WO2026008004A1 - Méthode de traitement du syndrome des antiphospholipides à l'aide d'une protéine de fusion taci-fc - Google Patents

Méthode de traitement du syndrome des antiphospholipides à l'aide d'une protéine de fusion taci-fc

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Publication number
WO2026008004A1
WO2026008004A1 PCT/CN2025/106768 CN2025106768W WO2026008004A1 WO 2026008004 A1 WO2026008004 A1 WO 2026008004A1 CN 2025106768 W CN2025106768 W CN 2025106768W WO 2026008004 A1 WO2026008004 A1 WO 2026008004A1
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taci
antibodies
seq
fusion protein
antiphospholipid syndrome
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Chinese (zh)
Inventor
杨程德
石慧
刘婷婷
王文祥
房健民
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Remegen Co Ltd
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Remegen Co Ltd
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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
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection

Definitions

  • This invention relates to a TACI-Fc fusion protein drug for treating antiphospholipid syndrome, a dosage regimen, dosing interval, and administration method.
  • Antiphospholipid syndrome is a systemic autoimmune disease mediated by antiphospholipid antibodies, characterized by thrombosis and/or obstetric complications, and is accompanied by persistent moderate to high positivity of antiphospholipid antibodies (aPLs) (Reference 1: Knight J S, Branch D W, Ortel T L. Antiphospholipid syndrome: advances in diagnosis, pathogenesis, and management BMJ 2023; 380:e069717 doi:10.1136/bmj-2021-069717).
  • Antiphospholipid antibodies are a group of antibodies, referring to the collective term for autoantibodies that target phospholipids and/or phospholipid-binding proteins.
  • antiphospholipid antibodies in clinical practice include anticardiolipin antibody (aCL), lupus anticoagulant (LAC), and anti- ⁇ 2 glycoprotein I antibody (a ⁇ 2GPI). These three are currently widely tested and are known as diagnostic standard antibodies.
  • non-diagnostic standard antibodies antiphosphatidylserine/prothrombin complex antibody, antithrombin antibody, anti- ⁇ 2-glycoprotein I domain 1 antibody, antiphosphatidylethanolamine antibody, anti-protein S and protein C antibody, antiphosphatidylinositol antibody, anti-vimentin/cardiolipin complex antibody, anti-annexin A2 and A5 antibody, and antiphosphatidic acid antibody. These are helpful supplements to the diagnostic standard antibodies and can assist in the diagnosis of antiphospholipid syndrome.
  • antiphospholipid syndrome is classified into primary antiphospholipid syndrome (PAPS) and secondary antiphospholipid syndrome (SAPS) based on whether it is accompanied by other autoimmune diseases.
  • Primary APS refers to systemic autoimmune diseases that occur without an associated autoimmune disease. When APS is associated with another disease, it is called secondary APS. These include systemic lupus erythematosus (SLE) and other autoimmune diseases, lymphoproliferative disorders, tumors, infections (bacteria, viruses, protozoa), and inflammation.
  • SLE systemic lupus erythematosus
  • thrombosis can occur in almost any blood vessel in the body, but it is most common in the blood vessels of the lower extremities.
  • a blood clot forms in a blood vessel in the brain, blood flow will be impaired, potentially leading to a stroke.
  • the clinical manifestations of APS are mostly caused by thrombosis, embolism, and post-embolism ischemia leading to organ dysfunction.
  • Antiphospholipid syndrome is more common in women, with a male-to-female ratio of 1:9.
  • the median age of onset for women is 30 years, and it is prevalent in young and middle-aged adults. It is estimated that 1 in 2,000 people has APS.
  • APS is usually diagnosed in relatively young individuals; in a study of 1,000 patients, only 12.7% were diagnosed with APS after age 50. It is estimated that 20% of stroke patients under 50 years of age and 10% to 15% of systemic lupus erythematosus (SLE) patients have APS.
  • SLE systemic lupus erythematosus
  • APS is rare in children but may be underdiagnosed for various reasons.
  • a study of 121 children reported a mean age of onset of 10.7 years for APS.
  • Nonthrombotic manifestations of antiphospholipid syndrome such as thrombocytopenia and autoimmune hemolytic anemia, may be more common in children (Reference 2: Knight J S, Branch D W, Ortel T L.
  • Antiphospholipid syndrome advances in diagnosis, pathogenesis, and management BMJ 2023; 380:e069717 doi:10.1136/bmj-2021-069717; National Library of Medicine https://medlineplus.gov/genetics/condition/antiphospholipid-syndrome/#resources).
  • Women with antiphospholipid syndrome have an increased risk of complications during pregnancy. These complications include gestational hypertension (preeclampsia), placental insufficiency (placental dysfunction), premature birth, or miscarriage. Furthermore, women with antiphospholipid syndrome have a higher risk of developing blood clots during pregnancy than at other times in their lives. Babies born to mothers with antiphospholipid syndrome may be short in stature and underweight. Blood clots or pregnancy complications are often the first symptom of antiphospholipid syndrome. This condition usually appears in early to mid-adulthood but can begin at any age.
  • CAPS catastrophic antiphospholipid syndrome
  • APS treatment The main goals of APS treatment are to prevent thrombosis and avoid pregnancy failure.
  • Treatment methods include anticoagulation, glucocorticoids and immunosuppressants, as well as symptomatic and supportive care.
  • Table 1 defines the profiles of high-titer antiphospholipid antibodies (aPL), low-risk, and high-risk antiphospholipid antibodies.
  • Table 2. Recommendations for the management of antiphospholipid syndrome in adults issued by the European League against Rheumatism (EULAR).
  • INR International Normalized Ratio, is the ratio of a patient's prothrombin time to a normal control's prothrombin time raised to the power of ISI (ISI: International Sensitivity Index, calibrated by the manufacturer at the time of reagent delivery). It is a standardized reporting method for prothrombin time measurements that corrects for differences in thrombin activation reagents.
  • the normal range for INR is 0.8–1.2.
  • the World Health Organization recommends an acceptable range of INR of 2.0–3.0 when using oral anticoagulants to treat deep vein thrombosis. Table 3.
  • Daratumumab can exert immune-mediated activity and, by modulating the immune microenvironment, may be suitable for APS patients unresponsive to anticoagulation therapy and standard immunosuppression.
  • a clinical trial of cetuzumab in pregnant APS patients is underway (ClinicalTrials.NCT03152058), but no results have been published yet.
  • Another open-label phase II trial using the complement C5 inhibitor olendalizumab to treat non-standard APS presentations was terminated due to low patient enrollment (clinicaltrials.NCT02128269).
  • Reference 4 Yun Z, Duan L, Liu X, Cai Q, Li C. An update on the biologics for the treatment of antiphospholipid syndrome. Front Immunol.
  • Telitacicept is a first-in-class recombinant TACI-Fc fusion protein targeting B-cell-related autoimmune diseases. It targets and neutralizes two key cell signaling molecules in the B-cell pathway, BLyS and APRIL. It is an antibody-like fusion protein composed of a truncated TACI and an immunoglobulin Fc whose sequence optimization reduces ADCC and CDC effects. It exhibits excellent biological activity and safety, and is currently approved for marketing in China for the treatment of systemic lupus erythematosus, rheumatoid arthritis, and myasthenia gravis.
  • Atacicept is a recombinant fusion protein containing the extracellular ligand-binding portion of the TACI receptor and the Fc portion of human IgG, which can bind to BLyS and APRIL.
  • This drug is being explored for the treatment of IgA nephropathy (stage III), lupus nephritis (stage III), systemic lupus erythematosus (stage III), and rheumatoid arthritis (stage II), and is currently in various clinical stages.
  • Povetacicept is an engineered Fc fusion protein with a TACI domain.
  • a Blys/APRIL dual antagonist As a Blys/APRIL dual antagonist, it is currently being explored for the treatment of various indications, including IgA nephropathy (Phase III), immune thrombocytopenic purpura (Phase II), cold agglutinin disease (Phase II), lupus nephritis (Phase II), autoimmune cytopenic purpura (Phase II), and systemic lupus erythematosus (Phase I).
  • IgA nephropathy Phase III
  • immune thrombocytopenic purpura Phase II
  • cold agglutinin disease Phase II
  • lupus nephritis Phase II
  • autoimmune cytopenic purpura Phase II
  • systemic lupus erythematosus Phase I
  • This invention has surprisingly discovered that the TACI-Fc fusion protein produces significant therapeutic effects in treating patients with antiphospholipid syndrome.
  • the present invention provides a method for treating antiphospholipid syndrome, the method comprising administering a therapeutically effective amount of a drug targeting Blys and/or APRIL to a patient having said antiphospholipid syndrome.
  • the present invention also provides the use of a drug targeting Blys and/or APRIL in the preparation of a medicament for treating or alleviating patients with antiphospholipid syndrome.
  • the present invention also provides the use of TACI-Fc fusion protein in the preparation of medicaments for treating or alleviating patients with antiphospholipid syndrome.
  • the present invention also provides the use of teltascept in the preparation of medicaments for the treatment or relief of patients with antiphospholipid syndrome.
  • the antiphospholipid syndrome is selected from primary antiphospholipid syndrome or secondary antiphospholipid syndrome; even further, the antiphospholipid syndrome is primary antiphospholipid syndrome.
  • the drug targeting Blys and/or APRIL is a TACI-Fc fusion protein.
  • the TACI-Fc fusion protein described in any of the above embodiments comprises: (i) the extracellular region of TACI or fragments thereof that bind Blys and/or APRIL; and (ii) Human immunoglobulin constant region fragment.
  • the TACI extracellular region or the fragment bound to Blys and/or APRIL contains the amino acid sequence shown in SEQ ID NO:1, SEQ ID NO:2, or SEQ ID NO:3.
  • amino acid sequence of the extracellular region of TACI or the fragment bound to Blys and/or APRIL is shown in SEQ ID NO:1.
  • human immunoglobulin mentioned is IgG1.
  • the human immunoglobulin constant region fragment comprises an amino acid sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:4.
  • SEQ ID NO:4 amino acid sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:4.
  • amino acid sequence of the human immunoglobulin constant region fragment is shown in SEQ ID NO:4.
  • human immunoglobulin constant region fragment contains amino acid modifications at sites 1, 2, 3, 4, 5, 6, 7, 8 or more compared to SEQ ID NO:4.
  • the modification is the substitution, deletion, or insertion of amino acids.
  • the replacement includes one or more of P3T, L8P, L14A, L15E, G17A, A110S, P111S and/or A173T.
  • the insertion involves inserting 1, 2, 3, 4, 5, 6, 7, 8 or more amino acids into the N-terminus of the human immunoglobulin constant region fragment.
  • the insertion involves inserting 5 amino acids at the N-terminus of the human immunoglobulin constant region fragment.
  • the insertion involves inserting the five amino acids EPKSS into the N-terminus of the human immunoglobulin constant region fragment.
  • human immunoglobulin constant region fragment comprises the amino acid sequence of SEQ ID NO:5.
  • SEQ ID NO:5 amino acid sequence of SEQ ID NO:5.
  • human immunoglobulin constant region fragment comprises the amino acid sequence of SEQ ID NO:6.
  • SEQ ID NO:6 amino acid sequence of SEQ ID NO:6
  • the TACI-Fc fusion protein has an amino acid sequence that is at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to SEQ ID NO:7.
  • SEQ ID NO:7 amino acid sequence that is at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to SEQ ID NO:7.
  • the TACI-Fc fusion protein has the amino acid sequence shown in SEQ ID NO:7.
  • the TACI-Fc fusion protein has the amino acid sequence shown in SEQ ID NO:8.
  • SEQ ID NO:8 SEQ ID NO:8
  • the TACI-Fc fusion protein has the amino acid sequence shown in SEQ ID NO:9.
  • SEQ ID NO:9 amino acid sequence shown in SEQ ID NO:9.
  • the TACI-Fc fusion protein is telitacicept, atacicept, or povetacicept.
  • the single-dose administration of the TACI-Fc fusion protein is approximately 0.1 to 10 mg/kg, further comprising the following values: 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5.
  • the single-dose dose of the TACI-Fc fusion protein is 40-300 mg, preferably 80-240 mg, more preferably 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, or 240 mg.
  • the method for detecting the protein content of the aforementioned drug is as follows: ultraviolet-visible spectrophotometry. Based on the fact that proteins have maximum ultraviolet absorption at 280 nm, the absorbance value of the teltascip sample at this wavelength is measured. After correcting for the absorbance at 320 nm, the absorbance value at 280 nm is found to be directly proportional to the protein concentration. The protein concentration is calculated using Lambert-Beer's law, thus determining the protein content.
  • ⁇ is the extinction coefficient of teltacil, with units of (mg/ml) ⁇ 1 ⁇ cm ⁇ 1 ;
  • A280 is the average absorbance of the sample solution at 280 nm;
  • a 280 (correction) is the average absorbance of the sample solution after correction at 280 nm.
  • the TACI-Fc fusion protein is used 1-4 times during a one-month interval, further including 1 time, 2 times, 3 times, or 4 times, that is, the administration frequency of the TACI-Fc fusion protein is once a month, twice a month, three times a month, or four times a month.
  • the TACI-Fc fusion protein is administered once a week, once every two weeks, once every three weeks, or once every four weeks.
  • the treatment lasts for approximately 2-50 weeks. More preferably, the treatment lasts for 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, and 50 weeks.
  • the TACI-Fc fusion protein is administered subcutaneously, intramuscularly, or intravenously, with the preferred administration site being the thigh, abdomen, or upper arm.
  • the TACI-Fc fusion protein is administered via subcutaneous injection, intramuscular injection, or intravenous injection.
  • the primary antiphospholipid syndrome is characterized by persistent moderate or high positivity for antiphospholipid antibodies.
  • the antiphospholipid antibodies include, but are not limited to, anticardiolipin antibodies, anti- ⁇ 2-glycoprotein I antibodies, lupus anticoagulants, antiphosphatidylserine/prothrombin complex antibodies, antithrombin antibodies, anti- ⁇ 2-glycoprotein I domain 1 antibodies, antiphosphatidylethanolamine antibodies, anti-protein S and protein C antibodies, antiphosphatidylinositol antibodies, anti-vimentin/cardiolipin complex antibodies, anti-annexin A2 and A5 antibodies, and antiphosphatidic acid antibodies.
  • the patients mentioned are either adult patients or pediatric patients.
  • the patient may have previously received treatment for primary antiphospholipid syndrome or may not have previously received treatment for primary antiphospholipid syndrome.
  • the patient may also have one or more other diseases.
  • the present invention also provides a method for treating primary antiphospholipid syndrome, the method comprising administering, in combination with other therapeutic agents, a therapeutically effective amount of TACI-Fc fusion protein to a patient with said primary antiphospholipid syndrome, wherein the TACI-Fc fusion protein comprises: (i) the extracellular region of TACI or fragments thereof that bind Blys and/or APRIL; and (ii) Human immunoglobulin-constant region fragment.
  • the other therapeutic agents mentioned include, but are not limited to, anticoagulants, belimumab, rituximab, and eculizumab.
  • anticoagulant drugs include, but are not limited to, antiplatelet drugs, vitamin K antagonists, heparin or low molecular weight heparin, hydroxychloroquine, and statins.
  • antiplatelet drugs mentioned include, but are not limited to, aspirin, dipyridamole, ticlopidine, and clopidogrel.
  • the TACI-Fc fusion protein provided by this invention has shown unexpected clinical efficacy and good safety in the treatment of patients with antiphospholipid syndrome.
  • Figure 1 shows the changes in anticardiolipin antibody titers during treatment in the SOC (Standard of Care) + Telitacicept group in Example 2.
  • Figure 2 shows the changes in anticardiolipin antibody titers during the treatment process in the SOC group in Example 2;
  • Figure 3 shows the change in anti- ⁇ 2-glycoprotein I antibody titer during the treatment process in the SOC+telitacicept group in Example 2;
  • Figure 4 shows the change in anti- ⁇ 2-glycoprotein I antibody titer during the treatment process in the SOC group in Example 2;
  • Figure 5 shows the changes in lupus anticoagulant titer during the treatment process in the SOC+telitacicept group in Example 2;
  • Figure 6 shows the changes in lupus anticoagulant titer during the treatment process in the SOC group in Example 2.
  • amino acid three-letter codes and single-letter codes used in this invention are as described in J. biol. chem, 243, p3558 (1968).
  • TACI transmembrane activator and CAML interactor, a member of the tumor necrosis factor receptor superfamily.
  • B lymphocyte stimulator a member of the TNF ligand superfamily existing in both membrane-bound and soluble forms. It is specifically expressed on the surface of bone marrow cells and selectively stimulates B lymphocyte proliferation and immunoglobulin production.
  • APRIL aproliferation-inducing ligand
  • TNF tumor necrosis factor
  • APRIL specifically binds to TACI and BCMA, preventing APRIL from binding to B cells and inhibiting the APRIL-induced primitive B cell proliferation response. Furthermore, APRIL competitively binds to receptors (BCMA and TACI) with BLys.
  • TACI-Fc fusion protein refers to a transmembrane activator, calcium regulator and cyclic protein ligand interactor (TACI)-immunoglobulin fusion protein (i.e., TACI-Fc fusion protein).
  • TACI-immunoglobulin fusion protein provided by this invention comprises: (i) the extracellular region of TACI or a fragment thereof binding to Blys and/or APRIL; and (ii) a fragment of the human immunoglobulin constant region.
  • TACI extracellular domain or a fragment thereof binding to Blys and/or APRIL can be specifically referred to in U.S. Patent Nos. 5,969,102, 6,316,222 and 6,500,428 and U.S. Patent Applications Nos. 09/569,245 and 09/627,206 (the contents of which are incorporated herein by reference) as the extracellular domain of TACI and specific fragments of the extracellular domain of TACI that can interact with TACI ligands, or the amino acid fragment of the extracellular domain of TACI disclosed in Chinese Patent Publication No. CN101323643A, which consists of amino acids 13-118 of the extracellular domain of TACI.
  • TACI-Fc fusion protein examples include teltascept (amino acid sequence: SEQ ID NO: 7), asceticip (amino acid sequence: SEQ ID NO: 8), and previtaccept (amino acid sequence: SEQ ID NO: 9).
  • the immunoglobulin portion is preferably IgG1, which may include a heavy chain constant region, such as the human heavy chain constant region.
  • a preferred "human immunoglobulin constant region fragment” of this invention is an amino acid fragment containing a partial hinge region domain, a CH2 domain, and a CH3 domain.
  • the amino acid sequence of the "human immunoglobulin constant region fragment" of this invention is as shown in SEQ ID NO:4, or contains an amino acid sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:4.
  • the amino acid sequence of the "human immunoglobulin constant region fragment" is as shown in SEQ ID NO:5.
  • treatment refers to a clinical intervention designed to alter the natural course of an individual or cell in a clinicopathological process. Desired therapeutic effects include reducing the rate of disease progression, improving or alleviating the disease state, and alleviating or improving prognosis. For example, if one or more symptoms associated with the treated disease or condition (such as cancer, inflammation, or an autoimmune disease) are reduced or eliminated.
  • treatment refers to effectively reducing the rate of disease progression, improving or alleviating the disease state, and alleviating or improving prognosis to a statistically significant degree or to a degree detectable by a person skilled in the art.
  • relief in this invention refers to the absence of clinical symptoms or signs associated with antiphospholipid syndrome at the start or end of treatment.
  • amino acid in this invention is understood in its broadest sense as a general term for a class of organic compounds containing amino and carboxyl groups.
  • amino acids involved in this invention are the main building blocks of proteins in living organisms, including but not limited to: glycine, alanine, valine, leucine, isoleucine, methionine, proline, tryptophan, serine, tyrosine, cysteine, phenylalanine, asparagine, glutamine, threonine, aspartic acid, glutamic acid, lysine, arginine, and histidine.
  • amino acids used in this invention are as described in J. Biol. Chem., 243, p3558 (1968).
  • There are various methods for numbering amino acid sites such as the Kabat numbering system, the EU numbering system, and sequential numbering. In this invention, the amino acid sites are numbered sequentially. For example, “sites 3, 8, 14, 15, 17, 110, 111, or 173 of SEQ ID NO:4" refers to the 3rd and 8th amino acids of SEQ ID NO:4, and so on.
  • P3T refers to changing the 3rd amino acid sequence of SEQ ID NO:4 from “P” to “T”
  • L8P refers to changing the 8th amino acid sequence of SEQ ID NO:4 from “L” to “P”, and so on.
  • the constant region of the immunoglobulin provided by the present invention can be modified by one or more amino acid changes, such as substitution (i.e., mutation), addition (i.e., insertion), or deletion (i.e., deletion).
  • the TACI-Fc fusion protein of the present invention can be administered via any and many routes, including but not limited to: oral, intravenous, intramuscular, intra-arterial, intramedullary, intraperitoneal, intrathecal, intracardiac, transdermal, transdermal, topical, subcutaneous, intranasal, intraintestinal, sublingual, vaginal, or rectal routes.
  • antiphospholipid syndrome in this invention refers to a non-inflammatory autoimmune disease clinically characterized by arterial and venous thrombosis, pathological pregnancy (early miscarriage and mid-to-late-term stillbirth), thrombocytopenia, and renal damage.
  • Serum contains one or more antiphospholipid antibodies, including anticardiolipin antibodies, lupus anticoagulants, anti- ⁇ 2 glycoprotein I antibodies, antiphosphatidylserine/prothrombin complex antibodies, antithrombin antibodies, anti- ⁇ 2-glycoprotein I domain 1 antibodies, antiphosphatidylethanolamine antibodies, anti-protein S and protein C antibodies, antiphosphatidylinositol antibodies, anti-vimentin/cardiolipin complex antibodies, anti-annexin A2 and A5 antibodies, and antiphosphatidic acid antibodies. These symptoms may coexist alone or in combination.
  • primary antiphospholipid syndrome in this invention refers to antiphospholipid syndrome that occurs alone without the presence of other autoimmune diseases.
  • second antiphospholipid syndrome in this invention refers to antiphospholipid syndrome secondary to other autoimmune diseases, including but not limited to lupus (such as systemic lupus erythematosus), rheumatoid arthritis, Sjögren's syndrome, etc.
  • lupus such as systemic lupus erythematosus
  • rheumatoid arthritis Sjögren's syndrome
  • aPL spectrum refers to the levels of anticardiolipin antibodies (IgG or IgM), anti- ⁇ 2-glycoprotein 1 antibodies (IgG or IgM), and lupus anticoagulants.
  • aPL refers to antiphospholipid antibodies present in the patient's body.
  • standard treatment regimen in this invention includes aspirin and/or vitamin K antagonists (VKA) and/or low molecular weight heparin.
  • heparin in this invention, also known as unfractionated heparin, is a sulfated aminoglucan extracted and refined from the intestinal mucosa of pigs or the lungs of cattle. It can bind to antithrombin III, inhibit the activity of thrombin, and thus prolong the blood clotting time. Clinically, it is mainly used for anticoagulation and antithrombosis.
  • low molecular weight heparin in this invention includes low molecular weight heparin sodium/calcium, enoxaparin, nadroparin, dalteparin, etc., which are a class of low molecular weight glucosamine sugars produced by chemical methods or enzymatic hydrolysis of unfractionated heparin.
  • vitamin K antagonist in this invention refers to drugs that inhibit the synthesis of vitamin K-dependent clotting factors, including warfarin, dicumarol, phenylpropanol, acenitrocoumarin, etc.
  • telitacicept previtaccept
  • APRIL homotrimer and Blys homotrimer were tested using enzyme-linked immunosorbent assay (ELISA), with null-IgG1 used as a blank control.
  • ELISA enzyme-linked immunosorbent assay
  • teltascept and previtaccept both showed good binding with APRIL and Blys.
  • Example 2 Clinical trial of telitacicept for the treatment of primary antiphospholipid syndrome
  • telitacicept on the antiphospholipid antibody (aPL) profile in patients with primary APS carrying a high-risk antiphospholipid antibody profile.
  • a secondary objective is to evaluate the effect of telitacicept on thrombotic recurrence in patients with primary APS, using single-cell RNA-sequencing (scRNAseq) of B cells to reveal heterogeneous changes in cellular gene characteristics and function before and after telitacicept treatment.
  • scRNAseq single-cell RNA-sequencing
  • ⁇ 18 years old.
  • ⁇ Primary antiphospholipid syndrome was clinically diagnosed according to the Sydney criteria.
  • ⁇ Inclusion criteria include persistent positive antiphospholipid antibody levels within the preceding 12 months (tested at least 12 weeks apart).
  • Antiphospholipid antibody profiles are stratified into high-risk profiles based on antibody levels, defined as meeting at least one of the following criteria: 1. Positive lupus anticoagulant (LAC) (tested according to ISTH guidelines); 2. Positive for two or three types of aPL (any two or all of lupus anticoagulant, anticardiolipin antibody, and anti- ⁇ 2 glycoprotein I antibody); 3. Or persistently high aPL titers. ⁇ No other autoimmune diseases occurred concurrently.
  • LAC Positive lupus anticoagulant
  • aPL any two or all of lupus anticoagulant, anticardiolipin antibody, and anti- ⁇ 2 glycoprotein I antibody
  • EULAR's recommendations on antiphospholipid syndrome a stable APS treatment regimen should be adopted.
  • ⁇ Vital signs are normal: including body temperature, respiration, blood pressure and heart rate; ⁇ Normal physical examination: including height (only during the screening period), weight, head, eyes, ears, nose, throat, neck, heart, chest (including lungs), abdomen, limbs, skin, lymph nodes, and nervous system; ⁇ Normal laboratory tests: including routine blood tests, biochemistry, liver and kidney function tests, coagulation function tests, etc.; ⁇ Other examinations, such as electrocardiogram and echocardiography, were all normal.
  • SOC Standard of Care
  • SOC + Telitacicept SOC + Telitacicept
  • Enrolled patients will receive SOC treatment for 48 weeks. Patients will be assessed on day 0 and then reassessed every 12 weeks for 48 weeks. SOC treatment in this study was based on patient clinical presentation and antiphospholipid antibody profile, using aspirin, vitamin K antagonists (VKA), and low molecular weight heparin (see EULAR recommendations for the management of antiphospholipid syndrome in adults. Tektonidou, M.G., et al., Ann Rheum Dis, 2019, Vol. 78, No. 10, pp. 1296-1304).
  • Major inspections including a safety assessment, will be conducted on day 0, followed by inspections every 12 weeks for a total of 48 weeks. There will be a total of 5 follow-up inspections.
  • the primary efficacy endpoint of this study was the proportion of patients whose antiphospholipid antibody titers decreased at week 48 after treatment.
  • Figure 1 shows the changes in anticardiolipin antibody titers
  • Figure 3 shows the changes in anti- ⁇ 2-glycoprotein I antibody titers
  • Figure 5 shows the changes in lupus anticoagulant titers in patients enrolled in the SOC + Telitacicept group after 48 weeks of Telitacicept treatment.
  • TA-1 to "TA-8” and "TA-10” represent other patients receiving SOC + Telitacicept treatment.
  • Figure 2 shows the changes in anticardiolipin antibody titers
  • Figure 4 shows the changes in anti- ⁇ 2-glycoprotein I antibody titers
  • Figure 6 shows the changes in lupus anticoagulant titers.
  • CON-1 to "CON-10" represent patients receiving SOC treatment.
  • teltascip experienced varying degrees of decrease in the titers of aCL IgG, aCL IgM, and aCL IgA. Overall, 88.9% of patients who completed treatment experienced a decrease in anticardiolipin antibody titers. Only one patient (TA-10) showed a slight increase in aCL IgG titer compared to baseline, but both aCL IgM and aCL IgA titers showed a decreasing trend compared to baseline ( Figure 1). In contrast, only 50% of patients in the SOC group showed a simultaneous decrease in the titers of aCL IgG, aCL IgM, and aCL IgA ( Figure 2).
  • teltascept significantly reduces antiphospholipid antibody levels and can effectively treat or alleviate primary antiphospholipid syndrome.

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Abstract

La présente invention concerne un médicament pour le traitement ou le soulagement du syndrome des antiphospholipides à l'aide d'une quantité efficace du médicament ciblant Blys et/ou APRIL, d'un régime posologique, d'un intervalle d'administration et d'un mode d'administration. Les résultats montrent que la quantité efficace fournie du médicament ciblant Blys et/ou APRIL présente une bonne sécurité et un excellent effet thérapeutique pendant le traitement du soulagement de patients atteints du syndrome des antiphospholipides.
PCT/CN2025/106768 2024-07-04 2025-07-03 Méthode de traitement du syndrome des antiphospholipides à l'aide d'une protéine de fusion taci-fc Pending WO2026008004A1 (fr)

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101854951A (zh) * 2007-11-12 2010-10-06 阿雷斯贸易股份有限公司 Taci-免疫球蛋白融合蛋白制剂
CN108135976A (zh) * 2015-07-23 2018-06-08 博灵格英格尔海姆国际股份公司 靶向il-23a和b细胞激活因子(baff)的化合物和其用途
CN113613675A (zh) * 2019-12-10 2021-11-05 荣昌生物制药(烟台)股份有限公司 TACI-Fc融合蛋白药物制剂
WO2022236335A1 (fr) * 2021-05-07 2022-11-10 Alpine Immune Sciences, Inc. Procédés de dosage et de traitement avec une protéine immunomodulatrice de fusion taci-fc
CN115812077A (zh) * 2020-05-08 2023-03-17 高山免疫科学股份有限公司 April和baff抑制性免疫调节蛋白及其使用方法
WO2024123675A2 (fr) * 2022-12-05 2024-06-13 Alexion Pharmaceuticals, Inc. Protéines de fusion taci-fc pour l'inhibition multifonctionnelle des récepteurs baff, april et fc néonatal

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101854951A (zh) * 2007-11-12 2010-10-06 阿雷斯贸易股份有限公司 Taci-免疫球蛋白融合蛋白制剂
CN108135976A (zh) * 2015-07-23 2018-06-08 博灵格英格尔海姆国际股份公司 靶向il-23a和b细胞激活因子(baff)的化合物和其用途
CN113613675A (zh) * 2019-12-10 2021-11-05 荣昌生物制药(烟台)股份有限公司 TACI-Fc融合蛋白药物制剂
CN115812077A (zh) * 2020-05-08 2023-03-17 高山免疫科学股份有限公司 April和baff抑制性免疫调节蛋白及其使用方法
WO2022236335A1 (fr) * 2021-05-07 2022-11-10 Alpine Immune Sciences, Inc. Procédés de dosage et de traitement avec une protéine immunomodulatrice de fusion taci-fc
WO2024123675A2 (fr) * 2022-12-05 2024-06-13 Alexion Pharmaceuticals, Inc. Protéines de fusion taci-fc pour l'inhibition multifonctionnelle des récepteurs baff, april et fc néonatal

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