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WO2019037067A1 - UTILISATION D'UN INHIBITEUR DE LA PROTÉINE-1β INFLAMMATOIRE DES MACROPHAGES (MIP-1β) DANS LE TRAITEMENT ET LA MAÎTRISE DE L'ATHÉROSCLÉROSE - Google Patents

UTILISATION D'UN INHIBITEUR DE LA PROTÉINE-1β INFLAMMATOIRE DES MACROPHAGES (MIP-1β) DANS LE TRAITEMENT ET LA MAÎTRISE DE L'ATHÉROSCLÉROSE Download PDF

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Publication number
WO2019037067A1
WO2019037067A1 PCT/CN2017/098977 CN2017098977W WO2019037067A1 WO 2019037067 A1 WO2019037067 A1 WO 2019037067A1 CN 2017098977 W CN2017098977 W CN 2017098977W WO 2019037067 A1 WO2019037067 A1 WO 2019037067A1
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Prior art keywords
macrophage inflammatory
inflammatory protein
mip
protein
inhibitor
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PCT/CN2017/098977
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English (en)
Chinese (zh)
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陈肇文
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法玛科技顾问股份有限公司
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Priority to PCT/CN2017/098977 priority Critical patent/WO2019037067A1/fr
Priority to US16/637,383 priority patent/US20200172609A1/en
Priority to PCT/US2018/046328 priority patent/WO2019033040A1/fr
Publication of WO2019037067A1 publication Critical patent/WO2019037067A1/fr

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    • 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
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to macrophage inflammatory protein-1 ⁇ (MIP-1 ⁇ ) inhibitors for regulating intravascular inflammatory response, reducing plaque area and thickening the thickness of plaque fibrous caps for treating and controlling atherosclerosis. use.
  • MIP-1 ⁇ macrophage inflammatory protein-1 ⁇
  • Atherosclerosis is a chronic inflammatory disease of the blood vessels. It is also a disease with high incidence and mortality in cardiovascular disease worldwide.
  • Low-density lipoprotein (LDL) is used in atherosclerosis.
  • An important factor in the formation process, low-density lipoprotein is highly susceptible to oxidative damage and thus forms oxidative LDL (oxLDL), which promotes mononuclear spheres when oxidized low-density lipoprotein is present in blood vessels.
  • lipids contained therein migrate to form a lipid core.
  • it is composed of Elastin and collagen.
  • the fibrous cap is placed around the lipid core to form an atherosclerotic plaque, which is the beginning of atherosclerosis; in addition, the oxidized low density
  • lipoproteins simultaneously change the permeability of the blood vessel wall, and promote leukocyte migration to the intima of the blood vessel, and repeatedly induce inflammation in the blood vessels, leading to endothelial function. Disorders, in turn, promote the development of atherosclerotic plaque, and more, will lead to complex vascular lesions; from the above, it can be known that the inflammatory response is closely related to the atherosclerosis and the deterioration of symptoms.
  • MIP-1 ⁇ macrophage inflammatory protein-1 ⁇
  • -1 ⁇ macrophage inflammatory protein-1 ⁇
  • these patients with higher concentrations of macrophage inflammatory protein-1 ⁇ have a higher risk of stroke and other cardiovascular diseases, suggesting that macrophage inflammatory protein-1 ⁇ may be a preventive And the treatment of cardiovascular related diseases.
  • the technical problem to be solved by the present invention is that most of the drugs currently used for treating cardiovascular related diseases are small molecule drugs, and most of them With serious side effects, the patient is uncomfortable, or the treatment is limited. In addition, most of the current cardiovascular-related diseases are only the area of atherosclerotic lesions, but can not slow the inflammatory response and stabilize the atherosclerotic lesions. Plaque.
  • the present invention attempts to reduce the inflammatory response of vascular tissue by regulating the action of inflammatory protein-1 ⁇ in macrophages in vivo, and to reduce the plaque of atherosclerotic lesions, thereby controlling atherosclerosis. Sclerosing lesions; in addition, it is also hoped to regulate blood fat by regulating the action of macrophage inflammatory protein-1 ⁇ in vivo, thereby supporting the treatment of cardiovascular diseases and the control of the disease.
  • the present invention finds that apolipoprotein E-knockout (apoE-KO) is used to establish an animal model of spontaneous atherosclerotic lesions, and the macrophage of the animal is inhibited by a single antibody.
  • apoE-KO apolipoprotein E-knockout
  • the effect of the cell inflammatory protein-1 ⁇ in order to achieve the effect of inhibiting the inflammatory response in the blood vessels, thus preventing the formation of atherosclerotic plaque, and avoiding the atherosclerosis caused by repeated inflammatory reactions after the formation of atherosclerotic plaques
  • the hardened plaque continues to grow.
  • the present invention can directly reduce the area of atherosclerotic plaque in blood vessels by inhibiting macrophage inflammatory protein-1 ⁇ in an animal to achieve a therapeutic effect, and can also thicken the atherosclerotic plaque around the atherosclerotic plaque. Fiber caps to reduce the rupture of atherosclerotic plaque to achieve stable plaque.
  • one aspect of the invention relates to the use of a macrophage inflammatory protein-1 beta inhibitor for the preparation of a pharmaceutical composition for the treatment and management of atherosclerosis, wherein said treating and controlling atherosclerosis It includes reducing the area of atherosclerotic lesions, stabilizing atherosclerotic lesions, slowing the inflammatory response and lowering blood fat.
  • the macrophage inflammatory protein-1 ⁇ inhibitor is a compound capable of reducing or inhibiting the biological activity of macrophage inflammatory protein-1 ⁇ .
  • the macrophage inflammatory protein-1 ⁇ inhibitor is a ligand compound having binding specificity for macrophage inflammatory protein-1 ⁇ , such as an anti-macrophage inflammatory protein- 1 ⁇ antibody or antagonist.
  • the anti-macrophage inflammatory protein-1 ⁇ antibody is a monoclonal antibody or a plurality of antibodies.
  • the anti-macrophage inflammatory protein-1 ⁇ antibody is a monoclonal antibody, or an antibody fragment thereof that binds to at least a peptide fragment of macrophage inflammatory protein-1 ⁇ .
  • the macrophage inflammatory protein-1 ⁇ peptide fragment comprises the amino acid sequence 46 SFVMDYYET 54 (SEQ ID NO: 1), or 62 AVVFLTKRGRQIC 74 (SEQ ID NO: 2) ).
  • the invention can achieve the following technical effects: the invention can directly reduce the area of the atherosclerotic plaque in the blood vessel by inhibiting the macrophage inflammatory protein-1 ⁇ in the animal to achieve the therapeutic effect, and can also thicken the atherosclerosis. A fibrous cap around the plaque to reduce the rupture of the atherosclerotic plaque to achieve stable plaque.
  • # P ⁇ 0.05 based sclerosis lesions compared to mice without antibody spontaneous atherosclerotic process.
  • # P ⁇ 0.05 compared to mice spontaneously sclerosis lesions of atherosclerotic without antibody treatment.
  • # P ⁇ 0.05 compared to a hardened atherosclerotic lesions in mice spontaneously without antibody treatment.
  • Macrophage Inflammatory protein-1 ⁇ -inhibitor (MIP-1 ⁇ -inhibitor) means that one can reduce the MIP-1 ⁇ protein content and/or decrease A compound of at least one activity of a MIP-1 ⁇ protein.
  • the MIP-1 ⁇ -inhibitor compound reduces at least one biological activity of the MIP-1 ⁇ protein by at least about 10%, 25%, 50%, 75% or more.
  • the MIP-1 ⁇ -inhibitor compound protects the pancreas and prevents elevated blood glucose by reducing the amount of MIP-1 ⁇ protein expression.
  • siRNA, antisense nucleic acid or ribozyme targeting MIP-1 ⁇ can be used to inhibit intracellular MIP-1 ⁇ gene expression.
  • the expression of the MIP-1 ⁇ protein can also be reduced by modulating the transcription of the gene encoding the MIP-1 ⁇ protein or by stabilizing the corresponding mRNA.
  • the MIP-1 ⁇ -inhibitor compound protects the pancreas and prevents or inhibits the biological activity of the MIP-1 ⁇ protein by binding to the MIP-1 ⁇ protein. Blood sugar rises.
  • an antibody against MIP-1 ⁇ can be used to compete with a MIP-1 ⁇ protein for binding to a receptor on the cell surface while inhibiting the biological activity of the MIP-1 ⁇ protein in vivo.
  • the antibodies may include full length monoclonal antibodies, polyclonal antibodies, multispecific antibodies (eg, bispecific antibodies), and antibody fragments.
  • antibody means an immunoglobulin molecule or a fragment thereof that has the ability to specifically bind to a particular antigen.
  • An “antibody fragment” comprises a portion of a full length antibody, preferably an antigen-binding region or variable region of an antibody.
  • antibody fragments include Fab, Fab', F(ab)2, F(ab')2, F(ab)3, Fv (representatively one of the one-armed VL and VH domains of the antibody), single-stranded Fv (scFv), dsFv, Fd fragments (representatively VH and CH1 domains) and dAb fragments (representatively VH domain); VH, VL and VhH domains; minibodies, dimers ( Diabodies), triabodies, tetrabodies, and kappa antibodies (see, Ill et al., Protein Eng 10:949-57, 1997); camel IgG; and one or more isolated CDRs from antibody fragments Or a multi-specific antibody fragment formed by a functional paratope in which the isolated or antigen-binding residues or polypeptides can bind or bind to each other to form a functional antibody fragment.
  • the MIP-1 ⁇ -inhibitor is a monoclonal antibody that specifically binds to a MIP-1 ⁇ protein.
  • the anti-MIP-1 ⁇ monoclonal antibody binds to a major functional site of the MIP-1 ⁇ protein structure.
  • the MIP-1 ⁇ -inhibitor eg, an anti-MIP-1 ⁇ monoclonal antibody
  • the MIP-1 ⁇ -inhibitor can be linked to an amino acid sequence comprising a MIP-1 ⁇ protein at positions 46-54: SSFMDYYET ( SEQ ID NO: 1), or the amino acid sequence of positions M62-74 of the MIP-1 ⁇ protein: epitope binding of AVVFLTKRGRQIC (SEQ ID NO: 2).
  • the antibody may be a humanized or fully humanized monoclonal antibody.
  • the pharmaceutical composition according to the invention may comprise at least one MIP-1 ⁇ -inhibitor and one or more physiologically acceptable carriers, diluents or excipients.
  • Appropriate pharmaceutical composition forms may be formulated according to the selected route of administration, including (but not limited to) oral preparations such as tablets, capsules, powders, etc., parenteral preparations such as subcutaneous, intramuscular or intraperitoneal injections. And a lyophilized powder combined with a physiological buffer solution before administration.
  • the present invention is directed to the blood vessels from MIP-1 ⁇ -inhibitors.
  • the effect of the internal inflammatory response was explored, and the subsequent effects of MIP-1 ⁇ -inhibitors on established atherosclerotic plaques were further confirmed. Finally, it was further confirmed whether the MIP-1 ⁇ -inhibitor can regulate the amount of fat in the blood vessels.
  • MIP-1 ⁇ -inhibitors can modulate spontaneous atherosclerotic lesions (apolipoprotein E-knockout (ApoE-KO) with apolipoprotein E gene knockout) Inflammatory response of vascular tissue
  • mice After 5 weeks old male apopopoprotein E-knockout (ApoE-KO) mice, they were divided into control group (immunoglobulin control group; IgG2a control) and low dose treatment group (1 ⁇ g anti-MIP-1 ⁇ monoclonal antibody; anti -MIP-1 ⁇ mAb) and high-dose treatment group (10 ⁇ g anti-MIP-1 ⁇ monoclonal antibody; anti-MIP-1 ⁇ mAb), starting MIP-1 ⁇ -inhibitor after feeding high fat diet (AIN-76A) for 7 weeks Injection of (anti-MIP-1 ⁇ mAb), three times a week for three weeks and another 5 weeks old Male C57BL/6 (B6) mice were used as control group (B6control), and B6 mice were fed with normal diet; each group of mice was banned before and after treatment with MIP-1 ⁇ -inhibitor and at week 2 and week 4 after treatment. After 5 hours of eating, the blood samples of the mice were collected separately, and the inflammatory response indicators Interleukin 6 (IL-6)
  • Fig. 1A and Fig. 1B The results of IL-6 and TNF- ⁇ quantification by Fig. 1A and Fig. 1B showed that mice treated with MIP-1 ⁇ -inhibitor and control group in the group of mice with spontaneous atherosclerotic lesion induced by ApoE-KO Compared with (IgG control), whether it is IL-6 or TNF- ⁇ , the amount of secretion in the blood before and after treatment with MIP-1 ⁇ -inhibitor showed a steady and no increase trend, and MIP-1 ⁇ -inhibitor treatment After ApoE-KO mice, the amount of IL-6 and TNF- ⁇ secreted in the blood was not different from that of the control group (B6control) (not shown); accordingly, by inhibiting macrophage inflammatory protein The action of -1 ⁇ can inhibit the inflammatory response of vascular tissue in mice with spontaneous atherosclerotic lesions.
  • MIP-1 ⁇ -inhibitor can reduce the plaque area of spontaneous atherosclerotic lesions
  • mice After 5 weeks of male apolopoprotein E-knockout (ApoE-KO) mice, they were divided into control group (IgG control), low-dose treatment group (1 ⁇ g anti-MIP-1 ⁇ mAb) and high-dose treatment group (10 ⁇ g anti-MIP).
  • control group IgG control
  • low-dose treatment group 1 ⁇ g anti-MIP-1 ⁇ mAb
  • high-dose treatment group 10 ⁇ g anti-MIP
  • MIP-1 ⁇ -inhibitor anti-MIP-1 ⁇ mAb
  • AIN-76A high-fat diet
  • MIP-1 ⁇ - After the treatment of the inhibitor, the aorta was isolated from the aortic head of the mouse to the end of the abdominal aorta, and the atherosclerotic plaque was analyzed by HE stain and Motic Images Plus 2.0. Block area.
  • Quantification of plaque area in Figure 2A showed that the plaque area of ApoE-KO-induced spontaneous atherosclerotic lesions was decreased compared with the control group (IgG control) after treatment with MIP-1 ⁇ -inhibitor.
  • the percentage change in plaque area in Figure 2B shows that the high-dose treatment group significantly reduced the plaque area (about 28%) compared with the control group, and the proportion of plaque area decreased with MIP-1 ⁇ -inhibition. The therapeutic dose was positively correlated.
  • Example 3 MIP-1 ⁇ -inhibitor can increase plaque fibrous cap thickness and reduce plaque necrosis area in spontaneous atherosclerotic lesions
  • aortic tissue of ApoE-KO-induced spontaneous atherosclerotic lesions was obtained by the experimental method described in Example 2, the aortic tissue was analyzed by collagen fiber staining (Elastica van Gieson) and image analysis software (Image J). Fiber cap thickness and necrotic areas in atherosclerotic plaques.
  • the thickness of the fibrous cap around the plaque can be increased, thereby reducing the risk of plaque rupture and simultaneously reducing atherosclerotic plaque.
  • the necrotic area has a stable effect on the lesion plaque on the vessel wall.
  • Example 4 MIP-1 ⁇ -inhibitor can reduce blood fat
  • mice The blood samples of the mice were obtained by the experimental method of the first embodiment, and the blood fat content indexes were analyzed: total cholesterol in the blood (T-CHO), triglyceride (TG), and non-high-density lipoprotein cholesterol (non-HDL). -C).
  • inhibition of macrophage inflammatory protein-1 ⁇ in the body can also reduce blood fat; in summary, based on the discussion of the above examples, by inhibiting the body giant The effect of phagocytic inflammatory protein-1 ⁇ can prevent the formation of atherosclerosis, treat atherosclerosis and slow the progression of atherosclerotic disease.

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Abstract

L'invention concerne un inhibiteur de la protéine-1β inflammatoire des macrophages (MIP-1β), utilisé à des fins de modulation de la réponse inflammatoire intravasculaire, de réduction de la surface des plaques d'athérosclérose et d'épaississement des capsules fibreuses des plaques pour le traitement et la maîtrise de l'athérosclérose.
PCT/CN2017/098977 2017-08-10 2017-08-25 UTILISATION D'UN INHIBITEUR DE LA PROTÉINE-1β INFLAMMATOIRE DES MACROPHAGES (MIP-1β) DANS LE TRAITEMENT ET LA MAÎTRISE DE L'ATHÉROSCLÉROSE WO2019037067A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
PCT/CN2017/098977 WO2019037067A1 (fr) 2017-08-25 2017-08-25 UTILISATION D'UN INHIBITEUR DE LA PROTÉINE-1β INFLAMMATOIRE DES MACROPHAGES (MIP-1β) DANS LE TRAITEMENT ET LA MAÎTRISE DE L'ATHÉROSCLÉROSE
US16/637,383 US20200172609A1 (en) 2017-08-10 2018-08-10 Method for preventing or treating atherosclerosis
PCT/US2018/046328 WO2019033040A1 (fr) 2017-08-10 2018-08-10 Méthode de prévention ou de traitement de l'athérosclérose

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/CN2017/098977 WO2019037067A1 (fr) 2017-08-25 2017-08-25 UTILISATION D'UN INHIBITEUR DE LA PROTÉINE-1β INFLAMMATOIRE DES MACROPHAGES (MIP-1β) DANS LE TRAITEMENT ET LA MAÎTRISE DE L'ATHÉROSCLÉROSE

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102782148A (zh) * 2009-08-28 2012-11-14 Vlst公司 与多种cc趋化因子结合的抗因子抗体
WO2016062282A1 (fr) * 2014-10-24 2016-04-28 法玛科技顾问股份有限公司 Utilisation de l'inhibiteur de la protéine inflammatoire des macrophages 1β (mip-1β) pour protéger le pancréas et empêcher l'augmentation de la glycémie

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102782148A (zh) * 2009-08-28 2012-11-14 Vlst公司 与多种cc趋化因子结合的抗因子抗体
WO2016062282A1 (fr) * 2014-10-24 2016-04-28 法玛科技顾问股份有限公司 Utilisation de l'inhibiteur de la protéine inflammatoire des macrophages 1β (mip-1β) pour protéger le pancréas et empêcher l'augmentation de la glycémie
WO2016062280A1 (fr) * 2014-10-24 2016-04-28 法玛科技顾问股份有限公司 Utilisation d'inhibiteur de la protéine inflammatoire des macrophages 1β (mip-1β) pour améliorer l'ischémie tissulaire et la vasculopathie diabétique en favorisant l'angiogenèse

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
BRAUNERSREUTHER V. ET AL.: "The specific role of chemokines in atherosclerosis", THROMB. HAEMOST., vol. 97, 4 April 2007 (2007-04-04), pages 714 - 721 *
MENG, XIN ET AL.: "Expression and Distribution of Macrophage Inflammatory Protein-1 a in Atherosclerotic Tunica Intima of Artery From Type 2 Diabetics", CHINESE JOURNAL OF ARTERIAL LEROSIS, vol. 15, no. 20, 31 October 2005 (2005-10-31), pages 3057 - 3060, 3064 *
ZHANG, XIN ET AL.: "Effects of Sappan Lignum Ethylacetate Extracts in MCP-1 0 Expression of Atherosclerotic Rats", INFORMATION ON TRADITIONAL CHINESE MEDICINE, vol. 30, no. 4, 31 December 2013 (2013-12-31), pages 22 - 24 *

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