Aptamer BB-031 and methods of use thereof

Abstract

The present disclosure provides a method of treating venous thrombosis in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of BB-031.

Description

Cross-references to related applications

[0001] This application claims priority to and benefits from U.S. Provisional Application No. 63 / 542,836, filed October 6, 2023, and U.S. Provisional Application No. 63 / 641,142, filed May 1, 2024, the disclosures of which are hereby expressly incorporated herein by reference in their entirety.

[0002] References to sequence lists The sequence list, submitted on 4 October 2024, created on 4 October 2024 as a .XML file with the title “103361-604WO1_ST26” and with a file size of 17,972 bytes, is hereby incorporated by reference in accordance with 37 CFR § 1.52(e)(5). Background Technology

[0003] The patient suffers from venous thrombosis and inflammation. Each year, approximately 1 to 3 out of every 1,000 adults in the United States develop venous thrombosis or pulmonary embolism. Up to 300,000 people die each year from venous thrombosis / pulmonary embolism. It is the third most common vascular disease, after heart disease and stroke. It can occur at any age, but is more common in people over 60. There is a need for treatment and prevention of venous thrombosis in this patient.

[0004] This document discloses compositions and methods for meeting these and other requirements. Summary of the Invention

[0005] Depending on the purpose of the materials and methods disclosed, as embodied and broadly described herein, the disclosed subject matter relates in one respect to adaptors and their methods of use.

[0006] Therefore, in one instance, a method for treating venous thrombosis in a subject in need is provided, the method comprising administering a therapeutically effective amount of BB-031 to the subject.

[0007] In a further example, a method for reducing the risk of venous thrombosis in a subject in need is provided, the method comprising administering a therapeutically effective amount of BB-031 to the subject.

[0008] Aptamil BB-031 is used for prophylactic and thrombolytic purposes to reduce inflammation and venous thrombosis.

[0009] Further advantages will be set forth in part in the description which follows, and will be apparent in part from the description, or may be learned by practicing the aspects described below. The advantages described below will be realized and obtained by means of the elements and combinations particularly pointed out in the appended claims. It should be understood that the foregoing general description and the following detailed description are exemplary and illustrative only, and not restrictive. Attached Figure Description

[0010] Figure 1 The MMP-9 concentration at sacrifice is shown. MMP-9 is an inflammatory marker. In patients receiving rTPA, increased MMP-9 levels were associated with an increased risk of intracranial hemorrhage. Dogs treated with BB-031 had reduced MMP-9 levels compared to animals treated with saline.

[0011] Figure 2 The heart rate (in the number of heartbeats per minute) is shown.

[0012] Figures 3A to 3D The data presented demonstrates that older males and females have different baseline blocking times. Figure 3A Data on older males and younger males are shown. Figure 3B Data for young females and young males are shown. Figure 3C Data on older females and younger females are shown. Figure 3D Data for older females and older males are shown.

[0013] Figures 4A to 4B The results showed that BB-031 exhibited a significantly longer blockage time compared to other treatments. Figure 4A The results of preventative treatment in females are shown. Figure 4B The results of preventative treatment in males are shown.

[0014] Figures 5A to 5B It is shown that when used as a preventative agent, BB-31 prevents clot formation and subsequent blockage. Figure 5A Data corresponding to preventative treatment for males are shown. Figure 5B Data corresponding to preventive treatments for females are shown.

[0015] Figures 6A to 6B The study showed that BB-031 promoted reperfusion after obstruction in both wild-type and obese mice compared to rTPA and heparin. Figure 6A Data related to venous thrombosis in mice are presented. Figure 6B Data related to venous thrombosis in male mice (DIO+ wild type) are shown.

[0016] Figures 7A to 7B BB-031 was shown to be particularly effective in females. Figure 7AData related to venous thrombosis in male mice are shown. Figure 7B Data related to venous thrombosis in female mice are presented.

[0017] Figure 8 The study showed that BB-031 was particularly effective in obese mice. More specifically, the data pertain to venous thrombosis in diet-induced obese mice.

[0018] Figure 9 The study showed that BB-031 was particularly effective in obese mice, while rTPA was less effective. More specifically, this data was correlated with venous thrombosis in male mice.

[0019] Figure 10 The data shows the von Willebrand level at the time of sacrifice. More specifically, the data correlates with VWF concentration at the time of sacrifice.

[0020] Figure 11 The study showed that von Willebrand factor (VWF) does not vary by sex. More specifically, the data correlated with VWF concentration at the time of sacrifice.

[0021] Figure 12 The levels of von Willebrand factor in obese mice at the time of sacrifice are shown. Detailed Implementation

[0022] The following description of this disclosure is provided as a facilitating teaching in its best currently known embodiments. Many modifications and other embodiments disclosed herein will occur to those skilled in the art upon which the disclosed compositions and methods pertain, thanks to the teachings presented in the foregoing description and the associated drawings. Therefore, it should be understood that this disclosure is not limited to the specific embodiments disclosed, and that modifications and other embodiments are intended to be included within the scope of the appended claims. Those skilled in the art will recognize many variations and adaptive modifications to the aspects described herein. These variations and adaptive modifications are intended to be included in the teachings of this disclosure and are covered by the claims herein.

[0023] Although specific terms are used in this article, they are used only in a general and descriptive sense and not for limiting purposes.

[0024] Those skilled in the art will understand upon reading this disclosure that each individual embodiment described and illustrated herein has discrete components and features that can be readily separated from or combined with features of any of the other several embodiments without departing from the scope or spirit of this disclosure.

[0025] Any described method may be performed in the order of the described events or in any other logically possible order. That is, unless expressly stated otherwise, it is not intended to interpret any method or aspect set forth herein as requiring its steps to be performed in a particular order. Therefore, where a method claim does not specifically state in the claims or specification that the steps are limited to a particular order, no inference is ever made in any respect. This applies to any possible non-expressive basis for interpretation, including matters of logic concerning the arrangement of steps or the flow of operations, the general meaning derived from grammatical organization or punctuation, or the number or type of aspects described in the specification.

[0026] All disclosures mentioned herein are incorporated herein by reference to disclose and describe methods and / or materials relating to the listed disclosures. The publications discussed herein are provided only for informational purposes prior to the filing date of this application. Nothing herein should be construed as an admission that the invention is not entitled to any prior art prior to such disclosure. Furthermore, the dates of the publications provided herein may differ from the actual publication dates, which may require independent verification.

[0027] It should also be understood that the terminology used herein is for descriptive purposes only and is not intended to be restrictive. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the disclosed compositions and methods pertain. It can be further understood that terms (such as those defined in common dictionaries) should be interpreted as having the meaning consistent with their meaning in the context of this specification and in the relevant field, and should not be interpreted in an idealized or overly formal sense unless expressly defined herein.

[0028] Before describing various aspects of this disclosure, the following definitions are provided and should be used unless otherwise indicated. Other terms may be defined elsewhere in this disclosure.

[0029] definition As used herein, “comprising” should be interpreted as specifying the presence of the referred feature, integer, step, or component, but does not preclude the presence or addition of one or more features, integers, steps, or components or groups thereof. Furthermore, each of the terms “through,” “comprising / comprise / comprised of,” “including / includes / included,” “involving / involves / involved,” and “such as” is used in its open, non-restrictive sense and may be used interchangeably. Further, the term “comprising” is intended to include instances and aspects covered by the terms “substantially constitutes” and “consistent with.” Similarly, the term “substantially constitutes” is intended to include instances covered by the term “consistent with.”

[0030] As used in the specification and appended claims, the singular forms “a,” “an,” and “the” include plural indicators unless the context clearly specifies otherwise. Thus, by way of example, references to “compound,” “composition,” or “symptom” include, but are not limited to, two or more such compounds, compositions, or symptoms.

[0031] It should be understood that ratios, concentrations, amounts, and other numerical data may be expressed in ranges herein. It can be further understood that each endpoint of a range is meaningful both relative to and independent of another endpoint. It should also be understood that many values ​​are disclosed herein, and in addition to the value itself, each value is disclosed as “about” that particular value. For example, if the value “10” is disclosed, then “about 10” is also disclosed. In this document, a range may be expressed as from “about” one particular value and / or to “about” another particular value. Similarly, when a value is expressed as an approximation, it can be understood that the particular value forms a further aspect by using the antecedent “about”. For example, if the value “about 10” is disclosed, then “10” is also disclosed.

[0032] When a range is expressed, a further aspect includes from one specific value and / or to another specific value. For example, when the range includes one or two limits, the range excluding any one or two of the included limits is also included within this disclosure; for example, the phrase “x to y” includes a range from 'x' to 'y', as well as ranges greater than 'x' and less than 'y'. A range can also be expressed as an upper limit, such as 'about x, y, z or less', and should be interpreted as including a specific range of 'about x', 'about y', and 'about z', as well as a range of 'less than x', 'less than y', and 'less than z'. Similarly, the phrase 'about x, y, z or greater' should be interpreted as including a specific range of 'about x', 'about y', and 'about z', as well as a range of 'greater than x', 'greater than y', and 'greater than z'. Additionally, the phrase “about 'x' to 'y'”, where 'x' and 'y' are numerical values, includes “about 'x' to about 'y'”.

[0033] It should be understood that this range format is used for convenience and brevity, and therefore should be interpreted flexibly to include not only the values ​​explicitly listed as range boundaries, but also all individual values ​​or subranges covered within that range, as if each value and subrange were explicitly listed. For example, the range “about 0.1% to 5%” should be interpreted to include not only the explicitly listed values ​​of about 0.1% to about 5%, but also individual values ​​(e.g., about 1%, about 2%, about 3%, and about 4%) and subranges (e.g., about 0.5% to about 1.1%; about 5% to about 2.4%; about 0.5% to about 3.2%, and about 0.5% to about 4.4%, and other possible subranges) within the specified range.

[0034] As used herein, the terms “about,” “approximately,” “equal to or about,” and “substantially” mean that the quantity or value in question may be an exact value or a value that provides an equivalent result or effect to that stated in the claims or taught herein. That is, it should be understood that quantities, dimensions, formulations, parameters, and other quantities and characteristics are not and need not be exact, but may be approximate and / or larger or smaller as required, reflecting tolerances, conversion factors, rounding, measurement errors, and other factors known to those skilled in the art, resulting in an equivalent result or effect. In some cases, it is not reasonable to determine a value that provides an equivalent result or effect. In such cases, it is generally understood that, as used herein, “about” and “equal to or about” mean a variation of ±10% of the indicated nominal value, unless otherwise indicated or inferred. Generally, quantities, dimensions, formulations, parameters, or other quantities or characteristics are “about,” “approximately,” or “equal to or about,” whether or not explicitly stated so. It should be understood that where “about,” “approximately,” or “equal to or about” is used before a quantitative value, unless otherwise specifically stated, the parameter also includes the specific quantitative value itself. As used herein, when used in the context of a composition or a component of a composition that is substantially non-existent, the term “substantially non-existent” is intended to refer to an amount of said material that is about 1% by weight or less based on the total weight of the composition, such as less than about 0.5% by weight, less than about 0.1% by weight, less than about 0.05% by weight, or less than about 0.01% by weight.

[0035] The term "subject" preferably refers to a person who needs to be treated with anticancer agents or treatments for any purpose, and more preferably a person who needs such treatment to treat cancer, or precancerous conditions or lesions. However, the term "patient" may also refer to a non-human animal that needs to be treated with anticancer agents or treatments, preferably a mammal, such as a dog, cat, horse, cow, pig, sheep, or non-human primate.

[0036] "Reduce" or other forms of the word, such as "reducing" or "reduction," means to reduce an event or characteristic. For example (Tumor growth). It should be understood that this is usually related to a standard or expected value; in other words, it is relative, but it is not always necessary to cite a standard or relative value. For example, "reducing tumor growth" means reducing the rate of tumor growth relative to a standard or control (e.g., untreated tumor).

[0037] The term "prevent" or other forms of the word such as "preventing" or "prevention" means to terminate a particular event or characteristic, stabilize or delay the development or progression of a particular event or characteristic, or minimize the chance of a particular event or characteristic occurring. Prevention does not require comparison with a control, as it is generally more absolute than, for example, reduction. As used herein, something can be reduced but not prevented, but something reduced can also be prevented. Similarly, something can be prevented but not reduced, but something prevented can also be reduced. It should be understood that, unless otherwise explicitly stated, the use of other terms is also explicitly disclosed in the context of reduction or prevention. For example, the terms "prevention" or "inhibition" can refer to treatment that prevents or slows the onset of a disease or condition or reduces the severity of a disease or condition. Thus, if a treatment can treat a disease in a subject with symptoms of the disease, it can also prevent or inhibit a disease in a subject who has not yet suffered some or all of the symptoms.

[0038] The term "treatment" refers to the medical management of a patient aimed at curing, improving, stabilizing, or preventing a disease, pathological condition, or symptom. This term includes active treatment, which is treatment specifically aimed at improving a disease, pathological condition, or symptom, and also includes etiological treatment, which is treatment aimed at eliminating the cause of the related disease, pathological condition, or symptom. Additionally, this term includes palliative treatment, which is treatment designed to relieve symptoms rather than cure a disease, pathological condition, or symptom; preventative treatment, which involves minimizing or partially or completely suppressing the development of a related disease, pathological condition, or symptom; and supportive treatment, which is treatment used to complement another specific therapy aimed at improving a related disease, pathological condition, or symptom.

[0039] The term "therapeuticly effective" means that the amount of the composition used is sufficient to improve one or more causes or symptoms of the disease or ailment. Such improvement requires only reduction or alteration, not elimination.

[0040] The term "pharmaceutically acceptable" refers to compounds, materials, compositions, and / or dosage forms that are suitable for use in contact with human and animal tissues without causing excessive toxicity, irritation, allergic reactions, or other problems or complications, within the bounds of reasonable medical judgment, and that are commensurate with a reasonable benefit / risk ratio.

[0041] The term "carrier" refers to a compound, composition, substance, or structure that, when combined with a compound or composition, helps or facilitates the preparation, storage, administration, delivery, effectiveness, selectivity, or any other characteristic of the compound or composition to achieve its intended use or purpose. For example, a carrier may be selected to minimize any degradation of the active ingredient and to minimize any adverse side effects on the subject.

[0042] method In one aspect, this disclosure provides a method for treating venous thrombosis in a subject of need, the method comprising administering a therapeutically effective amount of BB-031 to the subject.

[0043] BB-031 is an RNA aptamer that targets and inhibits von Willebrand factor, which is essential for blood clot formation and adhesion to the blood vessel wall. It has demonstrated efficacy in three mouse models and five canine models of vascular injury and stroke. Its efficacy has been confirmed in a venous model of vascular injury and in a canine model of stroke, reducing inflammation. In this paper, BB-031 is used to reduce inflammation and demonstrate its efficacy in venous thrombosis.

[0044] In a further example, BB-031 contains at least 60% (e.g., at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%) of the same sequence as SEQ ID NO.1.

[0045] In some instances, BB-031 contains SEQ ID NO.1.

[0046]

[0047] Venous thrombosis, also known as deep vein thrombosis (DVT), occurs when a blood clot (thrombus) forms in one or more deep veins in the body, typically in the leg. In some cases, the clot partially blocks blood flow through the vein. In further cases, the clot completely blocks blood flow through the vein. In some cases, venous thrombosis occurs in the calf, thigh, pelvis, or any combination thereof. In specific cases, venous thrombosis can occur in other parts of the body, such as, but not limited to, the arm, brain, intestines, liver, kidney, or any combination thereof. In some cases, venous thrombosis causes leg pain and / or swelling. In further cases, there are no obvious symptoms.

[0048] Venous thrombosis can be serious because a blood clot in a vein can become loose, potentially traveling across the bloodstream and lodging in the lungs, / or blocking blood flow. In some cases, a blood clot can develop in a subject's leg if the subject remains inactive for an extended period. This can happen, for example, when a subject hasn't moved much during a long trip, is bedridden due to surgery, is ill, or has been in an accident. In some cases, symptoms of deep vein thrombosis include leg swelling, leg pain, cramps or aches (which may begin in the calf), changes in leg skin color (such as red or purple, depending on skin color), a warm sensation in the affected leg, or any combination thereof. In further cases, symptoms of deep vein thrombosis include blood pooling, increased pressure within the veins, leg ulcers (also known as stasis ulcers), or any combination thereof.

[0049] In some instances, venous thrombosis includes deep vein thrombosis, portal vein thrombosis, renal vein thrombosis, jugular vein thrombosis, pulmonary embolism, femoral vein thrombosis, Paget-Schroetter syndrome, myocardial infarction, superior vena cava thrombosis, thrombotic stroke, cerebral venous sinus thrombosis, cavernous sinus thrombosis, retinal vein occlusion, May-Thurner syndrome, Budd-Chiari syndrome, or any combination thereof.

[0050] In specific instances, subjects had von Willebrand factor (vWF) at 2 ng / mL or less (e.g., 1.8 ng / mL or less, 1.6 ng / mL or less, 1.4 ng / mL or less, 1.2 ng / mL or less, 1 / 0 ng / mL or less, 0.8 ng / mL or less, 0.6 ng / mL or less, 0.4 ng / mL or less, or 0.2 ng / mL or less; 1.5 ng / mL or less, 1.0 ng / mL or less, or 0.5 ng / mL or less). In some instances, vWF is 1.5 ng / mL or less (e.g., 1.3 ng / mL or less, 1.1 ng / mL or less, 0.9 ng / mL or less, 0.7 ng / mL or less, 0.5 ng / mL or less, 0.3 ng / mL, 0.1 ng / mL or less).

[0051] In further instances, BB-031 is administered in combination with anticoagulants, surgery, endovascular therapy, thrombolytic agents, filters, or any combination thereof.

[0052] In some instances, anticoagulants include direct factor Xa inhibitors, direct thrombin inhibitors, indirect factor Xa inhibitors, low molecular weight heparin, fibrinolytic drugs, vitamin K antagonists, or any combination thereof.

[0053] In specific instances, direct factor Xa inhibitors include apixaban, edoxaban, rivaroxaban, or any combination thereof.

[0054] In some instances, direct thrombin inhibitors include dabigatran.

[0055] In a further example, indirect factor Xa inhibitors include fondaparinux sodium.

[0056] In some instances, low molecular weight heparin includes dalteparin sodium, enoxaparin sodium, or any combination thereof.

[0057] In specific instances, fibrinolytic drugs include alteplase, unfractionated heparin, or any combination thereof.

[0058] In some instances, vitamin K antagonists include warfarin.

[0059] In further examples, thrombolytic drugs include streptokinase, alteplase, reteplase, tenecteplase, urokinase, prourokinase, aniprase, or any combination thereof.

[0060] In some cases, the procedure includes thrombolytic therapy, thrombectomy, or any combination thereof.

[0061] In specific instances, filters include inferior vena cava (IVC) filters.

[0062] In some instances, BB-031 is administered for 3 to 12 months (e.g., 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months).

[0063] In some instances, BB-031 was administered at doses ranging from 1.0 mg / kg to 10 mg / kg. In other instances, BB-031 was administered at doses ranging from 1.0 mg / kg to 5.0 mg / kg or from 5.0 mg / kg to 10 mg / kg. In further examples, BB-031 is administered in doses of 1.0 mg / kg to 1.5 mg / kg, 1.5 mg / kg to 2.0 mg / kg, 2.0 mg / kg to 2.5 mg / kg, 2.5 mg / kg to 3.0 mg / kg, 3.0 mg / kg to 3.5 mg / kg, 3.5 mg / kg to 4.0 mg / kg, 4.0 to 4.5 mg / kg, 4.5 mg / kg to 5.0 mg / kg, 5.0 mg / kg to 5.5 mg / kg, 5.5 mg / kg to 6.0 mg / kg, 6.0 mg / kg to 6.5 mg / kg, 7.0 mg / kg to 7.5 mg / kg, 7.5 mg / kg to 8.0 mg / kg, 8.5 mg / kg to 9.0 mg / kg, 9.0 mg / kg to 9.5 mg / kg, or 9.5 mg / kg to 10.0 mg / kg.

[0064] In further examples, BB-031 is administered at dosages of 1.0 mg / kg to 1.5 mg / kg, 1.0 mg / kg to 2.0 mg / kg, 1.0 mg / kg to 2.5 mg / kg, 1.0 mg / kg to 3.0 mg / kg, 1.0 mg / kg to 3.5 mg / kg, 1.0 mg / kg to 4.0 mg / kg, 1.0 mg / kg to 4.5 mg / kg, 1.0 mg / kg to 5.0 mg / kg, 1.0 mg / kg to 5.5 mg / kg, 1.0 mg / kg to 6.0 mg / kg, 1.0 mg / kg to 6.5 mg / kg, 1.0 mg / kg to 7.0 mg / kg, 1.0 mg / kg to 7.5 mg / kg, 1.0 mg / kg to 8.0 mg / kg, 1.0 mg / kg to 8.5 mg / kg, 1.0 mg / kg to 9.0 mg / kg, or 1.0 mg / kg to 9.5 mg / kg. Administer at a dose of mg / kg.

[0065] In further examples, BB-031 is administered at doses of 4 mg / kg to 6 mg / kg. In some examples, BB-031 is administered at doses of 4 mg / kg to 4.2 mg / kg, 4.2 mg / kg to 4.4 mg / kg, 4.4 mg / kg to 4.6 mg / kg, 4.6 mg / kg to 4.8 mg / kg, 4.8 mg / kg to 5.0 mg / kg, 5.0 mg / kg to 5.2 mg / kg, 5.2 mg / kg to 5.4 mg / kg, 5.4 mg / kg to 5.6 mg / kg, 5.6 mg / kg to 5.8 mg / kg, or 5.8 mg / kg to 6.0 mg / kg. In further examples, BB-031 was administered at doses of 4.0 mg / kg to 4.4 mg / kg, 4.0 mg / kg to 4.6 mg / kg, 4.0 mg / kg to 4.8 mg / kg, 4.0 mg / kg to 5.0 mg / kg, 4.0 mg / kg to 5.2 mg / kg, 4.0 mg / kg to 5.4 mg / kg, 4.0 mg / kg to 5.6 mg / kg, or 4.0 mg / kg to 5.8 mg / kg.

[0066] In some instances, BB-031 was administered at doses of 4.5 mg / kg to 4.6 mg / kg, 4.6 mg / kg to 4.7 mg / kg, 4.8 mg / kg to 4.9 mg / kg, 4.9 mg / kg to 5.0 mg / kg, 5.0 mg / kg to 5.1 mg / kg, 5.1 mg / kg to 5.2 mg / kg, 5.2 mg / kg to 5.3 mg / kg, 5.3 mg / kg to 5.4 mg / kg, or 5.4 mg / kg to 5.5 mg / kg. In some instances, it was administered at doses of 4.5 mg / kg to 4.7 mg / kg, 4.5 mg / kg to 4.8 mg / kg, 4.5 mg / kg to 4.9 mg / kg, 4.5 mg / kg to 5.0 mg / kg, 4.5 mg / kg to 5.1 mg / kg, 4.5 mg / kg to 5.2 mg / kg, 4.5 mg / kg to 5.3 mg / kg, 4.5 mg / kg to 5.4 mg / kg, or 4.5 mg / kg to 5.5 mg / kg.

[0067] In a specific instance, BB-031 was administered at a dose of 5 mg / kg.

[0068] Unrestricted by theory, the mechanisms for treating and preventing venous thrombosis include those that prevent clots from forming, prevent clots from growing larger, prevent clots from breaking off and traveling to the lungs, and reduce the chance of another venous thrombosis forming.

[0069] In some instances, one method of reducing the risk of venous thrombosis in subjects in need involves administering a therapeutically effective dose of BB-031 to the subject.

[0070] In a further example, BB-031 was administered at doses ranging from 0.1 mg / kg to 1.0 mg / kg. In some instances, BB-031 is administered at dosages ranging from 0.1 mg / kg to 0.5 mg / kg, 0.5 mg / kg to 1.0 mg / kg, 1.0 mg / kg to 1.5 mg / kg, 1.5 mg / kg to 2.0 mg / kg, 2.0 mg / kg to 2.5 mg / kg, 2.5 mg / kg to 3.0 mg / kg, 3.0 mg / kg to 3.5 mg / kg, 3.5 mg / kg to 4.0 mg / kg, 4.0 to 4.5 mg / kg, 4.5 mg / kg to 5.0 mg / kg, 5.0 mg / kg to 5.5 mg / kg, 5.5 mg / kg to 6.0 mg / kg, 6.0 mg / kg to 6.5 mg / kg, 7.0 mg / kg to 7.5 mg / kg, 7.5 mg / kg to 8.0 mg / kg, 8.5 mg / kg to 9.0 mg / kg, and 9.0 mg / kg to 9.5 mg / kg. Administer at a dose of 9.5 mg / kg or 10.0 mg / kg.

[0071] In further examples, BB-031 is administered at dosages of 0.1 mg / kg to 1.0 mg / kg, 0.1 mg / kg to 1.5 mg / kg, 0.1 mg / kg to 2.0 mg / kg, 0.1 mg / kg to 2.5 mg / kg, 0.1 mg / kg to 3.0 mg / kg, 0.1 mg / kg to 3.5 mg / kg, 0.1 mg / kg to 4.0 mg / kg, 0.1 mg / kg to 4.5 mg / kg, 0.1 mg / kg to 5.0 mg / kg, 0.1 mg / kg to 5.5 mg / kg, 0.1 mg / kg to 6.0 mg / kg, 0.1 mg / kg to 6.5 mg / kg, 0.1 mg / kg to 7.0 mg / kg, 0.1 mg / kg to 7.5 mg / kg, 0.1 mg / kg to 8.0 mg / kg, 0.1 mg / kg to 8.5 mg / kg, and 0.1 mg / kg to 8.5 mg / kg. Administer at doses ranging from 0.1 mg / kg to 9.0 mg / kg or from 0.1 mg / kg to 9.5 mg / kg.

[0072] In specific instances, BB-031 is administered at doses ranging from 0.4 mg / kg to 0.6 mg / kg. In some instances, BB-031 is administered at doses ranging from 0.4 mg / kg to 0.42 mg / kg, 0.42 mg / kg to 0.44 mg / kg, 0.44 mg / kg to 0.46 mg / kg, 0.46 mg / kg to 0.48 mg / kg, 0.48 mg / kg to 0.50 mg / kg, 0.50 mg / kg to 0.52 mg / kg, 0.52 mg / kg to 0.54 mg / kg, 0.54 mg / kg to 0.56 mg / kg, 0.56 mg / kg to 0.58 mg / kg, or 0.58 mg / kg to 0.60 mg / kg. In further examples, BB-031 was administered in doses of 0.40 mg / kg to 0.44 mg / kg, 0.40 mg / kg to 0.46 mg / kg, 0.40 mg / kg to 0.48 mg / kg, 0.40 mg / kg to 0.50 mg / kg, 0.40 mg / kg to 0.52 mg / kg, 0.40 mg / kg to 0.54 mg / kg, 0.40 mg / kg to 0.56 mg / kg, or 0.40 mg / kg to 0.58 mg / kg.

[0073] In some instances, BB-031 was administered in doses of 0.45 mg / kg to 0.46 mg / kg, 0.46 mg / kg to 0.47 mg / kg, 0.48 mg / kg to 0.49 mg / kg, 0.49 mg / kg to 0.50 mg / kg, 0.50 mg / kg to 0.51 mg / kg, 0.51 mg / kg to 0.52 mg / kg, 0.52 mg / kg to 0.53 mg / kg, 0.53 mg / kg to 0.54 mg / kg, or 0.54 mg / kg to 0.55 mg / kg. In some instances, the dosage was applied at amounts of 0.45 mg / kg to 0.47 mg / kg, 0.45 mg / kg to 0.48 mg / kg, 0.45 mg / kg to 0.49 mg / kg, 0.45 mg / kg to 0.50 mg / kg, 0.45 mg / kg to 0.51 mg / kg, 0.45 mg / kg to 0.52 mg / kg, 0.45 mg / kg to 0.53 mg / kg, 0.45 mg / kg to 0.54 mg / kg, or 0.45 mg / kg to 0.55 mg / kg.

[0074] Several embodiments of this disclosure have been described. However, it should be understood that various modifications can be made without departing from the spirit and scope of the invention. Therefore, other embodiments are within the scope of the following claims.

[0075] PCT application PCT / US2017 / 052063 is incorporated herein by reference.

Claims

1. A method for treating venous thrombosis in a subject in need, the method comprising administering a therapeutically effective amount of BB-031 to the subject.

2. The method according to claim 1, wherein the venous thrombosis includes deep vein thrombosis, portal vein thrombosis, renal vein thrombosis, jugular vein thrombosis, pulmonary embolism, femoral vein thrombosis, Paget-Schroetter syndrome, myocardial infarction, superior vena cava thrombosis, thrombotic stroke, cerebral venous sinus thrombosis, cavernous sinus thrombosis, retinal vein occlusion, May-Thurner syndrome, Budd-Chiari syndrome, or any combination thereof.

3. The method according to any one of claims 1 to 2, wherein the BB-031 comprises at least 60% the same sequence as SEQ ID NO.

1.

4. The method according to any one of claims 1 to 2, wherein the BB-031 comprises SEQ ID NO.

1.

5. The method according to any one of claims 1 to 4, wherein the subject has von Willebrand factor (vWF) of 2 ng / mL or less.

6. The method of claim 5, wherein the vWF is 1.5 ng / mL or less.

7. The method according to any one of claims 1 to 6, wherein the BB-031 is administered together with an anticoagulant, surgery, endovascular therapy, thrombolytic drugs, a filter, or any combination thereof.

8. The method of claim 7, wherein the anticoagulant comprises a direct factor Xa inhibitor, a direct thrombin inhibitor, an indirect factor Xa inhibitor, low molecular weight heparin, a fibrinolytic agent, a vitamin K antagonist, or any combination thereof.

9. The method of claim 8, wherein the direct factor Xa inhibitor comprises apixaban, edoxaban, rivaroxaban, or any combination thereof.

10. The method of claim 8, wherein the direct thrombin inhibitor comprises dabigatran.

11. The method of claim 8, wherein the indirect factor Xa inhibitor comprises fondaparinux sodium.

12. The method of claim 8, wherein the low molecular weight heparin comprises dalteparin sodium, enoxaparin sodium, or any combination thereof.

13. The method of claim 8, wherein the fibrinolytic agent comprises alteplase, unfractionated heparin, or any combination thereof.

14. The method of claim 8, wherein the vitamin K antagonist comprises warfarin.

15. The method according to any one of claims 7 to 14, wherein the thrombolytic agent comprises streptokinase, alteplase, reteplase, tenecteplase, urokinase, prourokinase, aniprase, or any combination thereof.

16. The method according to any one of claims 7 to 15, wherein the procedure comprises thrombolytic therapy, thrombectomy, or any combination thereof.

17. The method according to any one of claims 7 to 16, wherein the filter comprises an inferior vena cava (IVC) filter.

18. The method according to any one of claims 7 to 17, wherein the BB-031 is applied for 3 to 12 months.

19. A method for reducing the risk of venous thrombosis in a subject in need, the method comprising administering a therapeutically effective amount of BB-031 to the subject.

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