Aptamer BB-031 and methods of using thereof

Abstract

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

Description

[0001] APTAMER BB-031 AND METHODS OF USING THEREOF

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims priority to, and the benefit of, U.S. Provisional Application No. 63 / 542,836 filed on October 6, 2023, and U.S. Provisional Application No. 63 / 641,142 filed on May 1, 2024, the disclosures of which are hereby expressly incorporated by reference herein in their entirety.

[0004] REFERENCE TO SEQUENCE LISTING

[0005] The sequence listing submitted on October 4, 2024, as an .XML file entitled “103361- 604WOl_ST26” created on October 4, 2024, and having a file size of 17,972 bytes is hereby incorporated by reference pursuant to 37 C.F.R. § 1.52(e)(5).

[0006] BACKGROUND

[0007] Patients suffer from venous thrombosis and inflammation. Every year, approximately 1 to 3 in every 1 ,000 adults in the United States develop venous thrombosis or pulmonary embolism. Up to 300,000 people die each year as a result of venous thrombosis / pulmonary embolism. It is the third most common vascular disease, behind heart attacks and strokes. It can occur at any age but is more common in those over 60 years old. There is a need to treat and prevent venous thrombosis in subjects.

[0008] Disclosed herein are compositions and methods that address these and other needs.

[0009] SUMMARY

[0010] In accordance with the purposes of the disclosed materials and methods, as embodied and broadly described herein, the disclosed subject matter, in one aspect, relates to aptamers and methods of using thereof.

[0011] Thus, in one example, a method of treating venous thrombosis in a subject in need thereof is provided, comprising administering a therapeutically effective amount of BB-031 to the subject.

[0012] In a further example, a method of reducing risk of venous thrombosis in a subject in need thereof is provided, comprising administering a therapeutically effective amount of BB-031 to the subject.

[0013] Aptamer BB-031 prophylactic and thrombolytic applications were applied to decrease inflammation and venous thrombosis.

[0014] Additional advantages will be set forth in part in the description that follows, and in part will be obvious from the description, or may be learned by practice of the aspects described below. The advantages described below will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive.

[0015] BRIEF DESCRIPTION OF THE FIGURES

[0016] FIG. 1 shows MMP-9 concentration at sacrifice.MMP-9 is an inflammatory marker. Increased MMP-9 levels correlated with increased risk of intracranial hemorrhage in patients receiving rTPA. BB-031 treated dogs had decreased MMP-9 levels compared to saline control treated animals.

[0017] FIG. 2 shows heart rate in beats per minute.

[0018] FIGS. 3A-3D show data demonstrating that aged males and females have different baseline times to occlusion. FIG. 3A shows data for aged males vs. young males. FIG. 3B shows data for young females vs. young males. FIG. 3C shows data for aged female vs. young female. FIG. 3D shows data for aged female vs. aged male.

[0019] FIGS. 4A-4B show that BB-031 demonstrates significantly longer times to occlusion compared to other treatments. FIG. 4A shows the results of female prophylactic treatment. FIG. 4B shows the results of male prophylactic treatment.

[0020] FIGS. 5 A-5B show that BB-31 prevents clot formation and subsequent occlusion when used as a prophylactic. FIG. 5A shows the data corresponding to male prophylactic treatment. FIG. 5B shows the data corresponding to female prophylactic treatment.

[0021] FIGS. 6A-6B show that BB-031 facilitates reperfusion following occlusion comparable to rTPA and heparin in both wild-type and obese mice. FIG. 6A shows the data pertaining to murine venous thrombosis. FIG. 6B shows data pertaining to male murine venous thrombosis (DlO+wild- type).

[0022] FIGS. 7A-7B show BB-031 is especially effective in females. FIG. 7A shows the data relating to male murine venous thrombosis. FIG. 7B shows data relating to female murine venous thrombosis.

[0023] FIG. 8 shows that BB-031 is especially effective in obese mice. More specifically, the data relates to the murine venous thrombosis diet-induced obese mice.

[0024] FIG. 9 shows that BB-031 is especially effective in obese mice, and rTPA is less effective in obese mice. More specifically, the data relates to male murine venous thrombosis.

[0025] FIG. 10 shows Von Willebrand levels at sacrifice. More specifically, the data relates to the VWF concentration at sacrifice. FIG. 11 shows Von Willebrand factors did not differ by sex. More specifically, the data relates to VWF concentration at sacrifice.

[0026] FIG. 12 shows Von Willebrand factor levels at sacrifice in obese mice.

[0027] DETAILED DESCRIPTION

[0028] The following description of the disclosure is provided as an enabling teaching of the disclosure in its best, currently known embodiments. Many modifications and other embodiments disclosed herein will come to mind to one skilled in the art to which the disclosed compositions and methods pertain having the benefit of the teachings presented in the foregoing descriptions and the associated drawings. Therefore, it is to be understood that the disclosures are not to be limited to the specific embodiments disclosed and that modifications and other embodiments are intended to be included within the scope of the appended claims. The skilled artisan will recognize many variants and adaptations of the aspects described herein. These variants and adaptations are intended to be included in the teachings of this disclosure and to be encompassed by the claims herein.

[0029] Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation.

[0030] As can be apparent to those of skill in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has discrete components and features which may be readily separated from or combined with the features of any of the other several embodiments without departing from the scope or spirit of the present disclosure.

[0031] Any recited method can be carried out in the order of events recited or in any other order that is logically possible. That is, unless otherwise expressly stated, it is in no way intended that any method or aspect set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not specifically state in the claims or descriptions that the steps are to be limited to a specific order, it is no way intended that an order be inferred, in any respect. This holds for any possible non-express basis for interpretation, including matters of logic with respect to arrangement of steps or operational flow, plain meaning derived from grammatical organization or punctuation, or the number or type of aspects described in the specification.

[0032] All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and / or materials in connection with which the publications are cited. The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided herein can be different from the actual publication dates, which can require independent confirmation.

[0033] It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting. Unless defined otherwise, 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 belong. It can be further understood that terms, such as those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the specification and relevant art and should not be interpreted in an idealized or overly formal sense unless expressly defined herein.

[0034] Prior to describing the various aspects of the present disclosure, the following definitions are provided and should be used unless otherwise indicated. Additional terms may be defined elsewhere in the present disclosure.

[0035] Definitions

[0036] As used herein, “comprising” is to be interpreted as specifying the presence of the stated features, integers, steps, or components as referred to, but does not preclude the presence or addition of one or more features, integers, steps, or components, or groups thereof. Moreover, each of the terms “by”, “comprising,” “comprises”, “comprised of,” “including,” “includes,” “included,” “involving,” “involves,” “involved,” and “such as” are used in their open, non-limiting sense and may be used interchangeably. Further, the term “comprising” is intended to include examples and aspects encompassed by the terms “consisting essentially of’ and “consisting of.” Similarly, the term “consisting essentially of’ is intended to include examples encompassed by the term “consisting of.”

[0037] As used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a compound”, “a composition”, or “a disorder”, includes, but is not limited to, two or more such compounds, compositions, or disorders, and the like.

[0038] It should be noted that ratios, concentrations, amounts, and other numerical data can be expressed herein in a range format. It can be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. It is also understood that there are a number of values disclosed herein, and that each value is also herein disclosed as “about” that particular value in addition to the value itself. For example, if the value “10” is disclosed, then “about 10” is also disclosed. Ranges can be expressed herein as from “about” one particular value, and / or to “about” another particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” it can be understood that the particular value forms a further aspect. For example, if the value “about 10” is disclosed, then “10” is also disclosed.

[0039] When a range is expressed, a further aspect includes from the one particular value and / or to the other particular value. For example, where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure, e.g., the phrase “x to y” includes the range from ‘x’ to ‘y’ as well as the range greater than ‘x’ and less than ‘y’. The range can also be expressed as an upper limit, e.g., ‘about x, y, z, or less’ and should be interpreted to include the specific ranges of ‘about x’, ‘about y’, and ‘about z’ as well as the ranges of ‘less than x’, less than y’, and Tess thanz’. Likewise, the phrase ‘about x, y, z, or greater’ should be interpreted to include the specific ranges of ‘about x’, ‘about y’, and ‘about z’ as well as the ranges of ‘ greater than x ’ , greater than y ’ , and ‘ greater than z ’ . In addition, the phrase “about ‘x’ to ‘y’”, where ‘x’ and ‘y’ are numerical values, includes “about ‘x’ to about ‘y’”.

[0040] It is to be understood that such a range format is used for convenience and brevity, and thus, should be interpreted in a flexible manner to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or subranges encompassed within that range as if each numerical value and sub-range is explicitly recited. To illustrate, a numerical range of “about 0.1% to 5%” should be interpreted to include not only the explicitly recited values of about 0.1% to about 5%, but also include individual values (e.g., about 1%, about 2%, about 3%, and about 4%) and the sub-ranges (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 sub-ranges) within the indicated range.

[0041] As used herein, the terms “about,” “approximate,” “at or about,” and “substantially” mean that the amount or value in question can be the exact value or a value that provides equivalent results or effects as recited in the claims or taught herein. That is, it is understood that amounts, sizes, formulations, parameters, and other quantities and characteristics are not and need not be exact but may be approximate and / or larger or smaller, as desired, reflecting tolerances, conversion factors, rounding off, measurement error and the like, and other factors known to those of skill in the art such that equivalent results or effects are obtained. In some circumstances, the value that provides equivalent results or effects cannot be reasonably determined. In such cases, it is generally understood, as used herein, that “about” and “at or about” mean the nominal value indicated ±10% variation unless otherwise indicated or inferred. In general, an amount, size, formulation, parameter or other quantity or characteristic is “about,” “approximate,” or “at or about” whether or not expressly stated to be such. It is understood that where “about,” “approximate,” or “at or about” is used before a quantitative value, the parameter also includes the specific quantitative value itself, unless specifically stated otherwise. As used herein, the term “substantially free,” when used in the context of a composition or component of a composition that is substantially absent, is intended to refer to an amount that is then about 1 % by weight or less, e.g., 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 of the stated material, based on the total weight of the composition.

[0042] The term “subject” preferably refers to a human in need of treatment with an anti-cancer agent or treatment for any purpose, and more preferably a human in need of such a treatment to treat cancer, or a precancerous condition or lesion. However, the term “patient” can also refer to non-human animals, preferably mammals such as dogs, cats, horses, cows, pigs, sheep, and nonhuman primates, among others, which are in need of treatment with an anti-cancer agent or treatment.

[0043] By “reduce” or other forms of the word, such as “reducing” or “reduction,” is meant lowering of an event or characteristic (e.g. , tumor growth). It is understood that this is typically in relation to some standard or expected value, in other words it is relative, but that it is not always necessary for the standard or relative value to be referred to. For example, “reduces tumor growth” means reducing the rate of growth of a tumor relative to a standard or a control (e.g., an untreated tumor).

[0044] By “prevent” or other forms of the word, such as “preventing” or “prevention,” is meant to stop a particular event or characteristic, to stabilize or delay the development or progression of a particular event or characteristic, or to minimize the chances that a particular event or characteristic will occur. Prevent does not require comparison to a control as it is typically more absolute than, for example, reduce. As used herein, something could be reduced but not prevented, but something that is reduced could also be prevented. Likewise, something could be prevented but not reduced, but something that is prevented could also be reduced. It is understood that where reduce or prevent are used, unless specifically indicated otherwise, the use of the other word is also expressly disclosed. For example, the terms “prevent” or “suppress” can refer to a treatment that forestalls or slows the onset of a disease or condition or reduced the severity of the disease or condition. Thus, if a treatment can treat a disease in a subject having symptoms of the disease, it can also prevent or suppress that disease in a subject who has yet to suffer some or all of the symptoms.

[0045] The term “treatment” refers to the medical management of a patient with the intent to cure, ameliorate, stabilize, or prevent a disease, pathological condition, or disorder. This term includes active treatment, that is, treatment directed specifically toward the improvement of a disease, pathological condition, or disorder, and also includes causal treatment, that is, treatment directed toward removal of the cause of the associated disease, pathological condition, or disorder. In addition, this term includes palliative treatment, that is, treatment designed for the relief of symptoms rather than the curing of the disease, pathological condition, or disorder; preventative treatment, that is, treatment directed to minimizing or partially or completely inhibiting the development of the associated disease, pathological condition, or disorder; and supportive treatment, that is, treatment employed to supplement another specific therapy directed toward the improvement of the associated disease, pathological condition, or disorder.

[0046] The term “therapeutically effective” refers to the amount of the composition used is of sufficient quantity to ameliorate one or more causes or symptoms of a disease or disorder. Such amelioration only requires a reduction or alteration, not necessarily elimination.

[0047] The term “pharmaceutically acceptable” refers to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications commensurate with a reasonable benefit / risk ratio.

[0048] The term “carrier” means a compound, composition, substance, or structure that, when in combination with a compound or composition, aids or facilitates preparation, storage, administration, delivery, effectiveness, selectivity, or any other feature of the compound or composition for its intended use or purpose. For example, a carrier can be selected to minimize any degradation of the active ingredient and to minimize any adverse side effects in the subject.

[0049] Method

[0050] The present disclosure, in one aspect, provides for a method of treating venous thrombosis in a subject in need thereof comprising administering a therapeutically effective amount of BB- 031 to the subject.

[0051] BB-031 is an RNA aptamer that targets and inhibits Von Willebrand Factor, necessary for blood clot formation and attachment to blood vessel walls. It has shown efficacy in three mouse models and five canine models of vascular injury and stroke. Efficacy has been demonstrated in a venous model of vascular injury and decreased inflammation in a canine model of stroke. Herein, BB-031 is used to reduce inflammation and efficacy in venous thrombosis.

[0052] In further examples, BB-031 comprises a sequence 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%) identical to SEQ ID NO. 1. In certain examples, BB-031 comprises SEQ ID NO. 1.

[0053] Venous thrombosis, also referred to as deep vein thrombosis (DVT), occurs when a blood clot (thrombus) forms in one or more of the deep veins in the body, often in the legs. In some examples, the blood clots partially block blood flow through the vein. In further examples, the blood clots completely block blood flow through the vein. In certain examples, venous thrombosis happens in the lower leg, thigh, pelvis, or any combination thereof. In specific examples, 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 examples, venous thrombosis causes leg pain and / or swelling. In further examples, there are no noticeable symptoms.

[0054] Venous Thrombosis can be serious because blood clots in the veins can break loose at which point the clots can then travel through the bloodstream and get stuck in the lungs and / or block blood flow. In some examples, a blood clot in the legs develops in a subject if they do not move for a lengthy period of time. For example, this can occur when a subject does not move a lot when traveling a long distance, is on bed rest due to surgery, has an illness, or is in an accident.

[0055] In some examples, symptoms of venous thrombosis include leg swelling, leg pain, cramping or soreness that can start in the calf, a change in skin color on the leg - such as a red or purple, depending on the color of the skin, a feeling of warmth on the affected leg, or any combination thereof. In further examples, symptoms of venous thrombosis include pooling of blood, increased pressure within the veins, leg ulcers, also known as venous stasis ulcers, or any combination thereof.

[0056] In some examples, the venous thrombosis comprises 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.

[0057] In specific examples, the subject has a Von Willebrand factor (vWF) of 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 examples, the 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)..

[0058] In further examples, the BB-031 is administered with an anticoagulant, surgery, endovascular treatment, a thrombolytic, a filter, or any combination thereof.

[0059] In certain examples, the anticoagulant comprises direct factor Xa inhibitors, direct thrombin inhibitors, indirect factor Xa inhibitors, low molecular weight heparin, fibrinolytics, vitamin K antagonists, or any combination thereof.

[0060] In specific examples, the direct factor Xa inhibitor comprises apixaban, edoxaban, rivaroxaban, or any combination thereof.

[0061] In some examples, the direct thrombin inhibitor comprises dabigatran.

[0062] In further examples, the indirect factor Xa inhibitor comprises fondaparinux.

[0063] In certain examples, the low molecular weight heparin comprises dalteparin, enoxaparin, or any combination thereof.

[0064] In specific examples, the fibrinolytics comprise alteplase, unfractionated heparin, or any combination thereof.

[0065] In some examples, the vitamin K antagonist comprises warfarin.

[0066] In further examples, the thrombolytic comprises streptokinase, alteplase, reteplase, Tenecteplase, urokinase, prourokinase, anistreplase, or any combination thereof.

[0067] In certain examples, the surgery comprises a thrombolysis, a thrombectomy, or any combination thereof.

[0068] In specific examples, the filter comprises an inferior vena cava (I VC) filter.

[0069] In some examples, the BB-031 is administered for from 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).

[0070] In some examples, the BB-031 is administered in an amount of from 1.0 mg / kg to 10 mg / kg. In some examples, the BB-031 is administered in an amount of from 1.0 mg / kg to 5.0 mg / kg, or 5.0 mg / kg to 10 mg / kg. In further examples, the BB-031 is administered in an amount of from 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.

[0071] In further examples, the BB-031 is administered in an amount of from 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

[0072] 9.5 mg / kg.

[0073] In further examples, the BB-031 is administered in an amount of from 4 mg / kg to 6 mg / kg. In some examples, the BB-031 is administered in an amount of from 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. In further examples, the BB-031 is administered in an amount of from 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.

[0074] In certain examples, the BB-031 is administered in an amount of from 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

[0075] 5.5 mg / kg. In some examples, is administered in an amount of from 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.

[0076] In specific examples, the BB-031 is administered in an amount of 5 mg / kg.

[0077] Without being limited by theory, the mechanisms of treating and preventing venous thrombosis include those such as preventing clots, preventing clots from getting bigger, preventing clots from breaking loose and traveling to the lungs, and reducing the chance of another venous thrombosis.

[0078] In some examples, a method of reducing risk of venous thrombosis in a subject in need thereof comprising administering a therapeutically effective amount of BB-031 to the subject.

[0079] In further examples, the BB-031 is administered in an amount of from 0.1 mg / kg to 1.0 mg / kg. In some examples, the BB-031 is administered in an amount of 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,

[0080] 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.

[0081] In further examples, the BB-031 is administered in an amount of from 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, 0.1 mg / kg to 9.0 mg / kg, or 0.1 mg / kg to 9.5 mg / kg.

[0082] In specific examples, the BB-031 is administered in an amount of from 0.4 mg / kg to 0.6 mg / kg. In some examples, the BB-031 is administered in an amount of 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. In further examples, the BB-031 is administered in an amount of from 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.

[0083] In certain examples, the BB-031 is administered in an amount of from 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 examples, is administered in an amount of from 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.

[0084] A number of embodiments of the disclosure have been described. Nevertheless, it will be understood that various modifications may be made without departing from the spirit and scope of the invention. Accordingly, other embodiments are within the scope of the following claims.

[0085] PCT application PCT / US2017 / 052063 is incorporated herein by reference.

Claims

CLAIMSWhat is claimed is:

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

2. The method of claim 1, wherein venous thrombosis comprises 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 of any one of claims 1-2, wherein BB-031 comprises a sequence at least 60% identical to SEQ ID NO. 1.

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

5. The method of any one of claims 1-4, wherein the subject has a 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 of any one of claims 1-6, wherein the BB-031 is administered with an anticoagulant, surgery, endovascular treatment, a thrombolytic, a filter, or any combination thereof.

8. The method of claim 7, wherein the anticoagulant comprises direct factor Xa inhibitors, direct thrombin inhibitors, indirect factor Xa inhibitors, low molecular weight heparin, fibrinolytics, vitamin K antagonists, 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.

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

13. The method of claim 8, wherein the fibrinolytics comprise alteplase, unfractionated heparin, or any combination thereof.

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

15. The method of any one of claims 7-14, wherein the thrombolytic comprises streptokinase, alteplase, reteplase, Tenecteplase, urokinase, prourokinase, anistreplase, or any combination thereof.

16. The method of any one of claims 7-15, wherein surgery comprises a thrombolysis, a thrombectomy, or any combination thereof.

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

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

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

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