anti-C5 monoclonal antibody [7] that binds with high affinity to the complement protein C5, thereby inhibiting its cleavage into C5a and C5b and preventing the generation of the terminal complement complex C5b-9 (MAC). Clovalimab has been demonstrated to inhibit terminal complement-mediated intravascular hemolysis in patients with paroxysmal nocturnal hemoglobinuria (PNH) [8].

[0005] Clovalimab is based on SMART-Ig (Recycling Antibody™) technology [7] with pH-dependent antigen binding. This results in efficient target disposal and enhanced neonatal fragment crystallizable receptor (FcRn) binding, improved antibody recycling efficiency, resulting in extended half-life and complement inhibition. Furthermore, the physicochemical properties of Clovalimab support the development of a highly concentrated formulation. The combination of SMART-Ig and a highly concentrated formulation allows for SC dosing every 4 weeks (Q4W).

[0006] The half-lives of IVIg and crovalimab depend on recycling through the FcRn receptor in endosomes, and the effect of IVIg coadministration on crovalimab PK takes into account the competition for binding of both molecules to the FcRn receptor to maintain C5 inhibition over 28 days. Summary of the Invention

[0007] This need is addressed by the present invention by providing the embodiments defined in the claims.

[0008] The present invention relates to an anti-C5 antibody for use in a method of treating or preventing GBS in a subject, the method comprising: (a) administering a single intravenous loading dose of 1500 mg of anti-C5 antibody to a subject; (b) subsequently administering at least one maintenance dose of 340 mg of anti-C5 antibody subcutaneously to the subject; The method includes the following continuous steps.

[0009] In the context of the present invention, the subject to be treated is preferably a patient weighing more than 100 kg. In the context of the present invention, the subject to be treated is a subject suffering from GBS.

[0010] Furthermore, the present invention relates to the use of anti-C5 antibodies for the treatment or prevention of GBS. In the context of the present invention, the present invention relates to the treatment or prevention of GBS in patients treated with a combination of an anti-C5 antibody, preferably clovalimab, and standard of care (SOC) intravenous immunoglobulin (IVIg). IVIg is a pool of immunoglobulins from the plasma of healthy donors, prepared by separating immunoglobulins from other components of the plasma. Examples of IVIg are Asceniv, Bivigam, Carimune, Cutaquig, Cuvitru, Flebogamma, Gammagard, GamaSTAN, Gammaked, Gammaplex, Gamunex-C, Hizentra, Hyqvia, Octagam, Panzyga, Privigen, Xembify. Thus, the dosage and administration regimen described herein of anti-C5 antibodies, particularly the anti-C5 antibody clovalimab, is given to patients treated with a combination of an anti-C5 antibody, preferably clovalimab, and IVIg.

[0011] Thus, the present invention relates to an anti-C5 antibody, preferably the anti-C5 antibody clovalimab, for use in a method of treating or preventing GBS in a subject, preferably a subject having a body weight of more than 100 kg, the method comprising: (a) administering a single intravenous loading dose of 1500 mg of anti-C5 antibody to a subject; (b) subsequently administering to the subject at least one loading dose of 340 mg of anti-C5 antibody subcutaneously; The method includes the following continuous steps.

[0012] "Loading dose" refers to the dose of anti-C5 antibody administered to a subject suffering from GBS at the beginning of treatment, i.e., at the beginning of a treatment regimen. In pharmacokinetics (PK), "loading dose" is the initial higher dose of drug that can be given to a patient at the beginning of a treatment course before being reduced to a lower dose. In the context of the present invention, a loading dose is given to a subject to be treated initially by intravenous administration. In the context of the present invention, a loading dose is given once at a dose of 1500 mg. Thus, in the context of the present invention, a loading dose of a composition formulated for intravenous administration is given once intravenously to a subject before one or more doses of a pharmaceutical composition formulated for subcutaneous administration are given subcutaneously.

[0013] According to the present invention, the initial dose is followed by subsequent doses of anti-C5 antibody in equal or smaller amounts at intervals sufficiently close to maintain the concentration of anti-C5 antibody above the effective target level. Thus, in the context of the present invention, (a) a maintenance dose is administered to the patient after the loading dose. "Maintenance dose" refers to a dose of anti-C5 antibody given to a subject suffering from a C5-related disease to maintain the concentration of anti-C5 antibody above a certain effective threshold of anti-C5 antibody concentration during the treatment period. In the context of the present invention, the target level of anti-C5 antibody is a median of approximately 100 μg / ml or more over the treatment period. The target level of anti-C5 concentration within the present invention can be determined in a biological sample of the subject to be treated. Means and methods for determining anti-C5 concentration in a biological sample are within the knowledge of a person skilled in the art and can be determined, for example, by immunoassay. Preferably, in the context of the present invention, the immunoassay is an ELISA. Preferably, the maintenance dose is administered to the patient subcutaneously in one or more doses of 340 mg of anti-C5 antibody. Thus, in the context of the present invention, at least one maintenance dose or more is given to the subject, and the maintenance dose is administered subcutaneously at a dose of 340 mg. In the context of the present invention, at least one maintenance dose of 340 mg of anti-C5 antibody is administered to the patient after intravenous administration of a loading dose of 1500 mg of anti-C5 antibody. The subcutaneous dose is administered subcutaneously at least once to the subject at 340 mg of anti-C5 antibody from 1 day to 3 weeks (21 days) after the start of intravenous administration of anti-C5 antibody. Thus, in the context of the present invention, a dose of 340 mg of anti-C5 antibody is administered subcutaneously to the subject at least once after 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or 21 days after the start of intravenous administration of anti-C5 antibody. Preferably, one day after the start of intravenous administration of anti-C5 antibody, a dose of 340 mg of anti-C5 antibody is administered subcutaneously to the subject. More preferably, one day after the start of intravenous administration, a single dose of 340 mg of anti-C5 antibody is administered subcutaneously. In the context of the present invention, at least one additional dose of 340 mg of anti-C5 antibody is administered subcutaneously to the subject one week (7 days), two weeks (14 days) or three weeks (21 days) after the start of intravenous administration of anti-C5 antibody.Most preferably, an additional dose of 340 mg of anti-C5 antibody is administered subcutaneously 1 week (7 days), 2 weeks (14 days) and 3 weeks (21 days) after the start of intravenous administration of anti-C5 antibody. Thus, in the context of the present invention, 1, 2, 3, 4 and / or 5 doses are administered to the subject, a loading dose is administered intravenously to the subject at a dose of 1500 mg, and 1, 2, 3 or 4 doses are administered subcutaneously to the patient at a dose of 340 mg. In the context of the present invention, subcutaneous administration of 4 loading doses, each with a dose of 340 mg of anti-C5 antibody, is preferred, with one additional dose administered subcutaneously 1 day after the start of intravenous administration of anti-C5 antibody, followed by one maintenance dose administered subcutaneously once a week 1 week, 2 weeks and 3 weeks after the start of intravenous administration of anti-C5 antibody. For example, a maintenance dose (a) corresponding to an intravenous administration of 1500 mg (day 1), followed by subcutaneous administration of 340 mg (day 2), 340 mg (day 8), 340 mg (day 15) and 340 mg (day 22) would provide a total of 2860 mg of anti-C5 antibody.

[0014] In particular, the present invention relates to an anti-C5 antibody for use in a method for treating or preventing a C5-associated disease in a subject, preferably a subject having a body weight of more than 100 kg, the method comprising: (i) administering a single intravenous loading dose of 1500 mg of anti-C5 antibody to the subject; (ii) administering a maintenance dose of 340 mg of anti-C5 antibody subcutaneously to the subject one day after initiation of intravenous administration of the anti-C5 antibody; (iii) administering a maintenance dose of 340 mg of anti-C5 antibody subcutaneously to the subject once weekly 1 week (7 days), 2 weeks (14 days), and 3 weeks (21 days) after initiation of intravenous administration of the anti-C5 antibody; The method includes the following continuous steps.

[0015] The term "intravenous administration" / "administering intravenously" in the context of the present invention refers to administration of an anti-C5 antibody into a subject's vein such that the body of the patient to be treated receives the anti-C5 antibody in approximately 15 minutes or less, preferably 5 minutes or less. For intravenous administration, the anti-C5 antibody must be formulated to be administered via a suitable device, such as, but not limited to, a syringe. In the context of the present invention, a formulation for intravenous administration comprises 50-350 mg of anti-C5 antibody, 1-100 mM buffer, such as histidine / aspartic acid with a pH of 5.5±1.0, 1-100 mM amino acid, such as arginine, and 0.01-0.1% non-ionic surfactant, such as poloxamer. Preferably in the context of the present invention, the formulation for intravenous administration is provided in a 2 mL glass vial containing the following components: 170 mg / ml of clovalimab, 30 mM histidine / aspartic acid (pH 5.8), 100 mM arginine hydrochloride and 0.05% Poloxamer 188™. The formulation is then administered to the patient within an acceptable period of time, such as 5 minutes, 15 minutes, 30 minutes, 90 minutes or less. Furthermore, the formulation for intravenous administration is given to the patient to be treated with an injection volume of 1 ml to 15 ml, preferably about 6 ml.

[0016] The term "subcutaneous administration" / "administering subcutaneously" in the context of the present invention refers to the introduction of anti-C5 antibody under the skin of an animal or human patient, preferably in a pocket between the skin and the underlying tissue, by relatively slow sustained delivery from a drug container. The pocket may be created by pulling the skin up and away from the underlying tissue. For subcutaneous administration, the anti-C5 antibody must be formulated so that it can be administered via a suitable device, such as, but not limited to, a syringe, a pre-filled syringe, an injection device, an infusion pump, a pen-type injector, a needle-free device, or via a subcutaneous patch delivery system. In the context of the present invention, a formulation for subcutaneous administration comprises 50-350 mg of anti-C5 antibody, 1-100 mM of a buffer, such as histidine / aspartic acid with a pH of 5.5±1.0, 1-100 mM of an amino acid, such as arginine, and 0.01-0.1% of a non-ionic surfactant, such as poloxamer. Preferably in the context of the present invention, the formulation for intravenous administration is provided in a 2.25 pre-filled syringe containing the following components: 170 mg / ml of clovalimab, 30 mM histidine / aspartic acid (pH 5.8), 100 mM arginine hydrochloride and 0.05% poloxamer 188™. In the context of the present invention, the formulation for subcutaneous administration is provided in a pre-filled syringe with a needle safety device. The injection device for subcutaneous administration contains about 1-15 ml or more, preferably 2.25 ml, of the formulation for subcutaneous administration containing the anti-C5 antibody. Under normal circumstances, the injection volume administered subcutaneously is 1-15 ml, preferably either 2 ml (340 mg clovalimab) or 4 ml (680 mg clovalimab). In the context of the present invention, subcutaneous administration refers to the introduction of anti-C5 antibody under the skin of the patient being treated by a relatively slow, sustained delivery from a drug reservoir over a period of time, including but not limited to, 30 minutes or less, 90 minutes or less. Optionally, administration may be performed by subcutaneous implantation of a drug delivery pump implanted under the skin of the patient being treated, the pump delivering a predetermined amount of anti-C5 antibody over a predetermined period of time, such as 30 minutes, 90 minutes, or a period spanning the length of the treatment regimen.

[0017] In the context of the present invention, the above dosage and treatment regimen can be useful for treating or preventing GBS in subjects who are co-administered with IVIg.For example, the treatment regimen of the present invention can be useful for treating patients with GBS, and the patients also receive standard treatment.Preferably, SOC is intravenous administration of IVIg.

[0018] The present invention also relates to a pharmaceutical composition for use in combination with IVIg to treat or prevent GBS, the composition comprising an anti-C5 antibody, preferably clovalimab, comprising the following administration steps: (a) administering a single intravenous loading dose of 1500 mg of anti-C5 antibody to a subject; (b) administering at least one maintenance dose of 340 mg of anti-C5 antibody subcutaneously to the subject; It is administered by

[0019] In one embodiment, (i) 1,500 mg of anti-C5 antibody is administered intravenously to the subject once (loading dose), (ii) One day after initiation of intravenous administration of anti-C5 antibody, the subject is administered 340 mg of anti-C5 antibody subcutaneously (maintenance dose).

[0020] In a further embodiment, the pharmaceutical composition comprising IVIg comprises: (a) administering 400 mg / kg of IVIg intravenously once to a subject on the same day as a loading dose of C5 antibody; (b) administering 400 mg / kg of IVIg intravenously to the subject daily, 1, 2, 3, and 4 days after the start of intravenous administration of anti-C5 antibody; It is administered by

[0021] The present invention also relates to a pharmaceutical composition for use in combination with an anti-C5 antibody, preferably clovalimab, for treating or preventing GBS, the composition comprising IVIg, the steps of: (a) administered intravenously once to a subject on the same day as a loading dose (1500 mg) of C5 antibody; (b) administering the anti-C5 antibody intravenously to the subject daily, starting 1, 2, 3, and 4 days after the start of intravenous administration; It is administered by

[0022] In one embodiment, the intravenous dose of IVIg in a) is 400 mg / kg. In a further embodiment, the intravenous dose of IVIg on days 2, 3 and 4 (step b) after the start of intravenous administration of anti-C5 antibody is 400 mg / kg per day.

[0023] In a further embodiment, a pharmaceutical composition comprising an anti-C5 antibody comprises: (i) administering 1500 mg of anti-C5 antibody intravenously to a subject (loading dose); (ii) one day after the start of intravenous administration of the anti-C5 antibody, 340 mg of the anti-C5 antibody is administered subcutaneously to the subject (maintenance dose); It is administered by

[0024] In particular, the present invention relates to a pharmaceutical composition comprising an anti-C5 antibody for use in a method for treating or preventing GBS in a subject, preferably a subject having a body weight of more than 100 kg, the method comprising: (i) administering a single intravenous loading dose of 1500 mg of anti-C5 antibody to the subject; (ii) administering a maintenance dose of 340 mg of anti-C5 antibody subcutaneously to the subject one day after initiation of intravenous administration of the anti-C5 antibody; (iii) administering a maintenance dose of 340 mg of anti-C5 antibody subcutaneously to the subject once weekly, 1 week (7 days), 2 weeks (14 days), and 3 weeks (21 days) after initiation of intravenous administration of the anti-C5 antibody. Including, Anti-C5 antibodies are used in combination with IVIg, (a) 400 mg / kg of IVIg is administered intravenously once to the subject on the same day as the loading dose of C5 antibody in (i); (b) One, two, three, and four days after the start of intravenous administration of anti-C5 antibody, subjects receive 400 mg / kg of IVIg intravenously daily.

[0025] The administration of the initial doses of anti-C5 antibody and IVIg may be administered together or separately. When anti-C5 antibody and IVIg are administered separately, they may be administered directly consecutive to each other or may be administered at an appropriate interval. For example, a loading dose of anti-C5 antibody may be given first, followed immediately by a loading dose of IVIg, or an IVIg loading dose may be administered first, followed immediately by a loading dose of anti-C5 antibody. Alternatively, the two loading doses may be administered at an appropriate interval, for example, the two loading doses may be administered at an interval of 5, 10, 15, 20, 30, 40, 50, 60 minutes, up to 2, 3, 4, 5, 6, 7, 8, 9, 10 hours, or 1-23 hours, 1-16 hours, 1-8 hours, 1-4 hours, 1-2 hours. For example, a loading dose of anti-C5 antibody is administered in the morning and the first dose of IVIg is administered in the evening, or alternatively, the first dose of IVIg is administered in the morning and a loading dose of anti-C5 antibody is administered in the evening.

[0026] The present invention also relates to a combination of an anti-C5 antibody and IVIg for use in a method for treating or preventing GBS in a subject, preferably a subject having a body weight of more than 100 kg, said method comprising: (i) administering a single loading dose of 1500 mg of anti-C5 antibody intravenously to a subject and a single intravenous administration of 400 mg / kg of IVIg on the same day; (ii) administering a maintenance dose of 340 mg of anti-C5 antibody subcutaneously to the subject one day after initiation of intravenous administration of the anti-C5 antibody, and administering 400 mg / kg of IVIg intravenously on the same day; (iii) administering 400 mg / kg of IVIg intravenously daily, 2, 3, and 4 days after the start of intravenous administration of anti-C5 antibody; (IV) administering a maintenance dose of 340 mg of anti-C5 antibody subcutaneously to the subject once a week, 1 week (7 days), 2 weeks (14 days), and 3 weeks (21 days) after initiation of intravenous administration of the anti-C5 antibody; The method includes the following continuous steps.

[0027] The administration of the initial doses of anti-C5 antibody and IVIg may be administered together or separately. When anti-C5 antibody and IVIg are administered separately, they may be administered directly consecutive to each other or may be administered at an appropriate interval. For example, a loading dose of anti-C5 antibody may be given first, followed immediately by a loading dose of IVIg, or an IVIg loading dose may be administered first, followed immediately by a loading dose of anti-C5 antibody. Alternatively, the two loading doses may be administered at an appropriate interval, for example, the two loading doses may be administered at an interval of 5, 10, 15, 20, 30, 40, 50, 60 minutes, up to 2, 3, 4, 5, 6, 7, 8, 9, 10 hours, or 1-23 hours, 1-16 hours, 1-8 hours, 1-4 hours, 1-2 hours. For example, a loading dose of anti-C5 antibody is administered in the morning and the first dose of IVIg is administered in the evening, or alternatively, the first dose of IVIg is administered in the morning and a loading dose of anti-C5 antibody is administered in the evening.

[0028] In the context of the present invention, a "week" refers to a period of 7 days.

[0029] In the context of the present invention, a "month" refers to a period of four weeks.

[0030] In the context of the present invention, a "treatment" includes a successive series of an "induction treatment" and at least one "maintenance treatment." Typically, a treatment according to the present invention includes an "induction treatment" and at least one "maintenance treatment." Typically, a treatment according to the present invention may be for 3 weeks to 1 month, for example 28 days.

[0031] The "induction treatment" consists of intravenously administering a loading dose, preferably a dose of 1500 mg, of anti-C5 antibody to the subject. As described herein above, the "maintenance treatment" consists of a successive series of (i) a maintenance period in which one or more maintenance doses are given subcutaneously to the subject. In the context of the present invention, it is preferred that a maintenance dose of 340 mg of anti-C5 antibody is given to the subject 1 day, 1 week (after 7 days), 2 weeks (after 14 days) and 3 weeks (after 21 days) after the intravenously administered loading dose is given to the subject. Preferably, the intravenously administered loading dose has a dose of 1500 mg. The maintenance dose given subcutaneously to the treated subject has a dose of 1360 mg. Thus, in the context of the present invention, a dose of 2360 mg of anti-C5 antibody is administered either intravenously or subcutaneously to the treated subject during the treatment period.

[0032] In the context of the present invention, the anti-C5 antibody is preferably clovalimab. Details of the sequence of the anti-C5 antibody clovalimab (CAS number: 1917321-26-6) are disclosed in the proposed list of International Non-proprietary Names for Pharmaceutical Substances (INN) No. 119, published in WHO Drug Information (2018), Vol. 32, No. 2, pages 302 and 303. The sequence of the anti-C5 antibody clovalimab is also shown in SEQ ID NO: 1 (heavy chain) and SEQ ID NO: 2 (light chain). The production of the anti-C5 antibody clovalimab used in the present invention is described in WO 2016 / 098356 (see Example 1.1 for details). Furthermore, in the context of the present invention, the anti-C5 antibody clovalimab is administered to the patient by a formulation for either intravenous or subcutaneous administration. In the context of the present invention, preferably (a) intravenous or subcutaneous administration of the dose provided herein as a fixed dose.

[0033] A formulation for intravenous administration comprises 50-350 mg of the anti-C5 antibody clovalimab, 1-100 mM of a buffering agent, such as histidine / aspartic acid with a pH of 5.5±1.0, 1-100 mM of an amino acid, such as arginine, and 0.01-0.1% of a non-ionic surfactant, such as poloxamer. Preferably in the context of the present invention, the formulation for intravenous administration is provided in a 2 mL glass vial containing the following components: 170 mg / ml clovalimab, 30 mM histidine / aspartic acid (pH 5.8), 100 mM arginine hydrochloride, and 0.05% poloxamer 188™.

[0034] A formulation for subcutaneous administration comprises 50-350 mg of the anti-C5 antibody clovalimab, 1-100 mM of a buffer, such as histidine / aspartic acid with a pH of 5.5±1.0, 1-100 mM of an amino acid, such as arginine, and 0.01-0.1% of a non-ionic surfactant, such as poloxamer. Preferably in the context of the present invention, a formulation for intravenous administration is provided in a 2.25 pre-filled syringe containing the following components: 170 mg / ml clovalimab, 30 mM histidine / aspartic acid (pH 5.8), 100 mM arginine hydrochloride, and 0.05% poloxamer 188™.

[0035] The patient described in the context of the present invention is a patient suffering from GBS. The preferred patient in the context of the present invention is a patient with a body weight of more than 100 kg. In the context of the present invention, the patient is preferably co-administered with IVIg.

[0036] Preferably, IVIg is administered to a subject suffering from GBS in combination with an anti-C5 antibody, 400 mg / kg of IVIg is (a) administered intravenously once to a subject on the same day as a loading dose (1500 mg) of C5 antibody; (b) 1, 2, 3, and 4 days after the start of intravenous administration of anti-C5 antibody, the subject is administered the antibody intravenously daily.

[0037] The present invention further provides a method of treating or preventing a C5-related disease in a subject, the method comprising: (a) administering a single intravenous loading dose of 1500 mg of anti-C5 antibody to a subject; (b) administering at least one maintenance dose of 340 mg of anti-C5 antibody subcutaneously to the subject; The method includes the following continuous steps.

[0038] In the context of the present invention, a method for treating or preventing a C5-related disease in a subject comprises the following administration steps: (i) administering a single intravenous loading dose of 1500 mg of anti-C5 antibody to the subject; (ii) administering a maintenance dose of 340 mg of anti-C5 antibody subcutaneously to the subject one day after initiation of intravenous administration of the anti-C5 antibody; (iii) administering a loading dose of 340 mg of anti-C5 antibody subcutaneously to the subject once weekly, 1 week, 2 weeks, and 3 weeks after the start of intravenous administration of the anti-C5 antibody; It is preferably carried out by:

[0039] In the context of the present invention, a method for treating or preventing a C5-related disease in a subject comprises administering to a subject: (i) administering a single loading dose of 1500 mg of anti-C5 antibody intravenously to a subject and a single intravenous administration of 400 mg / kg of IVIg on the same day; (ii) administering a maintenance dose of 340 mg of anti-C5 antibody subcutaneously to the subject one day after initiation of intravenous administration of the anti-C5 antibody, and administering 400 mg / kg of IVIg intravenously on the same day; (iii) administering 400 mg / kg of IVIg intravenously daily, 2, 3, and 4 days after the start of intravenous administration of anti-C5 antibody; (IV) administering a maintenance dose of 340 mg of anti-C5 antibody subcutaneously to the subject once a week, 1 week (7 days), 2 weeks (14 days), and 3 weeks (21 days) after initiation of intravenous administration of the anti-C5 antibody; It is even more preferable that the process is carried out by the steps of:

[0040] As explained above, in the context of the present invention, the anti-C5 antibody used in the context of dosage and administration regimen is preferably clovalimab.Furthermore, the above definitions also apply to the above method of treating or preventing C5-related disease.In addition, in the context of the present invention, the subject to be treated preferably has a body weight of more than 100 kg. [Brief description of the drawings]

[0041] The drawings show: [Figure 1] Radiolabeled IVIg pharmacokinetics in serum and total radioactivity as a percentage of injected dose. [Figure 2A] From Kendrick F, Evans ND, Berlanga O, Harding SJ, Chappell MJ.Parameter identification for a model of neonatal Fc receptor-mediated recycling of endogenous immunoglobulin G in humans.Front Immunol.10.(2019). [Diagram 2] Mean (SEM) M281 PK profile from a single ascending dose in a First-in-Human study in healthy volunteers for five different doses. Figure extracted from Momenta R&D Day 2018 presentation. [Diagram 3] Mean serum IgG concentrations as percentage of baseline (%) as a function of M281 dose in single ascending dose (SAD) and multiple ascending dose (MAD) studies. Figure extracted from Ling LE, Hillson JL, Tiessen RG, et al. M281, an Anti-FcRn Antibody: Pharmacodynamics, Pharmacokinetics, and Safety Across the Full Range of IgG Reduction in a First-in-Human Study. Clin Pharmacol Ther. (2018). [Figure 4]PK / PD model of clovalimab, C5, IgG, M281 in serum and their recycling in endosomes by FcRn. Each box corresponds to the concentration of the entity (nM) defined in Table 4. [Ab1], [Ab1Ag], [AgAb1Ag], [Ag], [IgG], [IgG*], [M281] are the concentrations in the central fraction. [Ab1]p, [Ab1Ag]p, [AgAb1Ag]p are the concentrations in the peripheral fraction. CLAb1 and CLAg are the clearance of free Ab1 and free Ag (L / day / kg). CLe, Ab1, CLe, Ab1Ag, CLe, AgAb1Ag, CLe, IgG, CLe, M281 are the clearance of Ab1, Ab1Ag, AgAb1Ag, IgG, and M281 to endosomes (L / day / kg). CLe, Ab1 recy, CLe, IgG recy, CLe, M281 recy are the clearances of Ab1, IgG and M281 from endosomes to plasma (L / day / kg). Ab1, IgG and M281 that are not bound to FcRn are cleared (once a day) at rates defined by the elimination constants ke, Ab1, ke, IgG and ke, M281. Vc, Vc IgG and Vc M281 are the volumes of the central fraction of Ab1 / Ag, IgG and M281 (L / kg). VpAb1, VpAb1Ag, Vp AgAb1Ag and Vp IgG are the volumes of the peripheral fraction (L / kg). Q Ab1 and Q IgG are the interfraction clearances (L / day / kg). kinAg:Ag generation rate (nmol / day), konAb1 (nM / day) and koffAb1 (1 / day) are the association and dissociation rates of Ab1 with Ag. [Diagram 5] ODE equation for the binding model of Ag and Ab1 in serum. [Figure 6] ODE formula for IgG, IgG*, and M281 in serum. [Figure 7] ODE expression of Ab1, IgG, IgG*, and M281 in endosomes. [Figure 8] FIG. 1 shows Ab1 disposition term from serum to endosomes and Ab1 recycling term from endosomes to serum. [Figure 9] Expression of Ab1 in endosomes. [Figure 10] Model individual fit for total Ab1, total Ag and free Ag for COMPOSER Part 1 (healthy volunteer subjects 11001-11007). Each column corresponds to a subject and the rows correspond to total Ab1 (aka [Ab1] total = [Ab1] + [Ab1Ag] + [AgAb1Ag]), total Ag (aka [Ag] total = [Ag] + [Ab1Ag] + 2 [AgAb1Ag]) and free Ag (aka [Ag]), respectively. Concentrations observed in the COMPOSER study (Example 2.1) are displayed as black dots and the solid lines are simulations performed using the empirical Bayes model parameter estimates for each subject. [Figure 11] Model individual fit for total Ab1, total Ag and free Ag for COMPOSER part 1 (healthy volunteer subjects 11008-11015). Each column corresponds to a subject and the rows correspond to total Ab1 (aka [Ab1] total = [Ab1] + [Ab1Ag] + [AgAb1Ag]), total Ag (aka [Ag] total = [Ag] + [Ab1Ag] + 2 [AgAb1Ag]) and free Ag (aka [Ag]), respectively. Concentrations observed in the COMPOSER study (Example 2.1) are displayed as black dots and the solid lines are simulations performed using the empirical Bayes model parameter estimates for each subject. [Figure 12] Model individual fits for Total Ab1, Total Ag and Free Ag in COMPOSER Part 2 (Naive PNH Patients). Each column corresponds to a subject and rows correspond to Total Ab1 (aka [Ab1] Sum = [Ab1] + [Ab1Ag] + [AgAb1Ag]), Total Ag (aka [Ag] Sum = [Ag] + [Ab1Ag] + 2 [AgAb1Ag]) and Free Ag (aka [Ag]), respectively. Concentrations observed in the COMPOSER study (Example 2.1) are displayed as black dots and the solid lines are simulations performed using the empirical Bayes model parameter estimates for each subject. [Figure 13]Model individual fits for Total Ab1, Total Ag and Free Ag in COMPOSER Part 4 (Naive PNH Patients). Each column corresponds to a subject and rows correspond to Total Ab1 (aka [Ab1] Sum = [Ab1] + [Ab1Ag] + [AgAb1Ag]), Total Ag (aka [Ag] Sum = [Ag] + [Ab1Ag] + 2 [AgAb1Ag]) and Free Ag (aka [Ag]), respectively. Concentrations observed in the COMPOSER study (Example 2.1) are displayed as black dots and the solid lines are simulations performed using the empirical Bayes model parameter estimates for each subject. [Figure 14] Model individual fits of radiolabeled IgG* in serum (top panel) and total body radioactivity normalized by injected dose (bottom panel). Each column corresponds to a subject and rows represent normalized IgG* in serum (i.e., [IgG*]*Vc IgG / dose), total radioactivity (i.e., [Vc IgG*[IgG*]+Vp IgG*[IgG*]p+Ve*([IgG*]e+[IgG*-FcRn]e)] / dose). Observations from the radiolabeled study (Example 2.2) are displayed in black. Dots and solid lines are simulations performed using the empirical Bayes model parameter estimates per subject. [Figure 15] Model individual fit for M281PK and endogenous IgG normalized by baseline IgG levels. Each column corresponds to the average data for each SAD and MAD study arm, and the rows correspond to the ratio of M281PK (aka [M281]) and endogenous IgG to its baseline value (aka [IgG] / [IgG] baseline). Observations from the M281 SAD and MAD studies (Example 2.3) are shown as black dots. The solid lines are simulations performed using the empirical Bayes model parameter estimates for each study arm. [Figure 16]Simulated median and min / max time profiles for 33 subjects receiving either clovalimab alone (black) or clovalimab with IVIg (blue). All concentrations are in uM. Simulated median (solid line) and min / max (dotted line) time profiles for 33 subjects receiving either clovalimab alone (black line) or clovalimab with IVIg (blue line); clovalimab regimen: 1000mg IV on day 1 for patients <100kg and 1500mg IV for patients >100kg, followed by 340mg SC on days 2, 8, 15, and 22. IVIg regimen: 400mg / kg on days 1, 2, 3, 4, and 5. Each panel corresponds to a different output of the model: total Crova = [Ab1] + [Ab1Ag] + [AgAb1Ag], total C5 = [Ag] + [Ab1Ag] + 2[AgAb1Ag], total IgG = [IgG], Crova free paratope = 2[Ab1] + [Ab1Ag], free crova = [Ab1], free C5 = [Ag]. All concentrations are expressed in uM. [Figure 17] Sensitivity analysis #1: Divide the [FcRn] total concentration by a factor of 2. Simulated median and min / max time profiles for 33 subjects receiving clovalimab alone (black) or clovalimab with IVIg (blue). All concentrations are in uM. Simulated median (solid line) and min / max (dotted line) time profiles for 33 subjects receiving either clovalimab alone (black line) or clovalimab with IVIg (blue line); clovalimab regimen: 1000 mg IV on day 1 for patients <100 kg, 1500 mg IV for patients >100 kg, followed by 340 mg SC on days 2, 8, 15, and 22. IVIg regimen: 400 mg / kg on days 1, 2, 3, 4, and 5. Each panel corresponds to a different output of the model: total Crova = [Ab1] + [Ab1Ag] + [AgAb1Ag], total C5 = [Ag] + [Ab1Ag] + 2[AgAb1Ag], total IgG = [IgG], Crova free paratope = 2[Ab1] + [Ab1Ag], free crova = [Ab1], free C5 = [Ag]. All concentrations are expressed in uM. [Figure 18]Sensitivity analysis #2: Ve multiplied by 10. Simulated median and min / max time profiles for 33 subjects receiving clovalimab alone (black) or clovalimab with IVIg (blue). All concentrations are in uM. Simulated median (solid line) and min / max (dotted line) time profiles for 33 subjects receiving either clovalimab alone (black line) or clovalimab with IVIg (blue line); clovalimab regimen: 1000 mg IV on day 1 for patients <100 kg and 1500 mg IV for patients >100 kg, followed by 340 mg SC on days 2, 8, 15, and 22. IVIg regimen: 400 mg / kg on days 1, 2, 3, 4 and 5. Each panel corresponds to a different output of the model, i.e. total Crova = [Ab1] + [Ab1Ag] + [AgAb1Ag], total C5 = [Ag] + [Ab1Ag] + 2[AgAb1Ag], total IgG = [IgG], Crova free paratope = 2[Ab1] + [Ab1Ag], free crova = [Ab1], free C5 = [Ag]. All concentrations are expressed in uM. [Figure 19] Sensitivity analysis #3: IgG baseline multiplied by 2. Simulated median and min / max time profiles for 33 subjects receiving clovalimab alone (black) or clovalimab with IVIg (blue). All concentrations are in uM. Simulated median (solid line) and min / max (dotted line) time profiles for 33 subjects receiving either clovalimab alone (black line) or clovalimab with IVIg (blue line); clovalimab regimen: 1000 mg IV on day 1 for patients <100 kg and 1500 mg IV for patients >100 kg followed by 340 mg SC on days 2, 8, 15, and 22. IVIg regimen: 400 mg / kg on days 1, 2, 3, 4, and 5. Each panel corresponds to a different output of the model, i.e., Total Crova = [Ab1] + [Ab1Ag] + [AgAb1Ag], Total C5 = [Ag] + [Ab1Ag] + 2 [AgAb1Ag], Total IgG = [IgG], Crova free paratope = 2. [Ab1] + [Ab1Ag], free crova = [Ab1], free C5 = [Ag]. All concentrations are expressed in uM. [Figure 20] Sensitivity analysis #4: C5 baseline multiplied by 2. Simulated median and min / max time profiles for 33 subjects receiving clovalimab alone (black) or clovalimab with IVIg (blue). All concentrations are in uM. Simulated median (solid line) and min / max (dotted line) time profiles for 33 subjects receiving either clovalimab alone (black line) or clovalimab with IVIg (blue line); clovalimab regimen: 1000 mg IV on day 1 for patients <100 kg and 1500 mg IV for patients >100 kg followed by 340 mg SC on days 2, 8, 15, and 22. IVIg regimen: 400 mg / kg on days 1, 2, 3, 4, and 5. Each panel corresponds to a different output of the model, i.e., Total Crova = [Ab1] + [Ab1Ag] + [AgAb1Ag], Total C5 = [Ag] + [Ab1Ag] + 2 [AgAb1Ag], Total IgG = [IgG], Crova free paratope = 2. [Ab1] + [Ab1Ag], free crova = [Ab1], free C5 = [Ag]. All concentrations are expressed in uM. [Figure 21]Simulated median and min / max time profiles for 33 subjects receiving clovalimab alone (black) or clovalimab with IVIg (blue). All concentrations are in uM. Simulated median (solid line) and min / max (dotted line) time profiles for 33 subjects receiving either clovalimab alone (black line) or clovalimab with IVIg (blue line); clovalimab regimen: 1000 mg IV on day 1 for patients <100 kg and 1500 mg IV for patients >100 kg followed by 340 mg SC on days 2, 8, 15, and 22. IVIg regimen: 400 mg / kg on days 1, 2, 3, 4, and 5. Each panel corresponds to a different output of the model, i.e., Total Crova = [Ab1] + [Ab1Ag] + [AgAb1Ag], Total C5 = [Ag] + [Ab1Ag] + 2 [AgAb1Ag], Total IgG = [IgG], Crova free paratope = 2. [Ab1] + [Ab1Ag], Free crova = [Ab1], Free C5 = [Ag], Endo:Free IgG = [IgG]e, Endo:Free Crova = [Ab1]e, Endo:Crova-FcRn = [Ab1-FcRn]e, Endo:Free IgG = [IgG]e, Endo:IgG-FcRn = [IgG-FcRn]e. All concentrations are expressed in uM. [Figure 22] Simulated individual, median and min / max time profiles for 33 subjects receiving clovalimab alone. All concentrations are in uM. Individual (continuous thick purple line), median (continuous thick black line) and min / max (dotted line) simulated time profiles for 33 subjects receiving clovalimab alone; clovalimab regimen: 1000mg IV on day 1 for patients <100kg and 1500mg IV for patients >100kg, followed by 340mg SC on days 2, 8, 15, and 22. Each panel corresponds to a different output of the model, i.e., Total Crova = [Ab1] + [Ab1Ag] + [AgAb1Ag], Total C5 = [Ag] + [Ab1Ag] + 2 [AgAb1Ag], Total IgG = [IgG], Crova free paratope = 2. [Ab1] + [Ab1Ag], free crova = [Ab1], free C5 = [Ag]. All concentrations are expressed in uM. [Diagram 23] Simulated individual, median and min / max time profiles for 33 subjects receiving clovalimab and IVIg. All concentrations are in uM. Individual (continuous thick purple line), median (continuous thick black line) and min / max (dotted line) simulated time profiles for 33 subjects receiving crovalimab and IVIg; crovalimab regimen: 1000 mg IV on day 1 for patients <100 kg and 1500 mg IV for patients >100 kg followed by 340 mg SC on days 2, 8, 15, and 22. IVIg regimen: 400 mg / kg on days 1, 2, 3, 4 and 5. Each panel corresponds to a different output of the model, i.e., Total Crova=[Ab1]+[Ab1Ag]+[AgAb1Ag], Total C5=[Ag]+[Ab1Ag]+2[AgAb1Ag], Total IgG=[IgG], Crova free paratope=2. [Ab1] + [Ab1Ag], free crova = [Ab1], free C5 = [Ag]. All concentrations are expressed in uM. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0042] Working Example The following examples illustrate the invention. Example 1: Antibodies and Clinical Trials 1.1 Clovalimab The sequence of the anti-C5 antibody clovalimab is shown in SEQ ID NO: 1 (heavy chain) and SEQ ID NO: 2 (light chain). Furthermore, the production of the anti-C5 antibody clovalimab used in the present invention is described in WO 2016 / 098356. Briefly, the gene encoding the heavy chain variable domain (VH) of 305LO15 (SEQ ID NO: 3) was combined with the gene encoding the modified human IgG1 heavy chain constant domain (CH) mutant SG115 (SEQ ID NO: 4). The gene encoding the light chain variable domain (VL) of 305LO15 (SEQ ID NO: 5) was combined with the gene encoding the human light chain constant domain (CL) (SK1, SEQ ID NO: 6). The antibody was expressed in HEK293 cells co-transfected with a combination of heavy and light chain expression vectors and purified by protein.

[0043] 1.2 Clinical Trials BN43118 is a Phase III randomized, double-blind, placebo-controlled, multicenter clinical study evaluating the efficacy, safety, pharmacokinetics (PK) and pharmacodynamics (PD) of clovalimab compared to placebo as add-on therapy to standard of care (SOC) for the treatment of patients with Guillain-Barré syndrome (GBS). The study will enroll approximately 136 participants randomized to double-blind treatment in a 1:1 ratio to receive either clovalimab or placebo in addition to background therapy. Blinded study medication (clovalimab or placebo) will be administered intravenously on day 1 and subcutaneously on days 2, 8, 15 and 22 in addition to SOC (IVIg). Patients who receive background therapy before study day 1 must be able to receive their first dose of blinded study medication before their last dose of background therapy. The study will consist of four periods: a 5-day screening period, a 4-week treatment period, and a 24-week post-treatment follow-up.

[0044] As the half-lives of IVIg and crovalimab depend on recycling by the FcRn receptor in endosomes [9], a mathematical model was constructed to describe the impact of IVIg coadministration on crovalimab PK, taking into account the binding competition of both molecules to the FcRn receptor. This model is an extension of the crovalimab PK / PD model that describes the binding of crovalimab to C5 developed for PNH-naive patients and reported in

[10] with the addition of FcRn competition between IVIg and crovalimab in endosomes. This report details the various components and assumptions of this model, as well as its calibration based on crovalimab COMPOSER clinical data

[11] and literature data on the pharmacokinetics (PK) of IVIg. Simulations were performed to measure the impact of IVIg infusion on the PK / PD of crovalimab and to evaluate whether complete C5 inhibition could be maintained over a 28-day period.

[0045] Example 2: Data used for modeling Three sets of data were pooled to calibrate the combined IVIg PK and crovalimab PK / PD model. · Crovalimab COMPOSER Clinical Study PK / PD Data: Individual patient data were used to estimate crovalimab PK as well as the binding parameters of crovalimab to C5. IVIg PK data: Radiolabeled PK time course profiles of IVIg

[12] were used to estimate IVIg PK parameters in serum and endosomes. · M281 PK / PD data: The PK time course of the monoclonal anti-FcRn antibody M281

[13] and its effect on endogenous IgG were used to estimate endosomal volume and FcRn receptor concentration.

[0046] Clovalimab COMPOSER data, IVIg PK data and M281 PK / PD data are described in Example 2.1, Example 2.2 and Example 2.3, respectively. The values ​​of clovalimab, IVIg and M281 binding to FcRn, required to establish the model, were fixed to their in vitro values ​​measured by surface plasmon resonance (SPR) as detailed in Example 2.4. Finally, the baseline value of IgG was fixed to a value representing the average level reported in the literature and described in Example 2.5. The data check and assembly process is the same as that described in

[10] .

[0047] 2.1 COMPOSER Research BP39144 COMPOSER is a four-part, first-in-human study

[11] designed to evaluate the safety, tolerability, PK, and PD of clovalimab in healthy volunteers (HV; part 1), as well as in eculizumab-naive PNH patients (parts 2 and 4) and in PNH patients switching from eculizumab to clovalimab (parts 3 and 4). Further details regarding the study design, doses and regimens used, and samples collected are presented in

[10] .

[0048] HV and naïve PNH patients (not previously treated with eculizumab) data available in the clinical database on the cutoff date of January 29, 2020 were included in this analysis. Of note, data from patients who switched from eculizumab to clovalimab (parts 3 and 4) were not used in this analysis because GBS patients enrolled in the BN43118 study were C5 inhibitor treatment naïve

[10] . Concentrations of clovalimab, total C5, and free C5 were converted in molar units (i.e., nM) using molecular weights of 190 kDa and 149 kDa for C5 and clovalimab, respectively. Dose amounts and dose rates were normalized by each subject's body weight at baseline and converted in molar units (i.e., amounts are in nmol / kg and infusion rates for IV administration are in nmol / day / kg).

[0049] The numbers of samples available for analysis from the COMPOSER study for total crovalimab, free and total C5 in serum are shown in Table 1. [Table 1]

[0050] 2.2 IVIG PK time profile The IVIg PK time profiles for six individuals shown in Figure 1 were extracted from the literature on the IVIg radiolabeled study by Kendrik et al.

[12] . Data for each subject consisted of the time course of the fraction of the injected dose of IVIg remaining in the serum and the time course of the fraction of the dose remaining in the body. Some individuals have health conditions that may result in different PK half-lives and increased or decreased serum IgG concentration levels. However, the subjects' health conditions were not considered in this analysis.

[0051] 2.3 M281 PK / PD Time Profile To quantify endosomal volume and the number of FcRn receptors available in endosomes, data from M281 monoclonal IgG1 anti-FcRn antibody

[13] , a high affinity FcRn binder (Kd = 28.7 pM at pH = 6.0), were used for model calibration. Mean PK profiles from a first-in-human (FIH) single ascending dose (SAD) study in healthy volunteers for doses of 3 mg / kg (n = 3), 10 mg / kg (n = 6), 30 mg / kg (n = 6) and 60 mg / kg (n = 6) were extracted from Figure 2 (reported in

[14] ). As the PK profile in the M281 MAD study was not available in the literature, only the SAD study informed the PK of the IgG. M281 has high affinity for FcRn at endosomal pH = 6.0 and blocks the binding of endogenous IgG to FcRn, lowering serum IgG concentrations. Figure 3 shows the decrease in the mean serum endogenous IgG profile for increasing doses of M281 in the SAD and MAD studies. These data provide information on the mean levels of FcRn receptors available for IgG recycling in endosomes. Mean serum IgG concentrations (as a percentage of baseline) were extracted from this figure for SAD doses of 3 mg / kg (n=3), 10 mg / kg (n=6), 30 mg / kg (n=6) and 60 mg / kg (n=5) and for MAD doses of 15 mg / kg (n=3), 30 mg / kg (n=3).

[0052] Note that the MAD time profile of IgG was used for model calibration even though the PK profile in the M281 MAD study was not available. Because individual subject data was not available for M281, we assume that each mean profile of the different dose arms in the SAD and MAD studies corresponds to a different "individual" in the data set used for model calibration (including individual data of clovalimab and individual radiolabeled IgG PK profiles).

[0053] 2.4 Binding of clovalimab, IVIG and M281 FcRn To model the interactions of clovalimab, IgG, and M281 with the FcRn receptor in endosomes, the in vitro association rate constants k and dissociation rate constants k between clovalimab, IgG, M281, and FcRn were obtained from the literature and reported in Table 2. [Table 2]

[0054] 2.5 IgG baseline concentration Because endogenous baseline IgG concentrations were not available in any of the data sets, we assume that all patients had the same baseline IgG concentration for model calibration and simulations. This concentration was fixed at 1 g / dL (i.e., 66.7 uM assuming a molecular weight of 150e3 g / mol for IgG) because the normal IgG concentration range in adults has been reported to be 0.767 g / dL–1.59 g / dL

[17] .

[0055] Example 3: Modeling 3.1 Method a) Model calibration strategy A pooled dataset consisting of the clovalimab COMPOSER, IVIg PK and M281 PK / PD data (and described in Example 2) was used for the joint calibration of the clovalimab PK / PD, IVIg PK and M281 PK / PD models. Population estimates were obtained using a Non-Linear Mixed Effect (NLME) approach, and individual parameter estimates were derived using empirical Bayes estimates (EBE) as described in

[10] .

[0056] 3b) Software Nonlinear mixed-effects analyses were performed using the Monolix software system, version 2019R2 (Lixoft, Paris, France) to obtain parameter estimates. Simulations were performed in the R package mlxR version 4.1.5 in the R environment version 3.6.3.

[0057] c) Patient Data Inclusion Criteria All available subject / patient data from COMPOSER parts 1, 2 and 4 listed in Table 1 were included in this analysis.

[0058] d) Notation In the following of the literature, the compact notation defined in Table 3 is used to represent the serum concentrations of clovalimab, C5, endogenous IgG or IVIg, radiolabeled IVIg, M281, and the complex formed by binding of clovalimab with C5. Some of these quantities are also estimated in the peripheral fraction (with the suffix p) and endosomes (with the suffix e). [Table 3]

[0059] 3.2. Model for Ab1, Ag, IVIg, and M281 with FcRn recycling in endosomes a) Model description A model illustrating the binding of Ab1 (Clovalimab) to Ag (C5) and competition with IgG for FcRn recycling in endosomes is shown in Figure 4. It includes the following components: □Ab1 PK / PD model in serum: The top part of Figure 4 includes two binding submodels (described in

[10] ) describing the sequential binding process of one Ag protein to one arm of the free Ab1 antibody to form the complex Ab1Ag, followed by a second Ag protein binding to the second arm of the same antibody to form the complex AgAb1Ag. We included peripheral distribution fractions for free and bound Ab1 with two different distribution volumes for free Ab1 and complex Ab1Ag and Ag Ab1Ag. During the modeling process, it was observed that the data did not support the addition of the peripheral fraction of Ag. The ordinary differential equations (ODEs) describing the concentrations of free Ab1 (i.e., [Ab1]), free Ag (i.e., [Ag]), and Ab1 bound to one Ag (i.e., [Ab1Ag]) and two Ags (i.e., [AgAb1Ag]) are shown in Figure 5. · IgG PK model in serum: The lower left part of Figure 4 is a two-compartment linear configuration model of endogenous IgG or IVIg and radiolabeled IVIg (annotated with an asterisk, i.e. IgG*). The volume of distribution and clearance are assumed to be identical for IgG and IgG*. The ODEs describing the concentrations of IgG and IgG* in serum are shown in Figure 6. · M281 PK model in serum: A one-compartment linear configuration model is used to describe M281 PK. The ODE describing the concentration of M281 in serum is shown in Figure 6. · Endosome model: After internalization into endosomes, clovalimab, IgG, IgG* and M281 antibodies can bind to FcRn and be recycled to serum. Antibodies that did not bind to FcRn are excluded from endosomes. Because Ab1 was engineered with pH-dependent recycling technology (i.e. SMART-Ig Recycle®), we hypothesize that when the antibody is internalized in endosomes, Ag dissociates from the antibody complexes Ab1Ag and AgAb1Ag due to a 1000-fold increase in the dissociation constant KdAb1 (see [7]). Therefore, only free Ab1 is present in endosomes. The ODE describing the binding to FcRn in endosomes is shown in Figure 7.

[0060] The definitions and descriptions of the model parameters are given in Table 4. [Table 4]

[0061] The binding constants konAb1-Ag and koffAb1-Ag represent the binding of one arm of the Ab1 antibody to an Ag. Thus, a free antibody with two available free Fab arms has twice the probability of binding to a free Ag than an antibody with one arm already bound to one Ag. This is reflected in the model equation as 2konAb1-Ag in the binding equation for free Ab1 in Figure 5. Similarly, an antibody bound to two Ags has twice the probability of losing an Ag molecule than an antibody bound to only one Ag. This is reflected in the equation describing the dissociation of two Ags bound to an antibody (i.e., AgAb1Ag) by a factor of two for the dissociation rate, i.e., 2 koffAb1 in Figure 5.

[0062] To account for endosomal internalization of Ab1 and FcRn recycling, a clearance term CLe,Ab1 is added with a negative sign to the ODE equation for Ab1 in serum as shown in FIG. 8. The same term appears with a positive sign (and after adjustment for the different distribution volumes between serum Vc and endosomes Ve) in the equation describing free Ab1 in endosomes as shown in FIG. 9. After binding to FcRn, Ab1 is recycled to serum via the clearance term CLe,Ab1 recy, which has a negative sign in the ODE equation for the complex Ab1-FcRn in endosomes in FIG. 9 and a positive sign in the serum equation for Ab1 in FIG. 8. Ab1 antibody not bound to FcRn in endosomes is eliminated with the term ke,Ab1 in FIG. 9.

[0063] Similar parameters and equations were introduced into the model to describe the internalization and recycling of IgG, IgG* and M281, as shown in FIG.

[0064] b) Summary of model assumptions The main hypotheses of the model are: · The binding rates of Ag to Ab1 (konAb1-Ag and koffAb1-Ag) are identical when the second arm of the Ab1 antibody is free or already bound to another Ag protein. · koffAb1 was set to a fixed value for each subject, assuming that in vitro surface plasmon resonance (SPR) estimation of this constant reflects the in vivo situation. · Binding of Ag to Ab1 occurs only in central compartments (not in peripheral tissues). · The production rate (kinAg) and excretion rate (CLAg) of endogenous Ag are constant over time. -Endosomal clearance is linear and not saturable In the endosome, the pH-dependent recycling technology SMART-Ig Recycling® assumes that Ab1 is not bound to Ag, so only free Ab1 antibody is recycled (i.e. Ab1Ag and AgAb1Ag are recycled as Ab1). Assume that total [FcRn] concentrations remain constant over time. The FcRn recycling process from endosomes to serum is hypothesized to be linear (after binding to FcRn) and not saturable. · Because albumin binds to a different FcRn epitope than IgG, we believe that albumin is not involved in the FcRn recycling saturation process of IgG antibodies. Only free Ab1, IgG, IgG* and M281 are cleared from endosomes (i.e. all molecules bound to FcRn are recycled to serum) We assume the same efflux constant in endosomes for Ab1, IgG, IgG* and M281, i.e. keAb1=keIgG=keM281. -We hypothesize that antibody clearance from the body occurs exclusively within endosomes. Therefore, other parallel processes that require the addition of other emission constants are not considered.

[0065] Example 4: Simulation and sensitivity analysis 4.1 Base case simulation Simulations of patients receiving either clovalimab alone or coadministered with IVIg (both treatments initiated on the same day) were performed using the following regimens: Clovalimab: 1000 mg IV on day 1 for patients <100 kg and 1500 mg IV for patients >100 kg, followed by 340 mg SC on days 2, 8, 15, and 22 IVIg: 400mg / kg on days 1, 2, 3, 4 and 5 Simulations were performed using EBEs obtained from the 33 subjects from the COMPOSER study included in the model calibration. EBEs from subjects from the radiolabeled IVIg and M281 studies were not used in the simulations as they do not contain information on C5 inhibition. For each subject, a baseline C5 concentration of 70ug / mL and an IgG concentration of 1g / dL were assumed. The primary outputs of these simulations are median and min / max time course profile values ​​for: Total Ab1 drug concentration (in uM) Total IgG concentration (in uM) Free Ab1 (in uM) Free Ab1 paratope concentration (uM), i.e. the number of free Ab1 arms available for binding to Ag. This amount is given by the sum 2 × [Ab1] + [Ab1Ag].

[0066] Additionally, endosomal time course profiles of free FcRn, free IgG, free clovalimab and complexed FcRn-clovalimab, FcRn-IgG are provided in the Appendix.

[0067] The primary metrics used to compare simulations of crovalimab alone and crovalimab plus IVIg were the maximum reduction in median PK concentrations at trough (upon administration of crovalimab) and duration of complete C5 inhibition.

[0068] 4.2 Sensitivity analysis To assess the robustness of the base case simulations, we performed sensitivity analyses to lower the threshold for saturating FcRn recycling in the following scenarios: Divide the concentration of FcRn receptors in endosomes by 2 Multiply the volume of the endosome by 10 Multiply the baseline IgG concentration by 2

[0069] Furthermore, because GBS is an acute condition, the individual variability in C5 levels is unknown, and therefore in this sensitivity analysis, simulations were performed assuming an increase in baseline C5 concentration from 70ug / mL to 140ug / mL.

[0070] All simulations were performed using the same dosing regimen, the same set of parameters representing the same 33 patients described in Example 4.1. Additionally, the same metrics were used to compare sensitivity analyses with and without IVIg coadministration.

[0071] Example 5: Results 5.1 Modeling A model (see FIG. 4) describing the binding of Ag (i.e., C5) to Ab1 (i.e., clovalimab) and its competition with IgG in endosomes was calibrated using data from 15 healthy volunteers in COMPOSER part 1, 10 and 8 naive PNH patients from parts 2 and 4, respectively, and the radiolabeled IgG* and M281 data described in Example 2. The number of samples available from COMPOSER parts 1, 2 and 4 for total Ab1, total Ag, and free Ag are shown in Table 1.

[0072] To reduce the uncertainty of the estimates due to the introduction of the endosomal part of the model, the parameters for the central distribution volume, the volume and interfractional clearance of Ab1 and its complexes with Ag, as well as Ag production and clearance rates were fixed to values ​​obtained without the endosomal model and described in

[10] . These values ​​are reported in Table 5.

[0073] The population values ​​obtained from the model calibration are reported in Table 6.

[0074] The individual goodness-of-fit plots reported in Figures 10, 11, 12 and 13 show that the concentration-time courses of total [Ab1], total [Ag] and free [Ag] from the COMPOSER study are adequately described by the model.

[0075] The individual fit plots in FIG. 14 show that the model well described dose-normalized radiolabeled IgG* in serum in the top panel and total body radioactivity in the bottom panel.

[0076] Similarly, FIG. 15 shows that M281 PK and its effect on baseline normalized endogenous IgG concentrations were well described by the models for each arm of the SAD and MAD studies. [Table 5] [Table 6]

[0077] Model parameters are defined in Table 4. RSE = relative standard error of estimate, CV = coefficient of variation, OFV = objective function value, AIC: Akaike information criterion, BIC: Bayesian information criterion, WT = body weight, a = additive error, b = proportional error SD. The effect of WT on clearance was applied to the following parameters: CLe, Ab1, CLe, Ab1Ag, CLe, AgAb1Ag, CLe, IgG, CLe, M281, Q IgG, CLe, Ab1 recy, CLe, IgG, recy, CLe, M281 rec

[0078] Example 6: Simulation and sensitivity analysis 6.1 Base case simulation Simulations were performed using individual parameter estimates (i.e., EBEs) for the 33 subjects from the COMPOSER study used for model calibration.

[0079] The results of the simulation for subjects receiving either clovalimab alone or clovalimab with IVIg are shown in FIG. 16, where time 0 corresponds to day 1 when treatment begins.

[0080] Median and min / max simulated profiles for concentrations of clovalimab and IgG in serum and endosomes are shown in Appendix 1 of Figure 21. Thirty-three individual profiles for subjects receiving clovalimab only or both clovalimab and IVIg are shown in Figures 22 and 23, respectively.

[0081] Decreased serum concentrations of clovalimab are observed when coadministered with IVIg at the recommended dose in GBS because clovalimab competes for FcRn recycling. Median trough concentrations of clovalimab were reduced by 19% on day 8 in the presence of IVIg.

[0082] The median clovalimab concentration over the simulated time period remains above approximately 100ug / mL threshold concentration, which is the value used as a reference for achieving complete C5 activity inhibition. Complete inhibition is observed. Looking at the expected free C5 profile, complete inhibition is confirmed. Furthermore, the minimum clovalimab free paratope always remains above 0, indicating that there is always clovalimab binding reserve to capture free C5 molecules over the 72-day period.

[0083] 6.2 Sensitivity analysis To assess the robustness of the assumptions made in the model, we performed sensitivity analyses on model parameters that affect the efficiency of FcRn recycling. Furthermore, because GBS is an acute condition, individual variability in C5 levels is unknown, and we then performed simulations assuming an increase in baseline C5 concentrations.

[0084] This analysis represents a potential “worst case scenario” with respect to reduced C5 inhibition induced by alterations in clovalimab PK. The following model parameters were purposefully modified one by one as follows: 1. Divide the total concentration of FcRn in endosomes [FcRn] Total by a factor of 22 and multiply the volume of endosomes Ve by a factor of 10. 3. The rate of endogenous IgG production increases twofold, resulting in a doubling of the baseline concentration of IgG to a value of 2 g / dL. 4. Baseline C5 levels increased 2-fold from 70ug / mL to 140ug / mL.

[0085] The results of sensitivity analysis No. 1 are shown in Figure 17. The impact of IVIg on the PK of clovalimab is greater when the concentration of FcRn in the endosomes [FcRn] total is divided by a factor of 2; in this scenario, the median concentration of clovalimab is reduced by 27% at day 8 at the trough in the presence of IVIg. Of note, in the base case simulation, this reduction was approximately 19%. Over the course of 40 days, the median profile remains above the 100ug / ml threshold, and the minimum of the paratope without clovalimab always remains strictly positive, ensuring complete C5 inhibition.

[0086] The results of sensitivity analysis #2 in Figure 18 demonstrate that increasing endosomal volume by 10-fold alters the PK profile of clovalimab, but does not show any difference in median clovalimab concentrations with or without IVIg coadministration.

[0087] In run #3, increasing baseline endogenous levels of IgG by a factor of two (from 1 g / dL to 2 g / dL) reduced median clovalimab concentrations by 22% on day 8, while clovalimab free paratope values ​​were always strictly positive over the 40-day period, as shown in Figure 19. Notably, in the base-case simulation, this reduction was approximately 19%.

[0088] Finally, in sensitivity analysis No 4, a simulation was performed assuming a two-fold increase in baseline C5 concentration (140ug / mL), and the results are provided in Figure 20. Median trough concentrations of clovalimab decreased by 22% on day 8.

[0089] These sensitivity analyses demonstrate that the proposed clovalimab dosing strategy is expected to provide adequate inhibition of C5 for at least 40 days based on the median PK profile, even when considering uncertainties in several key parameters that drive clovalimab recycling through FcRn.

[0090] Example 7 Observations A previously developed model for clovalimab reported in

[10] was extended to account for the saturation of FcRn recycling when IVIg was co-administered. A key assumption of this model is that antibody clearance only occurs in endosomes when the antibody is not bound to FcRn (as is usually assumed in literature [9]). Thus, the half-life of the antibody depends on how much the antibody can bind to FcRn receptors in endosomes and be recycled. Therefore, the concentration of FcRn receptors and the volume of the endosomes are important parameters to be estimated to quantify when FcRn recycling is saturated and affect clovalimab serum concentrations. The addition of the M281 PK / PD profile in our dataset provided the necessary information to estimate these two parameters, since the binding of M281 to FcRn clearly saturates the recycling of IgG from endosomes to serum as shown in Figure 3. We note that the population estimate for FcRn receptor concentration in endosomes reported in Table 6, [FcRn]tot=42.3 uM, is consistent with the value of 41.2 uM (i.e., [FcRn]tot=Rtot / v3=14 umol / 0.34 L) reported in Kendrik's publication

[12] . However, the estimated endosomal volume Ve=0.14 L (assuming a body weight of 70 kg) is 2.4 lower than that reported in the same publication (i.e., v3=0.34 L), motivating the use of the M281 data to estimate this parameter.

[0091] After calibration, the model provided an adequate goodness of fit for the PK of IVIg in Figure 14 and the PK / PD of clovalimab in C5 inhibition, as shown in Figures 10, 11, 12 and 13. However, as seen in the second column of Figures 10, 11, 12 and 13, some of the variability in total [Ag] could not be captured at the individual level. Because the model assumes that the rate of Ag generation (i.e., kinAg) is constant over time, the model does not have the ability to match the variability in total Ag. This is particularly highlighted in Figures 10 and 11 for six healthy volunteers receiving placebo (i.e., subjects 11002, 11003, 11006, 11010, 11012, 11015), who have a constant predicted total Ag concentration (i.e., horizontal green line), but measured total Ag varies within a range of 300 nM.

[0092] At the population level, due to limited individual data for IgG and M281, parameters were generally estimated with low precision (i.e., RSE >50%), as shown in Table 6.

[0093] These findings justified why, during the modeling construction process, we fixed the model parameters describing the PK / PD of clovalimab and C5 in serum to the population values ​​given in Table 5, reducing the uncertainty in the estimation of the parameters describing the FcRn recycling process. The values ​​in Table 5 were obtained using a model that does not explicitly describe the processes occurring within the endosomes and are given in

[10] .

[0094] To avoid propagating uncertainties in the population estimates, only simulations using individual EBE parameters were performed. These EBEs were obtained for the 33 subjects who received clovalimab in the COMPOSER clinical study. EBE parameters obtained for subjects from the radiolabeled IVIg and M281 studies were not used in the simulations because they did not have any information on the PK / PD of clovalimab.

[0095] Simulations showed that the selected clovalimab dosing regimen (1000 mg IV on day 1 for patients under 100 kg, 1500 mg IV for patients over 100 kg, followed by 340 mg SC on days 2, 8, 15, and 22) provided median clovalimab PK profiles above the reference threshold of 100 ug / mL (for complete C5 inhibition) when coadministered with IVIg at a dose of 400 mg / kg for 5 consecutive days. The maximum effect of IVIg coadministration occurred on day 8, with a 19% decrease in median serum clovalimab concentrations. Even taking into account the minimum of predictions observable in the individual profiles in Figure 23 (corresponding to a small number of subjects), the levels of free paratope remain strictly positive at all times over the 72 days.

[0096] Sensitivity analyses demonstrated the robustness of the results by evaluating the effects of decreasing the concentration of FcRn receptors by a factor of 2, increasing endosomal volume by a factor of 10, and increasing baseline levels of IgG by a factor of 2. In all of these cases, median clovalimab serum concentrations remained above 100ug / mL over 40 days, and minimum free paratope values ​​remained strictly positive over 40 days.

[0097] The increase in C5 baseline from 70ug / mL to 140ug / mL had a mild impact on median PK levels as the median decrease in serum clovalimab concentrations increased from 19% to 22% on day 8. This increase was driven by faster endosomal internalization of clovalimab-C5 complexes compared to free clovalimab (i.e., CLe, Ab1 = 0.00696 L / day / kg and CLe, Ab1Ag = CLe, AgAb1Ag = 0.0103 L / day / kg), resulting in an overall faster clearance of clovalimab.

[0098] The selected corvalimab dosing regimen is therefore expected to cover the therapeutic objective of maintaining sustained complete C5 inhibition over 28 days despite coadministration of IVIg.

[0099] Example 8 Summary / Conclusion The effect of IVIg infusion on the PK and PD profiles of crovalimab in subjects receiving both treatments simultaneously was investigated using a mechanistic mathematical model that describes the binding of crovalimab to C5 and predicts the concentrations of free C5 and free crovalimab paratope over time (quantifying the reserve of free crovalimab sites available to bind to C5 molecules).

[0100] The model also includes a PK model of endogenous IgG in serum, as well as the competition of IgG and clovalimab binding to FcRn receptors in endosomes. This part of the model allows for the quantification of the effect of the recommended therapeutic dose of IVIg on clovalimab PK concentrations. The model also includes a description of the M281 anti-FcRn antibody PK and PD, which are used to estimate the concentration of FcRn receptors and the volume of endosomes.

[0101] An ensemble approach was used to simultaneously calibrate the clovalimab PK / PD model, the IVIg PK model and the M281 PK / PD model.A pooled dataset including clovalimab COMPOSER data in 33 healthy volunteers and naïve PNH patients, radiolabeled IgG data from the literature

[12] in six subjects and published PK / PD SAD and MAD data for the M281 monoclonal anti-FcRn antibody [13, 14] was constructed and used for model calibration.

[0102] Simulation and sensitivity analyses were then performed to quantify the effect of IVIg coadministration on the PK and PD profiles of crovalimab using individual parameter estimates obtained from 33 subjects from the clinical study COMPOSER, whose data were included in the calibration dataset.

[0103] The following doses and dosing regimens of clovalimab and IVIg were used in these simulations: Clovalimab: 1000 mg IV on day 1 for patients <100 kg and 1500 mg IV for patients >100 kg, followed by 340 mg SC on days 2, 8, 15, and 22 IVIg: 400mg / kg on days 1, 2, 3, 4 and 5

[0104] IVIg dose and dosing regimen is based on standard treatment for acute GBS (400 mg / kg QD for 5 consecutive days).

[0105] The main conclusions of this modeling and simulation analysis are: When administered concomitantly with IVIg, the maximum predicted decrease in median crovalimab serum concentrations was 19% on day 8. Median crovalimab serum concentrations remained above approximately 100ug / mL for 72 days, the reference threshold expected to provide full C5 activity, covering the anticipated target treatment duration of the BN43118 study of 28 days. Free paratope levels remained strictly positive at all times, indicating that clovalimab binding reserve was always available. Sensitivity analyses demonstrated that full C5 inhibition was maintained over 40 days even when model parameters, including FcRn receptor concentration, baseline levels of IgG and C5, and endosomal volume, were altered in ways that reduced recycling of clovalimab by FcRn.

[0106] Overall, the simulation results and sensitivity analysis indicate that the selected clovalimab dosing regimen provides complete C5 inhibition for at least 40 days.

[0107] In summary, the presented modeling approach provides a tool to understand the interactions of IVIg and crovalimab on FcRn recycling and to quantify by simulation the effects of IVIg on crovalimab PK levels, crovalimab free binding sites and free C5.

[0108] According to the results of this study, the following dosing regimens will be selected to be tested in clinical study BN43118: Clovalimab: 1000 mg IV on day 1 for patients <100 kg and 1500 mg IV for patients >100 kg, followed by 340 mg SC on days 2, 8, 15, and 22

[0109] However, to ensure that the selected dose is sufficient to achieve complete C5 inhibition, a dose confirmation step is planned in Study BN43118 to evaluate actual PK data from 10 GBS subjects to confirm the appropriateness of the selected dose. [Table 7] TIFF2025511382000008.tif104170 [Table 8]

Claims

1. A pharmaceutical composition comprising an anti-C5 antibody for use in a method for treating or preventing Guillain-Barré syndrome (GBS) in a subject, wherein the method is a) A step of administering a 1500 mg loading dose of anti-C5 antibody intravenously once, and b) The next step is to subcutaneously administer at least one dose of 340 mg of anti-C5 antibody to the target population. A pharmaceutical composition containing the above.

2. The pharmaceutical composition according to claim 1, wherein a subcutaneous dose of 340 mg is administered to the subject at least once between one day and three weeks after the start of intravenous administration of the anti-C5 antibody.

3. The pharmaceutical composition according to claim 2, for use in combination with intravenous immunoglobulin (IVIg).

4. The pharmaceutical composition according to claim 3, wherein a dose of 400 mg / kg of IVIg is administered intravenously to the subject at least once.

5. The pharmaceutical composition according to claim 4, wherein a dose of 400 mg / kg of IVIg is administered intravenously to the subject daily on days 1, 2, 3, 4, and 5.

6. The pharmaceutical composition according to claim 2, wherein a subcutaneous dose of 340 mg of anti-C5 antibody is administered to the subject once, one day after the start of intravenous administration of the anti-C5 antibody.

7. The pharmaceutical composition according to claim 2, wherein at least one additional dose of 340 mg of anti-C5 antibody is administered subcutaneously to the subject one week or two weeks after the start of intravenous administration of the anti-C5 antibody.

8. The pharmaceutical composition according to claim 2, wherein an additional dose of 340 mg of anti-C5 antibody is administered subcutaneously to the subject once a week, one week and two weeks after the start of intravenous administration of the anti-C5 antibody.

9. The pharmaceutical composition according to claim 6, wherein a dose of 340 mg of anti-C5 antibody is administered subcutaneously to a target several times at intervals of at least four weeks.

10. The pharmaceutical composition according to claim 7, wherein a dose of 340 mg of anti-C5 antibody is administered subcutaneously to a target several times at time intervals of at least 4 weeks.

11. The above method comprises the following administration steps: (i) A step of administering a loading dose of 1500 mg of anti-C5 antibody intravenously as a single dose; (ii) A step of administering a 340 mg dose of anti-C5 antibody subcutaneously one day after the start of intravenous administration of anti-C5 antibody; (iii) A procedure in which a 340 mg dose of anti-C5 antibody is administered subcutaneously once a week, one week (7 days), two weeks (14 days), and three weeks (21 days) after the start of intravenous administration of anti-C5 antibody. The pharmaceutical composition according to claim 1, as implemented by [method].

12. A pharmaceutical composition according to claim 11 for use in combination with IVIg, wherein, (a) 400 mg / kg of IVIg was administered intravenously to the subject once on the same day as the loading dose of 1500 mg of anti-C5 antibody, and (b) A pharmaceutical composition comprising 400 mg / kg of IVIg administered intravenously to the subject daily, one day, two days, three days, and four days after the start of intravenous administration of an anti-C5 antibody.

13. The pharmaceutical composition according to any one of claims 1 to 12, wherein the subject has been pre-treated with at least one pharmacological product useful for the treatment or prevention of GBS, and a loading dose of 1500 mg of anti-C5 antibody administered intravenously is given to the subject after the final dose of the pharmacological product.

14. A pharmaceutical composition according to any one of claims 1 to 12, wherein the subject has a body weight exceeding 100 kg.

15. The pharmaceutical composition according to any one of claims 1 to 12, wherein the concentration of the anti-C5 antibody determined in the target biological sample is 100 μg / ml or more.

16. The pharmaceutical composition according to any one of claims 1 to 12, wherein the anti-C5 antibody is clobarimab.

17. A combination of an anti-C5 antibody and IVIg for use in a method to treat or prevent GBS in a subject, wherein the method is (i) A single intravenous dose of 1500 mg of anti-C5 antibody is administered to the target patient, followed by a single intravenous dose of 400 mg / kg of IVIg on the same day; (ii) One day after initiating intravenous administration of anti-C5 antibody, a maintenance dose of 340 mg of anti-C5 antibody is administered subcutaneously, followed by intravenous administration of 400 mg / kg of IVIg on the same day; (iii) The step of intravenously administering 400 mg / kg of IVIg daily, two, three, and four days after the start of intravenous administration of anti-C5 antibody; and (iv) Subcutaneous administration of a maintenance dose of 340 mg of anti-C5 antibody once a week, one week (7 days), two weeks (14 days), and three weeks (21 days) after the start of intravenous administration of anti-C5 antibody. A combination of anti-C5 antibody and IVIg, including a series of steps.

18. The combination for use according to claim 17, wherein the subject has been pre-treated with at least one pharmacological product useful for the treatment or prevention of GBS, and a loading dose of 1500 mg of anti-C5 antibody administered intravenously to the subject is administered after the final dose of the pharmacological product.

19. The combination for use according to claim 17, wherein the subject has a body weight exceeding 100 kg.

20. The combination for use according to claim 17, wherein the concentration of the anti-C5 antibody determined in the target biological sample is 100 μg / ml or more.

21. The combination for use according to claim 17, wherein the anti-C5 antibody is clobalimab.

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