WO2023016444A1 - 用TACI-Fc融合蛋白治疗IgA肾病的方法 - Google Patents

用TACI-Fc融合蛋白治疗IgA肾病的方法 Download PDF

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WO2023016444A1
WO2023016444A1 PCT/CN2022/111112 CN2022111112W WO2023016444A1 WO 2023016444 A1 WO2023016444 A1 WO 2023016444A1 CN 2022111112 W CN2022111112 W CN 2022111112W WO 2023016444 A1 WO2023016444 A1 WO 2023016444A1
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taci
fusion protein
amino acid
iga nephropathy
group
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PCT/CN2022/111112
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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 KR1020237041249A priority Critical patent/KR20240005815A/ko
Priority to AU2022325359A priority patent/AU2022325359A1/en
Priority to EP22855425.9A priority patent/EP4292603A1/en
Priority to US18/250,726 priority patent/US20240002468A1/en
Priority to BR112023018745A priority patent/BR112023018745A2/pt
Priority to CN202280013421.0A priority patent/CN116867507A/zh
Priority to CA3196569A priority patent/CA3196569A1/en
Priority to JP2023557036A priority patent/JP2024510636A/ja
Publication of WO2023016444A1 publication Critical patent/WO2023016444A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/30—Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/32—Fusion polypeptide fusions with soluble part of a cell surface receptor, "decoy receptors"

Definitions

  • the present invention relates to the medicine, dose scheme, dosing interval and administration mode for treating IgA nephropathy.
  • extracellular region of TACI or its fragment binding to Blys and/or APRIL has an amino acid sequence comprising SEQ ID NO:1.
  • the human immunoglobulin constant region has an amino acid sequence comprising SEQ ID NO: 2 or comprising 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%, at least 99% identical.
  • the human immunoglobulin constant region comprises amino acid modification at one or more positions corresponding to positions 3, 8, 14, 15, 17, 110, 111 or 173 of SEQ ID NO:2 , wherein the modification is preferably amino acid substitution, deletion or insertion.
  • human immunoglobulin constant region has an amino acid sequence comprising SEQ ID NO:3.
  • human immunoglobulin is IgG1.
  • amino acid sequence of the TACI-Fc fusion protein is shown in SEQ ID NO:4.
  • TACI-Fc fusion protein is Telitacicept (Telitacicept).
  • the dosage range of the TACI-Fc fusion protein is 160-240 mg each time; in some specific embodiments, the dosage of the TACI-Fc fusion protein is 160 mg each time; in other specific embodiments In an embodiment, the dosage of the TACI-Fc fusion protein is 240 mg each time.
  • the TACI-Fc fusion protein is used 2-4 times at intervals of one month.
  • the treatment lasts for about 2-50 weeks.
  • the administration of the TACI-Fc fusion protein is subcutaneous administration, intramuscular injection, oral administration or intravenous administration.
  • the IgA nephropathy is primary IgA nephropathy.
  • the patient is an adult patient or a child patient.
  • the present invention also relates to a method for treating IgA nephropathy.
  • the method is to administer a pharmaceutical composition containing TACI-Fc fusion protein to a patient, and the pharmaceutical composition further includes a pharmaceutically acceptable carrier.
  • the invention also relates to the use of a TACI-Fc fusion protein in the preparation of medicines for treating IgA nephropathy patients.
  • the results showed that the urinary protein level of patients in the tetacept treatment group was significantly lower than that of the baseline, and the difference was statistically significant compared with the placebo group. In addition, there were significant differences between the treatment group and the placebo control group in multiple secondary endpoints of the clinical trial.
  • Figure 1 shows the temporal changes of eGFR
  • Figure 2 shows the diachronic changes of UACR
  • Fig. 3 is the diachronic change of urine red blood cell count
  • Fig. 4 is the diachronic change of IgA level
  • Fig. 5 is the diachronic change of IgG level
  • Fig. 6 is the diachronic change of IgM level
  • Figure 7 is the time-lapse change of B lymphocyte (CD19+) count.
  • the present invention provides the application of a TACI-Fc fusion protein (also known as "TACI-immunoglobulin fusion protein", which can be used interchangeably in the present invention) in the treatment of IgA nephropathy, and the patients involved in the present invention are preferably breastfeeding Animals, such as humans; more preferably, the patients involved in the present invention are adults or children.
  • TACI-Fc fusion protein also known as "TACI-immunoglobulin fusion protein”
  • the TACI-immunoglobulin fusion protein provided by the present invention includes: 1) a polypeptide containing at least part of the same structural domain as the extracellular domain of TACI or a fragment thereof capable of binding BlyS and/or APRIL; and 2) a human immunoglobulin constant region.
  • U.S. Patent Nos. 5,969,102, 6,316,222, and 6,500,428 and U.S. Patent Applications 09/569,245 and 09/627,206, the contents of which are incorporated herein by reference disclose extracellular domains of TACI and TACI extracellular domains capable of interacting with TACI ligands Specific fragments, TACI ligands include BlyS and APRIL.
  • the Chinese patent publication No. CN101323643A discloses a TACI-Fc fusion protein comprising the 13th-118th amino acid fragment of the TACI extracellular domain.
  • TACI transmembrane activator and CAML interactor, which is a member of the tumor necrosis factor receptor superfamily.
  • B lymphocyte stimulator B lymphocyte stimulator
  • APRIL a proliferation-inducing ligand
  • TNF tumor necrosis factor
  • APRIL can specifically bind to TACI and BCMA, and after binding, it can prevent APRIL from binding to B cells and inhibit the proliferative response of primitive B cells stimulated by APRIL.
  • APRIL can compete with BLys for binding to receptors (BCMA, TACI).
  • immunoglobulin in the present invention refers to an animal protein with antibody activity, preferably human immunoglobulin.
  • immunoglobulin can be IgG, IgM, IgE, IgD or IgA, preferably immunoglobulin
  • the protein is IgG, more preferred immunoglobulins are IgG1, IgG4.
  • human immunoglobulin constant region in the present invention specifically refers to the human immunoglobulin heavy chain constant region.
  • the "human immunoglobulin constant region” is a complete human immunoglobulin heavy chain constant region; in other specific embodiments, the “human immunoglobulin constant region” It is a fragment with the partial amino acid sequence of "complete human immunoglobulin heavy chain constant region", that is, “human immunoglobulin heavy chain constant region fragment”.
  • the "complete human immunoglobulin heavy chain constant region” includes CH1 domain, hinge region, CH2 domain and CH3 domain;
  • "human immunoglobulin heavy chain constant region fragment” can have A variety of structural combinations, including but not limited to the following: the complete or partial amino acid sequence of the CH1 domain, the complete or partial amino acid sequence of the hinge region, the complete or partial amino acid sequence of the CH2 domain, and the complete or partial amino acid sequence of the CH3 domain , the complete or partial amino acid sequence of the CH1 domain and the complete or partial amino acid sequence of the hinge region, the complete or partial amino acid sequence of the CH1 domain and the complete or partial amino acid sequence of the CH2 domain, the complete or partial amino acid sequence of the CH1 domain and the CH3 Complete or partial amino acid sequence of domain, complete or partial amino acid sequence of hinge region and complete or partial amino acid sequence of CH2 domain, complete or partial amino acid sequence of hinge region and complete or partial amino acid sequence of CH3 domain, CH2 domain The complete or partial amino acid sequence of the
  • the "human immunoglobulin constant region” refers specifically to a fragment of the human immunoglobulin heavy chain constant region, which preferably includes a partial amino acid sequence of the hinge region and a complete amino acid sequence of the CH2 domain sequence and the complete amino acid sequence of the CH3 domain.
  • the "human immunoglobulin constant region” involved in the present invention exemplarily comprises the amino acid sequence shown in SEQ ID NO: 2 or SEQ ID NO: 3 or its identity sequence.
  • the immunoglobulin part of the TACI-immunoglobulin fusion protein provided by the present invention is preferably IgG1.
  • a preferred IgG1 heavy chain constant region of the invention is an IgG1 Fc fragment containing CH2 and CH3 regions, which may be a wild-type IgG1 Fc fragment or a mutated IgG1 Fc fragment.
  • the constant region of the immunoglobulin provided by the present invention can introduce one or more amino acid changes, such as substitutions (ie mutations), additions (ie insertions) or deletions (ie deletions).
  • terapéuticaally effective dose in the present invention refers to the commonly used dose of the drug, which is the effective dose range commonly used in clinical practice, generally an amount between the minimum effective dose and the extreme dose.
  • the minimum effective dose refers to the minimum dose of the drug that can cause pharmacological effects.
  • the extreme dose refers to the maximum therapeutic dose, that is, the limit of safe medication, and poisoning may occur if the extreme dose is exceeded.
  • the numbering ways of amino acid positions are carried out in the way of "sequence numbering", such as “sequence numbering” described in the present invention
  • the positions 3, 8, 14, 15, 17, 110, 111 or 173 of SEQ ID NO:2" refer to the 3rd amino acid, the 8th amino acid of SEQ ID NO: 2, and so on; as the present invention
  • the "P3T” refers to the mutation of the 3rd amino acid sequence of SEQ ID NO:2 from the previous "P" to "T”
  • “L8P” refers to the 8th amino acid sequence of SEQ ID NO:2 The sequence is mutated from the previous "L” to "P", and so on.
  • composition specifically refers to a preparation comprising a TACI-Fc fusion protein, which can be in different forms, such as an injectable solution or suspension; it can also be a solution suitable for dissolving in a liquid carrier or suspensions in solid pre-injection form (e.g. lyophilized composition for reconstitution in sterile water with preservative); can also be prepared for topical administration, e.g. as an ointment, cream or powder; can also be prepared For oral administration; also as a tablet or capsule, as a spray, or as a syrup (optionally flavored).
  • injectables are prepared, either as liquid solutions or suspensions, as well as solid forms suitable for solution in, or suspension in, liquid carriers prior to injection.
  • the TACI-Fc fusion protein or pharmaceutical composition of the present invention can be administered by any number of routes, including but not limited to: oral administration, intravenous injection, intramuscular injection, intraarterial injection, intramedullary injection, intraperitoneal injection, sheath Intravenous injection, intracardiac, transdermal, transdermal, topical, subcutaneous, intranasal, enteral, sublingual, vaginal or rectal routes.
  • the TACI-Fc fusion protein or its pharmaceutical composition provided by the invention is prepared and stored in the form of freeze-drying, aseptic and solution.
  • treatment as used in the present invention is related to a given disease or condition, including but not limited to: inhibiting the disease or condition, such as preventing the development of the disease or condition; alleviating the disease or condition, such as causing the disease or condition to regress or alleviate the symptoms caused by the disease or disorder, eg, alleviate, prevent or treat the symptoms of the disease or disorder.
  • the subject has received the basic treatment regimen including ACEI/ARB drugs for 12 weeks before randomization, and the dose of ACEI/ARB drugs (within the maximum tolerance range) is stable within 4 weeks before randomization.
  • the main endpoint index i.e. the analysis of the main efficacy index
  • the Security Data Set (SS) data is the same as the FAS set.
  • PPS per-protocol set
  • the average 24-hour urinary protein level of the subjects in the placebo group was basically unchanged, showing a decrease of 0.03g/24h (2.62%); the average urinary protein level of the subjects in the Taiai 240mg group decreased by 0.89 g/24h (49.29%), the average urine protein of subjects in Taiai 160mg group decreased by 0.32g/24h (24.71%) before and after administration.
  • the mean UACR values of subjects in the Taiai 160mg group and Taiai 240mg group decreased by 347.81mg/g and 627.55mg/g, respectively, and the mean UACR values of subjects in the placebo group decreased 16.77 mg/g.
  • the average IgA level of subjects in the placebo group changed slightly, showing a decrease of 0.01g/L (decrease rate of 1.11%), while the average IgA level of subjects in the Taiai 160mg group decreased 1.48g/L (45.75%), and the average IgA level of subjects in Taiai 240mg group decreased by 1.17g/L (15.83%).
  • the temporal changes of the average IgA levels of subjects in each group are shown in Figure 4.
  • the immunoglobulin G (IgG) level of subjects in the Taiai administration group continued to decline.
  • ANOVA analysis showed that, compared with the placebo group, the difference in immunoglobulin G (IgG) changes was statistically significant at the 4th week, p ⁇ 0.001, and lasted until the 24th week of treatment.
  • the IgG level of the subjects in the placebo group changed little, with an average increase of 0.10g/L (0.22%), and the IgG level of the subjects in the Taiai 160mg group decreased by 3.00g/L L (26.16%), the IgG level of subjects in Taiai 240mg group decreased by 2.56g/L (24.55%).
  • the temporal changes of the average IgA levels of subjects in each group are shown in Figure 5.
  • the level of immunoglobulin M (IgM) of subjects in the Taiai administration group continued to decline.
  • the statistical difference between the Taiai administration group and the placebo group lasted from the 8th week of administration to the 24th week of administration.
  • the average IgM level of the subjects in the placebo group remained basically unchanged, showing an increase of 0.03g/L (0.63%).
  • the average level of IgM of subjects in the Taiai 160mg group decreased by 0.76g/L (64.28%), and the average level of the subjects in the Taiai 240mg group decreased by 0.62g/L (65.34%).
  • the average B lymphocyte (CD19 + ) level of subjects in the placebo group decreased by 0.32/ ⁇ l (1.18 % ); The decrease was 108.36/ ⁇ l (26.23%); the average B lymphocyte (CD19 + ) of the subjects in the Taiai 240mg group decreased by 36.72/ ⁇ l (21.40%).
  • the B lymphocyte (CD19 + ) count of subjects in Taiai 240mg group was not significantly different from that in placebo group (p>0.05).
  • the B lymphocyte (CD19 + ) counts of subjects in the Taiai 160mg group were significantly different from those in the placebo group (p ⁇ 0.05).
  • the specific changes are shown in Figure 7.
  • the test data showed that after 24 weeks of medication, the 24-hour urine protein levels of subjects in the Taiai 240mg group and Taiai 160mg group were lower than the baseline. Among them, the average 24-hour urine protein of subjects in the Taiai 240mg group decreased by 0.89g/24h (49.29%); the average 24-hour urine protein of subjects in the Taiai 160mg group decreased by 0.32g/24h (24.71%). From the 16th week to the 24th week of medication, the urine protein level of subjects in the Taiai 240mg group decreased significantly compared with the placebo group, and the difference was statistically significant; Compared with the subjects in the placebo group, the difference was statistically significant.
  • the average estimated glomerular filtration rate (eGFR) of the long-term renal indicators of the subjects in the two Taiai administration groups increased, and the average level of immunoglobulins (IgA, IgG, and IgM) decreased significantly.
  • the inter-group differences in the changes of the above indicators were also statistically significant. Since there is currently no recognized targeted drug for the treatment of IgA nephropathy, there is currently no clinical data of positive drugs for horizontal comparison. However, the results obtained in this study are superior to most of the clinical trial data of IgA treatment drugs in the same period. Therefore, this study reveals the effectiveness of Taiai 240mg/week and Taiai 160mg/week in the treatment of IgA nephropathy.

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Abstract

涉及利用TACI-Fc融合蛋白治疗IgA肾病的药物、剂量方案、给药间隔及施用方式，结果显示，治疗组患者的尿蛋白水平与基线相比显著降低，相比安慰剂组，其差异具有统计学意义。此外，治疗组与安慰剂对照组之间在临床试验的多个次要终点也存在显著差异。

Description

用TACI-Fc融合蛋白治疗IgA肾病的方法 技术领域
本发明涉及治疗IgA肾病的药物、剂量方案、给药间隔及施用方式。
背景技术
IgA肾病(即免疫球蛋白a肾病，IgA Nephropathy，IgAN)是一种由免疫复合物引起的肾小球肾炎，表现为血尿、蛋白尿及不同比例的进展型肾衰竭。该病的发病机制非常复杂，目前认为遗传、环境和免疫因素共同决定了IgA肾病的发生，但主要认为，是由于多种因素导致产生过多异常糖基化的多聚IgA1分子在肾脏系膜区沉积，诱发系膜区炎症反应及补体过度激活，从而导致疾病的发生进展。患者最终会发展为肾衰竭或终末期肾脏疾病，多达50％的患者需要进行透析或肾脏移植。根据弗若斯特沙利文的资料，全球IgA肾病患者人数由2015年的880万人增加至2020年的930万人(包括中国220万人)。预计全球IgA肾病患者总数将于2025年达到970万人(包括中国230万人)，并于2030年达到1020万人(包括中国240万人)。因此，IgA肾病治疗领域在全球范围内存在巨大的临床需求。
然而目前，全球尚无获批用于IgA肾病的特效疗法或生物药。当前的标准疗法是肾-血管紧张素－醛固酮系统阻断及免疫抑制，包括皮质激素，往往有严重的毒副反应。截止到2021年07月20日，全球仅有11款生物新药处于IgA肾病的临床研究阶段(见表1)。
表1全球处于IgA肾病的临床研究阶段的生物新药
药物名称 研究机构 相关适应症全球最高研发状态
Telitacicept(泰它西普) 荣昌生物制药(烟台)股份有限公司 临床II期
Ravulizumab Alexion Pharmaceuticals Inc 临床II期
Narsoplimab Omeros 临床III期
AVB-S6-500 Aravive Biologics 临床II期
Atacicept(阿塞西普) Zymogenetics 临床II期
VIS-649 Visterra 临床II期
BION-1301 Aduro Biotech 临床II期
Blisibimod Anthera 临床III期
Valziflocept Suppremol 临床II期
CCL2-LPM Osprey Pharmaceuticals 临床I期
CR-002(CuraGen) Curagen；安进 临床I期
因此，无论是中国还是全球，IgA肾病治疗领域都存在巨大的临床需求。
发明内容
通过对一项临床数据深入分析，本发明提供的TACI-Fc融合蛋白在治疗IgA肾病的癌患者时，产生了显著的技术效果。
具体的，本发明提供了一种治疗IgA肾病的方法，所述方法包括向所述IgA肾病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，
进一步的，所述的TACI胞外区或其结合Blys和/或APRIL的片段具有包含SEQ ID NO:1的氨基酸序列。
Figure PCTCN2022111112-appb-000001
进一步的，所述的人免疫球蛋白恒定区具有包含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％、至少99％一致性的氨基酸序列。
Figure PCTCN2022111112-appb-000002
Figure PCTCN2022111112-appb-000003
进一步的，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。
进一步的，所述的取代选自以下组：P3T、L8P、L14A、L15E、G17A、A110S、P111S和A173T。
进一步的，所述的人免疫球蛋白恒定区具有包含SEQ ID NO:3的氨基酸序列。
Figure PCTCN2022111112-appb-000004
进一步的，所述的人免疫球蛋白为IgG1。
进一步的，所述的TACI-Fc融合蛋白的氨基酸序列如SEQ ID NO:4所示。
Figure PCTCN2022111112-appb-000005
进一步的，所述的TACI-Fc融合蛋白为Telitacicept(泰它西普)。
进一步的，所述TACI-Fc融合蛋白的给药剂量范围为每次160-240mg；在一些具体的实施例中，所述TACI-Fc融合蛋白的给药剂量为每次160mg；在另一些具体的实施例中，所述TACI-Fc融合蛋白的给药剂量为每次240mg。
进一步的，所述的TACI-Fc融合蛋白在一个月的间隔期间使用2-4次。
进一步的，所述的治疗持续约2-50周。
进一步的，所述的TACI-Fc融合蛋白的施用方式为皮下施用、肌肉注射、口服或静脉施用。
进一步的，所述的IgA肾病为原发性IgA肾病。
进一步的，所述的患者为成人患者或儿童患者。
本发明还涉及一种治疗IgA肾病的方法，所述方法为向患者施用一种包含TACI-Fc融合蛋白的药物组合物，所述的药物组合物还包括药学上可接受的载体。
本发明还涉及一种TACI-Fc融合蛋白在制备治疗IgA肾病患者药物中的用途。
本发明开展的一项临床研究中，结果显示，泰它西普治疗组患者的尿蛋白水平与基线相比显著降低，相比安慰剂组，其差异具有统计学意义。此外，治疗组与安慰剂对照组之间在临床试验的多个次要终点也存在显著差异。
附图说明
图1为eGFR的历时性变化；
图2为UACR的历时性变化；
图3为尿红细胞计数的历时性变化；
图4为IgA水平的历时性变化；
图5为IgG水平的历时性变化；
图6为IgM水平的历时性变化；
图7为B淋巴细胞(CD19+)计数的历时性变化。
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)。
本发明提供了一种TACI-Fc融合蛋白(也称“TACI-免疫球蛋白融合 蛋白”，其在本发明中可以互换使用)在治疗IgA肾病中的应用，本发明涉及的患者优选为哺乳动物，如人；更优选的，本发明涉及的患者为成年人或者儿童。
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区。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。
本发明中的术语“TACI”即transmembrane activator and CAML interactor，是一种肿瘤坏死因子受体超家族中的成员之一。本发明中的术语“BLys”是指B淋巴细胞刺激物(B lymphocyte stimulator)，它是一种以膜结合型和可溶型2种形式存在的TNF配体超家族成员之一,它特异性表达于骨髓细胞表面，并选择性刺激B淋巴细胞增殖和免疫球蛋白的产生；本发明中的术语“APRIL”(a proliferation-inducing ligand)是一种肿瘤坏死因子(TNF)类似物，它能激发体内的原始B细胞和T细胞增殖，促进B细胞累积并增加脾含量。APRIL能和TACI、BCMA特异性结合，结合后能阻止APRIL与B细胞结合，并抑制APRIL激发的原始B细胞增殖反应。而且APRIL能和BLys竞争性结合受体(BCMA、TACI)。
本发明术语“免疫球蛋白”是指具有抗体活性的动物蛋白，优选为人免疫球蛋白，在一些实施方案中，“免疫球蛋白”可以是IgG，IgM，IgE，IgD或IgA，优选的免疫球蛋白是IgG，更优选的免疫球蛋白是IgG1，IgG4。
本发明中的术语“人免疫球蛋白恒定区”特指人免疫球蛋白重链恒定区。在某一实施例中，所述的“人免疫球蛋白恒定区”为完整的人免疫球蛋白重链恒定区；在另一些具体的实施例中，所述的“人免疫球蛋白恒定区”为具有“完整的人免疫球蛋白重链恒定区”部分氨基酸序列的片段，即“人免疫球蛋白重链恒定区片段”。以人免疫球蛋白IgG1为例，“完整的人免疫球蛋白重链恒定区”包含CH1结构域、铰链区、CH2结构域和CH3结构域；“人免疫球蛋白重链恒定区片段”可以具有多种结构组合形式，包括当不限于如下：CH1结构域的完整或部分氨基酸序列，铰 链区的完整或部分氨基酸序列，CH2结构域的完整或部分氨基酸序列，CH3结构域的完整或部分氨基酸序列，CH1结构域的完整或部分氨基酸序列和铰链区完整或部分氨基酸序列，CH1结构域的完整或部分氨基酸序列和CH2结构域的完整或部分氨基酸序列，CH1结构域的完整或部分氨基酸序列和CH3结构域的完整或部分氨基酸序列，铰链区的完整或部分氨基酸序列和CH2结构域的完整或部分氨基酸序列，铰链区的完整或部分氨基酸序列和CH3结构域的完整或部分氨基酸序列，CH2结构域的完整或部分氨基酸序列和CH3结构域的完整或部分氨基酸序列，CH1结构域的完整或部分氨基酸序列、铰链区的完整或部分氨基酸序列和CH2结构域的完整或部分氨基酸序列，CH1结构域的完整或部分氨基酸序列、铰链区的完整或部分氨基酸序列和CH3结构域的完整或部分氨基酸序列，铰链区的完整或部分氨基酸序列、CH2结构域的完整或部分氨基酸序列和CH3结构域的完整或部分氨基酸序列。在本发明的一些优选实施例中，所涉及的“人免疫球蛋白恒定区”特指人免疫球蛋白重链恒定区片段，其优选的包含铰链区的部分氨基酸序列和CH2结构域完整的氨基酸序列以及CH3结构域完整的氨基酸序列。在一些优选的实施例中，本发明涉及的“人免疫球蛋白恒定区”示例性的具有包含SEQ ID NO:2或者SEQ ID NO:3所示的氨基酸序列或其同一性序列。
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。本发明优选的IgG1重链恒定区含有CH2和CH3区的IgG1Fc片段，其可以是野生型IgG1Fc片段或经突变的IgG1Fc片段。
作为一种可选择的实施方案，本发明提供的免疫球蛋白的恒定区可以引入一个或多个氨基酸的改变，如取代(即突变)、增加(即插入)或缺失(即删除)。
本发明中的术语“治疗有效量”是指药物的常用量，是临床常用的有效剂量范围，一般为介于最小有效量和极量之间的量。最小有效量是指应用药物能引起药理效应的最小剂量。极量是指治疗量的最大量，即安全用药的极限，超过极量就有可能发生中毒。
本发明中的术语“泰它西普”(或称“泰爱”，其在本发明中可以互换使用)是一种TACI-Fc融合蛋白，其INN名为Telitacicept，其氨基酸序列如SEQ ID NO:4所示，或参见https://extranet.who.int/soinn/mod/page/view.php？id＝137&inn_n＝10932所示。
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。氨基酸位点的编号方式有多种，如Kabat编号系统、EU编号系统、顺序编号等，在本发明中，氨基酸位点的编号方式采用“顺序编号”的方式进行，如本发明所述的“SEQ ID NO:2的位点3、8、14、15、17、110、111或173”是指SEQ ID NO:2的第3位氨基酸、第8位氨基酸，并依此类推；如本发明所述的“P3T”是指将SEQ ID NO:2的第3位氨基酸序列由之前的“P”突变为“T”，再如“L8P”是指将SEQ ID NO:2的第8位氨基酸序列由之前的“L”突变为“P”，并以此例类推。
本发明的术语“药物组合物”特指包含TACI-Fc融合蛋白的制剂，其可以为不同的形式，如可以为可注射的溶液或悬浮液；也可以为适于溶于液体载体中的溶液或悬浮液的注射前固体形式(例如冻干组合物，用于重配含防腐剂的无菌水)；也可以制备用于局部给药，例如作为软膏、乳膏或粉末；也可以可以制备用于口服给药；也可以作为片剂或胶囊，作为喷雾，或作为糖浆(可选有味道的)。典型地，其可以制备成可注射的液体溶液或悬浮液，也可以制备成适于溶于液体载体中的溶液或悬浮液的注射前固体形式。
本发明的TACI-Fc融合蛋白或药物组合物可以通过任意多种途径给药，其包括但不局限于：口服、静脉注射、肌肉内注射、动脉内注射、髓内注射、腹腔内注射、鞘内注射、心脑内、透皮、经皮肤、外用、皮下、鼻内、肠内、舌下、阴道内或直肠途经等多种途径。
本发明提供的TACI-Fc融合蛋白或其药物组合物以冻干、无菌、溶液形式制备和贮藏。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泰爱治疗IgA肾病患者的II期临床试验
一、人员入选标准
1)病理活检确诊为IgA肾病；
2)年龄≥18岁，≤70岁，男女不限；
3)在筛选期，访视1和访视2的24小时尿蛋白至少满足1次≥0.75g/24h，且访视3的24小时尿蛋白≥0.75g/24h；
4)测量的肾小球滤过率或估计GFR(使用CKD-EPI公式)>35mL/min per 1.73m 2；
5)在随机化前受试者已接受包括ACEI/ARB药物的基础治疗方案12周，并且在随机化前4周内ACEI/ARB药物的剂量(最大耐受范围内)稳定。
二、试验分组
(1)试验组
Figure PCTCN2022111112-appb-000006
(2)对照组
Figure PCTCN2022111112-appb-000007
三、终点指标
(1)主要终点指标(即主要疗效指标分析)
序号 指标 评价时间 终点指标选择
1 与基线期相比，在第24周24小时尿蛋白的变化。 第24周 有效性指标
(2)次要终点指标(即次要指标分析)
Figure PCTCN2022111112-appb-000008
Figure PCTCN2022111112-appb-000009
四、统计方法及分析数据集
连续变量采用均值、标准差、中位数、最小值和最大值进行描述，计数和等级资料采用频数和百分比进行描述。所有统计检验均为双侧检验，p小于或等于0.05(p≤0.05)将被认为所检验的差异有统计意义。疗效分析采用全分析集(FAS)和符合方案集(PPS)两个数据集，安全性分析采用安全数据集(SS)数据集。
本研究全分析集(FAS)共计纳入受试者44例，其中安慰剂组14例，泰爱160mg组16例，泰爱240mg组14例。安全数据集(SS)数据与FAS集相同。符合方案集(PPS)中剔除了自行退出的2例安慰剂组受试者，最终纳入受试者42例，其中安慰剂组12例，泰爱160mg组16例，泰爱240mg组14例。
五、主要结果
(1)主要疗效指标分析
用药24周时，安慰剂组受试者的平均24小时尿蛋白水平基本不变，表现为0.03g/24h(2.62％)的减少；泰爱240mg组受试者用药前后平均尿蛋白下降了0.89g/24h(49.29％)，泰爱160mg组受试者用药前后平均尿蛋白下降了0.32g/24h(24.71％)。泰爱240mg组内13例(92.86％)受试者24小时尿蛋白较基线水平下降，下降最多的3例受试者分别下降了1.89g/24h、1.77g/24h以及1.54g/24h；泰爱160mg组内有11例(68.75％)受试者的24小时尿蛋白在用药24周时较基线水平下降，其中下降最多的1例受试者的24小时尿蛋白水平较基线下降了1.40g/24h。
(2)次要疗效指标分析
A.估计肾小球滤过率(eGFR)的历时性分析
用药24周时，泰爱160mg组和泰爱240mg组受试者的估计肾小球滤过率(eGFR)的平均水平分别上升了4.32mL/min/1.73m 2和2.33mL/min/1.73m 2，而安慰剂组的平均水平下降5.70mL/min/1.73m 2。方差分析(ANOVA)显示，泰爱160mg组、泰爱240mg组受试者eGFR 的变化与安慰剂组比较，组间差异均有统计学意义，p分别为0.002，0.015。各组受试者eGFR的历时性变化如图1所示。
B.尿白蛋白肌酐比(UACR)的历时性分析
本试验中UACR为选择性收集数据，过程中共收集到37例受试者的UACR数据(安慰剂组13例；泰爱160mg组14例；泰爱240mg组10例)。如图2所示，给药期间，2个泰爱治疗组的UACR平均水平均呈现持续下降状态。ANOVA分析结果确证了2个泰爱给药组受试者UACR的下降与安慰剂受试者UACR变化的组间差异具有统计学意义(p≤0.05)。用药第12周，16周和第20周时，2个泰爱给药组受试者与安慰剂组受试者的24小时尿蛋白变化具有统计学差异。与基线水平相比，用药24周时，泰爱160mg组和泰爱240mg组受试者的UACR均值分别下降了347.81mg/g和627.55mg/g，安慰剂组受试者的UACR均值下降了16.77mg/g。
C.尿红细胞计数的历时性分析
用药前后各组尿红细胞数量波动小。ANOVA分析结果显示，各组间受试者尿红细胞的变化并无统计学差异。各组受试者尿红细胞计数的历时性变化如图3所示。
D.免疫球蛋白A(IgA)的历时性分析
自用药开始，泰爱给药组受试者的免疫球蛋白A(IgA)水平持续下降至用药第24周。从用药第8周开始，2个泰爱治疗组与安慰剂组间受试者的免疫球蛋白A(IgA)的组间差异开始有统计学意义，p<0.001，并且持续至用药第24周。相较于基线，用药24周时，安慰剂组受试者IgA平均水平变化微弱,表现为0.01g/L的下降(下降率为1.11％)，而泰爱160mg组受试者IgA平均水平下降1.48g/L(45.75％)，泰爱240mg组受试者IgA平均水平下降1.17g/L(15.83％)。各组受试者IgA平均水平的历时性变化如图4所示。
E.免疫球蛋白G(IgG)的历时性分析
给药后，泰爱给药组受试者的免疫球蛋白G(IgG)水平持续下降。ANOVA分析显示，2个泰爱用药组与安慰剂组比较，免疫球蛋白G(IgG)变化的差异在第4周开始有统计学意义，p<0.001，持续至用药第24周。用药24周时，与基线相比，安慰剂组受试者的IgG水平变化较小，平均值上升了0.10g/L(0.22％)，泰爱160mg组受试者IgG水平下降了3.00g/L (26.16％)，泰爱240mg组受试者IgG水平下降了2.56g/L(24.55％)。各组受试者IgA平均水平的历时性变化如图5所示。
F.免疫球蛋白M(IgM)的历时性分析
自用药开始，泰爱给药组受试者的免疫球蛋白M(IgM)水平持续下降。泰爱给药组与安慰剂组间变化值的统计学差异从用药第8周持续至用药第24周。与基线水平比较，用药第24周时，安慰剂组受试者的IgM平均水平基本保持不变，表现为0.03g/L(0.63％)的增加。泰爱160mg组受试者的IgM平均水平下降了0.76g/L(64.28％)，泰爱240mg组平均水平下降了0.62g/L(65.34％)。统计学分析显示，2个泰爱给药组与安慰剂组的IgM变化差异自第8周开始即有统计学意义(p<0.001)，这种统计学差异持续至用药第24周。各组受试者IgA平均水平的历时性变化如图6所示。
G. B淋巴细胞(CD19 +)计数的历时性分析
用药24周时，相对于基线，安慰剂组受试者平均B淋巴细胞(CD19 +)水平下降了0.32个/μl(1.18％)；泰爱160mg组受试者平均B淋巴细胞(CD19 +)减少了108.36个/μl(26.23％)；泰爱240mg组受试者平均B淋巴细胞(CD19 +)减少了36.72个/μl(21.40％)。整个试验过程中泰爱240mg组受试者的B淋巴细胞(CD19 +)计数与安慰剂组相比，组间差异无统计学意义(p>0.05)。在用药第20周和第24周时，泰爱160mg组受试者的B淋巴细胞(CD19 +)计数与安慰剂组相比，组间差异有统计学意义(p≤0.05)。具体变化如图7所示。
H.安全性评价
本研究初步揭示了泰爱在IgA肾病患者治疗中良好的安全性。试验过程中，无死亡病例、无因不良反应(AE)而退出试验的病例；除去2例因自身原因(无法按计划接受给药)而提前退出的受试者外，其余受试者全部按计划完成给药。各组间不良事件发生率(TEAE)、严重不良事件(SAE)和严重不良反应(SADR)发生率的组间差异无统计学意义(P>0.05)。ADR发生率的组间差异有统计学意义(p<0.05)，给药组受试者的不良反应(ADR)主要为注射部位反应，强度均在3级以下。
综上所述，试验数据显示，用药24周以后，泰爱240mg组和泰爱160mg组受试者的24小时尿蛋白水平均较基线下降。其中，泰爱240mg组受试者的平均24小时尿蛋白减少0.89g/24h(49.29％)；泰爱160mg 组受试者的平均24小时尿蛋白减少0.32g/24h(24.71％)。用药第16周至24周，泰爱240mg组受试者尿蛋白水平下降与安慰剂组比较，差异具有统计学意义；用药第16周至第20周，泰爱160mg组受试者的24小时尿蛋白下降与安慰剂组受试者比较，差异具有统计学意义。用药前后，2个泰爱给药组受试者的长期肾脏指标估计肾小球滤过率(eGFR)平均值上升，免疫球蛋白(IgA、IgG和IgM)平均水平明显下降。同安慰剂组比较，以上指标变化的组间差异同样具有统计学意义。由于目前没有公认的针对IgA肾病的针对性治疗药物，因此，暂未能有阳性药物的临床数据进行横向比较。然而，本研究所得结果优于大部分同期IgA治疗药物的临床试验数据。因此，本研究揭示了泰爱240mg/周和泰爱160mg/周在IgA肾病治疗中的有效性。
另外，本试验数据同时揭示了泰爱在IgA肾病治疗过程中良好的安全性。试验过程中无重大不良事件、无因不良事件而退出试验的受试者、无死亡。
以上结果显示，泰它西普治疗组患者的尿蛋白水平与基线相比显著降低，相比安慰剂组，其差异具有统计学意义。此外，治疗组与安慰剂对照组之间在临床试验的多个次要终点也存在显著差异。基于以上结果和分析，本研究揭示了泰爱(240mg/周)和泰爱(160mg/周)在IgA肾病治疗过程中的有效性和良好的安全性
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 (16)

  1. 一种治疗IgA肾病的方法，所述方法包括对具有所述IgA肾病的患者施用治疗有效量的TACI-Fc融合蛋白，其特征在于，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。
  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所示氨基酸的序列。
  3. 根据权利要求2所述的方法，其特征在于，所述的人免疫球蛋白恒定区具有包含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％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恒定区具有包含SEQ ID NO:3的氨基酸序列。
  8. 根据权利要求7所述的方法，其特征在于，所述的人免疫球蛋白为IgG1。
  9. 根据权利要求8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。
  10. 根据权利要求9所述的方法，其特征在于，所述的TACI-Fc融合蛋白为Telitacicept(泰它西普)。
  11. 根据权利要求1-10任一项所述的方法，其特征在于，其中，所述TACI-Fc融合蛋白的给药剂量范围为每次160-240mg，进一步优选为160mg或240mg。
  12. 根据权利要求1-10任一项所述的方法，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1-10所述的方法，其特征在于，所述的TACI-Fc融合蛋白的的施用方式为皮下注射、肌肉注射、口服或静脉施用。
  14. 根据权利要求1所述的方法，其特征在于，所述的IgA肾病为原发性IgA肾病。
  15. 一种治疗IgA肾病的方法，所述方法为向患者施用一种包含TACI-Fc融合蛋白的药物组合物，所述的药物组合物还包括药学可接受的载体。
  16. 一种TACI-Fc融合蛋白在制备治疗IgA肾病患者药物中的用途。
PCT/CN2022/111112 2021-08-10 2022-08-09 用TACI-Fc融合蛋白治疗IgA肾病的方法 WO2023016444A1 (zh)

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AU2022325359A AU2022325359A1 (en) 2021-08-10 2022-08-09 Method for treating iga nephropathy with taci-fc fusion protein
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US18/250,726 US20240002468A1 (en) 2021-08-10 2022-08-09 Method for treating iga nephropathy with taci-fc fusion protein
BR112023018745A BR112023018745A2 (pt) 2021-08-10 2022-08-09 Método para tratar nefropatia por iga com proteína de fusão de taci-fc
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