Use of Anti-angptl3 antibody in treating hyperlipidemia and method

Abstract

The present invention relates to use of an anti-ANGPTL3 antibody in treating hyperlipidemia and a method. Specifically, the present invention relates to use of an anti-ANGPTL3 antibody or an antigen-binding fragment thereof in preparing a drug for treating hyperlipemia patients, wherein the hyperlipemia patients are subject to the risk of atherosclerosis cardiovascular disease.

Description

Uses and methods of anti-ANGPTL3 antibodies for treating hyperlipidemia

[0001] The present disclosure claims priority to CN202410246641.9, and the entire contents of the aforementioned patent application are incorporated into the present disclosure by reference. Technical Field

[0002] The present disclosure belongs to the field of medicine and relates to methods and medical uses of anti-ANGPTL3 antibodies or antigen-binding fragments thereof for treating hyperlipidemia. Background Art

[0003] Cardiovascular disease (CVD) is a major threat to human health. Low-density lipoprotein cholesterol (LDL-C) is a major risk factor for the development and progression of atherosclerotic cardiovascular disease (ASCVD). Meta-analysis results indicate that for every 1.0 mmol / L decrease in LDLC, the risk of major vascular events (including coronary heart disease death, nonfatal myocardial infarction, coronary revascularization, and ischemic stroke) within 1 year decreases by approximately 22% and all-cause mortality decreases by 10%.

[0004] Angiopoietin-like protein 3 (ANGPTL3) is a secreted protein and a member of the angiopoietin-like protein family. It is primarily expressed in the liver. The amino-terminal coiled region of ANGPTL3 is associated with inhibiting lipoprotein lipase (LPL) activity, while the carboxy-terminal fibrinogen-like region is primarily involved in regulating triglyceride (TG) and angiogenesis. Therefore, this protein has the functions of regulating lipid metabolism and promoting angiogenesis.

[0005] ANGPTL3 primarily regulates lipoprotein metabolism by inhibiting LPL and endothelial lipase (EL). Currently, there are two types of ANGPTL3 inhibitors: ANGPTL3-ASO and ANGPTL3 monoclonal antibodies. These two inhibitors differ in their mechanisms and sites of action: ANGPTL3-ASO primarily acts on hepatocytes, while ANGPTL3 monoclonal antibodies circulate in the blood.

[0006] Although ANGPTL3 is a promising target for lipid-lowering, only one monoclonal antibody, evinacumab, has been approved for marketing. Evinacumab is administered via intravenous injection every four weeks. Long-term intravenous administration can be burdensome for patients and reduce compliance. Furthermore, according to the evinacumab package insert, its impact on cardiovascular morbidity and mortality remains uncertain. Therefore, there is a need for new, safe, and effective treatments targeting ANGPTL3 that are highly compliant with patients. Summary of the Invention

[0007] The present disclosure provides uses and methods of ANGPTL3 inhibitors (eg, anti-ANGPTL3 antibodies or antigen-binding fragments thereof) for treating hyperlipidemia.

[0008] In one aspect, the present disclosure provides use of an anti-ANGPTL3 antibody or an antigen-binding fragment thereof in the preparation of a medicament for treating patients with hyperlipidemia.

[0009] In another aspect, the present disclosure provides an anti-ANGPTL3 antibody or antigen-binding fragment thereof for use in treating a patient with hyperlipidemia.

[0010] In another aspect, the present disclosure provides use of an anti-ANGPTL3 antibody or antigen-binding fragment thereof in combination with a background lipid-lowering therapy in the preparation of a medicament for treating patients with hyperlipidemia.

[0011] In another aspect, the present disclosure provides use of an anti-ANGPTL3 antibody or antigen-binding fragment thereof in combination with a drug for background lipid-lowering therapy in the preparation of a medicament for treating patients with hyperlipidemia.

[0012] In another aspect, the present disclosure provides an anti-ANGPTL3 antibody or an antigen-binding fragment thereof for use in treating a patient with hyperlipidemia; wherein the patient with hyperlipidemia is also receiving background lipid-lowering therapy.

[0013] In another aspect, the present disclosure provides an anti-ANGPTL3 antibody or an antigen-binding fragment thereof for use in treating patients with hyperlipidemia; wherein the anti-ANGPTL3 antibody or the antigen-binding fragment thereof is administered in combination with a background lipid-lowering therapy drug.

[0014] In another aspect, the present disclosure provides use of an anti-ANGPTL3 antibody or an antigen-binding fragment thereof in the preparation of a medicament for lowering the levels of plasma low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B (ApoB), lipoprotein (a) (Lp(a)), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C) and / or apolipoprotein A1 (ApoA1) in patients with hyperlipidemia.

[0015] In another aspect, the present disclosure provides an anti-ANGPTL3 antibody or an antigen-binding fragment thereof for use in reducing the levels of plasma low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B (ApoB), lipoprotein (a) (Lp(a)), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C) and / or apolipoprotein A1 (ApoA1) in patients with hyperlipidemia.

[0016] In another aspect, the present disclosure provides use of an anti-ANGPTL3 antibody or antigen-binding fragment thereof, in combination with background lipid-lowering therapy, in the preparation of a medicament for lowering the levels of plasma low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B (ApoB), lipoprotein (a) (Lp(a)), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C) and / or apolipoprotein A1 (ApoA1) in patients with hyperlipidemia.

[0017] In another aspect, the present disclosure provides use of an anti-ANGPTL3 antibody or antigen-binding fragment thereof in combination with a drug for background lipid-lowering therapy for the preparation of a medicament for lowering the levels of plasma low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B (ApoB), lipoprotein (a) (Lp(a)), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C) and / or apolipoprotein A1 (ApoA1) in patients with hyperlipidemia.

[0018] In another aspect, the present disclosure provides an anti-ANGPTL3 antibody or antigen-binding fragment thereof for reducing the levels of plasma low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B (ApoB), lipoprotein (a) (Lp(a)), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C) and / or apolipoprotein A1 (ApoA1) in a hyperlipidemic patient; wherein the hyperlipidemic patient is also administered a background lipid-lowering therapy in combination with a drug.

[0019] In another aspect, the present disclosure provides an anti-ANGPTL3 antibody or antigen-binding fragment thereof for reducing the levels of plasma low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B (ApoB), lipoprotein (a) (Lp(a)), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C) and / or apolipoprotein A1 (ApoA1) in patients with hyperlipidemia; wherein the anti-ANGPTL3 antibody or antigen-binding fragment thereof is administered in combination with a background lipid-lowering therapy.

[0020] In another aspect, the present disclosure provides a method for treating a patient with hyperlipidemia, comprising administering an anti-ANGPTL3 antibody or an antigen-binding fragment thereof to a subject in need thereof.

[0021] In another aspect, the present disclosure provides a method for treating a patient with hyperlipidemia, comprising administering to a subject in need thereof a background lipid-lowering therapy and an anti-ANGPTL3 antibody or an antigen-binding fragment thereof.

[0022] Subjects

[0023] In some embodiments, the hyperlipidemia patient is at risk for atherosclerotic cardiovascular disease (ASCVD). In some specific embodiments, the hyperlipidemia patient is a hyperlipidemia patient with an intermediate risk or higher risk of ASCVD (e.g., moderate risk, high risk, very high risk, ultra-high risk) who has not reached the target LDL-C level after receiving lipid-lowering drug treatment.

[0024] In some embodiments, the hyperlipidemia patient is an ASCVD intermediate risk or higher hyperlipidemia patient whose LDL-C level is not at the target level after receiving lipid-lowering drug treatment.

[0025] In some embodiments, the hyperlipidemia patient is an ASCVD intermediate risk or higher hyperlipidemia patient who has received lipid-lowering drug treatment for at least 4 weeks and whose LDL-C level is not at the target level.

[0026] In some embodiments, the hyperlipidemia patient meets the following criteria:

[0027] (1) Received lipid-lowering drug treatment for at least 4 weeks and fasting LDL-C ≥ 1.4 mmol / L;

[0028] (2) receiving lipid-lowering drug treatment for at least 4 weeks and fasting LDL-C ≥1.8 mmol / L;

[0029] (3) Received lipid-lowering drug treatment for at least 4 weeks, with fasting LDL-C ≥ 2.6 mmol / L; or,

[0030] (4) Fasting LDL-C ≥ 2.6 mmol / L.

[0031] In some embodiments, the fasting LDL-C of the hyperlipidemia patient with ASCVD intermediate risk or above who has not reached the target LDL-C after receiving lipid-lowering drug treatment involves the following conditions:

[0032] (1) The patients with hyperlipidemia received stable treatment with moderate-intensity or higher-dose statins for 4 weeks or more: 1) Fasting LDL-C ≥ 1.4 mmol / L, ASCVD risk is very high risk; 2) Fasting LDL-C ≥ 1.8 mmol / L, ASCVD risk is very high risk; 3) Fasting LDL-C ≥ 2.6 mmol / L, ASCVD risk is moderate or high risk.

[0033] (2) The hyperlipidemia patients do not meet other conditions of receiving stable treatment with moderate-intensity or higher-dose statins for 4 weeks or more, fasting LDL-C ≥ 2.6 mmol / L, and ASCVD risk is 1) very high risk, 2) extremely high risk, 3) moderate or high risk.

[0034] In some embodiments, the fasting triglyceride level of the hyperlipidemia patient with ASCVD intermediate risk or above whose LDL-C level does not reach the target level after receiving lipid-lowering drug treatment is ≤5.6 mmol / L.

[0035] In some embodiments, the ASCVD risk assessment is determined according to clinical treatment guidelines, for example, the "China Blood Lipid Management Guidelines (2023)", the "2018 AHA / ACC / AACVPR / AAPA / ABC / ACPM / ADA / AGS / APhA / ASPC / NLA Guideline on the Management of Blood Cholesterol: Executive Summary", the "2019ESC / EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk", etc.

[0036] In some embodiments, ASCVD risk is determined according to the "Guidelines for Blood Lipid Management in China (2023)".

[0037] In some embodiments, the lipid-lowering drug therapy refers to background lipid-lowering drug therapy.

[0038] In some embodiments, the background lipid-lowering therapeutic drug includes a statin and / or a non-statin drug. For example, statins include but are not limited to atorvastatin, rosuvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, simvastatin, and / or Xuezhikang. Non-statin drugs include but are not limited to cholesterol absorption inhibitors (such as ezetimibe) and / or PCSK9 inhibitors (such as alirocumab and evolocumab).

[0039] In some embodiments, the background lipid-lowering drug selection and dosage are determined according to clinical treatment guidelines. For example, the "China Blood Lipid Management Guidelines (2023)", "2018

[0040] AHA / ACC / AACVPR / AAPA / ABC / ACPM / ADA / AGS / APhA / ASPC / NLA Guideline on the Management of Blood Cholesterol:Executive Summary", "2019ESC / EAS Guidelines for the management of dyslipidaemias:lipid modification to reduce cardiovascular risk".

[0041] In some embodiments, the moderate and higher intensity doses of statins include but are not limited to the following drug types (daily dose): atorvastatin ≥ about 10 mg; rosuvastatin ≥ about 5 mg; fluvastatin ≥ about 80 mg; lovastatin ≥ about 40 mg; pitavastatin ≥ about 2 mg; pravastatin ≥ about 40 mg; simvastatin ≥ about 20 mg; and Xuezhikang ≥ about 1.2 g.

[0042] In some embodiments, the moderate-intensity dose of statins includes but is not limited to the following types of drugs (daily dose): atorvastatin about 10 mg to about 20 mg; rosuvastatin about 5 mg to about 10 mg; fluvastatin about 80 mg; lovastatin about 40 mg; pitavastatin about 2 mg to about 4 mg; pravastatin about 40 mg; simvastatin about 20 to about 40 mg; and Xuezhikang about 1.2 g.

[0043] Anti-ANGPTL3 antibodies or antigen-binding fragments thereof

[0044] In some embodiments, the anti-ANGPTL3 antibody or antigen-binding fragment thereof is administered once a week, once every 2 weeks, once every 4 weeks, once every 6 weeks, once every 8 weeks, once every 10 weeks, or once every 12 weeks.

[0045] In some embodiments, the anti-ANGPTL3 antibody or antigen-binding fragment thereof is administered less frequently than once every 4 weeks. Exemplarily, the anti-ANGPTL3 antibody or antigen-binding fragment thereof is administered once every 4 weeks, once every 6 weeks, once every 8 weeks, once every 10 weeks, or once every 12 weeks.

[0046] In some embodiments, the anti-ANGPTL3 antibody or antigen-binding fragment thereof is administered once every 4 weeks, or once every 8 weeks.

[0047] In some embodiments, the anti-ANGPTL3 antibody or antigen-binding fragment thereof is administered at a dose selected from about 50 to about 1500 mg, about 100 to about 1000 mg, about 150 to about 600 mg, about 50 to about 800 mg, or about 100 to about 600 mg.

[0048] In some embodiments, the anti-ANGPTL3 antibody or antigen-binding fragment thereof is administered at a dose selected from about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 640 mg, about 650 mg, about 660 mg, about 670 mg, about 680 mg, about 690 mg, about 700 mg, about 710 mg, about 720 mg, about 730 mg, about 740 mg 60mg, about 270mg, about 280mg, about 290mg, about 300mg, about 310mg, about 320mg, about 330mg, about 340mg, about 350mg, about 360mg, about 370mg, about 380mg, about 390mg, about 400mg, about 410mg, about 420mg, about 430mg, about 440mg, about 450mg, about 460mg, about 470mg, about 480mg, about 490mg, about 500mg, About 510mg, about 520mg, about 530mg, about 540mg, about 550mg, about 560mg, about 570mg, about 580mg, about 590mg, about 600mg, about 610mg, about 620mg, about 630mg, about 640mg, about 650mg, about 660mg, about 670mg, about 680mg, about 690mg, about 700mg, about 710mg, about 720mg, about 730mg, about 740mg, about 750mg g, about 760 mg, about 770 mg, about 780 mg, about 790 mg, about 800 mg, about 810 mg, about 820 mg, about 830 mg, about 840 mg, about 850 mg, about 860 mg, about 870 mg, about 880 mg, about 890 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, etc. (including any numerical value between the above any point values).

[0049] In some specific embodiments, the anti-ANGPTL3 antibody or antigen-binding fragment thereof is administered at a dose selected from about 150 mg, about 300 mg, about 600 mg, or about 1200 mg.

[0050] In some specific embodiments, the dosage and frequency of administration of the anti-ANGPTL3 antibody or antigen-binding fragment thereof are selected from any one of the following:

[0051] (1) The anti-ANGPTL3 antibody or antigen-binding fragment thereof is administered at a dosage of 150-600 mg / time (e.g., about 150 mg / time, about 200 mg / time, about 250 mg / time, about 300 mg / time, about 350 mg / time, about 400 mg / time, about 450 mg / time, about 550 mg / time, about 550 mg / time, about 600 mg / time). The administration frequency is once every two weeks.

[0052] (2) The anti-ANGPTL3 antibody or antigen-binding fragment thereof is administered at a dosage of 150-600 mg / time (e.g., about 150 mg / time, about 200 mg / time, about 250 mg / time, about 300 mg / time, about 350 mg / time, about 400 mg / time, about 450 mg / time, about 550 mg / time, about 550 mg / time, about 600 mg / time), with a dosing frequency of once every four weeks.

[0053] (3) The anti-ANGPTL3 antibody or antigen-binding fragment thereof is administered at a dosage of 150-600 mg / time (e.g., about 150 mg / time, about 200 mg / time, about 250 mg / time, about 300 mg / time, about 350 mg / time, about 400 mg / time, about 450 mg / time, about 550 mg / time, about 550 mg / time, about 600 mg / time), with a dosing frequency of once every six weeks.

[0054] (4) The anti-ANGPTL3 antibody or antigen-binding fragment thereof is administered at a dosage of 150-600 mg / time (e.g., about 150 mg / time, about 200 mg / time, about 250 mg / time, about 300 mg / time, about 350 mg / time, about 400 mg / time, about 450 mg / time, about 550 mg / time, about 550 mg / time, about 600 mg / time), with a dosing frequency of once every 8 weeks.

[0055] (5) The anti-ANGPTL3 antibody or antigen-binding fragment thereof is administered at a dosage of 150-600 mg / time (e.g., about 150 mg / time, about 200 mg / time, about 250 mg / time, about 300 mg / time, about 350 mg / time, about 400 mg / time, about 450 mg / time, about 550 mg / time, about 550 mg / time, about 600 mg / time). The administration frequency is once every 10 weeks.

[0056] (6) The anti-ANGPTL3 antibody or antigen-binding fragment thereof is administered at a dosage of 150-600 mg / time (e.g., about 150 mg / time, about 200 mg / time, about 250 mg / time, about 300 mg / time, about 350 mg / time, about 400 mg / time, about 450 mg / time, about 550 mg / time, about 550 mg / time, about 600 mg / time). The administration frequency is once every 12 weeks.

[0057] (7) The dosage of the anti-ANGPTL3 antibody or antigen-binding fragment thereof is 150-1200 mg / time (e.g., about 150 mg / time, about 200 mg / time, about 250 mg / time, about 300 mg / time, about 350 mg / time, about 400 mg / time, about 450 mg / time, about 550 mg / time, about 550 mg / time, about 600 mg / time, about 700 mg / time, about 800 mg / time, about 1000 mg / time, about 1200 mg / time). The administration frequency is once every 12 weeks.

[0058] (8) The anti-ANGPTL3 antibody or antigen-binding fragment thereof is administered at a dosage of 600-1200 mg / time (e.g., about 600 mg / time, about 700 mg / time, about 800 mg / time, about 1000 mg / time, about 1200 mg / time), with a dosing frequency of once every 12 weeks.

[0059] In some specific embodiments, the dosage and frequency of administration of the anti-ANGPTL3 antibody or antigen-binding fragment thereof are selected from any one of the following:

[0060] The dosage of the anti-ANGPTL3 antibody or antigen-binding fragment thereof is about 150 mg / time, about 300 mg / time, about 600 mg / time, about 1000 mg / time, or about 1200 mg / time; the administration frequency is once every four weeks. Alternatively,

[0061] The dosage of the anti-ANGPTL3 antibody or antigen-binding fragment thereof is about 150 mg / time, about 300 mg / time, about 600 mg / time, about 1000 mg / time, or about 1200 mg / time; the administration frequency is once every 8 weeks. Alternatively,

[0062] The dosage of the anti-ANGPTL3 antibody or antigen-binding fragment thereof is about 150 mg / time, about 300 mg / time, about 600 mg / time, about 1000 mg / time, or about 1200 mg / time; the administration frequency is once every 12 weeks.

[0063] In some embodiments, the anti-ANGPTL3 antibody or antigen-binding fragment thereof is any of the anti-ANGPTL3 antibodies or antigen-binding fragments disclosed in WO2023001228 and WO2021147984. The present disclosure incorporates the antibody sequences, preparation methods, compositions, and other related contents of the above patents into the present disclosure by reference.

[0064] In some embodiments, the anti-ANGPTL3 antibody or antigen-binding fragment thereof comprises any one, any two, any three, any four, any five, or six CDRs selected from HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 1 to SEQ ID NO: 6.

[0065] In some embodiments, the anti-ANGPTL3 antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the anti-ANGPTL3 antibody or antigen-binding fragment thereof comprises HCDR1, HCDR2, and HCDR3 in the heavy chain variable region of the amino acid sequence set forth in SEQ ID NO:7, and / or the light chain variable region comprises LCDR1, LCDR2, and LCDR3 in the light chain variable region of the amino acid sequence set forth in SEQ ID NO:8.

[0066] In some embodiments, an anti-ANGPTL3 antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region comprises HCDR1, HCDR2, and HCDR3 as shown in SEQ ID NO:1, SEQ ID NO:2, and SEQ ID NO:3, respectively; and / or the light chain variable region comprises LCDR1, LCDR2, and LCDR3 as shown in SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6, respectively.

[0067] The aforementioned CDR sequences are shown in Table 1 below:

[0068] The above-mentioned CDRs are defined according to the Kabat, IMGT, Chothia, AbM or Contact numbering systems. In some specific embodiments, the CDRs are defined according to the Kabat numbering system.

[0069] In some embodiments, the anti-ANGPTL3 antibody or antigen-binding fragment thereof is a humanized antibody. In some specific embodiments, the VH of the anti-ANGPTL3 antibody or antigen-binding fragment thereof comprises the amino acid sequence set forth in SEQ ID NO:7, or an amino acid sequence having at least 80% or 90% sequence identity thereto; and the VL comprises the amino acid sequence set forth in SEQ ID NO:8, or an amino acid sequence having at least 80% or 90% sequence identity thereto.

[0070] >P8B heavy chain variable region sequence:

[0071] >P8B light chain variable region sequence:

[0072] Note: The underlined part in the sequence is the CDR sequence determined according to the Kabat numbering system, and the italicized part is the FR sequence.

[0073] In some embodiments, the anti-ANGPTL3 antibody or antigen-binding fragment thereof is a humanized antibody comprising any one or two of the aforementioned VH and VL.

[0074] In some embodiments, the anti-ANGPTL3 antibody or antigen-binding fragment thereof further comprises an antibody constant region; for example, the heavy chain constant region of the antibody constant region is selected from human IgG1, IgG2, IgG3, and IgG4 constant regions and variants thereof; and the light chain constant region of the antibody constant region is selected from human antibody κ and λ chain constant regions and variants thereof.

[0075] Exemplarily, the antibody heavy chain constant region is selected from the human IgG4-YTE variant with a sequence as shown in SEQ ID NO: 11, and the light chain constant region is selected from the constant region of the human κ chain with a sequence as shown in SEQ ID NO: 12.

[0076] >Human IgG4-YTE variant heavy chain constant region sequence:

[0077] >Human kappa chain light chain constant region sequence:

[0078] Exemplarily, the above-mentioned light chain / heavy chain constant regions are combined with the aforementioned variable regions of P8B to form a complete anti-ANGPTL3 antibody: P8BG. The light chain / heavy chain sequences of the antibody are as follows:

[0079] >P8BG heavy chain sequence:

[0080] >P8BG light chain sequence:

[0081] In some embodiments, the anti-ANGPTL3 antibody or antigen-binding fragment thereof comprises a heavy chain and a light chain, wherein the heavy chain variable region comprises an amino acid sequence as set forth in SEQ ID NO:9, or at least 80% or 90% identical thereto, and the light chain variable region comprises an amino acid sequence as set forth in SEQ ID NO:10, or at least 80% or 90% identical thereto.

[0082] In some embodiments, the anti-ANGPTL3 antibody or antigen-binding fragment thereof comprises any one or two of the aforementioned heavy and light chains.

[0083] In the context of the present disclosure, "at least 80%" and "at least 90%" encompass 80% and above, for example at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, 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%, at least 99%, and any numerical range therebetween.

[0084] In some embodiments, the anti-ANGPTL3 antibody or antigen-binding fragment thereof is administered orally, parenterally, or transdermally. In some specific embodiments, the anti-ANGPTL3 antibody or antigen-binding fragment thereof is administered by subcutaneous injection.

[0085] In some embodiments, the anti-ANGPTL3 antibody or antigen-binding fragment thereof is formulated in an injectable form. Exemplarily, the injectable form of the anti-ANGPTL3 antibody or antigen-binding fragment thereof is an injection solution or a lyophilized powder injection, which comprises the anti-ANGPTL3 antibody or antigen-binding fragment thereof and one or more pharmaceutically acceptable excipients.

[0086] In some embodiments, the pharmaceutical composition comprising an anti-ANGPTL3 antibody or antigen-binding fragment thereof further comprises a buffer, a stabilizer, and / or a surfactant.

[0087] Exemplarily, the aforementioned buffer is selected from any one of acetic acid-sodium acetate, histidine-hydrochloride, sodium dihydrogen phosphate-disodium hydrogen phosphate, succinic acid-sodium succinate and citric acid-sodium citrate buffers. Exemplarily, the surfactant can be selected from polysorbate 20, polysorbate 80, polyhydroxyalkylene, Triton, sodium dodecyl sulfate, sodium lauryl sulfate, sodium octyl glucoside, lauryl-sulfobetaine, myristyl-sulfobetaine, linoleyl-sulfobetaine, stearyl-sulfobetaine, lauryl-sarcosine, myristyl-sarcosine, linoleyl-sarcosine, stearyl-sarcosine, linoleyl-betaine, myristyl-betaine, cetyl-betaine Betaine, lauroyl propyl-betaine, cocamidopropyl-betaine, linoleyl propyl-betaine, myristamidopropyl-betaine, palmitamidopropyl-betaine, isostearamidopropyl-betaine, myristamidopropyl-dimethylamine, palmitamidopropyl-dimethylamine, isostearamidopropyl-dimethylamine, methyl cocoyl sodium, methyl oleyl taurate sodium, polyethylene glycol, polypropylene glycol, copolymer of ethylene and propylene glycol, etc. Exemplarily, the stabilizer is selected from sugars or amino acids, and the sugar comprises a conventional composition (CHO) n and their derivatives, including monosaccharides, disaccharides, trisaccharides, polysaccharides, sugar alcohols, reducing sugars, non-reducing sugars, and the like. Sugars can be selected from glucose, sucrose, trehalose, lactose, fructose, maltose, dextran, glycerol, erythritol, glycerol, arabitol, xylose, sorbitol, mannitol, milibiose, melezitose, raffinose, mannotriose, stachyose, maltose, lactulose, maltulose, sorbitol, maltitol, lactitol, iso-maltulose, and the like. Amino acids can be selected, for example, from glycine, methionine, and proline. WO2023001228 relates to compositions of anti-ANGPTL3 antibodies, and this disclosure incorporates the entire disclosure of this patent.

[0088] Combination therapy

[0089] In some embodiments, the method or use of any of the preceding items, wherein the hyperlipidemia patient receives background lipid-lowering therapy and the anti-ANGPTL3 antibody or antigen-binding fragment thereof.

[0090] In some embodiments, the method or use of any of the foregoing, wherein the dosing regimen for the hyperlipidemia patient comprises:

[0091] 1) an introduction phase, wherein the hyperlipidemia patient is administered background lipid-lowering therapy drugs;

[0092] 2) During the treatment phase, the hyperlipidemia patient is administered background lipid-lowering therapy and an anti-ANGPTL3 antibody or an antigen-binding fragment thereof.

[0093] In some embodiments, the lead-in period is maintained for ≥ 4 weeks, for example, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 10 weeks, etc.

[0094] In some embodiments, the background lipid-lowering therapy includes a statin, with or without a non-statin. In some specific embodiments, the statin includes but is not limited to atorvastatin, rosuvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, simvastatin, and / or Xuezhikang. In some specific embodiments, the non-statin is a cholesterol absorption inhibitor (such as ezetimibe) and / or a PCSK9 inhibitor (such as alirocumab and evolocumab).

[0095] In some embodiments, the selection and dosage of background lipid-lowering therapy drugs are determined according to clinical treatment guidelines, such as the "Chinese Guidelines for Blood Lipid Management (2023)", the "2018 AHA / ACC / AACVPR / AAPA / ABC / ACPM / ADA / AGS / APhA / ASPC / NLA Guideline on the Management of Blood Cholesterol: Executive Summary", and the "2019 ESC / EAS Guidelines for the Management of Dyslipidaemias: Lipid Modification to Reduce Cardiovascular Risk".

[0096] In some specific embodiments, the dosage of atorvastatin is about 10 mg and above, for example, about 10 mg to about 40 mg, about 10 mg to about 50 mg, about 10 mg to about 60 mg, about 10 mg to about 80 mg, about 10 mg to about 100 mg. In some specific embodiments, the dosage of atorvastatin is about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 90 mg, about 100 mg, etc.

[0097] In some specific embodiments, the administration frequency of atorvastatin is once a day, once every two days, or twice a day. In some specific embodiments, the administration frequency of atorvastatin is once a day.

[0098] In some specific embodiments, the administration frequency of atorvastatin is once a day, and the dosage is about 10 mg and above, about 10 mg to about 40 mg, about 10 mg to about 50 mg, about 10 mg to about 60 mg, about 10 mg to about 80 mg, or about 10 mg to about 100 mg.

[0099] In some specific embodiments, the dosage of rosuvastatin is about 5 mg and above, for example, about 5 mg to about 10 mg, about 5 mg to about 20 mg, about 5 mg to about 40 mg, about 5 mg to about 50 mg, about 5 mg to about 60 mg, about 5 mg to about 80 mg, about 5 mg to about 100 mg. In some specific embodiments, the dosage of rosuvastatin is about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 90 mg, about 100 mg, etc.

[0100] In some specific embodiments, the administration frequency of rosuvastatin is once a day, once every two days, or twice a day. In some specific embodiments, the administration frequency of rosuvastatin is once a day.

[0101] In some specific embodiments, the administration frequency of rosuvastatin is once a day, and the dosage is about 5 mg and above, about 5 mg to about 10 mg, about 5 mg to about 20 mg, about 5 mg to about 40 mg, about 5 mg to about 50 mg, about 5 mg to about 60 mg, about 5 mg to about 80 mg, or about 5 mg to about 100 mg.

[0102] In some embodiments, after completing the lead-in period, patients with hyperlipidemia who meet the following criteria receive background lipid-lowering therapy and treatment with an anti-ANGPTL3 antibody or antigen-binding fragment thereof:

[0103] 1) Patients with ultra-high ASCVD risk: fasting LDL-C ≥ 1.4 mmol / L before randomization; patients with extremely high ASCVD risk: fasting LDL-C ≥ 1.8 mmol / L before randomization; patients with moderate or high ASCVD risk: fasting LDL-C ≥ 2.6 mmol / L before randomization;

[0104] 2) Fasting triglyceride ≤5.6mmol / L before randomization.

[0105] In some embodiments, according to any of the foregoing methods or uses, the hyperlipidemia patient has at least one of the following improved indicators after receiving treatment with the anti-ANGPTL3 antibody or antigen-binding fragment thereof:

[0106] Reduced plasma low-density lipoprotein cholesterol (LDL-C) levels;

[0107] Reduced triglyceride (TG) levels;

[0108] Lowered levels of non-HDL-C;

[0109] Reduced levels of apolipoprotein B (ApoB);

[0110] Decreased levels of lipoprotein(a) (Lp(a));

[0111] Lowered total cholesterol (TC) levels;

[0112] Lowered high-density lipoprotein cholesterol (HDL-C) levels;

[0113] Reduced levels of apolipoprotein A1 (ApoA1).

[0114] For example, according to certain embodiments of the present disclosure, administration of an anti-ANGPTL3 antibody or antigen-binding fragment thereof to a suitable subject will result in:

[0115] a mean percent reduction from baseline in serum low-density lipoprotein cholesterol (LDL-C) of at least about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, 30%, 40%, 50%, 60% or greater;

[0116] a mean percent reduction from baseline in triglycerides (TG) of at least about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, 30%, 40%, 50%, 60% or greater;

[0117] a mean percent reduction from baseline in non-HDL-C of at least about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, 30%, 40%, 50%, 60% or greater;

[0118] a mean percent decrease from baseline in apolipoprotein B (ApoB) of at least about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, 30%, 40%, 50%, 60% or greater;

[0119] a mean percent reduction from baseline in Lp(a) of at least about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, 30%, 40%, 50%, 60% or greater;

[0120] a mean percent reduction from baseline in total cholesterol (TC) of at least about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, 30%, 40%, 50%, 60% or greater;

[0121] a mean percent reduction from baseline in high-density lipoprotein cholesterol (HDL-C) of at least about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, 30%, 40%, 50%, 60% or greater; and / or,

[0122] A mean percent reduction from baseline in apolipoprotein Al of at least about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, 30%, 40%, 50%, 60% or greater.

[0123] The anti-ANGPTL3 antibodies disclosed herein can lower LDL-C levels in patients with hyperlipidemia, potentially reducing the risk of cardiovascular events and preventing the development of ASCVD, with high safety and efficacy. Furthermore, the anti-ANGPTL3 antibodies are administered via subcutaneous injection, requiring less frequent dosing and resulting in good patient compliance.

[0124] In some embodiments, the anti-ANGPTL3 antibodies disclosed herein demonstrate promising efficacy in reducing LDL-C and TG levels in patients at high ASCVD risk, demonstrating greater LDL-C lowering and enhanced targeted inhibitory efficacy compared to existing treatments (e.g., Zodasiran). The Q4 / Q8 subcutaneous dosing regimen of anti-ANGPTL3 antibodies significantly improves treatment convenience, particularly in patients with chronic conditions requiring long-term management. In this study, patient compliance was as high as 97%, and the incidence of injection site reactions was low (3.4%). The incidence of TRAEs (19.5%) with the anti-ANGPTL3 antibodies was not statistically different from that in the placebo group (13.4%). Furthermore, the anti-ANGPTL3 antibodies demonstrated minimal effects on liver function (the incidence of ALT elevations was comparable to that of placebo), which contrasts with the potential risk of liver enzyme abnormalities associated with evinacumab, suggesting that the anti-ANGPTL3 antibodies disclosed herein may have a better liver safety profile.

[0125] the term

[0126] In order to make the present disclosure more easily understood, certain technical and scientific terms are specifically defined below. Unless otherwise explicitly defined herein, all other technical and scientific terms used herein have the meanings commonly understood by those skilled in the art to which the present disclosure belongs.

[0127] Unless the context clearly requires otherwise, throughout the specification and claims, the words "comprising," "having," "including," etc. should be construed to have an inclusive sense rather than an exclusive or exhaustive sense; that is, in the sense of "including but not limited to."

[0128] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.

[0129] "About" and "approximately" refer to values ​​that are within an acceptable error range for the specific value as determined by one of ordinary skill in the art, which value depends in part on how it is measured or determined (i.e., the limits of the measurement system). For example, "about" can mean within 1 or more than 1 standard deviation. Alternatively, "about" or "substantially comprising" can mean a range of up to 20%, such as between 1% and 15%, between 1% and 10%, between 1% and 5%, between 0.5% and 5%, between 0.5% and 1%, and in this disclosure, each instance of a number or numerical range preceded by the term "about" also includes embodiments of the given number. Unless otherwise stated, when a specific value appears in the application and claims, the meaning of "about" or "substantially comprising" should be assumed to be within an acceptable error range for that specific value.

[0130] The term "and / or," such as "X and / or Y," should be understood to mean "X and Y" or "X or Y" and should be used to provide clear support for both meanings or either meaning.

[0131] The three letter and one letter codes for amino acids used in this disclosure are as described in J. biol. chem, 243, p3558 (1968).

[0132] "Antibody" is used in the broadest sense to encompass various antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies; monospecific antibodies, multispecific antibodies (e.g., bispecific antibodies), full-length antibodies, and antibody fragments (or antigen-binding fragments, or antigen-binding portions), as long as they exhibit the desired antigen-binding activity. An antibody may refer to an immunoglobulin, a tetrapeptide chain structure composed of two identical heavy chains and two identical light chains connected by interchain disulfide bonds. Immunoglobulins differ in their antigenicity due to the amino acid composition and arrangement order of their heavy chain constant regions. Consequently, immunoglobulins can be divided into five classes, or isotypes, namely IgM, IgD, IgG, IgA, and IgE, corresponding to μ, δ, γ, α, and ε chains, respectively. Within the same class of Ig, different subclasses can be formed based on the amino acid composition of the hinge region and the number and location of heavy chain disulfide bonds. For example, IgG can be divided into IgG1, IgG2, IgG3, and IgG4. Light chains are classified as either κ or λ chains based on differences in their constant regions. Each of the five classes of Ig can have either kappa or lambda chains. The approximately 110 amino acids near the N-terminus of both the heavy and light chains of antibodies vary greatly in sequence and constitute the variable region (V region); the remaining amino acid sequences near the C-terminus are relatively stable and constitute the constant region (C region). The variable region consists of three hypervariable regions (CDRs) and four framework regions (FRs) whose sequences are relatively conserved. These three hypervariable regions determine the specificity of the antibody and are also known as complementarity-determining regions (CDRs). Each light chain variable region (VL) and heavy chain variable region (VH) consists of three CDRs and four FRs, arranged from the amino terminus to the carboxyl terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The three CDRs of the light chain are referred to as LCDR1, LCDR2, and LCDR3; the three CDRs of the heavy chain are referred to as HCDR1, HCDR2, and HCDR3.

[0133] For the determination or definition of CDRs, the definitive delineation of CDRs and the identification of residues comprising the binding site of the antibody can be accomplished by resolving the structure of the antibody and / or resolving the structure of the antibody-ligand complex. This can be accomplished by any of the various techniques known to those skilled in the art, such as X-ray crystallography. A variety of analytical methods can be used to identify CDRs, including but not limited to the Kabat numbering system, the Chothia numbering system, the AbM numbering system, the IMGT numbering system, contact definitions, and conformational definitions.

[0134] The amino acid sequence boundaries of CDRs can be determined by various well-known schemes, for example: "Kabat" numbering convention (see Kabat et al. (1991), "Sequences of Proteins of Immunological Interest", 5th edition, Public Health Service, National Institutes of Health, Bethesda, MD), "Chothia" numbering convention, "ABM" numbering convention, "contact" numbering convention (see Martin, ACR. Protein Sequence and Structure Analysis of Antibody Variable Domains [J]. 2001) and ImMunoGenTics (IMGT) numbering convention (Lefranc, MP et al., Dev. Comp. Immunol., 27, 55-77 (2003); Front Immunol. 2018 Oct 16; 9: 2278), etc.

[0135] The term "antigen-binding fragment" or "functional fragment" or "antigen-binding portion" refers to one or more fragments of an intact antibody that retains the ability to specifically bind to an antigen. It has been shown that fragments of a full-length antibody can be used to perform the antigen-binding function of an antibody. Exemplary binding fragments encompassed by the term "antigen-binding fragment" include: (i) a Fab fragment, a monovalent fragment consisting of the VL, VH, CL, and CH1 domains; (ii) a F(ab')2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; (iii) a Fd fragment consisting of the VH and CH1 domains; (iv) an Fv fragment consisting of the VH and VL domains of a single arm of an antibody; (v) a dsFv, a stable antigen-binding fragment formed by an interchain disulfide bond between VH and VL; (vi) scFv; (vii) diabodies, bispecific antibodies, and multispecific antibodies comprising fragments such as scFv, dsFv, and Fab.

[0136] "Homology" refers to the sequence similarity between two polynucleotide sequences or between two polypeptides. When a position in the two compared sequences is occupied by the same base or amino acid monomer subunit, for example, if every position in two DNA molecules is occupied by adenine, then the molecules are homologous at that position. The percentage homology between two sequences is a function of the number of matching or homologous positions shared by the two sequences divided by the number of positions compared × 100. For example, if 6 out of 10 positions in the two sequences match or are homologous when the sequences are optimally aligned, then the two sequences are 60% homologous; if 95 out of 100 positions in the two sequences match or are homologous, then the two sequences are 95% homologous. Typically, when aligning two sequences, the comparison is performed to give the maximum percentage homology. For example, the comparison can be performed using the BLAST algorithm, where the parameters of the algorithm are selected to give the maximum match between each sequence over the entire length of each reference sequence. The following references relate to the BLAST algorithm commonly used for sequence analysis: BLAST ALGORITHMS: Altschul, SF et al., (1990) J. Mol. Biol. 215: 403-410; Gish, W. et al., (1993) Nature Genet. 3: 266-272; Madden, TL et al., (1996) Meth. Enzymol. 266: 131-141; Altschul, SF et al., (1997) Nucleic Acids Res. 25: 3389-3402; Zhang, J. et al., (1997) Genome Res. 7: 649-656. Other conventional BLAST algorithms, such as those provided by NCBI BLAST, are also well known to those skilled in the art.

[0137] "Administer," "give," and "treat" as applied to an animal, a human, a laboratory subject, a cell, a tissue, an organ, or a biological fluid, refers to the contact of an exogenous drug, therapeutic agent, diagnostic agent, or composition with an animal, a human, a subject, a cell, a tissue, an organ, or a biological fluid. "Administer," "give," and "treat" can refer to, for example, therapeutic, pharmacokinetics, diagnostics, research, and experimental procedures. Treatment of cells includes contact of an agent with a cell, and contact of an agent with a fluid, wherein the fluid is in contact with the cell. "Administer," "give," and "treat" also mean the in vitro and ex vivo treatment of, for example, a cell, by an agent, a diagnostic, a binding composition, or by another cell. "Treatment," as applied to a human, veterinary, or research subject, refers to therapeutic treatment, prophylactic or preventative measures, research, and diagnostic applications.

[0138] "Treatment" means administering an internal or external therapeutic agent, such as a composition comprising any of the binding compounds of the present disclosure, to a patient who has one or more symptoms of a disease for which the therapeutic agent is known to have a therapeutic effect. Typically, the therapeutic agent is administered in an amount effective to alleviate one or more symptoms of the disease in the patient or population being treated, to induce regression of such symptoms or to inhibit the progression of such symptoms to any clinically measurable degree. The amount of a therapeutic agent effective to alleviate any specific disease symptom (also referred to as a "therapeutically effective amount") can vary according to a variety of factors, such as the patient's disease state, age, and weight, and the ability of the drug to produce the desired therapeutic effect in the patient. Whether the symptoms of the disease have been alleviated can be assessed by any clinical test method commonly used by a physician or other health care professional to assess the severity or progression of the symptoms. Although embodiments of the present disclosure (e.g., methods of treatment or articles of manufacture) may not be effective in alleviating every symptom of the target disease, they should alleviate the target disease symptoms in a statistically significant number of patients as determined by any statistical test known in the art, such as Student's t-test, chi-square test, U test according to Mann and Whitney, Kruskal-Wallis test (H test), Jonckheere-Terpstra test, and Wilcoxon test.

[0139] An "effective amount" encompasses an amount sufficient to ameliorate or prevent the symptoms or conditions of a medical condition. An effective amount also means an amount sufficient to permit or facilitate diagnosis. The effective amount for a particular patient or veterinary subject may vary depending on factors such as the condition to be treated, the patient's overall health, the route and dosage of administration, and the severity of side effects. An effective amount can be the maximum dose or dosage regimen that avoids significant side effects or toxic effects.

[0140] The terms "subject" and "patient" refer to mammals, particularly primates, and especially humans. DETAILED DESCRIPTION

[0141] The present disclosure is further described below with reference to the following examples, but these examples are not intended to limit the scope of the present disclosure. Experimental methods in the examples herein where specific conditions are not specified generally follow conventional conditions, such as those in the Cold Spring Harbor Laboratory's "Antibody Techniques Laboratory Manual" and "Molecular Cloning Manual," or according to the conditions recommended by the raw material or product manufacturer. Reagents where the specific source is not specified are commercially available.

[0142] Example 1. Preparation of anti-ANGPTL3 antibodies

[0143] The anti-ANGPTL3 antibody, prepared according to the method described in WO2023001228, is designated P8BG antibody. The heavy and light chain sequences of the anti-ANGPTL3 antibody are shown in SEQ ID NOs: 9 and 10 in this disclosure. The dosage form is an injection solution with the following specifications: 1.5 mL: 150 mg, 2 mL: 0.3 g, and 2 mL: 0.3 g.

[0144] >P8BG heavy chain sequence:

[0145] >P8BG light chain sequence:

[0146] Example 2. Efficacy and safety of multiple subcutaneous injections of ANGPTL3 injection combined with lipid-lowering drugs in the stable treatment of patients with hyperlipidemia with poor blood lipid control

[0147] 1. Trial Drug

[0148] 1) The anti-ANGPTL3 antibody prepared in Example 1.

[0149] 2) The placebo injection is exactly the same as the anti-ANGPTL3 antibody injection in color and transparency.

[0150] 2. Enrollment of subjects

[0151] 1) Fasting LDL-C at screening meets the following conditions (Table 2):

[0152] 2) Fasting triglyceride ≤5.6mmol / L;

[0153] *Moderate-strength statins (daily dose): atorvastatin 10-20 mg; rosuvastatin 5-10 mg; fluvastatin 80 mg; lovastatin 40 mg; pitavastatin 2-4 mg; pravastatin 40 mg; simvastatin 20-40 mg; Xuezhikang 1.2 g.

[0154] 3. Experimental Plan

[0155] This study is divided into five phases, including screening phase, lead-in phase, treatment phase (core treatment phase, extended treatment phase), and safety follow-up phase.

[0156] I. Introduction period:

[0157] During the run-in period, the subjects adjusted their low-fat diet, lifestyle, and background lipid-lowering drug treatment and achieved a stable state for ≥4 weeks. At the end of the run-in period, the compliance and randomization / exclusion criteria were assessed.

[0158] Background lipid-lowering therapy refers to taking statins of the type and dose specified in this study, with or without other lipid-lowering drugs, as detailed below:

[0159] (1) The statin and dosage specified in this study: atorvastatin calcium tablets 10 mg daily or above, or rosuvastatin 5 mg daily or above; the type and dosage of medication will be determined by the researcher based on the subject's condition;

[0160] (2) The non-statin lipid-lowering drugs allowed for use in this study are cholesterol absorption inhibitors (such as ezetimibe) and PCSK9 inhibitors (such as alirocumab and evolocumab). If the subjects are currently using the above lipid-lowering drugs at the time of screening, they may continue to use or stop using them under the guidance of the researchers. If they continue to use them, the type and dosage must be kept stable from the lead-in period to the end of the extended treatment period.

[0161] (3) The types and doses of lipid-lowering drugs allowed for use in this study must be adjusted to a stable state during the lead-in period and maintained unchanged for ≥4 weeks (for PCSK9 inhibitors, ≥8 weeks are required).

[0162] II. Dosage regimen during treatment period:

[0163] Experimental group:

[0164] Anti-ANGPTL3 antibody, 150 mg Q4W, subcutaneous injection;

[0165] Anti-ANGPTL3 antibody, 300 mg Q4W, subcutaneous injection;

[0166] Anti-ANGPTL3 antibody, 600 mg Q4W, subcutaneous injection;

[0167] Anti-ANGPTL3 antibody, 600 mg every 8 weeks, subcutaneous injection.

[0168] Control group:

[0169] Placebo 150 mg Q4W, subcutaneous injection;

[0170] Placebo 300 mg Q4W, subcutaneous injection;

[0171] Placebo 600 mg Q4W, subcutaneous injection;

[0172] Placebo 600 mg Q8W, subcutaneous injection.

[0173] 4. Results Evaluation

[0174] 4.1 Patient Baseline Characteristics

[0175] Between November 24, 2023, and April 17, 2024, a total of 335 patients were randomized. Of these, 333 patients received at least one treatment (anti-ANGPTL3 antibody, n=266; placebo, n=67) and were included in the efficacy and safety analyses. A total of 93.9% to 97.0% of patients in all groups completed the 16-week study.

[0176] At baseline, demographic and disease characteristics were generally balanced across the study groups (Table 3). In the study cohort, 99.1% of patients were receiving statins, 0.9% (n = 3) had missing data for unrelated reasons, 12.0% were receiving cholesterol absorption inhibitors, and 0.9% were receiving PCSK9 inhibitors.

[0177] Table 3. Baseline characteristics of patients

[0178] 4.2 Validity

[0179] After 16 weeks of treatment, the anti-ANGPTL3 antibody, at doses of 150 mg Q4W, 300 mg Q4W, 600 mg Q4W, and 600 mg Q8W, significantly reduced LDL-C levels compared with placebo. The least squares mean changes in LDL-C levels compared with placebo were -21.7 (95% CI: -28.5, -14.9), -27.3 (95% CI: -34.1, -20.4), -29.9 (95% CI: -36.7, -23.1), and -22.5 (95% CI: -29.3, -15.7), respectively (Table 4).

[0180] Compared with placebo, the anti-ANGPTL3 antibody further reduced LDL-C by the least squares mean absolute values ​​of -0.6 mmol / L (95% CI: -0.8 to -0.4 mmol / L), -0.7 mmol / L (95% CI: -0.9 to -0.6 mmol / L), -0.9 mmol / L (95% CI: -1.0 to -0.7 mmol / L), and -0.7 mmol / L (95% CI: -0.9 to -0.5 mmol / L) for the 150 mg Q4W, 300 mg Q4W, 600 mg Q4W, and 600 mg Q8W doses, respectively (Table 4). By week 16, the LDL-C goal achievement rate in the anti-ANGPTL3 antibody group ranged from 59.1% to 71.2%, which was higher than the placebo group (30.8% to 31.2%), demonstrating the efficacy of the anti-ANGPTL3 antibody in lowering LDL-C levels. All anti-ANGPTL3 antibody groups showed a sustained upward trend in the percentage reduction in LDL-C levels from baseline with increasing dose and duration of treatment.

[0181] Table 4 also shows the results of other lipid parameters at week 16. At week 16, the anti-ANGPTL3 antibody significantly reduced the least squares mean percentages of TG (difference: -63.2% to -51.7%), non-HDL-C (difference: -34.5% to -26.8%), apolipoprotein B (ApoB) (difference: -19.2% to -13.5%), total cholesterol (TC) (difference: -32.6% to -25.7%), and apolipoprotein A1 (ApoA1) (difference: -36.2% to -29.1%) compared with the corresponding placebo group (P < 0.0001 for each comparison).

[0182] Table 4. Results of main and some secondary lipid parameters

[0183] 4.3 Security

[0184] During the 16-week treatment period, mean treatment adherence ranged from 97.0% to 97.8% in the anti-ANGPTL3 antibody group and 97.8% in the placebo group, while adherence ranged from 97.1% to 99.7% in the background statin group. Overall, 145 of 266 patients (54.5%) receiving the anti-ANGPTL3 antibody experienced at least one treatment-related adverse event (AE) during the 16-week period, compared with 29 of 67 patients (43.3%) receiving placebo. Treatment-related adverse events (TRAEs) occurred in 52 patients (19.5%) in the anti-ANGPTL3 antibody group and in 9 patients (13.4%) in the placebo group (Table 5). Most TRAEs were mild and occurred at similar rates across the different dosing regimens. No treatment-related deaths occurred during the study. The most common TRAEs were hyperuricemia (2.6% in the anti-ANGPTL3 antibody group and 3.0% in the placebo group), increased blood creatine kinase (0% in the anti-ANGPTL3 antibody group and 3.0% in the placebo group), and nausea (0.8% in the anti-ANGPTL3 antibody group and 3.0% in the placebo group).

[0185] Table 5. Adverse events (AEs)

[0186] Example 3. Evaluation of the efficacy and safety of multiple subcutaneous injections of anti-ANGPTL3 antibody injection in patients with poorly controlled hyperlipidemia - a multicenter, randomized, double-blind, placebo-controlled phase II clinical study

[0187] 1. Trial Drug

[0188] 1) The anti-ANGPTL3 antibody prepared in Example 1.

[0189] 2) The placebo injection is exactly the same as the anti-ANGPTL3 antibody injection in color and transparency.

[0190] 2. Enrollment of subjects

[0191] 1) Fasting LDL-C at screening meets the following conditions (Table 2):

[0192] 2) Fasting triglyceride ≤5.6mmol / L;

[0193] *Moderate-strength statins (daily dose): atorvastatin 10-20 mg; rosuvastatin 5-10 mg; fluvastatin 80 mg; lovastatin 40 mg; pitavastatin 2-4 mg; pravastatin 40 mg; simvastatin 20-40 mg; Xuezhikang 1.2 g.

[0194] 3. Experimental Plan

[0195] This study is divided into five phases, including screening phase, lead-in phase, treatment phase (core treatment phase, extended treatment phase), and safety follow-up phase.

[0196] I. Introduction Period

[0197] The run-in period lasts 4 to 8 weeks. The run-in period begins on the day of drug initiation. During the run-in period, participants undergo adjustments to their low-fat diet, lifestyle, and background lipid-lowering medications. After achieving a stable state for ≥ 4 weeks (e.g., 8 weeks for PCSK9 inhibitors), adherence and randomization / exclusion criteria will be assessed at the end of the run-in period.

[0198] Background lipid-lowering therapy refers to taking statins of the type and dose specified in this study, with or without other lipid-lowering drugs, as detailed below:

[0199] (1) The statin and dosage specified in this study: atorvastatin calcium tablets 10 mg daily or above, or rosuvastatin 5 mg daily or above; the type and dosage of medication will be determined by the researcher based on the subject's condition;

[0200] (2) If the subject is currently taking a statin other than that specified in this study at the time of screening, he / she should be switched to the statin treatment specified in this study under the guidance of the research physician and the dose should be adjusted until the dose meets the requirements of this study and the dose is maintained unchanged. This is considered the start of stable treatment;

[0201] (3) The non-statin lipid-lowering drugs allowed for use in this study are cholesterol absorption inhibitors (such as ezetimibe) and PCSK9 inhibitors (such as alirocumab and evolocumab). If the subjects are currently using the above lipid-lowering drugs at the time of screening, they may continue to use them under the guidance of the research physician (if using PCSK9 inhibitors, they cannot be discontinued). The type and dosage of these drugs must be kept stable from the lead-in period to the end of the treatment period.

[0202] II. Dosage regimen during treatment period:

[0203] Experimental group:

[0204] anti-ANGPTL3 antibody, 600 mg Q12W, subcutaneous injection;

[0205] Anti-ANGPTL3 antibody, 1200 mg every 12 weeks, subcutaneous injection.

[0206] Control group:

[0207] Placebo 600 mg Q12W, subcutaneous injection;

[0208] Placebo 1200 mg Q12W, subcutaneous injection.

[0209] 4. Safety and efficacy evaluation

[0210] Efficacy Evaluation: Blood samples were collected from subjects at planned visit times for efficacy evaluation. Levels of LDL-C, triglycerides, non-HDL-C, ApoB, Lp(a), TC, HDL-C, and ApoA1 were measured. The percentage change from baseline and the value of the change from baseline for each indicator were calculated and compared between the anti-ANGPTL3 antibody injection and placebo as specified in the protocol.

[0211] Safety evaluation: The incidence and severity of adverse events (AEs), adverse events of special interest (AESIs), and serious adverse events (SAEs) of the subjects throughout the study period were collected; vital signs, physical examinations, laboratory tests, 12-lead electrocardiograms, and other examinations were performed; the incidence and severity of injection site reactions were recorded, etc.

[0212] Example 4. Randomized, Double-Blind, Placebo-Controlled Phase I Study of Anti-ANGPTL3 Antibodies in Healthy Subjects

[0213] 1. Research objectives:

[0214] This Phase I single-dose study aims to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics and immunogenicity of the anti-ANGPTL3 antibody in healthy subjects.

[0215] 2. Research Methods

[0216] Six doses are planned for the study, including 100, 300, 450, 750, 900 (optional), and 1200 mg. Healthy subjects will be randomly assigned to receive a single subcutaneous injection of an anti-ANGPTL3 antibody or placebo. Subjects will be observed for seven days after dosing, with follow-up to day 148 for the 100 mg group and day 190 for the other dose groups. The primary endpoints are safety and tolerability.

[0217] 3. Research Results:

[0218] A total of 72 subjects were enrolled in six dose cohorts ranging from 100 mg to 1200 mg (anti-ANGPTL3 antibody, n=54; placebo, n=18). The anti-ANGPTL3 antibody was well tolerated at the doses tested. Treatment-emergent adverse events (TEAEs) were reported in 49 (90.7%) subjects in the anti-ANGPTL3 antibody group and 17 (94.4%) subjects in the placebo group. All TEAEs were mild or moderate in severity. There were no serious adverse events or TEAEs resulting in death. Serum concentrations of the anti-ANGPTL3 antibody generally increased with increasing doses. Maximum serum concentrations were reached 8.0 to 10.0 days after injection, with a mean t 1 / 2 The duration of follow-up ranged from 29.4 to 53.3 days. Exposure to the anti-ANGPTL3 antibody was slightly more than dose-proportional from 100 mg to 1200 mg. Serum LDL-C and triglyceride levels decreased significantly and rapidly across all anti-ANGPTL3 antibody dose groups, remaining below baseline in the high-dose group until the end of follow-up, while they remained above baseline in the placebo group for most of the follow-up visits. In the 750 mg to 1200 mg groups, the maximum reductions in low-density lipoprotein cholesterol (LDL-C) compared to baseline values ​​ranged from -46.5% to -49.1%, and the maximum reductions in total cholesterol (TG) ranged from -67.4% to -82.8%. At day 85, the high-dose groups maintained reductions in LDL-C of 36.9% to 39.0%, and in triglycerides of 59.9% to 79.1%. No anti-drug antibodies were detected in the anti-ANGPTL3 antibody-treated subjects.

[0219] 4. Results:

[0220] The anti-ANGPTL3 antibody was well tolerated and showed significant efficacy in healthy subjects.

Claims

1. Use of an anti-ANGPTL3 antibody or an antigen-binding fragment thereof in the preparation of a medicament for treating hyperlipidemia, wherein: The hyperlipidemia patients are at risk of atherosclerotic cardiovascular disease (ASCVD).

2. The use according to claim 1, wherein The hyperlipidemia patients are patients with moderate or higher ASCVD risk. Preferably, the patient is an ASCVD intermediate risk or higher hyperlipidemia patient whose LDL-C level is not at the target level after receiving lipid-lowering drug treatment, and more preferably, the patient is an ASCVD intermediate risk or higher hyperlipidemia patient who has received background lipid-lowering drug treatment for at least 4 weeks and whose LDL-C level is not at the target level.

3. The use according to claim 1 or 2, wherein The fasting LDL-C of the hyperlipidemia patient is selected from: LDL-C < 1.8 mmol / L, 1.8 ≤ LDL-C < 2.6, or LDL-C ≥ 2.6; and / or, the fasting triglyceride of the hyperlipidemia patient is ≤ 5.6 mmol / L.

4. The use according to any one of claims 1 to 3, wherein The hyperlipidemia patients meet the following criteria: (1) Received lipid-lowering drug treatment for at least 4 weeks and fasting LDL-C ≥ 1.4 mmol / L; (2) receiving lipid-lowering drug treatment for at least 4 weeks and fasting LDL-C ≥1.8 mmol / L; (3) Received lipid-lowering drug treatment for at least 4 weeks, with fasting LDL-C ≥ 2.6 mmol / L; or, (4) fasting LDL-C ≥ 2.6 mmol / L; Preferably, the lipid-lowering drug is selected from statins and / or non-statin drugs, preferably statins of moderate or higher strength.

5. The use according to any one of claims 1 to 4, wherein The anti-ANGPTL3 antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein: The heavy chain variable region comprises HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3, respectively; and The light chain variable region comprises LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6, respectively.

6. The method of any one of claims 1 to 5, wherein the anti-ANGPTL3 antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein: The heavy chain variable region comprises an amino acid sequence as shown in SEQ ID NO: 7 or at least 90% identical thereto, and the light chain variable region comprises an amino acid sequence as shown in SEQ ID NO: 8 or at least 90% identical thereto.

7. The method according to any one of claims 1 to 6, wherein: The anti-ANGPTL3 antibody or antigen-binding fragment thereof comprises a heavy chain and a light chain, wherein the heavy chain comprises an amino acid sequence as set forth in SEQ ID NO:9, or at least 90% identical thereto, and the light chain comprises an amino acid sequence as set forth in SEQ ID NO:10, or at least 90% identical thereto.

8. The method according to any one of claims 1 to 7, wherein: The anti-ANGPTL3 antibody or antigen-binding fragment thereof is administered by subcutaneous injection.

9. The use according to any one of claims 1 to 8, wherein The anti-ANGPTL3 antibody or antigen-binding fragment thereof is administered at a dosage of about 50 mg to about 1500 mg, about 50 mg to about 1000 mg, about 100 mg to about 1000 mg, or about 150 to about 600 mg; preferably, the anti-ANGPTL3 antibody or antigen-binding fragment thereof is administered at a dosage selected from the group consisting of: about 50 mg, about 150 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 800 mg, about 1000 mg, or about 1200 mg; The anti-ANGPTL3 antibody or antigen-binding fragment thereof is administered once a week, once every two weeks, once every four weeks, once every six weeks, once every eight weeks, once every ten weeks, or once every 12 weeks; preferably, once every four weeks or once every eight weeks. Preferably, the administration regimen of the anti-ANGPTL3 antibody or antigen-binding fragment thereof is selected from: The dosage is about 150 mg, and the frequency of administration is once every 4 weeks; The dosage is approximately 300 mg, and the frequency of administration is once every 4 weeks; The dosage is about 600 mg, and the frequency of administration is once every 4 weeks; The dosage is approximately 600 mg, and the frequency of administration is once every 8 weeks; The dosage is approximately 600 mg, administered once every 12 weeks; or The dosage is approximately 1200 mg, and the administration frequency is once every 12 weeks.

10. The use according to any one of claims 1 to 9, wherein the anti-ANGPTL3 antibody or antigen-binding fragment thereof in combination with a background lipid-lowering therapy; Preferably, the background lipid-lowering therapy drugs include statins and / or non-statin drugs, preferably include at least one of statins, cholesterol absorption inhibitors, and PCSK9 inhibitors.

11. The use according to any one of claims 1 to 10, wherein The anti-ANGPTL3 antibody or antigen-binding fragment thereof reduces at least one of the following indicators in patients with hyperlipidemia: Reduces plasma low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B (ApoB), lipoprotein (a) (Lp(a)), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C) and apolipoprotein A1 (ApoA1) in patients with hyperlipidemia.

12. Use of an anti-ANGPTL3 antibody or antigen-binding fragment thereof in combination with a background lipid-lowering therapy in the preparation of a medicament for treating patients with hyperlipidemia; Preferably, the anti-ANGPTL3 antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein: The heavy chain variable region comprises HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3, respectively; and, the light chain variable region comprises LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6, respectively; or, The heavy chain variable region comprises an amino acid sequence as shown in SEQ ID NO: 7 or at least 90% identical thereto, and the light chain variable region comprises an amino acid sequence as shown in SEQ ID NO: 8 or at least 90% identical thereto; or The anti-ANGPTL3 antibody or antigen-binding fragment thereof comprises a heavy chain and a light chain, wherein the heavy chain comprises an amino acid sequence as set forth in SEQ ID NO:9, or at least 90% identical thereto, and the light chain comprises an amino acid sequence as set forth in SEQ ID NO:10, or at least 90% identical thereto.

13. The use according to claim 12, wherein The background lipid-lowering therapy drugs include statins and / or non-statin drugs, preferably include at least one of statins, cholesterol absorption inhibitors, and PCSK9 inhibitors.

14. The use according to claim 12 or 13, wherein: The hyperlipidemia patient is selected from any one of the following: The hyperlipidemia patients are at risk for atherosclerotic cardiovascular disease (ASCVD); The hyperlipidemia patients are patients with moderate or higher ASCVD risk; Patients with hyperlipidemia at intermediate or higher risk of ASCVD whose LDL-C level has not reached the target level after receiving lipid-lowering drug treatment; Patients with hyperlipidemia at intermediate or higher risk of ASCVD who have received lipid-lowering drugs for at least 4 weeks and whose LDL-C levels have not reached the target.

15. The use according to any one of claims 12 to 14, wherein The fasting LDL-C of the hyperlipidemia patient is selected from: LDL-C < 1.8 mmol / L, 1.8 ≤ LDL-C < 2.6, or LDL-C ≥ 2.6; and / or, the fasting triglyceride of the hyperlipidemia patient is ≤ 5.6 mmol / L.

16. The use according to any one of claims 12 to 15, wherein The hyperlipidemia patients meet the following criteria: (1) Received lipid-lowering drug treatment for at least 4 weeks and fasting LDL-C ≥ 1.4 mmol / L; (2) receiving lipid-lowering drug treatment for at least 4 weeks and fasting LDL-C ≥1.8 mmol / L; (3) Received lipid-lowering drug treatment for at least 4 weeks, with fasting LDL-C ≥ 2.6 mmol / L; or, (4) fasting LDL-C ≥ 2.6 mmol / L; Preferably, the lipid-lowering drug is selected from statins and / or non-statin drugs, preferably statins of moderate or higher strength.

17. The use according to any one of claims 12 to 16, wherein: The anti-ANGPTL3 antibody or antigen-binding fragment thereof is administered at a dosage of about 50 mg to about 1500 mg, about 50 mg to about 1000 mg, about 100 mg to about 1000 mg, or about 150 to about 600 mg; preferably, the anti-ANGPTL3 antibody or antigen-binding fragment thereof is administered at a dosage selected from the group consisting of: about 50 mg, about 150 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 800 mg, about 1000 mg, or about 1200 mg; The anti-ANGPTL3 antibody or antigen-binding fragment thereof is administered once a week, once every two weeks, once every four weeks, once every six weeks, once every eight weeks, once every ten weeks, or once every 12 weeks; preferably, once every four weeks or once every eight weeks. Preferably, the administration regimen of the anti-ANGPTL3 antibody or antigen-binding fragment thereof is selected from: The dosage is about 150 mg, and the frequency of administration is once every 4 weeks; The dosage is approximately 300 mg, and the frequency of administration is once every 4 weeks; The dosage is about 600 mg, and the frequency of administration is once every 4 weeks; The dosage is approximately 600 mg, and the frequency of administration is once every 8 weeks; The dosage is approximately 600 mg, administered once every 12 weeks; or The dosage is approximately 1200 mg, and the administration frequency is once every 12 weeks.

18. A method for reducing plasma low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B (ApoB), lipoprotein (a) (Lp(a)), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C) and / or apolipoprotein A1 (ApoA1) levels in a patient with hyperlipidemia, comprising administering an anti-ANGPTL3 antibody or an antigen-binding fragment thereof to a subject in need thereof; in, The anti-ANGPTL3 antibody or antigen-binding fragment thereof is as defined in any one of claims 5 to 9; Preferably, the hyperlipidemia patient is preferably as defined in any one of claims 1 to 4; Preferably, the anti-ANGPTL3 antibody or antigen-binding fragment thereof is a drug for background lipid-lowering therapy; Preferably, the background lipid-lowering therapy drugs include statins and / or non-statin drugs, preferably include at least one of statins, cholesterol absorption inhibitors, and PCSK9 inhibitors.

19. A method for treating hyperlipidemia, wherein: The method comprises administering an anti-ANGPTL3 antibody or an antigen-binding fragment thereof to a subject in need thereof; wherein the hyperlipidemia patient is at risk for atherosclerotic cardiovascular disease (ASCVD); Wherein, the anti-ANGPTL3 antibody or antigen-binding fragment thereof is as defined in any one of claims 5 to 9; Preferably, the hyperlipidemia patient is preferably as defined in any one of claims 1 to 4; Preferably, the anti-ANGPTL3 antibody or antigen-binding fragment thereof is a drug for background lipid-lowering therapy; Preferably, the background lipid-lowering therapy drugs include statins and / or non-statin drugs, preferably include at least one of statins, cholesterol absorption inhibitors, and PCSK9 inhibitors.