WO2023236967A1 - 用TACI-Fc融合蛋白治疗重症肌无力的方法 - Google Patents

用TACI-Fc融合蛋白治疗重症肌无力的方法 Download PDF

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WO2023236967A1
WO2023236967A1 PCT/CN2023/098731 CN2023098731W WO2023236967A1 WO 2023236967 A1 WO2023236967 A1 WO 2023236967A1 CN 2023098731 W CN2023098731 W CN 2023098731W WO 2023236967 A1 WO2023236967 A1 WO 2023236967A1
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myasthenia gravis
taci
fusion protein
weeks
patient
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PCT/CN2023/098731
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French (fr)
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房健民
王文祥
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荣昌生物制药(烟台)股份有限公司
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Priority to CA3236667A priority Critical patent/CA3236667A1/en
Priority to AU2023283931A priority patent/AU2023283931A1/en
Priority to CN202380015358.9A priority patent/CN118475598A/zh
Priority to EP23819132.4A priority patent/EP4442702A1/en
Publication of WO2023236967A1 publication Critical patent/WO2023236967A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/70575—NGF/TNF-superfamily, e.g. CD70, CD95L, CD153, CD154
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/70578—NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95

Definitions

  • the present invention relates to drugs, dosage regimens, dosing intervals and administration methods for treating myasthenia gravis.
  • MG Myasthenia gravis
  • AchR-Ab acetylcholine receptor antibody
  • ChoR-Ab acetylcholine receptor antibody
  • LRP4-Ab low-density lipoprotein receptor-related protein 4 antibody
  • MG patients have thymic tissue abnormalities, mainly manifested as thymic hyperplasia, cysts, necrosis, hypertrophy, or different types of thymoma.
  • the incidence of myasthenia gravis is related to the age, gender and race of the population.
  • the incidence of myasthenia gravis is different in different countries and regions.
  • MG can occur at all ages. Before the age of 40, the incidence rate is higher in women than in men; 40 The incidence rate is similar in men and women until the age of 50 years; after the age of 50, the incidence rate in men is slightly higher than that in women.
  • Childhood MG is rare in Western populations but is prevalent in Asian countries, with approximately 50% of patients younger than 15 years of age. According to statistics, in the United States, 20 out of every 100,000 people suffer from myasthenia gravis, and the incidence rate of MG in my country is about 0.68/100,000 people.
  • Myasthenia gravis is a lifelong disease with no cure.
  • Current treatments for MG mainly include the following treatments: 1 Cholinesterase inhibitors (such as pyridostigmine bromide, neostigmine). These drugs can inhibit the degradation of acetylcholine and increase the availability of acetylcholine in synapses.
  • 1 Cholinesterase inhibitors such as pyridostigmine bromide, neostigmine.
  • the MG subgroup usually responds well to this treatment, but individual differences are large, the symptoms are treated but not the root cause, and a single drug cannot be used for a long time, which has poor effect on MuSK-MG patients;
  • 2 Immunosuppressants such as cyclophosphamide, cyclosporine
  • Mycophenolate A mycophenolate mofetil
  • tacrolimus methotrexate
  • azathioprine etc.
  • Intravenous immunoglobulin is used. This method is mainly suitable for MG patients with acute disease progression and preoperative preparation.
  • immunosuppressive drugs that have a slow onset or large doses that may induce myasthenic crisis.
  • the combined use of glucocorticoids will take effect about 5 to 10 days after use, and the curative effect lasts for about 2 months; 4Plasma exchange, which is a method of using equipment to remove harmful antibodies from plasma and replacing it with high-quality plasma or substitute plasma Methods. It is mainly used for patients in the acute progression stage of the disease, patients with myasthenic crisis, pre-thymectomy and perioperative management, and the initial stage of immunosuppressive treatment.
  • the FDA has approved three targeted biologics for the treatment of MG in recent years, including eculizumab (October 23, 2017), Efgartigimod (December 17, 2021), and Ravulizumab (April 28, 2022).
  • Eculizumab (trade name: Soliris) is a recombinant human monoclonal antibody that inhibits terminal complement C5 and can prevent the production of membrane attack complex (MAC) caused by anti-AChR antibodies.
  • MAC membrane attack complex
  • the dose of eculizumab was 900 mg on day 1 and weeks 1, 2, and 3; 1200 mg at week 4; and a maintenance dose of 1200 mg every two weeks thereafter. Vaccination against Neisseria meningitidis is necessary.
  • Ultomiris is an improved long-acting preparation based on the first-generation C5 monoclonal antibody eculizumab. Compared with eculizumab, the half-life of the Ravulizumab group is extended. It is now approved for the treatment of adult patients with generalized myasthenia gravis (gMG) who are anti-acetylcholine receptor (AChR) antibody-positive. In a 26-week global phase 3 randomized, double-blind, placebo-controlled, multicenter study, the safety and efficacy of ravulizumab in adult patients with gMG who had not previously received complement inhibitor drugs were evaluated. sex.
  • gMG generalized myasthenia gravis
  • AChR anti-acetylcholine receptor
  • the Myasthenia Gravis Foundation of America (MGFA) clinical classification is II-IV at the time of screening.
  • the study will assess change from baseline in the Myasthenia Gravis Activities of Daily Living Scale (MG-ADL) total score at Week 26 (the primary endpoint), as well as multiple secondary endpoints assessing improvements in disease-related and quality-of-life measures.
  • the data showed that the study met its primary endpoint: from baseline to week 26, there was a statistically significant change in the MG-ADL total score in the Ravulizumab group compared with the placebo group (Ravulizumab group: -3.1, placebo: -1.4 , treatment difference: -1.6, p ⁇ 0.001).
  • QMG quantitative myasthenia gravis
  • Adverse events were comparable between the Ravulizumab and placebo groups during the randomized controlled period (26 weeks).
  • Vyvgart (efgartigimod) is an antibody fragment that binds to the neonatal Fc receptor (FcRn), preventing the FcRn from recycling immunoglobulin G (IgG) back into the blood.
  • the drug causes a decrease in overall levels of IgG, including the abnormal AChR antibodies present in myasthenia gravis, and is currently approved to treat generalized myasthenia gravis (gMG) in adults who test positive for anti-acetylcholine receptor (AChR) antibodies.
  • gMG generalized myasthenia gravis
  • AChR anti-acetylcholine receptor
  • Vyvgart's first trial had more antibodies on a measure that assesses the impact of myasthenia gravis on daily functioning, compared with patients who received placebo (30%). Cycles respond to treatment. More patients who received Vyvgart also showed a response to muscle weakness compared to placebo.
  • the most common side effects associated with the use of Vyvgart include respiratory infections, headaches, and urinary tract infections. But by Vyvgart will cause a decrease in IgG levels, so the risk of infection will be significantly increased.
  • the present invention surprisingly discovered that TACI-Fc fusion protein produced significant therapeutic effects when treating patients with myasthenia gravis.
  • the present invention provides a method for treating myasthenia gravis, which method includes administering a therapeutically effective amount of TACI-Fc fusion protein to a patient with the myasthenia gravis, and the TACI-Fc fusion protein includes:
  • the present invention also provides a method for treating myasthenia gravis, which method includes (1) determining whether the patient has received a standard treatment regimen for myasthenia gravis, and (2) if the patient has received a standard treatment regimen for myasthenia gravis Treatment, administering an effective amount of a TACI-Fc fusion protein to a patient having myasthenia gravis.
  • the standard treatment plan includes: cholinesterase inhibitor alone, cholinesterase inhibitor combined with glucocorticoid or other immunosuppressant specified in the plan, glucocorticoid combined with other immunosuppressant specified in the plan, choline Esterase inhibitors combined with corticosteroids and other immunosuppressants as specified by the protocol.
  • the present invention also provides the use of a TACI-Fc fusion protein in preparing drugs for treating patients with myasthenia gravis.
  • the TACI extracellular region or its Blys and/or APRIL-binding fragment contains the amino acid sequence of SEQ ID NO: 1.
  • the human immunoglobulin constant region contains the amino acid sequence of SEQ ID NO:2 or contains at least 90%, at least 91%, at least 92%, at least 93%, at least 95%, Amino acid sequences that are at least 96%, at least 97%, at least 98%, or at least 99% identical.
  • the human immunoglobulin constant region comprises amino acids corresponding to one or more amino acids at positions 3, 8, 14, 15, 17, 110, 111 or 173 of SEQ ID NO:2 Modification, wherein the modification is preferably amino acid substitution, deletion or insertion.
  • substitution is selected from the following group: P3T, L8P, L14A, L15E, G17A, A110S, P111S and A173T.
  • the human immunoglobulin constant region includes the amino acid sequence of SEQ ID NO: 3.
  • the human immunoglobulin is IgG1.
  • the TACI-Fc fusion protein is Telitacicept, and its amino acid sequence is shown in SEQ ID NO: 4.
  • the single dosage of the TACI-Fc fusion protein is about 0.1 to 10 mg/kg.
  • the single dose of the TACI-Fc fusion protein is 160-240 mg, further preferably 160 mg or 240 mg.
  • the TACI-Fc fusion protein is used 2-4 times during a one-month interval; or the one-month interval is 2 times a month, 3 times a month, or 4 times a month.
  • the administration frequency of the TACI-Fc fusion protein is once a week.
  • the treatment lasts for about 2-50 weeks. Further preferably, the treatment lasts for 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks , 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 weeks, 49 weeks, 50 weeks.
  • the administration mode of the TACI-Fc fusion protein is subcutaneous, intramuscular or intravenous administration, and the administration location is preferably the thigh, abdomen or upper arm.
  • the TACI-Fc fusion protein is administered by subcutaneous injection, intramuscular injection, or intravenous injection.
  • the TACI-Fc fusion protein is injected at the same or different site each time.
  • the site of each injection of the TACI-Fc fusion protein is the same; in other specific embodiments, the site of each injection of the TACI-Fc fusion protein is different.
  • the myasthenia gravis is generalized myasthenia gravis (gMG).
  • the myasthenia gravis is acetylcholine receptor antibody (acetylcholine receptor antibody, AchR-Ab) positive.
  • the myasthenia gravis is positive for muscle specific tyrosine kinase antibody (MuSK-Ab).
  • the myasthenia gravis is clinically classified as type II or type III according to the Myasthenia Gravis Foundation of America (MGFA).
  • the quantitative myasthenia gravis score is ⁇ 8 points and ⁇ 4 items are scored at least 2 points or more.
  • the patient is diagnosed, acetylcholine receptor antibody (acetylcholine receptor antibody, AchR-Ab) positive or muscle-specific receptor tyrosine kinase antibody
  • acetylcholine receptor antibody acetylcholine receptor antibody, AchR-Ab
  • AchR-Ab muscle-specific receptor tyrosine kinase antibody
  • gMG generalized myasthenia gravis
  • MuSK-Ab muscle specific tyrosine kinase antibody
  • Type the quantitative myasthenia gravis score (QMG) during screening is ⁇ 8 points and ⁇ 4 items score at least 2 points.
  • Generalized myasthenia gravis is an autoimmune disease that affects the neuromuscular junction, causing symptoms of weakness.
  • the severity of the patient's condition can be quantitatively assessed through scale scoring, thereby more intuitively evaluating the patient's condition, which is helpful for clinical observation and judgment of drug efficacy.
  • the present invention uses the quantitative myasthenia gravis scale (QMG) and the MG clinical absolute rating scale to evaluate the effectiveness of treatment.
  • QMG mainly measures the patient's muscle strength and endurance. It was proposed by the American Myasthenia Gravis Foundation in 2000. Its use requires the assistance of testing equipment, including handheld dynamometers and stopwatches.
  • QMG includes 13 items including diplopia, eyelid ptosis, facial muscle strength, swallowing, articulation, left and right arm raising, vital capacity (VC) as a percentage of expected, head head, left and right hand grip strength, and left and right leg supine raising, with a total score of 0 ⁇ 39 points, the higher the score, the more serious the condition.
  • QMG needs to be evaluated 8 hours after the last dose of a cholinesterase inhibitor.
  • the clinical absolute score of myasthenia gravis mainly reflects the severity of muscle weakness and fatigability of the affected muscle groups of MG.
  • the scale mainly involves the upper eyelid weakness score, upper eyelid fatigue test, eyeball horizontal movement limitation score, and upper limb fatigue test.
  • lower limb fatigue test facial muscle weakness score, chewing and swallowing function score, respiratory muscle function score, a total of 8 items, with a total score of 0 to 60 points. The higher the score, the more serious the condition.
  • the absolute clinical score for myasthenia gravis needs to be assessed 8 hours after the last dose of a cholinesterase inhibitor.
  • the Myasthenia Gravis Foundation of America strongly recommended the QMG scale in 2000 for prospective clinical research related to MG.
  • the MG clinical absolute score method reflects the severity of muscle weakness and fatigue of affected muscle groups in MG patients by the clinical absolute score. It can sensitively reflect changes in clinical conditions and is an ideal quantitative method for observing changes in the condition of MG patients. .
  • the patient is an adult patient or a pediatric patient.
  • the patient has received a stable standard treatment regimen for myasthenia gravis in the past.
  • the standard treatment plan includes: cholinesterase inhibitor alone, cholinesterase inhibitor combined with glucocorticoid or other immunosuppressants specified in the plan, glucocorticoid combined with the plan specified of other immunosuppressants, cholinesterase inhibitors combined with glucocorticoids, and other immunosuppressants as specified by the protocol.
  • the TACI-Fc fusion protein provided by the present invention shows unexpected clinical efficacy and good safety in the treatment of patients with myasthenia gravis.
  • Figure 1 shows the temporal analysis of QMG score changes from baseline
  • Figure 2 shows the proportion of subjects with varying degrees of improvement in QMG scores at each visit
  • Figure 3 shows the temporal analysis of the change value of MG clinical absolute score from baseline
  • Figure 4 shows the temporal analysis of the change rate of immunoglobulin IgG levels compared with the baseline
  • Figure 5 shows the temporal analysis of the change rate of immunoglobulin IgA levels compared with the baseline
  • Figure 6 shows the temporal analysis of the change rate of immunoglobulin IgM levels compared with the baseline
  • Figure 7 shows the temporal analysis of the change rate of CD19+B cell numbers compared with the baseline.
  • the present invention provides the use of transmembrane activators, calcium regulators and cyclophilin ligand interacting agents (TACI)-immunoglobulin fusion proteins (ie, TACI-Fc fusion proteins) in the treatment of myasthenia gravis.
  • the TACI-immunoglobulin fusion protein provided by the present invention includes: 1) a polypeptide containing a domain that is at least partially identical to the TACI extracellular domain or its fragment capable of binding BlyS and/or APRIL; and 2) a human immunoglobulin constant chain.
  • 09/569,245 and 09/627,206 disclose the extracellular domain of TACI and the TACI extracellular domain capable of interacting with TACI ligands.
  • Fragment-specific, TACI ligands include BlyS and APRIL.
  • Chinese patent publication number CN101323643A discloses a TACI-Fc fusion protein containing amino acid fragments 13-118 of the TACI extracellular domain.
  • the immunoglobulin portion of the TACI-immunoglobulin fusion protein provided by the present invention is preferably IgG1, which may include a heavy chain constant region, such as a human heavy chain constant region.
  • the preferred IgG1 heavy chain constant region of the present invention is an IgG1 Fc fragment containing CH2 and CH3 regions, which can be a wild-type IgG1 Fc fragment or a mutated IgG1 Fc fragment.
  • the TACI-Fc fusion protein may be administered to a patient by any appropriate route of administration, including but not limited to intravenous, intramuscular, or subcutaneous administration.
  • TACI-Fc fusion protein provided by the present invention is prepared and stored in a lyophilized, sterile, solution form.
  • Such formulations may contain other active ingredients, excipients or others, such as sodium chloride, phosphate buffer and sodium hydroxide or others.
  • TACI-Ig formulations can be administered to patients in combination with other medications, and can be administered before, simultaneously with, or after other treatments.
  • treatment relates to a given disease or condition, including but not limited to: inhibiting the disease or condition, such as preventing the progression of the disease or condition; alleviating the disease or condition, such as causing regression of the disease or condition ; or reduce the symptoms caused by the disease or condition, such as reducing, preventing or treating the symptoms of the disease or condition.
  • This study is a multi-center, randomized, open clinical study with the purpose of preliminary evaluation of the effectiveness and safety of tatasercept in the treatment of patients with generalized myasthenia gravis.
  • the study included patients with systemic MG who were AChR-Ab positive or MuSK-Ab positive, received standard treatment but still had a QMG score of ⁇ 8 points, and had MGFA type II/III.
  • the subjects were randomly assigned to the Tatasercept 160 mg group and the Tatasercept 240 mg group.
  • the study drug was administered once a week for a total of 24 times.
  • acetylcholine receptor antibody AchR-Ab
  • MusSK-Ab muscle specific tyrosine kinase antibody
  • Tatacept is administered by subcutaneous injection into the thigh, abdomen, or upper arm. The drug was administered once a week for a total of 24 times. Each injection should be given at a different injection point.
  • Full analysis set The full analysis set refers to the set of all randomly assigned cases that used the trial drug at least once.
  • the per-protocol set is a data set generated by subjects who are fully compliant with the trial protocol. Compliance includes the treatment received, the availability of the primary endpoint indicator measurement, and no major changes in the trial protocol. violation, etc.
  • SS Safetyty data set
  • This trial screened 41 patients and randomly enrolled 29 patients. All 29 cases completed the 24-week trial observation and were included in the full analysis set (FAS), per-protocol set (PPS) and safety data set (SS). There were 14 cases of FAS, 14 cases of PPS, and 14 cases of SS in the 160 mg group of tatasercept; 15 cases of FAS, 15 cases of PPS, and 15 cases of SS in the 240 mg group of tatasercept.
  • FAS full analysis set
  • PPS per-protocol set
  • SS safety data set
  • the average age of the 29 subjects was 44.1 years old, and 55.2% were female. All subjects were positive for AChR antibodies; 28 subjects had MuSK-Ab levels tested (1 subject in the Tatacept 160 mg group was not tested), and the results were all negative.
  • the median disease duration of the subjects was 25.4 months, the average QMG score was 18.9 points, and the average MG clinical absolute score was 24.0 points.
  • the clinical classification of MGFA in 16 subjects (55.2%) was type II, and the clinical classification of MGFA in 13 subjects (44.8%) was type III.
  • the primary efficacy endpoint of this study is the average change in QMG score at week 24 compared with baseline.
  • Analysis of covariance was used, with group as a fixed effect and the baseline value as a covariate.
  • ANCOVA was used to compare the least squares mean (LSMEANS) difference in QMG score changes from baseline at week 24 between the tatascept 160 mg group and the tatascept 240 mg group.
  • the LSMEANS of the change in QMG score from baseline in the tatasercept 160 mg group was -7.96 (95% CI: -10.07 to -5.85), and the LSMEANS of the change in QMG score from baseline in the tatasercept 240 mg group was -. 9.37 (95% CI: -11.40 ⁇ -7.33).
  • the difference in LSMEANS between the two groups was -1.40 (95% CI: -4.34 ⁇ 1.53). See Table 2.
  • the average change in QMG score at week 12 from baseline is one of the secondary efficacy indicators of this study, and a t test was used to compare differences between groups.
  • the average change in MG clinical absolute score from baseline at weeks 12 and 24 is one of the secondary efficacy indicators of this study, and the t test was used to compare differences between groups.
  • the change values (Mean ⁇ SD) of the absolute clinical scores of the subjects' MG from the baseline were: -10.4 ⁇ 4.40 in the 160 mg group of Tatacept; -11.2 ⁇ 9.88 in the 240 mg group of Tatacept.
  • the absolute change values of subjects' MG clinical scores from baseline were: -13.8 ⁇ 7.30 in the 160 mg group of Tatacept and -14.1 ⁇ 9.78 in the 240 mg group of Tatacept. See Table 4.
  • the proportion of subjects with varying degrees of QMG score improvement in the 240 mg group was higher than that in the 160 mg group.
  • the proportions of subjects whose QMG scores improved by ⁇ 3 points in the tatasercept 160 mg group and the tatasercept 240 mg group were 92.9% and 100.0% respectively; the proportions of subjects whose QMG scores improved by ⁇ 4 points were respectively 78.6% and 93.3%; the proportions of subjects with QMG score improvement ⁇ 5 points were 57.1% and 86.7% respectively; the proportions of subjects with QMG score improvement ⁇ 6 points were 50.0% and 80.0% respectively; QMG score improvement ⁇ 7
  • the proportions of subjects with QMG scores were 42.9% and 73.3% respectively; the proportions of subjects with QMG scores improved by ⁇ 8 points were 42.9% and 66.7% respectively.
  • the change rate (%) (Mean ⁇ SD) of subjects’ IgG levels compared with baseline were: Tatacept 160mg group, -26.827 ⁇ 17.127; Tatacept 240mg group, -30.595 ⁇ 13.037 .
  • the change rate (%) (Mean ⁇ SD) of subjects' IgA levels compared to baseline were: Tatasercept 160mg group, -52.475 ⁇ 17.954; Tatasercept 240mg group, -56.850 ⁇ 14.781 .
  • the change rate (%) (Mean ⁇ SD) of subjects' IgM levels compared to baseline was: in the 160 mg group of tatasercept, subjects -61.747 ⁇ 17.299; in the 240 mg group of tatasercept, - 68.203 ⁇ 10.821.
  • tatasercept 160 mg and 240 mg showed sustained improvement in clinical efficacy in patients with generalized myasthenia gravis.
  • both the QMG score and the absolute MG clinical score continued to decrease from week 4 to week 24.
  • the QMG score of subjects in the 160 mg group of tatasercept decreased by an average of 7.7 points
  • the QMG score of subjects in the 240 mg group of tatasercept decreased by an average of 9.6 points.
  • the absolute clinical MG score of subjects in the 160 mg group of tatasercept was reduced by an average of 13.8 points, and the absolute clinical score of MG of subjects in the 240 mg group of tatasercept was reduced by an average of 14.1 points.
  • both Tatacept 160mg and Tatacept 240mg significantly reduced subjects' IgG, IgA, and IgM levels.
  • tatascept 160 mg and tatascept 240 mg were administered once weekly to treat It has a good safety profile in the treatment of patients with systemic myasthenia gravis.
  • the severity of adverse events/adverse reactions were mostly mild and moderate (CTCAE grade 1 and 2).
  • Only 1 subject in the Tatacept 160 mg group experienced 1 CTCAE grade 3 adverse event (lowering of lymphocyte count). ; No CTCAE grade 4 and 5 adverse events/adverse reactions occurred.
  • one subject in the Tatacept 160 mg group suffered a serious adverse event, which was infectious pneumonia.
  • the researcher judged that it might not be related to the study drug, so the administration of the study drug was not stopped, and the patient recovered after treatment.
  • the adverse reactions that occurred in this study were all foreseeable risks of Tatacept, and no new safety risk signals were discovered.
  • Tatacept 160 mg and 240 mg showed good clinical efficacy and safety in the treatment of patients with generalized myasthenia gravis.

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Abstract

提供了利用TACI-Fc融合蛋白治疗重症肌无力的药物、剂量方案、给药间隔及施用方式，结果显示，提供的TACI-Fc融合蛋白在治疗重症肌无力患者过程中表现出较好的临床疗效和良好的安全性。

Description

用TACI-Fc融合蛋白治疗重症肌无力的方法 技术领域
本发明涉及治疗重症肌无力的药物、剂量方案、给药间隔及施用方式。
背景技术
重症肌无力(myasthenia gravis，MG)是一种由乙酰胆碱受体抗体(acetylcholine receptor antibody，AchR-Ab)介导、细胞免疫依赖、补体参与，累及神经肌肉接头突触后膜，引起神经肌肉接头传递障碍，导致骨骼肌收缩无力的获得性自身免疫性疾病。极少部分MG患者由肌肉特异性酪氨酸激酶抗体(muscle specific tyrosine kinase antibody，MuSK-Ab)、低密度脂蛋白受体相关蛋白4抗体(low-density lipoprotein receptor-related protein 4antibody，LRP4-Ab)介导。MG患者全身骨骼肌均可受累。但在发病早期可单独出现眼外肌、咽喉肌或肢体肌肉无力。经常从一组肌群无力开始，逐渐累及其他肌群，直到全身肌无力。部分患者短期内出现全身肌肉收缩无力，甚至发生肌无力危象，其中呼吸肌无力致使呼吸困难可使患者在短时间内窒息死亡。80％～90％的MG患者存在胸腺组织异常，主要表现为胸腺增生、囊肿、坏死、肥大或伴有不同类型的胸腺瘤。
重症肌无力的发病率与人群的年龄、性别和种族有关，不同国家和地区的重症肌无力发病率不同，MG在各个年龄阶段均可发病，在40岁之前，女性发病率高于男性；40～50岁男女发病率相当；50岁之后，男性发病率略高于女性。儿童期MG在西方人群中很少见，但在亚洲国家很流行，约50％的患者年龄小于15岁。据统计，在美国，每10万人中就有20人患有重症肌无力，我国MG发病率约为0.68/10万人。
重症肌无力是一种终身疾病，目前尚没有治愈手段。目前对MG的治疗，主要包括一下治疗方法：①胆碱酯酶抑制剂(如：溴吡斯的明、新斯的明)，这些药物能抑制乙酰胆碱的降解，增加突触中乙酰胆碱的可用性，MG亚组通常对这种治疗反应良好，但个体差异较大，治标不治本，且不能单药长期应用，对MuSK-MG患者效果不佳；②免疫抑制剂(如：环磷酰胺、环孢霉素A、吗替麦考酚酯、他克莫司、甲氨蝶呤、硫唑嘌呤等)，这些药物通过抑制异常抗体的产生来提高肌肉力量，但是可能会引 起严重的副作用；③静脉注射用免疫球蛋白，该方法主要适用于病情急性进展、手术术前准备的MG患者，可与起效较慢的免疫抑制药物或可能诱发肌无力危象的大剂量糖皮质激素联合使用，多于使用后5～10天左右起效，疗效时间可持续2个月左右；④血浆置换，它是一种利用仪器去除血浆中有害抗体，并用优质血浆或替代血浆替换的方法。主要用于病情急性进展期、出现肌无力危象患者、胸腺切除术前和围手术期处理以及免疫抑制治疗初始阶段，能够暂时缓解重症肌无力患者的症状，但如不辅助其他治疗方式，其疗效不超过2个月，并且长期重复使用并不能增加远期疗效；⑤胸腺摘除手术治疗，适用于在16～60岁之间发病的全身型、无手术禁忌证的重症肌无力患者；⑥其他治疗方法，例如进行呼吸肌训练和在轻型MG患者中进行力量锻炼等。总体来说，MG的常见治疗方案存在一定的风险性和局限性、治疗效果也不尽如人意，MG从发病机制来看是一种抗体介导的疾病，因此开发新的有效靶向药物成为了当前MG治疗的迫切需求。
FDA近年批准三种靶向生物制剂用于MG的治疗，包括eculizumab(2017年10月23日)、Efgartigimod(2021年12月17日)和Ravulizumab(2022年4月28日)。
Eculizumab(依库珠单抗，商品名：Soliris)是一种抑制末端补体C5的重组人源型单克隆抗体，可防止抗AChR抗体导致的膜攻击复合物(MAC)产生。针对难治性MG、随访26周的研究中，依库珠单抗在第1天以及第1、2和3周的剂量为900mg；第4周1200mg；此后每两周给予1200mg的维持剂量。有必要对脑膜炎奈瑟菌进行疫苗接种。研究结果显示，从基线到随访结束之间，治疗组与安慰剂组之间的统计学差异仅见于次要结局(MG加重，抢救治疗需要)，而主要终点(MG日常活动评分)无差异。该治疗的疗效在4-8周内出现。试验中最常见的副作用是头痛和上呼吸道感染。尽管依库珠单抗已被批准用于难治性MG患者，但其极其昂贵的价格(每年至少45万欧元)可能是其使用的主要限制。
Ultomiris(Ravulizumab，雷夫利珠单抗)是在第一代C5单抗依库珠单抗的基础上进行改进后的长效制剂，与依库珠单抗相比，Ravulizumab组的半衰期延长，现已批准用于治疗抗乙酰胆碱受体(AChR)抗体阳性的全身型重症肌无力(gMG)成人患者。在一项为期26周的全球3期随机、双盲、安慰剂对照、多中心研究，评估了Ravulizumab组对先前未接受过补体抑制剂药物治疗的gMG成人患者的安全性和有效 性。该研究在北美、欧洲、亚太地区和日本入组了175名患者，这些患者在筛查前至少6个月内确诊MG、抗AChR抗体检测为血清学阳性、进入研究时MG-ADL总评分至少6分、在筛查时美国重症肌无力基金会(MGFA)临床分类为II-IV。研究中，患者按1:1的比例随机接受Ravulizumab组或安慰剂治疗，共26周。患者在第1天接受单次基于体重的负荷剂量，然后从第15天开始，每8周接受一次基于体重的常规维持剂量。研究将评估第26周重症肌无力日常生活能力量表(MG-ADL)总评分相对基线的变化(主要终点)，以及评估疾病相关和生活质量指标改善的多个次要终点。数据显示，研究达到了主要终点：从基线检查到第26周，Ravulizumab组与安慰剂组相比，MG-ADL总评分在统计学上有显著变化(Ravulizumab组：-3.1，安慰剂：-1.4，治疗差异：-1.6，p<0.001)。此外，前瞻性定义的次要终点：从基线检查到第26周，在定量重症肌无力(QMG)总评分(医生对MG临床严重程度的评估)以及QMG改善至少5分的患者比例方面，Ravulizumab组也显示出有临床意义和统计学意义的改善(分别为p<0.001和p＝0.005)。与安慰剂组相比，Ravulizumab组有3倍比例的患者QMG得分至少提高了5分(30.0％vs 11.3％)。这些MG-ADL和QMG评分的改善早在第1周就观察到，并持续到第26周。在随机对照期(26周)，Ravulizumab组和安慰剂组的不良事件具有可比性。最常见的不良反应是头痛(Ravulizumab组18.6％；安慰剂组25.8％)、腹泻(Ravulizumab组15.1％，安慰剂组12.4％)、恶心(Ravulizumab组10.5％，安慰剂组10.1％)。最常见的严重不良事件是MG危象(Ravulizumab组1.2％)和MG恶化(安慰剂组3.4％)。但是，Ravulizumab同样也面临着价格昂贵的问题。
Vyvgart(efgartigimod)是一种与新生儿Fc受体(FcRn)结合的抗体片段，可防止FcRn将免疫球蛋白G(IgG)再循环回血液。该药物会导致IgG的整体水平降低，包括重症肌无力中存在的异常AChR抗体，目前已被批准用于治疗抗乙酰胆碱受体(AChR)抗体检测呈阳性的成人全身性重症肌无力(gMG)。在一项为期26周的临床研究中评估了Vyvgart的安全性和有效性，该研究对167名重症肌无力患者进行了评估，这些患者随机接受Vyvgart或安慰剂治疗。该研究表明，与接受安慰剂的患者(30％)相比，在评估重症肌无力对日常功能的影响的措施中，有更多抗体的重症肌无力患者(68％)在Vyvgart的第一个周期对治疗有反应。与安慰剂相比，更多接受Vyvgart的患者也表现出对肌肉无力的反应。与使用Vyvgart相关的最常见副作用包括呼吸道感染、头痛和尿路感染。但是由 于Vyvgart会导致IgG水平的降低，因此感染风险会大幅度增加。
自上个世纪60年代始，重症肌无力被认为是“第二癌症”，病人终身都伴随疲劳无力，逐渐发展到死亡。尽管近年来MG治疗领域发展迅速，但是无论是中国还是全球，重症肌无力治疗领域都存在巨大的未满足的临床需求。
发明内容
本发明惊奇的发现了TACI-Fc融合蛋白在治疗重症肌无力的患者时，产生了显著的治疗效果。
具体的，本发明提供了一种治疗重症肌无力的方法，所述方法包括对具有所述重症肌无力的患者施用治疗有效量的TACI-Fc融合蛋白，所述的TACI-Fc融合蛋白包含：
(i)TACI胞外区或其结合Blys和/或APRIL的片段；和
(ii)人免疫球蛋白恒定区片段。
具体的，本发明还提供了一种治疗重症肌无力的方法，该方法包括(1)确定患者是否已经接受过重症肌无力标准治疗方案，并(2)如果该患者已经接受过重症肌无力标准治疗，对具有所述重症肌无力的患者施用有效量的TACI-Fc融合蛋白。所述的标准治疗方案包含：单用胆碱酯酶抑制剂、胆碱酯酶抑制剂联合糖皮质激素或方案指定的其他免疫抑制剂、糖皮质激素联合方案指定的其他免疫抑制剂、胆碱酯酶抑制剂联合糖皮质激素和方案指定的其他免疫抑制剂。
具体的，本发明还提供了一种TACI-Fc融合蛋白在制备治疗重症肌无力患者药物中的用途。
优选的，所述的TACI胞外区或其结合Blys和/或APRIL的片段包含SEQ ID NO:1的氨基酸序列。
进一步优选的，所述的人免疫球蛋白恒定区包含SEQ ID NO:2的氨基酸序列或者包含与SEQ ID NO:2至少90％、至少91％、至少92％、至少93％、至少95％、至少96％、至少97％、至少98％、或至少99％一致性的氨基酸序列。
进一步优选的，所述的人免疫球蛋白恒定区包含对应于SEQ ID NO:2的位点3、8、14、15、17、110、111或173的一个或多个位点上的氨基酸的修饰，其中，所述的修饰优选为氨基酸的取代、删除或插入。
进一步优选的，所述的取代选自以下组：P3T、L8P、L14A、L15E、G17A、A110S、P111S和A173T。
进一步优选的，所述的人免疫球蛋白恒定区包含SEQ ID NO:3的氨基酸序列。
进一步优选的，所述的人免疫球蛋白为IgG1。
进一步优选的，所述的TACI-Fc融合蛋白为泰它西普(Telitacicept)，其氨基酸序列如SEQ ID NO:4所示。
进一步优选的，所述的TACI-Fc融合蛋白的单次给药剂量为约0.1至10mg/kg。
进一步优选的，所述TACI-Fc融合蛋白的单次给药剂量为160-240mg，进一步优选为160mg或240mg。
进一步优选的，所述的TACI-Fc融合蛋白在一个月的间隔期间使用2-4次；或一个月的间隔期间是每月2次或每月3次或每月4次。
进一步优选的，所述的TACI-Fc融合蛋白的给药频次为每周1次。
进一步优选的，所述的治疗持续约2-50周。进一步优选的，所述的治疗持续2周、3周、4周、5周、6周、7周、8周、9周、10周、11周、12周、13周、14周、15周、16周、17周、18周、19周、20周、21周、22周、23周、24周、25周、26周、27周、28周、29周、30周、31周、32周、33周、34周、35周、36周、37周、38周、39周、40周、41周、42周、43周、44周、45周、46周、47周、48周、49周、50周。
进一步优选的，所述的TACI-Fc融合蛋白的施用方式为皮下、肌肉或静脉施用，施用位置优选为大腿、腹部或者上臂。在一些具体的实施例中，所述的TACI-Fc融合蛋白的施用方式为皮下注射、肌肉注射或静脉注射。
进一步优选的，所述的TACI-Fc融合蛋白每次注射的位点相同或者不同。在一些具体的实施例中，所述的TACI-Fc融合蛋白每次注射的位点相同；在另一些具体的实施例中，所述的TACI-Fc融合蛋白每次注射的位点不同。
进一步优选的，所述的重症肌无力为全身型重症肌无力(generalized myasthenia gravis,gMG)。
进一步优选的，所述的重症肌无力为乙酰胆碱受体抗体(acetylcholine receptor antibody，AchR-Ab)阳性。
进一步优选的，所述的重症肌无力为肌肉特异性受体酪氨酸激酶抗体(muscle specific tyrosine kinaseantibody，MuSK-Ab)阳性。
进一步优选的，所述的重症肌无力按照美国重症肌无力基金会(MGFA)临床分型为Ⅱ型或者Ⅲ型。
进一步优选的，所述的重症肌无力定量评分(QMG)≥8分且≥4个项目评分至少2分以上。
进一步优选的，所述患者为确诊的、乙酰胆碱受体抗体(acetylcholine receptor antibody，AchR-Ab)阳性或肌肉特异性受体酪氨酸激酶抗体 (muscle specific tyrosine kinaseantibody，MuSK-Ab)阳性的接受稳定标准治疗的全身型重症肌无力(generalized myasthenia gravis,gMG)成人患者，按照美国重症肌无力基金会(MGFA)临床分型为Ⅱ型或者Ⅲ型，筛选时重症肌无力定量评分(QMG)≥8分且≥4个项目评分至少2分以上。
全身型重症肌无力是一种自身免疫性疾病，累及神经肌肉接头，引起无力症状。通过量表评分，可以对患者的病情严重程度进行定量评估，从而更为直观地评价患者病情，有助于进行临床观察、判断药物疗效。本发明采用重症肌无力定量评分(quantitative myasthenia gravis scale，QMG)、MG临床绝对评分量表来评估治疗的有效性。
QMG主要是测量患者的肌力和耐力情况，其于2000年由美国重症肌无力基金会提出，使用时需要测试设备辅助，包括手持握力计和秒表计时。QMG包括复视、眼睑下垂、面部肌力、吞咽、构音、左右手臂平举、肺活量(vital capacity，VC)占预期百分比、抬头、左右手握力、左右腿仰卧抬高13个条目，总分0～39分，得分越高提示病情越重。QMG需要在最后一次服用胆碱酯酶抑制剂8小时后进行评估。
重症肌无力临床绝对评分主要反映了MG受累肌群肌无力和易疲劳性的严重程度，该量表主要涉及上睑无力计分、上睑疲劳试验、眼球水平活动受限计分、上肢疲劳试验、下肢疲劳试验、面肌无力计分、咀嚼吞咽功能计分、呼吸肌功能评分，共8个项目，总分0～60分，得分越高提示病情越重。重症肌无力临床绝对评分需要在最后一次服用胆碱酯酶抑制剂8小时后进行评估。
美国重症肌无力基金会(MGFA)于2000年强烈推荐QMG量表用于MG相关的前瞻性临床研究。MG临床绝对评分法以临床绝对计分的高低反映MG病人受累肌群肌无力和疲劳的严重程度，能敏感地反映出临床病情的变化，是一种观察MG病人病情变化的较为理想的量化方法。
进一步优选的，所述的患者为成人患者或儿童患者。
进一步优选的，所述的患者既往接受稳定的重症肌无力标准治疗方案。在一些具体的实施例中，所述的标准治疗方案包含：单用胆碱酯酶抑制剂、胆碱酯酶抑制剂联合糖皮质激素或方案指定的其他免疫抑制剂、糖皮质激素联合方案指定的其他免疫抑制剂、胆碱酯酶抑制剂联合糖皮质激素和方案指定的其他免疫抑制剂。
本发明提供的TACI-Fc融合蛋白在治疗重症肌无力患者过程中表现出意料不到的临床疗效和良好的安全性。
附图说明
图1为QMG评分较基线变化值历时性分析；
图2为各访视QMG评分不同程度改善的受试者比例；
图3为MG临床绝对评分较基线变化值历时性分析；
图4为免疫球蛋白IgG水平较基线变化率历时性分析；
图5为免疫球蛋白IgA水平较基线变化率历时性分析；
图6为免疫球蛋白IgM水平较基线变化率历时性分析；
图7为CD19+B细胞数较基线变化率历时性分析。
具体实施方式
除非另有定义，本文使用的所有科技术语具有本领域普通技术人员所理解的相同含义。关于本领域的定义及术语，专业人员具体可参考Current Protocols in Molecular Biology(Ausubel)。
本发明所用氨基酸三字母代码和单字母代码如J.biol.chem，243，p3558(1968)中所述。
本发明提供了跨膜激活剂、钙调节剂和亲环蛋白配体相互作用剂(TACI)-免疫球蛋白融合蛋白(即TACI-Fc融合蛋白)在治疗重症肌无力中的应用。本发明提供的TACI-免疫球蛋白融合蛋白包括：1)含有与TACI胞外结构域或其能结合BlyS和/或APRIL的片段至少部分相同的结构域的多肽；和2)人免疫球蛋白的恒定链。美国专利NO.5,969,102、6,316,222和6,500,428和美国专利申请09/569,245和09/627,206(其内容纳入本文作参考)公开了TACI的胞外结构域以及能与TACI配体相互作用的TACI胞外结构域特定片段，TACI配体包括BlyS和APRIL。公开号为CN101323643A的中国专利公开包含TACI胞外结构域第13-118位氨基酸片段的TACI-Fc融合蛋白。
本发明提供的TACI-免疫球蛋白融合蛋白的免疫球蛋白部分优选为IgG1，其可以包含重链恒定区，如人的重链恒定区。本发明优选的IgG1重链恒定区是含有CH2和CH3区的IgG1 Fc片段，其可以是野生型IgG1 Fc片段或经突变的IgG1 Fc片段。
给予患者TACI-Fc融合蛋白可按任何适当的给药途径给药，包括但不限于静脉内、肌肉或皮下给药。
本发明提供的TACI-Fc融合蛋白的制剂以冻干、无菌、溶液形式制备和贮藏。这样的制剂可包含其它活性成分、赋形剂或其他，例如氯化钠、磷酸盐缓冲液和氢氧化钠或其他。TACI-Ig制剂可与其它药物联合给予患者，并且可以早于、同时或后于其它治疗方法给药。
本发明涉及的术语“治疗”与某给定的疾病或病症相关，包括但不限于：抑制该疾病或病症，例如阻止疾病或病症的发展；减轻该疾病或病症，例如导致该疾病或病症消退；或减轻该疾病或病症引起的症状，例如减轻、预防或治疗该疾病或病症的症状。
下面将结合实施例对本发明的实施方案进行详细描述，但是本领域技术人员将会理解，下面实施例仅用于说明本发明，而不应视为限定本发明的范围。
实施例1泰它西普治疗重症肌无力的临床试验
1.研究方法
本研究是一项多中心、随机、开放的临床研究，目的是初步评估泰它西普治疗全身型重症肌无力患者的有效性和安全性。研究纳入AChR-Ab阳性或MuSK-Ab阳性、接受标准治疗但QMG评分仍≥8分、MGFA分型为Ⅱ/Ⅲ型的全身型MG患者。受试者随机分配至泰它西普160mg组和泰它西普240mg组，研究药物每周给药1次，共给药24次。
2.入选患者
受试者为确诊的、乙酰胆碱受体抗体(acetylcholine receptor antibody，AchR-Ab)阳性或肌肉特异性受体酪氨酸激酶抗体(muscle specific tyrosine kinaseantibody，MuSK-Ab)阳性的接受稳定标准治疗的全身型重症肌无力(generalized myasthenia gravis,gMG)成人患者，要求美国重症肌无力基金会(MGFA)临床分型为Ⅱ型或者Ⅲ型，筛选时重症肌无力定量评分(QMG)≥8分且≥4个项目评分至少2分以上。
3.给予的治疗
受试者随机分配至泰它西普160mg或泰它西普240mg组。泰它西普给药方式为皮下注射，注射部位可为大腿、腹部或上臂。每周给药1次，共给药24次。每次注射应在不同的注射点进行注射。
4.评价标准
4.1疗效指标
4.1.1主要疗效指标
第24周QMG评分相比基线的平均变化量。
4.1.2次要疗效指标
第12、24周重症肌无力临床绝对评分相比基线的平均变化量；
第12周QMG评分相比基线的平均变化量。
4.1.3安全性终点
不良事件的发生率和严重程度。
5.人口统计学和基线特征
本研究有3个分析集：
●全分析集(FAS)：全分析集指所有经随机化分组，至少使用一次试验药物的病例集合。
●符合方案集(PPS)：符合方案集是由充分依从于试验方案的受试者所产生的数据集，依从性包括所接受的治疗、主要终点指标测量的可获得性以及对试验方案没有大的违背等。
●安全数据集(SS)：至少接受一次治疗，且有安全性指标记录的实际数据。不良反应的发生率以安全集的病例数作为分母。
本试验筛选41例患者，随机入组29例。29例全部完成24周试验观察，全部纳入全分析集(FAS)、符合方案集(PPS)和安全数据集(SS)。泰它西普160mg组FAS 14例，PPS 14例，SS 14例；泰它西普240mg组FAS 15例，PPS 15例，SS 15例。
29例受试者平均年龄44.1岁，55.2％为女性。所有受试者AChR抗体均为阳性；28例受试者进行了MuSK-Ab水平检测(泰它西普160mg组1例受试者未检测)，结果均为阴性。受试者中位病程为25.4个月，QMG评分平均18.9分，MG临床绝对评分平均24.0分。16例(55.2％)受试者MGFA临床分型为Ⅱ型，13例(44.8％)受试者MGFA临床分型为Ⅲ型。9例(31.0％)受试者仅使用胆碱酯酶抑制剂治疗，13例(44.8％)受试者采用胆碱酯酶抑制剂联合糖皮质激素/方案指定的其他免疫抑制剂治疗，7例(24.1％)受试者采用胆碱酯酶抑制剂联合糖皮质激素和方案 指定的其他免疫抑制剂治疗。
6.疗效结果
6.1疗效分析
疗效分析基于FAS和PPS进行分析。由于本研究中所有随机入组的29例受试者均纳入FAS和PPS，FAS和PPS的分析结果相同，因此下述对于疗效结果的描述不再区分FAS和PPS。
6.2主要疗效终点
本研究的主要疗效终点是第24周QMG评分相比基线的平均变化量，采用协方差分析(analysis ofcovariance，ANCOVA)，以组别作为固定效应，基线值作为协变量。
第24周时，受试者QMG评分较基线的变化值(Mean±SD)分别为：泰它西普160mg组，-7.7±5.34；泰它西普240mg组，-9.6±4.29。见表1。
表1第24周QMG评分较基线变化值
采用ANCOVA比较泰它西普160mg组和泰它西普240mg组第24周时QMG评分较基线变化值的最小二乘均数(LSMEANS)差值。第24周时，泰它西普160mg组QMG评分较基线变化值的LSMEANS为-7.96(95％CI：-10.07～-5.85)，泰它西普240mg组QMG评分较基线变化值的LSMEANS为-9.37(95％CI：-11.40～-7.33)。两组的LSMEANS差值为-1.40(95％CI：-4.34～1.53)。见表2。
表2第24周QMG评分较基线变化值LSMEANS比较

6.3次要疗效终点
6.3.1第12周QMG评分相比基线的平均变化量
第12周QMG评分较基线的平均变化量是本研究的次要疗效指标之一，采用t检验比较组间差异。
第12周时，受试者QMG评分较基线的变化值(Mean±SD)分别为：泰它西普160mg组，-5.8±5.85；泰它西普240mg组，-9.5±5.03。见表3。
表3第12周QMG评分较基线变化值
6.3.2第12、24周MG临床绝对评分相比基线的平均变化量
第12、24周MG临床绝对评分较基线的平均变化量是本研究的次要疗效指标之一，采用t检验比较组间差异。
第12周时，受试者MG临床绝对评分相比基线的变化值(Mean±SD)分别为：泰它西普160mg组，-10.4±4.40；泰它西普240mg组，-11.2±9.88。第24周时，受试者MG临床绝对评分较基线变化值(Mean±SD)分别为：泰它西普160mg组，-13.8±7.30，泰它西普240mg组，-14.1±9.78。见表4。
表4第12、24周MG临床绝对评分较基线变化值

6.4其他疗效结果
6.4.1 QMG评分较基线变化值历时性分析
QMG评分较基线变化值历时性分析结果如图1所示。自第4周起，泰它西普160mg组和泰它西普240mg组受试者QMG评分较基线均明显降低，持续至第24周。
6.4.2 QMG评分改善的受试者比例
各访视QMG评分不同程度改善(即QMG评分分别下降≥3分，≥4分，≥5分，≥6分，≥7分，≥8分)的受试者比例见图2。
从第4周访视至第24周访视，泰它西普240mg组QMG评分不同程度改善的受试者比例均高于160mg组。第24周时，泰它西普160mg组和泰它西普240mg组QMG评分改善≥3分的受试者比例分别为92.9％和100.0％；QMG评分改善≥4分的受试者比例分别为78.6％和93.3％；QMG评分改善≥5分的受试者比例分别为57.1％，和86.7％；QMG评分改善≥6分的受试者比例分别为50.0％和80.0％；QMG评分改善≥7分的受试者比例分别为42.9％和73.3％；QMG评分改善≥8分的受试者比例分别为42.9％和66.7％。
6.4.3 MG临床绝对评分较基线变化值历时性分析
MG临床绝对评分较基线变化值历时性分析结果如图3所示。自第4周起，泰它西普160mg组和泰它西普240mg组受试者MG临床绝对评分较基线均明显降低，持续至第24周。
6.4.4免疫学指标
6.4.4.1免疫球蛋白(IgG、IgA、IgM)
免疫球蛋白(IgG、IgA、IgM)水平相比基线的变化率历时性分析结果见图4-6。从第4周开始，泰它西普160mg组和240mg组受试者IgG、IgA、IgM水平(g/L)均明显下降，持续至第24周。
第24周时，受试者IgG水平相比基线的变化率(％)(Mean±SD)分别为：泰它西普160mg组，-26.827±17.127；泰它西普240mg组，-30.595±13.037。
第24周时，受试者IgA水平相比基线的变化率(％)(Mean±SD)分别为：泰它西普160mg组，-52.475±17.954；泰它西普240mg组，-56.850±14.781。
第24周时，受试者IgM水平相比基线的变化率(％)(Mean±SD)分别为：泰它西普160mg组，受试者-61.747±17.299；泰它西普240mg组，-68.203±10.821。
6.4.4.2 CD19+B细胞
CD19+B细胞数较基线变化率的历时性分析结果见图7。与基线相比，接受泰它西普240mg给药后，受试者CD19+B细胞数中位值呈现先上升后下降的趋势，第24周时，受试者CD19+B细胞数中位值相比基线明显降低。而接受泰它西普160mg给药的受试者CD19+B细胞数中位值呈波动性，变化趋势不明显。
6.5有效性结果
在本研究中，泰它西普160mg和240mg治疗全身型重症肌无力患者表现出持续改善的临床疗效。受试者接受泰它西普160mg和240mg每周给药一次治疗后，从第4周至第24周，QMG评分和MG临床绝对评分均持续下降。第24周时，与基线相比，泰它西普160mg组受试者QMG评分平均降低7.7分，泰它西普240mg组受试者QMG评分平均降低9.6分。第24周时，与基线相比，泰它西普160mg组受试者MG临床绝对评分平均降低13.8分，泰它西普240mg组受试者MG临床绝对评分平均降低14.1分。第24周时，泰它西普160mg组92.9％受试者QMG评分改善≥3分，泰它西普240mg组100％受试者QMG评分改善≥3分。此外，泰它西普160mg和泰它西普240mg均明显降低受试者IgG、IgA、IgM水平。
6.6安全性结果
在本研究中，泰它西普160mg和泰它西普240mg每周给药一次治 疗全身性重症肌无力患者具有良好的安全性。不良事件/不良反应严重程度多为轻度和中度(CTCAE 1级和2级)，仅泰它西普160mg组1例受试者出现1例次CTCAE 3级不良事件(淋巴细胞计数降低)；无CTCAE 4级和5级不良事件/不良反应发生。未发生导致研究药物停用/退出研究/受试者死亡的不良事件/不良反应，无严重不良反应发生。研究期间泰它西普160mg组1例受试者发生严重不良事件，为感染性肺炎，研究者判断与研究药物可能无关，未停止研究药物给药，经治疗后痊愈。本研究中发生的不良反应均为泰它西普的可预期风险，无新的安全性风险信号发现。
6.7结论
在本研究中，泰它西普160mg和240mg治疗全身型重症肌无力患者表现良好的临床疗效和安全性。
以上描述地仅是优选实施方案，其只作为示例而不限制实施本发明所必需特征的组合。所提供的标题并不意指限制本发明的多种实施方案。术语例如“包含”、“含”和“包括”不意在限制。此外，除非另有说明，没有数词修饰时包括复数形式，以及“或”、“或者”意指“和/或”。除非本文另有定义，本文使用的所有技术和科学术语的意思与本领域技术人员通常理解的相同。
本申请中提及的所有公开物和专利通过引用方式并入本文。不脱离本发明的范围和精神，本发明的所描述的方法和组合物的多种修饰和变体对于本领域技术人员是显而易见的。虽然通过具体的优选实施方式描述了本发明，但是应该理解所要求保护的本发明不应该被不适当地局限于这些具体实施方式。事实上，那些对于相关领域技术人员而言显而易见的用于实施本发明的所描述的模式的多种变体意在包括在随附的权利要求的范围内。

Claims (20)

  1. 一种治疗重症肌无力的方法，所述方法包括对具有所述重症肌无力的患者施用治疗有效量的TACI-Fc融合蛋白，其中，所述的TACI-Fc融合蛋白包含：
    (i)TACI胞外区或其结合Blys和/或APRIL的片段；和
    (ii)人免疫球蛋白恒定区片段。
  2. 根据权利要求1所述的方法，其特征在于，所述的TACI胞外区或其结合Blys和/或APRIL的片段包含SEQ ID NO:1所示的氨基酸序列。
  3. 根据权利要求1所述的方法，其特征在于，所述的人免疫球蛋白恒定区包含SEQ ID NO:2的氨基酸序列或者包含与SEQ ID NO:2至少90％、至少91％、至少92％、至少93％、至少95％、至少96％、至少97％、至少98％、或至少99％一致性的氨基酸序列。
  4. 根据权利要求3所述的方法，其特征在于，所述的人免疫球蛋白恒定区包含对应于SEQ ID NO:2的位点3、8、14、15、17、110、111或173的一个或多个位点上的氨基酸的修饰。
  5. 根据权利要求4所述的方法，其特征在于，所述的修饰是氨基酸的取代、删除或插入。
  6. 根据权利要求5所述的方法，其特征在于，所述的取代选自以下组：P3T、L8P、L14A、L15E、G17A、A110S、P111S和A173T。
  7. 根据权利要求6所述的方法，其特征在于，所述的人免疫球蛋白为IgG1或者所述恒定区包含SEQ ID NO:3的氨基酸序列。
  8. 根据权利要求1所述的方法，其特征在于，所述的TACI-Fc融合蛋白具有SEQ ID NO:4所示的氨基酸序列。
  9. 根据权利要求9所述的方法，其特征在于，所述的TACI-Fc融合蛋白为泰它西普(Telitacicept)。
  10. 根据权利要求9所述的方法，其特征在于，所述的TACI-Fc融合蛋白的单次给药剂量为约0.1至10mg/kg。
  11. 根据权利要求9所述的方法，其特征在于，其中，所述TACI-Fc融合蛋白的单次给药剂量为160-240mg，进一步优选为160mg或240mg。
  12. 根据权利要求10或11所述的方法，其特征在于，所述的TACI-Fc融合蛋白在一个月的间隔期间使用2-4次和/或治疗持续约2-50周。
  13. 根据权利要求12所述的方法，其特征在于，所述的TACI-Fc融合蛋白的施用方式为皮下、肌肉或静脉施用或者施用部位为大腿、腹部或者上臂。
  14. 根据权利要求13所述的方法，其特征在于，所述的重症肌无力为全身型重症肌无力(generalized myasthenia gravis,gMG)或乙酰胆碱受体抗体(acetylcholine receptor antibody，AchR-Ab)阳性的重症肌无力或肌肉特异性受体酪氨酸激酶抗体(muscle specific tyrosine kinaseantibody，MuSK-Ab)阳性的重症肌无力或按照美国重症肌无力基金会(MGFA)临床分型为Ⅱ型或者Ⅲ型的重症肌无力。
  15. 根据权利要求14所述的方法，其特征在于，所述的重症肌无力定量评分(QMG)≥8分且≥4个项目评分至少2分以上。
  16. 根据权利要求15所述的方法，其特征在于，所述的患者为成人患者或儿童患者或既往接受过稳定的重症肌无力标准治疗方案。
  17. 根据权利要求16所述的方法，其特征在于，所述的标准治疗方案包含：单用胆碱酯酶抑制剂、胆碱酯酶抑制剂联合糖皮质激素或方案指定的其他免疫抑制剂、糖皮质激素联合方案指定的其他免疫抑制剂、胆碱酯酶抑制剂联合糖皮质激素和方案指定的其他免疫抑制剂。
  18. 一种治疗已经接受过重症肌无力标准治疗方案的重症肌无力患者的方法，该方法包括(1)确定患者是否已经接受过重症肌无力标准治疗方案，并(2)如果该患者已经接受过重症肌无力标准治疗，对具有所述重症肌无力的患者施用有效量的TACI-Fc融合蛋白。
  19. 根据权利要求18所述的方法，其特征在于，所述的标准治疗方案包含：单用胆碱酯酶抑制剂、胆碱酯酶抑制剂联合糖皮质激素或方案指定的其他免疫抑制剂、糖皮质激素联合方案指定的其他免疫抑制剂、胆碱酯酶抑制剂联合糖皮质激素和方案指定的其他免疫抑制剂。
  20. 一种TACI-Fc融合蛋白在制备治疗重症肌无力患者药物中的用途。
PCT/CN2023/098731 2022-06-08 2023-06-07 用TACI-Fc融合蛋白治疗重症肌无力的方法 WO2023236967A1 (zh)

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