Treatment of multiple sclerosis with anti-CD40L antibodies

Abstract

This invention relates to the treatment of relapsing forms of multiple sclerosis using an anti-human CD40L monoclonal antibody.

Description

Technical Field

[0001] Cross - reference to related applications This application claims priority to European Patent Application Nos. 23174655.3 and 23174657.9, both filed on May 22, 2023. The disclosures of those priority applications are hereby incorporated by reference in their entirety into this specification.

[0002] Sequence Listing This application includes a sequence listing submitted electronically in XML format, which is hereby incorporated by reference in its entirety into this specification. The electronic copy of the sequence listing (created on May 16, 2024) has the name 022548.WO033_SL.xml and a size of 10,366 bytes.

Background Art

[0003] Multiple sclerosis (MS) is a chronic immune - mediated inflammatory and neurodegenerative disease that affects the central nervous system. It is characterized by loss of motor and sensory functions due to inflammation, demyelination, and axonal injury and loss (Friese et al., Nat Rev Neurol. (2014) 10(4):225 - 38; Trapp and Nave, Ann Rev Neurosci. (2008) 231:247 - 69). MS affects over 2 million people worldwide and occurs at least 2 - 3 times more frequently in women than in men. MS patients present a wide range of severe clinical symptoms, including increasing physical disability, fatigue, pain, and cognitive impairment as the disease progresses. This has a significant impact on the quality of life of patients and shortens the average lifespan of patients by an average of 5 - 10 years.

[0004] Immunomodulatory drugs are the mainstay of MS therapy. Beyond existing strategies that modulate the cellular elements of adaptive immunity, there is growing evidence that innate immunity is involved in many neurodegenerative forms of MS that persist despite the use of disease-modifying therapies approved to prevent acute relapses. Even recent treatments primarily act on adaptive immunity in the periphery, possessing only moderate or transient ability to halt neuroinflammatory and neurodegenerative processes and stop disease progression. There remains a significant unmet need for therapies targeting neuroinflammation in the CNS aimed at halting long-term disability and neurodegeneration in people with relapsing MS and those with progressive forms of MS. Therefore, there is growing interest in developing MS treatments with novel modes of action that include not only adaptive immunity but also innate immunity.

[0005] Human differentiation antigen group 40 ligand (CD40L), also known as CD154, is a TNF family member primarily expressed on activated T cells and binding to CD40 on antigen-presenting cells. The CD40 / CD40L costimulatory pathway is crucial for humoral immune responses, as well as for inflammatory cytokine secretion by macrophages and mutual costimulation between T lymphocytes and antigen-presenting cells. Disruption of the CD40 / CD40L pathway in autoimmune diseases, particularly autoimmune diseases such as MS where a pathogenic B-cell response is a key feature of the disease, can affect both cellular and humoral responses and may have therapeutic benefits.

[0006] The importance of the CD40 / CD40L pathway in MS immune signaling is indirectly supported by the observed increase in soluble CD40L in individuals with MS. In association with increased CD40L expression on immune cells, higher levels of soluble CD40L have been observed in individuals with RRMS compared to patients with SPMS, suggesting different involvement of this pathway in the two MS types.

[0007] Given the medical needs that can be addressed by targeting CD40L, there is a need for improved MS therapies that target CD40L. [Overview of the Initiative] [Means for solving the problem]

[0008] The present invention provides a method for the treatment of MS using flexalimab or related antibodies, which are anti-human CD40L antibodies.

[0009] In some embodiments, the present disclosure provides methods for treating relapsing multiple sclerosis (MS) in human patients in need. Relapsing MS may be, for example, relapsing-remitting MS or secondary progressive MS with relapses.

[0010] In certain embodiments, the treatment comprises intravenous administration of a monoclonal anti-human CD40L antibody to the patient, wherein the heavy chain CDR1-3 and light chain CDR1-3 of the antibody comprise SEQ ID NOs: 1-6, respectively, and the antibody is administered to the patient in doses of 1000-2000 mg (e.g., every four weeks or approximately every month). In some embodiments, the dose is 1200 mg. In certain embodiments, the initial administration of the antibody is a first dose (e.g., a "loading dose"), and subsequent administrations are second doses. The first dose may be higher than the second dose. For example, in certain embodiments, the first dose may be 1800 mg and / or the second dose may be 1200 mg.

[0011] In certain embodiments, the treatment comprises administering a monoclonal anti-human CD40L antibody to the patient, wherein the heavy chain CDR1-3 and light chain CDR1-3 of the antibody comprise SEQ ID NOs: 1-6, respectively, and the antibody is administered to the patient in doses of 1800 mg (e.g., approximately every four weeks or approximately every month). In certain embodiments, the antibody is administered subcutaneously. In some embodiments, the initial administration of the antibody is via one route, and subsequent administrations are via other routes. For example, the initial administration of the antibody may be intravenous, and subsequent administrations may be subcutaneous.

[0012] In some embodiments, the antibody is of the isotype subtype IgG1.

[0013] In some embodiments, the antibody includes a heavy chain variable domain and a light chain variable domain, respectively, comprising SEQ ID NOs. 7 and 8.

[0014] In some embodiments, the antibody comprises a heavy chain and a light chain, respectively, including SEQ ID NOs. 9 and 10.

[0015] In some embodiments, the present disclosure provides a method for treating recurrent MS in a patient in need thereof, comprising administering to the patient by intravenous infusion a monoclonal anti-human CD40L antibody comprising a heavy chain and a light chain, respectively, comprising SEQ ID NOs: 9 and 10, wherein the antibody is administered in a first dose of 1800 mg and a subsequent dose of 1200 mg, with an interval of about 4 weeks or about 1 month between doses.

[0016] In some embodiments, the present disclosure provides a method for treating recurrent MS in a patient in need thereof, comprising administering to the patient a monoclonal anti-human CD40L antibody comprising a heavy chain and a light chain, respectively, comprising SEQ ID NOs: 9 and 10, wherein the antibody is administered in a dose of 1800 mg, with a first dose administered intravenously and subsequent doses administered subcutaneously, with an interval of approximately 4 weeks or approximately 1 month between doses.

[0017] This disclosure also provides monoclonal anti-human CD40L antibodies listed herein for use in treating human patients in the therapies listed herein, and the use of monoclonal anti-human CD40L antibodies listed herein for manufacturing pharmaceuticals for treating human patients in the therapies listed herein. Kits and articles containing the listed anti-human CD40L antibodies (for example, for use in the therapies listed herein) are also provided.

[0018] Other features, purposes, and advantages of the present invention will become apparent in the detailed description below. However, it should be understood that this detailed description, while illustrating embodiments and aspects of the present invention, is provided for illustrative purposes only and not limiting. From this detailed description, various modifications and alterations within the scope of the present invention will become apparent to those skilled in the art. [Modes for carrying out the invention]

[0019] This disclosure provides a safe and effective treatment for relapsed MS (RMS) with flexalimab or related antibodies (such as antibodies described herein, e.g., antibodies having the same heavy and light chain CDRs as flexalimab, or antibodies having the same heavy and light chain variable domains). Flexalimab is a humanized anti-human CD40L IgG1 antibody that has high affinity for human CD40L, induces immune tolerance, and blocks humoral immunity without inducing thrombotic or coagulation reactions. See also U.S. Patent No. 10,874,738B2 (this disclosure is incorporated herein by reference in its entirety).

[0020] The heavy chain sequence of flexaliumab (SEQ ID NO: 9) is shown below, its variable domain sequence is shown in bold and italics (SEQ ID NO: 7), and its CDR1-3 (SEQ ID NOs: 1-3, respectively) is underlined: [ka]

[0021] The light chain sequence of flexaliumab (SEQ ID NO: 10) is shown below, its variable domain sequence is shown in bold and italics (SEQ ID NO: 8), and its CDR1-3 (SEQ ID NOs: 4-6, respectively) is underlined: [ka]

[0022] In some embodiments, the MS therapy described herein uses an anti-CD40L antibody that is abatacept or a related antibody (e.g., an antibody described herein), or an antigen-binding portion of said anti-CD40L antibody. In some embodiments, the anti-CD40L antibody comprises the six CDR amino acid sequences of abatacept. The CDRs can be assigned, for example, according to the IMGT® definition (Lefranc et al., Dev Comp Immunol. (2003) 27(1):55-77); or according to the Kabat definition, Sequences of Proteins of Immunological Interest (National Institutes of Health, Bethesda, MD (1987 and 1991)); see Chothia & Lesk, J Mol Biol. (1987) 196:901-17; Chothia et al., Nature (1989) 342:878-83; MacCallum et al., J Mol Biol. (1996) 262:732-45; or Honegger and Plueckthun, J Mol Biol. (2001) 309(3):657-70. In certain embodiments, the anti-CD40L antibody comprises the H-CDR1-3 and L-CDR1-3 amino acid sequences of SEQ ID NOs: 1-6, respectively.

[0023] In some embodiments, the anti-CD40L antibody can comprise a heavy chain variable domain (VH) that is at least 90% (e.g., at least 95%, 98%, or 99%) identical in sequence to SEQ ID NO: 7 and a light chain variable domain (VL) that is at least 90% (e.g., at least 95%, 98%, or 99%) identical in sequence to SEQ ID NO: 8. Optionally, the antibody can comprise the six CDRs of abatacept. In some embodiments, the anti-CD40L antibody comprises the heavy chain variable domain amino acid sequence and the light chain variable domain amino acid sequence of abatacept. In certain embodiments, the anti-CD40L antibody comprises a VH comprising SEQ ID NO: 7 and a VL comprising SEQ ID NO: 8.

[0024] In some embodiments, the anti-CD40L antibody comprises a heavy chain (HC) having a sequence that is at least 90% (e.g., at least 95%, 98%, or 99%) identical to SEQ ID NO: 9, and a light chain (LC) having a sequence that is at least 90% (e.g., at least 95%, 98%, or 99%) identical to SEQ ID NO: 10. Optionally, the antibody may comprise the six CDRs of infliximab or VH and VL. In certain embodiments, the anti-CD40L antibody comprises an HC comprising SEQ ID NO: 9 and an LC comprising SEQ ID NO: 10.

[0025] Infliximab and related antibodies described herein can be expressed in mammalian host cells such as, for example, CHO cells, NS0 cells, COS cells, 293 cells, and SP2 / 0 cells. In some embodiments, the C-terminal lysine of the heavy chain of the antibody is removed. The antibody can be provided in a powder form (e.g., lyophilized form) that is reconstituted in a suitable pharmaceutical solution or in an aqueous pharmaceutical solution, for example, prior to administration to a patient. In certain embodiments, the antibody is provided in a pharmaceutical composition that further comprises L-histidine HCl, L-histidine, L-arginine HCl, sucrose, polysorbate-80, and water. In a particular embodiment, the pH of the pharmaceutical composition is 5.6.

[0026] In some embodiments, a pharmaceutical composition comprising an anti-CD40L antibody (e.g., infliximab) listed herein is provided as a manufactured article or kit, such as one that includes one or more containers containing the composition and a label associated with the container. The container can be a single-use container (e.g., for intravenous or subcutaneous delivery), such as a single-use pouch or vial, or a single-use prefilled syringe or syringe. In some embodiments, the container contains a single dose (e.g., a dose listed herein) of the anti-CD40L antibody, and the container can be a vial or a prefilled syringe or syringe.

[0027] In some embodiments, the manufactured article or kit comprises a first container and / or subsequent containers, the first container containing a different (e.g., higher) dose of antibody than the subsequent containers. For example, the first container may contain a single dose of 1800 mg of anti-CD40L antibody (e.g., flexalimab), and the subsequent containers, the subsequent containers, may contain a single dose of 1200 mg of the same antibody, for example, the containers may be designed for intravenous administration of the antibody.

[0028] In some embodiments, the manufactured article or kit comprises a container containing a single dose of 1800 mg of anti-CD40L antibody (e.g., flexalimab), the container being designed for subcutaneous administration of the antibody.

[0029] In some embodiments, the manufactured article or kit comprises a first container and / or subsequent containers, the first and subsequent containers being designed for different routes of administration (e.g., intravenous and subcutaneous). For example, the first container may contain a single dose of 1800 mg of anti-CD40L antibody (e.g., flexalimab) and may be designed for intravenous administration of the antibody, while the subsequent containers may contain a single dose of 1800 mg of the same antibody and may be designed for subcutaneous administration of the antibody.

[0030] I. Types of relapsing multiple sclerosis MS, also known as disseminated sclerosis, is a complex disease characterized by considerable heterogeneity in its clinical, pathological, and radiological presentation. It is an autoimmune condition in which the immune system attacks the central nervous system, leading to demyelination (Compston and Coles, Lancet (2008) 372(9648):1502-17). MS destroys the myelin sheath, a layer of fat that surrounds and electrically insulates nerve fibers. Almost all neurological symptoms can appear with the disease, often progressing to physical and cognitive impairments (Compston and Coles, see above). New symptoms can occur in discrete episodes (recurrent form) or slowly accumulate over time (progressive form) (Lublin et al., Neurology (1996) 46(4):907-11). Between episodes, symptoms may completely disappear (remission), but persistent neurological problems often occur, especially as the disease progresses (Lublin et al., see above). Several subtypes, or patterns of progression, have been described, and these are important for determining prognosis and treatment. In 1996, the United States National Multiple Sclerosis Society standardized four subtype definitions: relapsing-remitting, secondary progressive, primary progressive, and progressive-relapsing (Lublin et al., see above).

[0031] Relapsing-remitting multiple sclerosis (RRMS) is characterized by unpredictable acute attacks called exacerbations or relapses, followed by relatively quiet periods of remission lasting several months to several years with no new signs of disease activity. This describes the initial course of most individuals with MS. RRMS is the most heterogeneous and complex phenotype of the disease, characterized by varying levels of disease activity and severity, particularly in the early stages. Inflammation is dominant, but neurodegeneration also occurs. Demyelination occurs during acute relapses lasting several days to several months, followed by partial or complete recovery during periods of remission. RRMS accounts for approximately 65–70% of the MS population and tends to progress to secondary progressive MS.

[0032] Secondary progressive MS (SPMS) begins with a relapsing-remitting cycle, followed by occasional relapses, mild remissions, or plateaus, but progresses to progressive neurological decline between acute attacks without clear periods of remission. Before approved disease-modifying therapies became available, data from natural history studies of MS demonstrated that half of RRMS patients progressed to SPMS within 10 years, and 90% within 25 years. SPMS occurs in approximately 20–25% of all people with MS.

[0033] The primary progressive subtype of MS (PPMS) is characterized by a slow but steady progression of disability without apparent remission, following the appearance of initial MS symptoms (Miller et al., Lancet Neurol (2007) 6(10):903-12). It is characterized by progression of disability from the onset, sometimes accompanied by minor improvements or periods of stagnation. A small percentage of PPMS patients may experience relapses. Approximately 10% of all individuals with MS have PPMS. The age of onset for the primary progressive subtype is usually later than for other subtypes (Miller et al., see above). Men and women are equally affected.

[0034] Progressive relapsing MS (PRMS) is characterized by stable neurological decline accompanied by acute attacks, sometimes with some degree of recovery, and sometimes without. This is the rarest of all the subtypes described above.

[0035] Cases exhibiting atypical behavior have also been described, sometimes referred to as borderline morphologies of MS (see Fontaine, Rev Neurol. (Paris) (2001) 157 (8-9 Pt2): 929-34). These morphologies include Devic's disease, Balo concentric sclerosis, Schilder diffuse sclerosis, and Marburg multiple sclerosis (Capello et al., Neurol Sci. (2004) 25 Suppl 4: S361-3; Hainfellner et al., J Neurol Neurosurg Psychiatr. (1992) 55 (12): 1194-6).

[0036] In some embodiments, the terms “recurrent MS” or “recurrent morphological MS” (RMS) refer to three distinct patient subtypes: RRMS, SPMS with recurrence, and clinically isolated demyelinating events with evidence of temporal and spatial lesion dissemination on MRI (see, for example, European Medicines Agency, Committee for Medicinal Products for Human Use, “Guideline on Clinical Investigation of Medicinal Products for the Treatment of Multiple Sclerosis” (Rev. 2, 2015)).

[0037] Relapse of MS is defined herein as a monophasic, acute, or subacute onset of new neurological symptoms or an exacerbation of previous neurological symptoms accompanied by objective changes on neurological examination. In some embodiments, the symptoms are: a) It is caused by MS. b) It must last for more than 24 hours, regardless of whether recovery occurs. c) Body temperature is normal (i.e., no infection, excessive exercise, or excessively high fever), d) Clinical stability for 30 days or more (excluding previous relapses) precedes the previous period. It must be any combination of e)a)~d). In certain embodiments, the symptoms of MS relapse include all of a) to d).

[0038] II. Patient Selection The present invention relates to the treatment of MS patients with relevant anti-CD40L antibodies, such as flexalimub or the anti-CD40L antibodies described herein. In the context of the present invention, an MS patient is a patient diagnosed with a form of MS by a medical history and neurological examination, with the help of tests such as magnetic resonance imaging (MRI), spinal puncture, evoked potential testing, and laboratory analysis of blood samples. In some embodiments, the patient treated by the treatment described herein has relapsing MS (RMS), such as relapsing-remitting MS or secondary progressive MS with relapses. In certain embodiments, the patient is diagnosed with RMS according to the MacDonald Diagnostic Criteria 2017 Revised.

[0039] In some embodiments, the patient meets any combination of the inclusion and exclusion criteria listed in Example 1. In a particular embodiment, the patient meets all of the inclusion and exclusion criteria listed in Example 1.

[0040] In some embodiments, the patient a) Being an adult (for example, over 18 years of age or between 18 and 55 years of age (including both extremes)); b) Having had at least one or at least two documented relapses in the past one to two years (e.g., at least one documented relapse in the previous year, or at least two documented relapses in the past two years); c) Body weight is between 45 and 120 kg (including both extremes), and 18.0 to 35.0 kg / m² 2 It is within the range; or d) Any combination of a) to c). In a particular embodiment, the patient meets one, two, or all of criteria a) to c).

[0041] In some embodiments, the patient e) Diagnosed with PPMS or non-recurrent SPMS (e.g., according to the McDonald's Diagnostic Criteria 2017 Revised); f) No history of T lymphocyte or T lymphocyte receptor vaccination, transplantation (including solid organ transplantation, stem cell transplantation, bone marrow transplantation), and / or anti-rejection therapy; g) No history of progressive multifocal leukoencephalopathy (PML) or evidence of MRI findings suggestive of PML; h) No severe systemic viral, bacterial, or fungal infection (e.g., pneumonia, nephritis); infection requiring hospitalization or IV antibiotics; or no serious chronic viral, bacterial, or fungal infection (e.g., osteomyelitis) (e.g., within 30 days prior to and during treatment); i) No history of invasive opportunistic infections, including but not limited to histoplasmosis, listeriosis, coccidioidomycosis, candidiasis, Pneumocystis jirovecii infection, and aspergillosis; j) Not having symptomatic herpes zoster (e.g., within 3 months prior to treatment), k) For example, no evidence of active or latent tuberculosis (TB) as documented by medical history and examination, chest X-ray (posterior-anterior and lateral), and / or TB testing (for example, either a positive tuberculin skin test (TST; defined as a skin induration of <5 mm at 48-72 hours, regardless of Bacillus Calmette-Guerin [BCG] or other vaccination history) or a positive QuantiFERON®-TB Gold test (not pending or inconclusive)); l) In some embodiments, the patient has no history of malignant tumors (e.g., within 10 years prior to treatment), except for cervical cancer effectively treated in situ or non-metastatic squamous cell carcinoma or basal cell carcinoma of the skin that has been appropriately treated; m) No history of alcohol or drug abuse (e.g., within the year prior to treatment); n) No history of any mental illness, behavioral condition, or depression requiring hospitalization (e.g., within the two years prior to treatment); o) No current liver disease or chronic liver disease history, or known liver or biliary tract abnormalities (excluding Gilbert's syndrome or asymptomatic gallstones); p) No history of thromboembolic events, or myocardial infarction, stroke, and / or antiphospholipid syndrome, and no clinical evidence, suspicion, or significant risk demonstrated, and no need for antithrombotic therapy; q) No allergy to humanized monoclonal antibodies, or severe post-treatment hypersensitivity reactions other than local injection site reactions to any biological molecule; r) Not receiving any of the following medications, or not having received any of them within the listed period prior to treatment;

[0042] [Table 1]

[0043] s) The patient does not have an Expanded Disability Status Scale (EDSS) score of >5.5 before starting treatment; t) No relapses during the 30 days prior to the start of treatment; u) Not positive for human immunodeficiency virus (HIV) serological testing (anti-HIV1 and anti-HIV2 antibodies), or not having a known history of active or remission HIV infection; v) No abnormal clinical laboratory results at levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin (e.g., unless the patient has documented Gilbert's syndrome), hemoglobin, lymphocytes, neutrophils, platelets, and / or estimated glomerular filtration rate as defined in Example 1, prior to initiating treatment; w) Failure to demonstrate the presence of hepatitis B surface antigen (HBsAg) and anti-hepatitis B core antibody (anti-HBcAb) within 3 months prior to the start of treatment; x) Not showing a positive result for hepatitis C antibody test (e.g., within 3 months prior to the start of treatment); or Do not show any combination of y)e)~x). In a particular embodiment, the patient satisfies one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, sixteen, seventeen, eighteen, nineteen, or a total of twenty criteria from criteria e) to x). In a particular embodiment, the patient satisfies one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty, twenty, twenty-two, twenty-two, or a total of twenty-four criteria from criteria a) to x).

[0044] III. Treatment of Multiple Sclerosis The present invention relates to treating MS with flexalimab or an associated anti-CD40L antibody (e.g., the anti-CD40L antibody described herein) in patients as described herein, for example. In some embodiments, the treatment is intended for relapsing MS, such as relapsing-remitting MS or secondary progressive MS with relapses.

[0045] This therapy can be used as a first-line treatment for patients who have not received prior treatment, i.e., patients who have not been treated with MS medications (e.g., any of the MS medications listed herein). This therapy can also be used to treat patients who have been treated with MS medications (e.g., any of the MS medications listed herein), but these patients may not have responded to previous treatment or may have experienced subsequent disease exacerbation or new disease activity.

[0046] This therapy can be used alone or in combination with other MS medications. Currently available MS medications include, for example, Aubagio® (teriflunomide), Gilenya® (fingolimod), Tecfidera® (dimethyl fumarate), Vumerity® (diroximel fumarate), Bafiertam® (monomethyl fumarate), Mayzent® (siponimod), Zeposia® (ozanimod), Ponvory® (ponesimod), and Mavenclad®. Examples include oral medications such as cladribine; injectable medications such as Lemtrada (registered trademark) (alemtuzumab), Tysabri (registered trademark) (natalizumab), and Ocrevus (registered trademark) (ocrelizumab); and injectable medications such as Rebif (registered trademark) (interferon-beta 1a), Plegridy (registered trademark) (pegylated interferon-beta 1a), Copaxone (registered trademark) (glatiramer acetate), and Zinbryta (registered trademark) (daclizumab).

[0047] The anti-CD40L antibody may be administered, for example, intravenously or subcutaneously. In some embodiments, the antibody is administered in doses of 1000–2000 mg, for example, about 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, or 2000 mg, for example, every 1, 2, 3, 4, 5, 6, 7, or 8 weeks. In certain embodiments, the dose is 1200 mg. In certain embodiments, the antibody is administered every 4 weeks or every 1 month. In some embodiments, the antibody is administered subcutaneously in a dose of 1800 mg, for example, every 4 weeks or every 1 month. Each SC dose may be administered to the patient as a single injection or multiple injections.

[0048] In some embodiments, the anti-CD40L antibody may be administered intravenously to MS patients in two or more doses (e.g., the doses described above). For example, the initial dose of the antibody may be a first dose (e.g., a loading dose), and subsequent doses may be second doses. In certain embodiments, the first dose is higher than the second dose. In certain embodiments, the patient receives an intravenous dose of 1800 mg of the first antibody, followed by a subsequent dose(s) of 1200 mg. In certain embodiments, the interval between doses is approximately 4 weeks or approximately 1 month.

[0049] In some embodiments, anti-CD40L antibodies may be administered to MS patients using two or more routes of administration. For example, the initial dose of the antibody may be administered via a first route of administration (e.g., intravenous), and subsequent doses of the antibody may be administered via another route of administration (e.g., intravenous). In certain embodiments, the patient is administered an antibody dose of 1800 mg, with the initial dose being intravenous and subsequent doses subcutaneously. In certain embodiments, the interval between doses is approximately 4 weeks or approximately 1 month.

[0050] The anti-CD40L antibody therapy of the present invention is intended to be effective in patients with recurrent malabsorption syndrome (RMS). The treatment may, for example, reduce inflammatory activity in the patient. Efficacy may be indicated by measures such as reduction of new or total gadolinium-enhanced (GdE) T1 lesions, reduction of new or expanding T2 lesions, or any combination thereof. Efficacy may also be indicated by measures such as reduction of annual relapse rate (ARR) and / or time to relapse; delay of disability progression; improvement in disability, relapse, MRI-derived parameters, neurological assessment scales, cognitive impairment, fatigue scales, ambulatory index, and measures of the overall clinical impression of changes assessed by patient and physician; and absence of disease activity (e.g., absence of activity, relapse, and progression on MRI). Means for measuring effectiveness may include, for example, the use of the Comprehensive Disability Rating Scale (EDSS) and patient-reported outcomes (e.g., the Multiple Sclerosis Impact Scale (MSIS)-29, the Patient Reported Outcome Measurement Information System (PROMIS)-Fatigue-MS-8, the Patient's Qualitative Assessment of Treatment Version 3 (PQATv3), and / or the Patient's Overall Impression of Change and Severity Scales (PGIC-Fatigue and PGIS-Fatigue)).

[0051] Unless otherwise defined herein, scientific and technical terms used in connection with this disclosure shall have meanings generally understood by those skilled in the art. Exemplary methods and materials are described below, but similar or equivalent methods and materials may also be used in the practice or testing of this disclosure. In case of any conflict, this specification, including definitions, shall prevail. Furthermore, unless otherwise required by context, singular terms shall include plural terms, and plural terms shall include singular terms. Throughout this specification and the embodiments, the terms “have” and “comprise,” or variations such as “has,” “having,” “comprises,” or “comprising,” shall be understood to include the integer or set of integers described, but not to exclude any other integer or set of integers. All publications and other references referenced herein are incorporated by reference in their entirety. This specification references numerous documents, but such references do not constitute an endorsement that any of those documents form part of the common technical knowledge in the art. As used herein, the terms “approximately” or “about” refer to values ​​similar to the reference value described, when applied to one or more values ​​of interest. In certain embodiments, unless otherwise stated or evident from the context, the terms refer to a range of values ​​that fall within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less than either of the reference values ​​described (greater than or less than).

[0052] According to this disclosure, backreferences in dependent claims mean abbreviated notation to any direct and obvious disclosure of any combination of claims indicated by the backreference. Any therapeutic method disclosed herein can be used to treat any individual as defined herein. Furthermore, the headings herein are provided for ease of organization and are not intended to limit in any way the scope of the claimed invention.

[0053] To better understand the present invention, the following examples are provided. These examples are for illustrative purposes only and should not be construed as limiting the scope of the present invention in any way. [Examples]

[0054] Example 1: Flexalimab Clinical Trial Flexalimab was studied as a treatment for MS in a randomized, double-blind, placebo-controlled clinical trial. Two dosing regimens of flexalimab were tested in men and women aged 18–55 years with relapsing MS (including relapsing-remitting MS and secondary progressive MS with relapse). The trial period was 12 weeks, preceded by a screening period starting 4 weeks earlier than day 1. The primary objective of the trial was to determine the efficacy of flexalimab, measured by a reduction in the number of new active brain lesions. Secondary objectives included evaluating the efficacy of flexalimab against disease activity assessed by other MRI measures and assessing the safety and tolerability of flexalimab in participants with RMS.

[0055] The primary endpoint was the number of new gadolinium (Gd)-enhanced T1-high signal (GdET1) lesions at week 12 (compared to week 8), as measured by magnetic resonance imaging (MRI). This radiographic result has been established as a reliable predictive biomarker of clinical efficacy in major MS clinical trials and has been demonstrated as a predictive biomarker of clinical efficacy (reduction in annual relapse rate [ARR]) in trials of other MS treatments.

[0056] Secondary endpoints for determining the potential benefit of flexalimab in neuroinflammation included the number of new or expanding T2 lesions at week 12 (compared to week 8) and the total number of GdET1 lesions (at week 12), as measured by brain MRI.

[0057] Other secondary endpoints included the number of adverse and serious adverse events; clinically significant abnormalities in laboratory tests, electrocardiograms, and vital signs; and assessment of the safety and tolerability of flexaliumab by analyzing criteria such as anti-drug antibodies.

[0058] The final secondary endpoints were the evaluation of flexaliumab pharmacokinetics, including plasma concentrations over time and pharmacokinetic parameters.

[0059] Exploratory evaluations included advanced MRI techniques.

[0060] Table 1 below summarizes the primary, secondary, and exploratory objectives and endpoints of the clinical trial:

[0061] [Table 2]

[0062] [Table 3]

[0063] In this trial, a total of 129 participants were randomly assigned to four cohorts. This example discusses the treatment regimens and outcomes of the first and third cohorts. The first cohort (52 participants) received an intravenous (IV) dose of flexalimab every four weeks (Q4W) with a loading dose of 1800 mg on day 1, followed by 1200 mg at weeks 4 and 8. The third cohort (12 participants) received IV placebo Q4W. Unless otherwise specified, references to the "flexalimab group" or "flexalimab treatment group" in this example refer to the first cohort, and references to the "placebo group" refer to the third cohort. The second and fourth cohorts relate to different treatment regimens and their placebo arms. The treatment regimens and outcomes of these cohorts are not discussed herein.

[0064] Table 2 below outlines the trial interventions for cohorts 1 and 3. Participants in cohorts 1 and 3 were switched to open-label flexaliumab treatment from week 12 onward, with an expected treatment duration of 8 to 76 weeks. Participants from the flexaliumab treatment arm continued their previous IV treatment. Participants from the placebo arm received flexaliumab IV Q4W (1800 mg loading dose, followed by a 1200 mg follow-up dose) starting at the week 12 visit.

[0065] [Table 4]

[0066] The flexalimab drug solution consisted of flexalimab, L-histidine HCl, L-histidine, L-arginine HCl, sucrose, polysorbate-80, and water for injection. The pH of the formulation solution was 5.6.

[0067] Baseline demographic characteristics were similar in both the treatment and placebo cohorts, however, participants in the placebo group were younger and had a higher total number of baseline GdeT1 and T2 lesions compared to participants in the flexalimab-treated group. Of the participants, 50 in the first cohort and 11 in the third cohort had relapsing-remitting multiple sclerosis (MS). Two in the first cohort and one in the third cohort had relapsing secondary progressive MS.

[0068] The following inclusion and exclusion criteria were used when selecting patients eligible to participate in the study: Inclusion Criteria Participants must be between 18 and 55 years old at the time of signing the informed consent form. Participants must be diagnosed with RMS (relapsing-remitting MS or secondary progressive MS with relapses) according to the 2017 revised McDonald's diagnostic criteria. Participants must have a record of at least one relapse within the past year, or two or more relapses within the past two years, or one or more active Gd-enhancing brain lesions on MRI scans in the past six months and prior to screening. Body Mass Index (BMI) at the time of screening, within the range of 45-120 kg (including both extremes) and 18.0-35.0 kg / m2 (including both extremes). Exclusion criteria Participants must have been diagnosed with PPMS or non-recurrent SPMS according to the 2017 revised McDonald's diagnostic criteria. Participants may be in, but are not limited to, the following conditions or circumstances that could negatively affect their participation in this study: • If the principal investigator or internist determines that the patient has a short life expectancy due to their existing health condition. • A medical condition or comorbidity, as determined by the principal investigator, that makes evaluation of the primary endpoint impossible or would adversely affect participation in this study. • If the principal investigator determines that an adjunct therapy is necessary that may bias the evaluation of the primary endpoint. • If you have a contraindication to MRI, namely, the presence of a pacemaker, metal implants in high-risk areas (such as artificial heart valves, aneurysms / vascular clips), metal objects in high-risk areas (such as shrapnel), a known history of allergy to contrast agents, or a history of claustrophobia, and you are unable to complete all MRI examinations planned in the treatment plan. • Contraindications for the use of Gd contrast agents for MRI. • If a participant has, or currently has, any of the following medical conditions or clinical symptoms that would adversely affect their participation in this study, they may not be eligible to participate: • If you have a history of T lymphocyte or T lymphocyte receptor vaccination, transplantation (including solid organ transplantation, stem cell transplantation, bone marrow transplantation), and / or anti-rejection therapy. • If there is a history of diagnosis of progressive multifocal leukoencephalopathy (PML), or if baseline MRI shows findings suggestive of PML. • Severe systemic viral, bacterial, or fungal infection (e.g., pneumonia, nephritis), infection requiring hospitalization or IV antibiotics, or severe chronic viral, bacterial, or fungal infection (e.g., osteomyelitis) within 30 days prior to or during screening. Participants with a history of invasive opportunistic infections, such as histoplasmosis, listeriosis, coccidioidomycosis, candidiasis, Pneumocystis jirovecii infection, and aspergillosis, regardless of whether the infection has resolved. Symptomatic herpes zoster within 3 months prior to screening. • Evidence of active or latent tuberculosis (TB) documented by medical history and examination, chest X-ray (posterior-anterior and lateral), and TB testing: • Positive tuberculin skin test (TST; defined as a skin induration of <5 mm at 48-72 hours, regardless of Bacillus Calmette-Guerin [BCG] or other vaccination history) or positive QuantiFERON®-TB Gold test. • If the principal investigator determines that there is another active infection that could adversely affect participation in this study or administration of IMP. • A history of malignant tumor within 10 years prior to the initial screening visit (excluding non-invasive cervical cancer that has received effective treatment, or non-metastatic squamous cell carcinoma or basal cell carcinoma that has received adequate treatment). • If you have a history of alcohol or drug abuse within one year prior to your initial screening visit. • If you have a history of a mental illness, behavioral condition, or depression requiring hospitalization within two years prior to your initial screening visit. • If the principal investigator determines that a screening test value or electrocardiogram value is outside the normal range, it is considered clinically significant. • Current or chronic history of liver disease, or known liver or biliary tract abnormalities (excluding Gilbert's syndrome or asymptomatic gallstones). • If any participant has a history, clinical evidence, suspected or significant risk of thromboembolic events, as well as myocardial infarction, stroke and / or antiphospholipid syndrome, and requires antithrombotic therapy. • Severe post-treatment hypersensitivity reactions other than allergies to humanized monoclonal antibodies or local injection site reactions to any biological molecule (including, but not limited to, severe erythema multiforme, linear IgA dermatopathy, toxic epidermal necrolysis, and exfoliative dermatitis). • Previous therapies / combination therapies • If a participant has received any of the following drugs / treatments within the specified period prior to baseline assessment (washout is not required for interferon beta or glatiramer acetate treatment):

[0069] [Table 5]

[0070] [Table 6]

[0071] • Past / contemporary clinical research experience • If the participant has taken another investigational drug within the three months prior to the screening visit or within five half-lives, whichever is longer. • Diagnostic evaluation • If the participant's EDSS score is >5.5 at the time of their initial screening visit. • If a participant has experienced a relapse in the 30 days prior to randomization. • If you have a known history of HIV infection, whether it is active or in remission, or if you are positive for human immunodeficiency virus (HIV) serological testing (anti-HIV1 and anti-HIV2 antibodies). • Abnormal clinical test values ​​during screening: • Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2.0 × ULN • Bilirubin > 1.5 × ULN; unless the participant has documented Gilbert's syndrome (isolated bilirubin > 1.5 × ULN is acceptable if the bilirubin is fractionated and direct bilirubin < 35%). • In men, hemoglobin levels should be <11g / 100mL, and in women, <10g / 100mL. Lymphocytes <1000 / mm³ • Neutrophils <1500 / mm3 (excluding <1000 / mm3 for participants of African descent) Platelets <140,000 / mm³ • Estimated glomerular filtration rate <60 mL / min / 1.73 m² (Renal function estimation formula (Modification of Diet in Renal Disease) [MDRD]) • Presence of hepatitis B surface antigen (HBsAg) and anti-hepatitis B core antibody (anti-HBcAb) at the time of screening or within 3 months prior to the first dose of the trial intervention. If anti-HBs is negative and anti-HBc is positive: Confirmation will be made by performing a hepatitis B virus DNA test. • If the hepatitis C antibody test result was positive at the time of screening or within 3 months prior to the start of the trial intervention. Note: Participants who tested positive for hepatitis C antibodies due to a previously resolved disease can only be enrolled if a confirmatory hepatitis C RNA test is available.

[0072] A. Efficacy Results Primary efficacy endpoints: This trial demonstrated that the number of new active GdET1 lesions detected by brain MRI was reduced in the flexalimab-treated group compared to the placebo group at 12 weeks (compared to week 8). An 89% reduction (62%–97%) in the adjusted monthly mean number of new GdET1 lesions was observed in the flexalimab group compared to the placebo group. See Table 3 below.

[0073] [Table 7]

[0074] The reduction in new GdET1 lesions lasted for at least 24 weeks in the flexalimab-treated group. The number of lesions was numerically very low in participants receiving flexalimab (n=37 / 38 without new GdE lesions).

[0075] Secondary efficacy endpoints The results for the two primary secondary endpoints were consistent with the results of the primary analysis, showing that the flexalimab-treated group had a reduction in new or expanding T2 lesions and a reduction in the total number of GdET1 lesions over time compared to placebo. See Tables 4 and 5 below:

[0076] [Table 8]

[0077] [Table 9]

[0078] B. Safety results No participants experienced fatal adverse events (TEAEs), serious adverse events (SAEs), or severe TEAEs during the investigational treatment. See Table 6 below. The most common adverse events (≥4% in the flexaliumab treatment group) were COVID-19 and headache.

[0079] [Table 10]

[0080] C. Drug-mediated results The pharmacokinetic results obtained from clinical trials are shown in Table 7 below.

[0081] [Table 11]

[0082] D. Conclusion Flexalimab administered according to the regimen described above demonstrated efficacy in treating relapsed MS, reducing the number of new GdET1 lesions by only 89% over 12 weeks. The regimen was well-tolerated and demonstrated an acceptable safety profile. No safety concerns arose from the double-blind, periodic analysis of this trial.

Claims

1. A method for treating relapsing multiple sclerosis (MS) in a human patient in need, comprising intravenous administration of a monoclonal anti-human CD40L antibody to the patient, wherein the heavy chain CDR1-3 and light chain CDR1-3 of the antibody each comprise SEQ ID NOs: 1-6, and the antibody is administered to the patient at a dose of 1000-2000 mg approximately every four weeks or approximately every month.

2. The method according to claim 1, wherein the antibody comprises a heavy chain variable domain and a light chain variable domain, respectively, comprising SEQ ID NOs: 7 and 8.

3. A method for treating relapsing multiple sclerosis (MS) in a human patient in need, comprising intravenous administration of a monoclonal anti-human CD40L antibody to the patient, wherein the heavy chain and light chain of the antibody comprise SEQ ID NOs: 9 and 10, respectively, and the antibody is administered to the patient at a dose of 1000 to 2000 mg approximately every four weeks or approximately every month.

4. The method according to any one of claims 1 to 3, wherein the dose is 1200 mg.

5. The method according to any one of claims 1 to 3, wherein the initial dose of the antibody is a first dose, the subsequent dose of the antibody is a second dose, and the first dose is higher than the second dose.

6. The method according to claim 5, wherein the first dose is 1800 mg.

7. The method according to claim 5 or 6, wherein the second dose is 1200 mg.

8. A method for treating relapsing multiple sclerosis (MS) in a human patient in need, comprising administering a monoclonal anti-human CD40L antibody to the patient, wherein the heavy chain CDR1-3 and light chain CDR1-3 of the antibody each comprise SEQ ID NOs: 1-6, and the antibody is administered to the patient at a dose of 1800 mg approximately every four weeks or approximately every month.

9. The method according to claim 8, wherein the antibody comprises a heavy chain variable domain and a light chain variable domain, respectively, comprising SEQ ID NOs: 7 and 8.

10. A method for treating relapsing multiple sclerosis (MS) in a human patient in need, comprising administering a monoclonal anti-human CD40L antibody to the patient, wherein the heavy chain and light chain of the antibody comprise SEQ ID NOs: 9 and 10, respectively, and the antibody is administered to the patient at a dose of 1800 mg approximately every four weeks or approximately every month.

11. The method according to any one of claims 8 to 10, wherein the antibody is administered subcutaneously.

12. The method according to any one of claims 8 to 10, wherein the initial administration of the antibody is intravenous, and the subsequent administration of the antibody is subcutaneous.

13. The method according to any one of claims 1 to 12, wherein the patient has relapsing-remitting MS.

14. The method according to any one of claims 1 to 12, wherein the patient has secondary progressive MS with relapses.

15. A method for treating relapsing multiple sclerosis (MS) in a human patient in need, comprising administering monoclonal anti-human CD40L antibodies, each containing a heavy chain and a light chain, respectively, including SEQ ID NOs: 9 and 10, to the patient by intravenous infusion, wherein the antibodies The first dose is 1800 mg, and It was administered as a subsequent dose of 1200 mg. A method in which the interval between administrations is approximately 4 weeks or approximately 1 month.

16. A method for treating relapsing multiple sclerosis (MS) in a human patient in need, comprising administering to the patient monoclonal anti-human CD40L antibodies comprising heavy chains and light chains, respectively, including SEQ ID NOs: 9 and 10, The antibody was administered at a dose of 1800 mg. The initial dose is administered intravenously, and subsequent doses are administered subcutaneously. A method in which the interval between administrations is approximately 4 weeks or approximately 1 month.

17. A monoclonal anti-human CD40L antibody for use in the treatment of a human patient according to any one of claims 1 to 16.

18. Use of a monoclonal anti-human CD40L antibody for the manufacture of a pharmaceutical product for the treatment of a human patient according to any one of claims 1 to 16.

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