Treatment of von willebrand disease

Abstract

Disclosed herein are methods of treating Von Willebrand Disease (VWD) in a subject in need. The methods include administering to the subject a therapeutically effective amount of a Protein S antibody, either subcutaneously or intravenously. The antibody may be administered using a body weight-based dosing regimen with one or more doses of about 0.1 mg / kg to about 10 mg / kg each, or a non-body weight-based dosing regimen with one or more doses of about 100 mg / dose to about 1000 mg / dose. The selected treatment methods result in an antibody plasma concentration of about 1μg / ml to about 200 μg / ml upon administration and increased thrombin generation and / or other pharmacodynamic biomarkers in the subject.

Description

TREATMENT OF VON WILLEBRAND DISEASECROSS REFERENCE TO RELATED APPLCATIONS

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 648,615, filed on May 16, 2024, to U.S. Provisional Patent Application No. 63 / 716,097, filed on November 4, 2024, and to U.S. Provisional Patent Application No. 63 / 800,343, filed on May 5, 2025, the contents of which are incorporated by reference herein in their entirety.REFERENCE TO AN ELECTRONIC SEQUENCE LISTING

[0002] The contents of the electronic sequence listing (VEGA_004_03WO_SeqList_ST26.xml; Size: 27,061 bytes; and Date of Creation: May 14, 2025) are herein incorporated by reference in its entirety.BACKGROUND

[0003] Von Willebrand Disease (VWD) is the most common inherited bleeding disorder with significant disease burden and unmet need. VWD may be characterized by deficient or defective von Willebrand factor (VWF) and can be associated with decreased Factor VIII (FVIII), which can lead to insufficient platelet adhesion and reduced thrombin generation. Patients with VWD can present with various bleed types, such as joint, mucocutaneous (GI, nose, gingival, heavy menstrual bleeding), and bleed types associated with surgery and trauma. Current VWD treatments have limitations in effectiveness and ease of use, and there is an unmet need for new therapeutic options. Disclosed herein are compositions and methods that address this need.SUMMARY

[0004] Disclosed herein are methods of treating Von Willebrand Disease (VWD) in a human subject in need thereof. In one aspect, the method comprises administering to the human subject a therapeutically effective amount of a Protein S antibody, where a plasma concentration of about Ipg / ml to about 200 pg / ml is reached upon administration of the antibody.

[0005] In another aspect, the method comprises administering to the human subject a therapeutically effective amount of a Protein S antibody using a body weight-based regimen,where the antibody is administered at one or more doses of about 0.1 mg / kg to about 10 mg / kg each. In yet another aspect, the method comprises administering to the human subject a therapeutically effective amount of a Protein S antibody using a non-body weight-based regimen, where the antibody is administered at one or more doses of about 100 mg / dose to about 1000 mg / dose each. The Protein S antibody is administered to the subject either intravenously or subcutaneously. In some embodiments the antibody comprises the complementarity determining region (CDR) sequences of SEQ ID NO: 4, an amino acid sequence of DAS, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, and SEQ ID NO: 9. In some embodiments the antibody comprises: a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 11 or an amino acid sequence with at least 80% sequence identity thereto; and a light chain variable region (VL) of the antibody comprising the amino acid sequence of SEQ ID NO: 10, or an amino acid sequence with at least 80% sequence identity thereto. In some embodiments the antibody comprises: a heavy chain comprising the amino acid sequence of SEQ ID NO: 12, or an amino acid sequence with at least 80% sequence identity thereto; and a light chain comprising the amino acid sequence of SEQ ID NO: 13, or an amino acid sequence with at least 80% sequence identity thereto. In some embodiments, the antibody comprises: a heavy chain encoded by the nucleic acid sequence of SEQ ID NO: 17, or a nucleic acid sequence with at least 80% sequence identity thereto; and a light chain encoded by the nucleic acid sequence of SEQ ID NO: 18, or a nucleic acid sequence with at least 80% sequence identity thereto. In some embodiments, the antibody is specific for a Thrombin Sensitive Region (TSR) domain and / or a Gia domain of Protein S.

[0006] In some embodiments, the antibody comprises a Fc domain. In some embodiments, the Fc domain exhibits a reduced FcRn binding. In some embodiments, the Fc domain exhibits a reduced effector function. In some embodiments, the Fc domain is engineered to increase the half-life of the antibody. In some embodiments, the Fc domain is selected from the group consisting of human IgGl, IgG2, IgG3, and IgG4. In some embodiments, the Fc domain of the antibody is a human IgG4, and comprises at least one amino acid substitution relative to SEQ ID NO: 3, wherein the position numbers of the amino acid residues are of the EU numbering scheme. In some embodiments, the Fc domain of the antibody is a human IgG4, and comprises substitutions S228P, L235E, M428L, and N434S, relative to SEQ ID NO: 3, wherein the position numbers of the amino acid residues are of the EU numbering scheme.

[0007] In some embodiments, the antibody is administered to the subject subcutaneously. In some embodiments, the antibody is administered to the subject intravenously. In some embodiments, the antibody is administered to the subject daily. In some embodiments, the antibody is administered to the subject once weekly. In some embodiments, the antibody is administered to the subject once about every two weeks. In some embodiments, the antibody is administered to the subject once every about three weeks. In some embodiments, the antibody is administered to the subject once about every four weeks. In some embodiments, the treatment comprises the administration of a plurality of doses. In some embodiments, the treatment comprises one or more loading doses. In some embodiments, the treatment comprises one or more loading doses and one or more maintenance doses. In some embodiments the loading dose is administered subcutaneously or intravenously. In some embodiments the one or more maintenance doses are administered subcutaneously or intravenously. In some embodiments, the route of administration may change from administration of the loading dose(s) and / or maintenance dose(s). In some embodiments, the first two doses administered are administered intravenously and the remaining doses are administered subcutaneously. In some embodiments, the loading dose is administered on Day 1 and one or more maintenance doses are administered on Day 8 followed by every 4 weeks. In some embodiments, a plasma concentration of about 1 pg / ml - 200 pg / ml is reached upon administration of the antibody. In some embodiments, the one or more doses is selected from the group consisting of: 150 mg / dose, 225mg / dose, 300 mg / dose, 450 mg / dose, 600 mg / dose, and 900 mg / dose. In some embodiments, the method comprises administering one or more doses having a concentration of at least about 0.1 mg / kg to about 1.0 mg / kg. In some embodiments, the method comprises one or more doses having a concentration of at least about 1.0 mg / kg to about 10.0 mg / kg.

[0008] In an exemplary embodiment a loading dose is administered on Day 1 and one or more maintenance doses are administered on Day 8 followed by every 4 weeks. In a further exemplary embodiment, a 225 mg / dose is administered subcutaneously on Day 1, Day 8, and every month thereafter.

[0009] In some embodiments, the VWD subtype is selected from the group consisting of: VWD type 1, VWD type 2A, VWD type 2B, VWD type 2M, VWD type 2N, and VWD type 3. In some embodiments, the method results in an increase in thrombin generation of at least 10% frombaseline. In some embodiments, the method results in an increase in D-dimer of at least 0.3 pg / ml. In some embodiments, the method results in an increase in Prothrombin Fl +2 of at least 10% from baseline. In some embodiments, the method results in a restoration of hemostasis. In some embodiments, the method reduces the frequency, duration, and / or severity of a bleed in the subject.

[0010] In some embodiments, the subject is an infant, about 29 days to about 23 months. In some embodiments, the subject is a child, about 2 years of age to about 12 years of age. In some embodiments, the subject is an adolescent, about 12 years of age to about 17 years of age. In some embodiments, the subject is an adult, ages at least 18 years. In some embodiments, the subject is a male. In some embodiments, the subject is a female. In some embodiments, the method results in a restoration of a normal menstrual bleed in the female subject.

[0011] In some embodiments, the subject is administered a therapeutically effect amount of the Protein S antibody for routine prophylaxis. In some embodiments, the subject is administered a therapeutically effect amount of Protein S antibody for on-demand prophylaxis. In some embodiments, the on-demand prophylaxis is for perioperative management of bleeding. In some embodiments, the on-demand prophylaxis is for management of an anticipated trauma.

[0012] In some embodiments, the subject is at risk of suffering from a bleed selected from the group consisting of intercranial hemorrhage, mouth bleeds, epistaxis, hematemesis, pulmonary hemorrhage, gastrointestinal bleeds, joint bleeds, muscle bleeds, hematomas, bruising, menorrhagia, and hematuria. In some embodiments, the antibody is administered as part of a pharmaceutical composition comprising the Protein S antibody and a pharmaceutically acceptable excipient or carrier. In some embodiments, the subject suffers from at least one additional bleeding disorder selected form the group consisting of hemophilia A, hemophilia B, menorrhagia including menorrhagia due to a congenital or acquired factor deficiency, Factor I deficiency, Factor II deficiency, Factor V deficiency, Factor VII deficiency, Factor X deficiency, Factor XI deficiency (hemophilia C), Factor VIII deficiency (hemophilia A), Factor IX deficiency (hemophilia B), trauma, and hereditary hemorrhagicBRIEF DESCRIPTION OF THE DRAWINGS

[0013] FIG. 1 depicts a schematic of the pathophysiology of the cell-based model of coagulation in a VWD subject.

[0014] FIG. 2 depicts a schematic of the pathophysiology of the cell-based model of coagulation in a VWD subject after administration of an exemplary Protein S antibody (e.g., VGA039) of the disclosure.

[0015] FIG. 3 demonstrates in vitro thrombin generation in plasma samples in the absence of added activated protein C (APC), in the presence of added APC, and in the presence of added APC with increasing concentrations of VGA039. The plasma samples were taken from human donors having either VWD type 1, VWD Type 2 A, VWD Type 2B, or VWD Type 3.

[0016] FIGS. 4A depicts mucosal bleed times over time in an experimentally induced, severe VWD Non-Human Primate (NHP) animal model either with or without administration of VGA039.

[0017] FIG. 4B depicts hemoglobin levels over time in an experimentally induced, severe VWD NHP animal model either with or without administration of VGA039.

[0018] FIG. 5 depicts a protocol design for a single ascending dose study using different routes of administration for delivery of VGA039 to human subjects.

[0019] FIG. 6A is a graph of mean drug concentrations of subjects in four different cohorts over time administered VGA039 using intravenous (IV) route of administration.

[0020] FIG. 6B is a graph of mean drug concentrations of subjects over time, in three different cohorts administered VGA039 using subcutaneous (SC) route of administration.

[0021] FIG. 7 is a graph of drug concentrations through 8 weeks post administration in a cohort of subjects administered 1 mg / kg SC VGA039 or a cohort of subjects administered 1 mg / kg IV VGA039.

[0022] FIG. 8 A is a graph of thrombin generation through 168 hours post administration in three cohorts of subjects administered SC VGA039.

[0023] FIG. 8B is a graph of mean D-dimer levels through 1344 hours post administration in three cohorts of subjects administered SC VGA039.

[0024] FIG. 8C is a graph of mean % change from baseline of Prothrombin Fl +2 through 1344 hours post administration in three cohorts of subjects administered SC VGA039.

[0025] FIG. 9A is a graph of mean VGA039 systemic concentrations over time for subjects administered 3.0 mg / kg, 4.5 mg / kg, and 7.0 mg / kg SC VGA039.

[0026] FIG. 9B is a graph of mean peak thrombin generation over time for subjects administered 3.0 mg / kg, 4.5 mg / kg, and 7.0 mg / kg VGA039 SC.

[0027] FIG. 9C is a graph of mean % change from baseline of Prothrombin Fl +2 over time for subjects administered 3.0 mg / kg, 4.5 mg / kg, and 7.0 mg / kg VGA039 SC.

[0028] FIG. 10 is a graph of Central D-dimer levels over time for subjects administered 3.0 mg / kg, 4.5 mg / kg, and 7.0 mg / kg VGA039 SC.DETAILED DESCRIPTION

[0029] Where elements are presented in a list format (e.g., in a Markush group), it should be understood that each possible subgroup of the elements is also disclosed, and that any one or more elements can be removed from the list or group.

[0030] It should be understood that, unless clearly indicated, in any method described or disclosed herein that includes more than one act, the order of the acts is not necessarily limited to the order in which the acts of the method are recited, but the disclosure encompasses exemplary embodiments in which the order of the acts is so limited.

[0031] The terms used throughout the specification are defined as follows unless otherwise limited in specific instances. As used in the specification and the claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. All technical and scientific terms, acronyms, and abbreviates used in the specification and claims have the same meaning as commonly understood by one of ordinary skill in the art to which the disclosure pertains, unless defined or stated otherwise. All numerical ranges are inclusive of thevalues defining the range as well as all integer values in between, unless indicated or defined otherwise.

[0032] When an amino acid sequence is said to have a certain percent “sequence identity” or “identity” or is a certain percent “identical” to another nucleic acid or amino acid sequence, that percentage of bases or amino acids are the same, and in the same relative position, when the sequences are aligned, when comparing the two sequences. As used herein, the terms “identity” and “identical,” when referring to a comparison of two sequences, refers to the percentage of exact matching residues in an alignment of a sequence provided herein to a reference sequence, such as an alignment generated by a BLAST algorithm or other alignment algorithms known in the art. Identity may be calculated based on an alignment of a full-length sequence provided herein and a full-length reference sequence. Identity may also be calculated based on a partial alignment of a sequence provided herein and a reference sequence, if the reference sequence is longer than a sequence provided herein. Identity may also be calculated based on a partial alignment of a sequence provided herein and a reference sequence, if the reference sequence is shorter than a sequence provided herein. Thus, when aligning two sequences, according to the aforementioned, a query sequence “shares at least x % identity to” a subject sequence if in the alignment of the two sequences, at least x % (rounded down) of the residues in the subject sequence are aligned as an exact match to a corresponding residue in the query sequence, wherein the numerator is the number of exact matches and the denominator is the length of the query sequence. In some embodiments, the denominator may alternatively be the length of the query sequence minus any gaps of two or more non-matching residues. Where the subject sequence has variable positions (e.g., residues denoted X), an alignment to any residue in the query sequence is counted as a match.

[0033] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.A. Methods of Treating VWD

[0034] In VWD, defective or low amounts of VWF and FVIII leads to insufficient platelet adhesion (primary hemostasis) and thrombin generation (secondary hemostasis), as seen in the schematic of FIG. 1. Functioning and concentrations of Protein S, a circulating plasma proteininvolved in coagulation, on the other hand, is unaffected in VWD across its types and sub-types and is in similar distribution in healthy individuals compared to those who have a bleeding disorder such as VWD. Without being held to theory or mechanism, the Protein S antibodies may be useful for treating VWD by attenuating Protein S cofactor activity for TFPIa and aPC, augmenting and restoring thrombin generation during the initiation and propagation phases of coagulation, as seen in the schematic of FIG. 2. FIG. 2 depicts a schematic of the mechanism of action of an exemplary Protein S antibody that promotes thrombin generation after its administration in VWD. By attenuating Protein S cofactor activity for TFPIa and aPC, administration of the Protein S antibodies to a subject in need thereof is predicted to augment and restore thrombin generation during the initiation and propagation phases of coagulation, leading to stable clot formation.

[0035] Accordingly, disclosed herein are methods of treating VWD in a subject in need, comprising administering to the subject a therapeutically effective amount of a Protein S antibody of the disclosure. It is noted that the Protein S antibody may be administered to the subject subcutaneously or intravenously, to reach a target plasma concentration, using a body weight-based regimen, or non-body weight-based regimen. The methods provided herein are useful for the treatment of any type of VWD, including, but not limited to, VWD type 1, VWD type 2A, VWD type 2B, VWD type 2M, VWD type 2N, and VWD type 3.Target Plasma Concentrations

[0036] In some embodiments, the Protein S antibody is administered to achieve a specific plasma concentration of the Protein S antibody in the subject to achieve the desired therapeutic effects. In some embodiments, the specific plasma concentration is associated with a physiologically relevant marker associated with the restoration of hemostasis in the subject, including but not limited to a reduction in frequency, duration, and / or the severity of bleeding in a subject, an increase in thrombin generation, an increase in D-Dimer concentrations, and an increase in Prothombin Fl+2 concentrations. In some embodiments, the duration of bleeding is reduced by about 5%, by about 10%, by about 20%, by about 30%, by about 40%, by about 50%, by about 60%, by about 70%, by about 80%, by about 90%, or by about 100%. In some embodiments, the frequency of bleeding is reduced by about 5%, by about 10%, by about 20%, by about 30%, by about 40%, by about 50%, by about 60%, by about 70%, by about 80%, byabout 90%, or by about 100%. In some embodiments, the severity of bleeding is reduced by about 5%, by about 10%, by about 20%, by about 30%, by about 40%, by about 50%, by about 60%, by about 70%, by about 80%, by about 90%, or by about 100%.

[0037] In some embodiments, the therapeutically effective amount of the Protein S antibody results in an antibody plasma concentration of about 1 pg / ml to about 200 pg / ml upon administration. In some embodiments, a plasma concentration of about 1 pg / ml to about 10 pg / ml may be reached upon administration of the antibody to the subject. In some embodiments, a plasma concentration of about 10 pg / ml to about 100 pg / ml may be reached upon administration of the antibody to the subject. In some embodiments, a plasma concentration of about 10 pg / ml to about 50 pg / ml may be reached upon administration of the antibody. In some embodiments, a plasma concentration of about 5 pg / ml to about 50 pg / ml is reached upon administration of the antibody to the subject. In some embodiments, a plasma concentration of about 20 pg / ml to about 25 pg / ml is reached upon administration of the antibody to the subject. In some embodiments, a plasma concentration of about 50 pg / ml to about 200 pg / ml is reached upon administration of the antibody to the subject. In some embodiments, a plasma concentration of about 75 pg / ml to about 200 pg / ml is reached upon administration of the antibody to the subject. In some embodiments, a plasma concentration of about 100 pg / ml to about 200 pg / ml is reached upon administration of the antibody to the subject.

[0038] In some embodiments, an antibody plasma concentration of about 10 pg / ml to about 20 pg / ml, about 20 pg / ml to about 30 pg / ml, about 30 pg / ml to about 40 pg / ml, 40 pg / ml to about 50 pg / ml, about 50 pg / ml to about 60 pg / ml, about 60 pg / ml to about 70 pg / ml, about 70 pg / ml to about 80 pg / ml, about 80 pg / ml to about 90 pg / ml, about 90 pg / ml to about 100 pg / ml, about 100 pg / ml to about 110 pg / ml, about 110 pg / ml to about 120 pg / ml, 120 pg / ml to about 130 pg / ml, 130 pg / ml to about 140 pg / ml, 140 pg / ml to about 150 pg / ml, about 150 pg / ml to about 160 pg / ml, about 160 pg / ml to about 170 pg / ml, about 170 pg / ml to about 180 pg / ml, about 180 pg / ml to about 190 pg / ml, or about 190 pg / ml to about 200 pg / ml is reached upon administration of the Protein S antibody to the subject.

[0039] In some embodiments, an antibody plasma concentration of about 1 pg / ml, 2 pg / ml, about 3 pg / ml, about 4 pg / ml, about 5 pg / ml, about 6 pg / ml, about 7 pg / ml, about 8 pg / ml,about 9 pg / ml, about 10 pg / ml, aboutl5 pg / ml, about 20 pg / ml, about 25 pg / ml, about 30 pg / ml, about 35 pg / ml, about 40 pg / ml, about 45 pg / ml, about 50 pg / ml, about 55 pg / ml, about 60 pg / ml, about 65 pg / ml, about 70 pg / ml, about 75 pg / ml, about 80 pg / ml, about 85 pg / ml, about 90 pg / ml, about 95 pg / ml, about 100 pg / ml, about 105 pg / ml, about 110 pg / ml, about 115 pg / ml, about 120 pg / ml, about 125 pg / ml, about 130 pg / ml, about 135 pg / ml, about 140 pg / ml, about 145 pg / ml, about 150 pg / ml, about 155 pg / ml, about 160 pg / ml, about 165 pg / ml, about 170 pg / ml, about 175 pg / ml, about 180 pg / ml, about 185 pg / ml, about 190 pg / ml, about 195 pg / ml, or about 200 pg / ml is reached upon administration of the Protein S antibody to the subject.

[0040] It is understood that the desired plasma concentrations described above may be achieved with either body -weight-based dosing regimens or non-body weight-based dosing regimens further described below.Body Weight-Based Dosing Regimens

[0041] In some embodiments, the methods of treating VWD in the subject comprises administering to the subject a therapeutically effective amount of a Protein S antibody of the disclosure, wherein the Protein S antibody is administered to the subject at one or more doses, using a body weight-based dosing regimen. A body weight-based dosing regimen comprises a subject receiving a dose based on body weight (e.g., mg / kg per dose). For example, In some embodiments, the Protein S antibody is administered to the subject at one or more dosage of about 0.1 mg / kg to about 18 mg / kg each. In some embodiments, the Protein S antibody is administered at one or more doses of least about 0.1 mg / kg to about 1.0 mg / kg. In some embodiments, the Protein S antibody is administered at one or more doses of least about 1.0 mg / kg to about 10.0 mg / kg. In some embodiments, the Protein S antibody is administered at one or more doses of at least about 1.0 mg / kg to about 3.0 mg / kg. In some embodiments, the Protein S antibody is administered at one or more doses of at least about 3.0 mg / kg to about 6.0 mg / kg, about 4.5 mg / kg to about 9 mg / kg, about 6.0 mg / kg to about 12.0 mg / kg, or about 9.0 mg / kg to about 18 mg / kg. In some embodiments, wherein the Protein S antibody is administered to the subject at one or more doses using a weight-based dosage, the Protein S antibody may be administered to the subject subcutaneously or intravenously.

[0042] In some embodiments, administering one or more doses of the Protein S antibody to the subject in need thereof includes administering one or more doses at a concentration of about 0.05mg / kg to about O.lmg / kg, of about O.lmg / kg to about 0.3mg / kg, of about 0.3mg / kg to about 0.5mg / kg, of about 0.5mg / kg to about l.Omg / kg, of about l.Omg / kg to about 3.0mg / kg, about 3.0mg / kg to about 6.0mg / kg, about 4.5 mg / kg to about 9.0 mg / kg, about 3.0 mg / kg to about 10.0 mg / kg, about 6.0 mg / kg to about 12.0 mg / kg, or about 9.0 mg / kg to about 18.0 mg / kg.

[0043] In some embodiments, administering one or more doses of the Protein S antibody to a subject in need thereof includes administering one or more doses at a concentration of about 0.5 mg / kg, about 0.6 mg / kg, about 0.7 mg / kg, about 0.8 mg / kg, about 0.9 mg / kg, about 1.0 mg / kg, about 1.1 mg / kg, about 1.2 mg / kg, about 1.3 mg / kg, about 1.4 mg / kg, about 1.5 mg / kg, about 1.6 mg / kg, about 1.7 mg / kg, about 1.8 mg / kg, about 1.9 mg / kg, about 2.0 mg / kg, about 2.1 mg / kg, about 2.2 mg / kg, about 2.3 mg / kg, about 2.4 mg / kg, about 2.5 mg / kg, about 2.6 mg / kg, about 2.7 mg / kg, about 2.8 mg / kg, about 2.9 mg / kg, or about 3.0 mg / kg. In some embodiments, administering one or more doses of the Protein S antibody to the subject includes administering one or more doses as a concentration of about 3.1 mg / kg, about 3.2 mg / kg, about 3.3 mg / kg, about 3.4 mg / kg, about 3.5 mg / kg, about 3.6 mg / kg, about 3.7 mg / kg, about 3.8 mg / kg, about 3.9 mg / kg, about 4.0 mg / kg, about 4.1 mg / kg, about 4.2 mg / kg, about 4.3 mg / kg, about 4.4 mg / kg, about 4.5 mg / kg, about 4.6 mg / kg, about 4.7 mg / kg, about 4.8 mg / kg, about 4.9 mg / kg, about 5.0 mg / kg, about 5.1 mg / kg, about 5.2 mg / kg, about 5.3 mg / kg, about 5.4 mg / kg, about 5.5 mg / kg, about 5.6 mg / kg, about 5.7 mg / kg, about 5.8 mg / kg, about 5.9 mg / kg, about 6.0 mg / kg, about 6.1 mg / kg, about 6.2 mg / kg, about 6.3 mg / kg, about 6.4 mg / kg, about 6.5 mg / kg, about 6.6 mg / kg, about 6.7 mg / kg, about 6.8 mg / kg, about 6.9 mg / kg, about 7.0 mg / kg, about 7.1 mg / kg, about 7.2 mg / kg, about 7.3 mg / kg, about 7.4 mg / kg, about 7.5 mg / kg, about 7.6 mg / kg, about 7.7 mg / kg, about 7.8 mg / kg, about 7.9 mg / kg, about 8.0 mg / kg, about 8.1 mg / kg, about 8.2 mg / kg, about 8.3 mg / kg, about 8.4 mg / kg, about 8.5 mg / kg, about 8.6 mg / kg, about 8.7 mg / kg, about 8.8 mg / kg, about 8.9 mg / kg, about 9.0 mg / kg, about 9.1 mg / kg, about 9.2 mg / kg, about 9.3 mg / kg, about 9.4 mg / kg, about 9.5 mg / kg, about 9.6 mg / kg, about 9.7 mg / kg, about 9.8 mg / kg, about 9.9 mg / kg, or about 10.0 mg / kg.

[0044] In some embodiments, administering one or more doses of the Protein S antibody to the subject includes administering one or more doses as a concentration of about 10.1 mg / kg,about 10.2 mg / kg, about 10.3 mg / kg, about 10.4 mg / kg, about 10.5 mg / kg, about 10.6 mg / kg, about 10.7 mg / kg, about 10.8 mg / kg, about 10.9 mg / kg, about 11.0 mg / kg, about 11.1 mg / kg, about 11.2 mg / kg, about 11.3 mg / kg, about 11.4 mg / kg, about 11.5 mg / kg, about 11.6 mg / kg, about 11.7 mg / kg, about 11.8 mg / kg, about 11.9 mg / kg, about 12.0 mg / kg, about 12.1 mg / kg, about 12.2 mg / kg, about 12.3 mg / kg, about 12.4 mg / kg, about 12.5 mg / kg, about 12.6 mg / kg, about 12.7 mg / kg, about 12.8 mg / kg, about 12.9 mg / kg, about 13.0 mg / kg, about 13.1 mg / kg, about 13.2 mg / kg, about 13.3 mg / kg, about 13.4 mg / kg, about 13.5 mg / kg, about 13.6 mg / kg, about 13.7 mg / kg, about 13.8 mg / kg, about 13.9 mg / kg, about 14.0 mg / kg, about 14.1 mg / kg, about 14.2 mg / kg, about 14.3 mg / kg, about 14.4 mg / kg, about 14.5 mg / kg, about 14.6 mg / kg, about 14.7 mg / kg, about 14.8 mg / kg, about 14.9 mg / kg, about 15.0 mg / kg, about 15.1 mg / kg, about 15.2 mg / kg, about 15.3 mg / kg, about 15.4 mg / kg, about 15.5 mg / kg, about 15.6 mg / kg, about 15.7 mg / kg, about 15.8 mg / kg, about 15.9 mg / kg, about 16.0 mg / kg, about 16.1 mg / kg, about 16.2 mg / kg, about 16.3 mg / kg, about 16.4 mg / kg, about 16.5 mg / kg, about 16.6 mg / kg, about 16.7 mg / kg, about 16.8 mg / kg, about 16.9 mg / kg, about 17.0 mg / kg, about 17.1 mg / kg, about 17.2 mg / kg, about 17.3 mg / kg, about 17.4 mg / kg, about 17.5 mg / kg, about 17.6 mg / kg, about 17.7 mg / kg, about 17.8 mg / kg, about 17.9 mg / kg, or about 18.0 mg / kg.

[0045] In some embodiments, administering one or more doses of the Protein S antibody to a subject in need thereof includes administering one or more doses at a concentration of about 0.05 mg / kg to about 10.0 mg / kg including about 0.05mg / kg to about O.lmg / kg, of about O. lmg / kg to about 0.3 mg / kg, of about 0.3 mg / kg to about 0.5 mg / kg, of about 0.5 mg / kg to about l.Omg / kg, of about l.Omg / kg to about 3.0mg / kg, about 3.0mg / kg to about 5.0mg / kg, about 5.0 mg / kg to about 8.0 mg / kg, or about 8.0 mg / kg to about 10.0 mg / kg. For example, in some embodiments, the one or more doses of the Protein S antibody of the disclosure may be administered to the subject in need thereof at a concentration of about 0.5 mg / kg, about 1.0 mg / kg, about 1.5 mg / kg, about 2.0 mg / kg, about 2.5 mg / kg, about 3.0 mg / kg, about 3.5 mg / kg, about 4.0 mg / kg, about 4.5 mg / kg, about 5.0 mg / kg, about 5.5 mg / kg, about 6.0 mg / kg, about 6.5 mg / kg, about 7.0 mg / kg, about 7.5 mg / kg, about 8.0 mg / kg, about 8.5 mg / kg, about 9.0 mg / kg, about 9.5 mg / kg, or about 10.0 mg / kg.Non-Body Weight-Based Dosing Regimen

[0046] In some embodiments, administering one or more doses of the Protein S antibody to the subject includes administering the one or more doses of the Protein S antibody using a nonbody weight dosing regimen. In some embodiments, a non-body weight dosing regimen may comprise a subject being administered one or more doses at a set amount per dose (fixed dose). In some embodiments, the non-body weight dosing regimen includes a body weight range dosing regimen, wherein the subject is administered a fixed amount per dose with subject with smaller body weight are administered a lower set amount(e.g., lower mg / dose) and subjects with larger body weight are administered a higher set amount(e.g., higher mg / dose). In some embodiments, for the non-body weight dosing regimen, the subject may be administered the protein S antibody either subcutaneously or intravenously. In preferred embodiments of the non- body weight-based dosing regimen, the fixed amount of the dose is administered subcutaneously.

[0047] For example, the method includes administering one or more non-body weight-based doses of the Protein S antibody to the subject at an amount of about Img per dose to about 1000 mg per dose, and all amounts in between. For example, in some embodiments, the one or more fixed doses of the Protein S antibody may be administered at an amount of about 1 mg per dose, about 2 mg per dose, about 3 mg per dose, about 4 mg per dose, about 5 mg per dose, about 6 mg per dose, about 7 mg per dose, about 8 mg per dose, about 9 mg per dose, about 10 mg per dose, about 20 mg per dose, about 30 mg per dose, about 40 mg per dose, about 50 mg per dose, about 60 mg per dose, about 70 mg per dose, about 80 mg per dose, about 90 mg per dose or about 100 mg per dose. In some embodiments, the one or more doses of the Protein S antibody may be administered to the subject at a amount of about 110 mg per dose, about 120 mg per dose, about 130 mg per dose, about 140 mg per dose, about 150 mg per dose, about 160 mg per dose, about 170 mg per dose, about 180 mg per dose, about 190 mg per dose, about 200 mg per dose, 201 mg per dose, 202 mg per dose, 203 mg per dose, 204 mg per dose, 205 mg per dose, 206 mg per dose, 207 mg per dose, 208 mg per dose, 209 mg per dose, about 210 mg per dose, 211 mg per dose, 212 mg per dose, 213 mg per dose, 214 mg per dose, 215 mg per dose, 216 mg per dose, 217 mg per dose, 218 mg per dose, 219 mg per dose, about 220 mg per dose, about 221 mg per dose, about 222 mg per dose, about 223 mg per dose, about 224 mg per dose, about 225 mg per dose, about 226 mg per dose, about 227 mg per dose, about 228 mg per dose, about 229 mg per dose, about 230 mg per dose, about 231 mg per dose, about 232 mg per dose, about 233mg per dose, about 234 mg per dose, about 235 mg per dose, about 236 mg per dose, about 237 mg per dose, about 238 mg per dose, about 239 mg per dose, about 240 mg per dose, about 241 mg per dose, about 242 mg per dose, about 243 mg per dose, about 244 mg per dose, about 245 mg per dose, about 246 mg per dose, about 247 mg per dose, about 248 mg per dose, about 249 mg per dose, about 250 mg per dose, about 260 mg per dose, about 270 mg per dose, about 280 mg per dose, about 290 mg per dose, about 300 mg per dose, about 310 mg per dose, about 320 mg per dose, about 330 mg per dose, about 340 mg per dose, about 350 mg per dose, about 360 mg per dose, about 370 mg per dose, about 380 mg per dose, about 390 mg per dose, or about 400 mg per dose. In some embodiments, the one or more doses of the Protein S antibody may be administered to the subject at a amount of about 410 mg per dose, about 420 mg per dose, about 430 mg per dose, about 440 mg per dose, about 450 mg per dose, about 460 mg per dose, about 470 mg per dose, about 480 mg per dose, about 490 mg per dose, about 500 mg per dose, about 510 mg per dose, about 520 mg per dose, about 530 mg per dose, about 540 mg per dose, about 550 mg per dose, about 560 mg per dose, about 570 mg per dose, about 580 mg per dose, about 590 mg per dose, about 600 mg per dose, about 610 mg per dose, about 620 mg per dose, about 630 mg per dose, about 640 mg per dose, about 650 mg per dose, about 660 mg per dose, about 670 mg per dose, about 680 mg per dose, about 690 mg per dose, or about 700 mg per dose. In some embodiments, the one or more doses of the Protein S antibody may be administered to the subject at a amount of about 710 mg per dose, about 720 mg per dose, about 730 mg per dose, about 740 mg per dose, about 750 mg per dose, about 760 mg per dose, about 770 mg per dose, about 780 mg per dose, about 790 mg per dose, about 800 mg per dose, about 810 mg per dose, about 820 mg per dose, about 830 mg per dose, about 840 mg per dose, about 850 mg per dose, about 860 mg per dose, about 870 mg per dose, about 880 mg per dose, about 890 mg per dose, or about 900 mg per dose. In some embodiments, the one or more doses of the Protein S antibody may be administered to the subject at an amount of about 910 mg per dose, 920 mg per dose, 930 mg per dose, 940 mg per dose, 950 mg per dose, 960 mg per dose, 970 mg per dose, 980 mg per dose, 990 mg per dose, or about 1000 mg per dose. In some embodiments, the Protein S antibody is administered to the subject at an amount of about 150 mg / dose, about 225 mg / dose, about 300 mg / dose, about 450 mg / dose, about 600 mg / dose, or 900 mg / dose.Dosing Regimens and Schedules

[0048] The dosing described above may comprise the administration of a plurality of doses of the Protein S antibody to the subject over time. In some embodiments, timing, and frequency of the administration of the Protein S antibody may take into account desired plasma concentration and half-life of the Protein S antibody. In some embodiments, the treatment may comprise one or more loading doses preceding a maintenance dose. In some embodiments, the treatment may comprise one or more loading doses and one or more maintenance doses. In some embodiments, the one or more loading doses and the one or more maintenance doses may be the same. In some embodiments, the one or more loading doses and the one or more maintenance doses may be different. In some embodiments, the one or more loading doses may be administered to the subject at an amount greater than the amount of the one or more maintenance doses. In some embodiments, the one or more loading doses may be administered to the subject at an amount lower than the amount of the one or more maintenance doses.

[0049] In some embodiments, the Protein S antibody is administered to the subject daily, about once every 2 days, about once every 3 days, about once every 4 days, about once every, 5 days, about once every 6 days, at least once weekly, once weekly, about once every 8 days, about once every 9 days, about once every 10 days, about once every 11 days, about once every 12 days, about once every 13 days, once about every two weeks, once about every three weeks, once about every four weeks, once about every month, once about every five weeks, once about every six weeks, once about every seven weeks, once about every eight weeks, once about every two months, once about every three months, or once about every six months.

[0050] In some embodiments, the Protein S antibody is administered to the subject, daily, at least one time per two days, at least one time per three days, at least one time per four days, at least one time per five days, at least one time per six days, or at least one time per seven days.

[0051] In some embodiments, the Protein S antibody is administered to the subject, at least one time during the range of about 1 day to about 12 months. In some embodiments, the Protein S antibody is administered to the subject in need thereof, at least one time per five weeks, at least one time per six weeks, at least one time per seven weeks, at least one time per eight weeks, at least one time per nine weeks, at least one time per ten weeks, at least one time per eleven weeks, or at least one time per twelve weeks.

[0052] In some embodiments, the Protein S antibody is administered to the subject indefinitely. In some embodiments, the Protein S antibody is administered to the subject for a set period of time, discontinued for a period of time, after which the treatment may be restarted.

[0053] In some embodiments, the subject may be administered one or more loading doses. In some embodiments, after the subject has been administered one or more loading doses, the subject may be administered one or more maintenance doses.

[0054] In some embodiments, the loading dose of the Protein S antibody may be administered to the subject daily, about once every 2 days, about once every 3 days, about once every 4 days, about once every, 5 days, about once every 6 days, about once weekly, about once every 8 days, about once every 9 days, about once every 10 days, about once every 11 days, about once every 12 days, about once every 13 days, about once every two weeks, about once every three weeks, about once about every four weeks, or about once about every month. In some embodiments, the loading dose is administered on day 1. In some embodiments, the loading dose is administered on day 1 and day 8. In some embodiments, the loading dose is administered on day 1 and maintenance doses are administered starting on day 8.

[0055] In some embodiments, the one or more maintenance doses may be administered to the subject daily, about once every 2 days, about once every 3 days, about once every 4 days, about once every, 5 days, about once every 6 days, at least once weekly, about once weekly, about once every 8 days, about once every 9 days, about once every 10 days, about once every 11 days, about once every 12 days, about once every 13 days, about once every two weeks, about once every three weeks, about once about every four weeks, or about once about every month, at least one time per five weeks, at least one time per six weeks, at least one time per seven weeks, at least one time per eight weeks, at least one time per nine weeks, at least one time per ten weeks, at least one time per eleven weeks, at least one time per twelve weeks, and the like.

[0056] In some embodiments, the one or more loading doses and one or more maintenance doses may be administered at the same concentrations or at different concentrations. In some embodiments, wherein the one or more loading doses and one or more maintenance doses are administered at different concentrations, the one or more loading doses may be administered at a higher concentration than the one or more maintenance doses. In some embodiments, whereinthe one or more loading doses and one or more maintenance doses are administered at different concentrations, the one or more loading doses may be administered at a lower concentration than the one or more maintenance doses.Subjects and Indications

[0057] Provided herein are treatment regimens for human subjects. In some embodiments, the human subject is a male human subject. In some embodiments, the subject is a female human subject. In some embodiments, the human subject is an infant (aged 29 days to less than 2 years of age as per the FDA), a child (2 years of age to less than 12 years of age as per the FDA), an adolescent (about 12 years of age to about 17 years of age, per the FDA), or an adult (greater than 18 years of age, per the FDA). In some embodiments, the subject is between about 18 years of age and about 60 years of age. In some embodiments, the subject may be over 60 years of age.

[0058] In some embodiments, the subject is administered the Protein S antibody for routine prophylaxis for the management of VWD.

[0059] In some embodiments the subject is administered the Protein S antibody for one-time or otherwise short-term prophylaxis (e.g. not for routine prophylaxis). For example, in some embodiments, the subject is administered the Protein S antibody peri operatively to prevent or address bleeding issues during or after surgery. Surgeries include, but are not limited to: dental surgery, arthroscopic surgery, orthopedic surgery, gynecological surgery, urological surgery, cystoscopy, hysterectomy, cosmetic surgeries, general surgery, hernias, vascular surgery, caesarean section, coronary artery bypass, appendectomy, neurosurgery, bariatric surgery, carotid endarterectomy, cholecystectomy, skin grafts, mastectomy, prostatectomy, and tonsillectomy. In other embodiments, the subject is administered the Protein S antibody for onetime or short-term prophylaxis to prevent or address bleeding issues associated with an anticipated trauma, e.g., if a subject with VWD were to engage in physical activity (e.g., a grueling, vigorous, strenuous, or physically interactive sport or activity, manual labor, or the like), in which the likelihood of a bleed to occur was increased.

[0060] In some embodiments, the subject is diagnosed with a specific type of VWD including, but not limited to, VWD type 1, VWD type 2 A, VWD type 2B, VWD type 2M, VWD type 2N,and VWD type 3. In some embodiments, the subject is at risk of suffering from a bleed selected from the group consisting of: intercranial hemorrhage, mouth bleeds, epistaxis, hematemesis, pulmonary hemorrhage, gastrointestinal bleeds, joint bleeds, muscle bleeds, hematomas, bruising, menorrhagia, and hematuria. In some embodiments, the subject may have a history of clinical bleeding and / or bruising. In some embodiments, the subject may have had prior on- demand or prophylactic treatment. In some embodiments, the subject may not have had any prior history of thromboembolism or thrombophilia according to prior laboratory testing. In some embodiments, the subject may not have or have had an increased clinical risk of thromboembolism. In some embodiments, the subject may have FVIII activity less than or equal to 50 or 150 lU / dL.

[0061] In some embodiments, the subject is diagnosed with VWD and one or more additional diseases or disorders. In some embodiments, the one or more additional diseases or disorders is another bleeding disorder. In some embodiments, the bleeding disorder is selected from the group consisting of hemophilia A, hemophilia B, menorrhagia including menorrhagia due to a congenital or acquired factor deficiency, Factor I deficiency, Factor II deficiency, Factor V deficiency, Factor VII deficiency, Factor X deficiency, Factor XI deficiency (hemophilia C), Factor VIII deficiency (hemophilia A), Factor IX deficiency (hemophilia B), trauma, and hereditary hemorrhagic telangiectasia. In some embodiments, the bleeding is associated with surgery, e.g. in a subject with a type of hemophilia. In some embodiments, the bleeding is associated with a medical procedure, e.g., a dental procedure. In some embodiments, the menorrhagia is associated with any one or more bleeding disorders and / or platelet disorders. In some embodiments, the subject is a hemophilia carrier. In some embodiments, the subject is a hemophilia carrier and suffers from menorrhagia. In some embodiments, the one or more additional diseases or disorders is a platelet disorder. In some embodiments, the platelet disorder includes but is not limited to Bernard-Soulier syndrome, Glanzmann’s thrombasthenia, and platelet storage pool deficiencies. In some embodiments, the platelet disorder is a platelet storage pool deficiency. In some embodiments, the platelet storage pool deficiency includes but is not limited to: Gray platelet syndrome, Quebec platelet disorder, and MYH9- related thrombocytopenia (MYH9RD).In some embodiments, the subject is diagnosed with VWD and at least one other congenital coagulation factor deficiency that may contribute to increased bleeding such as Factor I, FII, FV, FVII, FVIII (hemophilia A), FIX (hemophilia B),FX, FXI (hemophilia C), Factor XII, and Factor XIII deficiencies, in addition to other non-factor deficiency related bleeding conditions including, but not limited to glanzmann thrombasthenia, bernard soulier syndrome, and hereditary hemorrhagic telangiectasia. In some embodiments, the one or more additional diseases or disorders is iron deficiency. In some embodiments, the treatment results in a resolution of iron deficiency.

[0062] In some embodiments, administration of the Protein S antibody to a female subject may result in a restoration of normal menstrual bleeding. In some embodiments, normal menstrual bleeding includes, for example, up to 12 menstrual cycles per year that range in duration from 3-7 days per cycle and entail less than 80 ccs of total menstrual blood loss per cycle.Treatment Indicia / Biomarkers

[0063] In some embodiments, the administration of Protein S antibody to the subject may result in one or more of indicia of hemostasis, including but not limited to an increase in thrombin generation, an increase in D-dimer levels, an increase in Prothrombin Fl +2 levels, a reduction in the frequency of a bleed, a reduction in the duration of a bleed, and a reduction in the severity of a bleed in the subject. These indicia of hemostasis may be self-reported or quantified. In some embodiments, administration of the Protein S antibodies provided herein to a subject in need thereof results in the promotion of the generation of a marker associated with coagulation activity, and this can be exhibited in vitro (e.g., in a sample taken from a subject administered the Protein S antibody) and / or in vivo (e.g., following administration of the Protein S antibody to a subject). Such markers include, but are not limited to, thrombin generation, fibrinogen, D-dimer, bleeding time, thrombin-antithrombin complex, fibrin degradation products, and prothrombin fragment Fl +2.

[0064] In some embodiments, the generation of thrombin after administration of a Protein S antibody to a subject in need thereof does not exceed a predetermined threshold level. In some embodiments, the generation of thrombin is partially restored after administration of the Protein S antibody. In some embodiments, the generation of thrombin does not exceed a predetermined percentage of a maximum peak thrombin generation after administration of the Protein S antibody. In some embodiments, the generation of thrombin in VWD subjects afteradministration of the Protein S antibody does not exceed a predetermined percentage of peak thrombin generation in unaffected subjects. In some embodiments, the generation of thrombin does not exceed a predetermined percentage of a maximum area under the curve of thrombin generation after administration of the Protein S antibody. In some embodiments, the generation of thrombin in VWD subjects after administration of the Protein S antibody does not exceed a predetermined percentage of an area under the curve of thrombin generation in unaffected subjects. In some embodiments, thrombin generation may be increased by about 1-fold to 50- fold, e.g., by about 1-fold, about 2-fold, about 3-fold, about 4-fold, about 5-fold, by about 10- fold, by about 15-fold, by about 20-fold, by about 25-fold, by about 30-fold, by about 35-fold, by about 40-fold, by about 45-fold, or even by about 50-fold, following administration of the Protein S antibody.

[0065] In some embodiments, administration of the Protein S antibody to the subject may result in an increase in thrombin generation in the subject from a baseline (“baseline”) of thrombin generation before administration of the Protein S antibody. In some embodiments, the increase in thrombin generation from baseline may be in the range of about 1% to about 10%, about 1% to about 20%, about 1% to 30%, about 1% to 40%, about 1% to about 50%, about 1% to about 60%, about 1% to about 70%, about 1% to about 80%, about 1% to about 90%, about 1% to about 100%. In some embodiments, the increase in thrombin generation may be at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 11%, at least about 12%, at least about 13%, at least about 14%, at least about 15%, at least about 16%, at least about 17%, at least about 18%, at least about 19%, at least about 20%, at least about 21%, at least about 22%, at least about 23%, at least about 24%, at least about 25%, at last about 26%, at least about 27%, at least about 28%, at least about 29%, at least about 30%, at least about 31%, at least about 32%, at least about 33%, at least about 34%, at least about 35%, at least about 36%, at least about 37%, at least about 38%, at least about 39%, at least about 40%, at least about 41%, at least about 42%, at least about 43%, at least about 44%, at least about 45%, at least about 46%, at least about 47%, at least about 48%, at least about 49%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 100%.

[0066] In some embodiments, administration of the Protein S antibody to the subject may result in an increase in D-dimer in the subject compared to D-dimer levels before the administration of the Protein S antibody to the subject. For example, the D-dimer level following administration of the Protein S antibody may be in the range of O.Olpg / ml to about lO.Opg / ml including from about O.Ol pg / ml to about 0.1 pg / ml, from about 0.1 pg / ml to about 1.0 pg / ml, from about 1.0 pg / ml to about 2.5 pg / ml, from about 2.5 pg / ml to about 5 pg / ml, from about 5 pg / ml to about 7.5 pg / ml, or from about 7.5 pg / ml to about 10.0 pg / ml. In some embodiments, the increase in D-dimer may be about 0.01 pg / ml, about 0.02 pg / ml, about 0.03 pg / ml, about 0.04 pg / ml, about 0.05 pg / ml, about 0.06 pg / ml, about 0.07 pg / ml, about 0.08 pg / ml, about 0.09 pg / ml, about 0.1 pg / ml, about 0.12 pg / ml, about 0.13 pg / ml, about 0.14 pg / ml, about 0.15 pg / ml, about 0.16 pg / ml, about 0.17 pg / ml, about 0.18 pg / ml, about 0.19 pg / ml, about 0.2 pg / ml, about 0.21 pg / ml, about 0.22 pg / ml, about 0.23 pg / ml, about 0.24 pg / ml, about 0.25 pg / ml, about 0.26 pg / ml, about 0.27 pg / ml, about 0.28 pg / ml, about 0.29 pg / ml, about 0.3 pg / ml, about 0.31 pg / ml, about 0.32 pg / ml, about 0.33 pg / ml, about 0.34 pg / ml, about 0.35 pg / ml, about 0.36 pg / ml, about 0.37 pg / ml, about 0.38 pg / ml, about 0.39 pg / ml, about 0.4 pg / ml, about 0.41 pg / ml, about 0.42 pg / ml, about 0.43 pg / ml, about 0.44 pg / ml, about 0.45 pg / ml, about 0.46 pg / ml, about 0.47 pg / ml, about 0.48 pg / ml, about 0.49 pg / ml, about 0.5 pg / ml, about 0.51 pg / ml, about 0.52 pg / ml, about 0.53 pg / ml, about 0.54 pg / ml, about 0.55 pg / ml, about 0.56 pg / ml, about 0.57 pg / ml, about 0.58 pg / ml, about 0.6 pg / ml, about 0.61 pg / ml, about 0.62 pg / ml, about 0.63 pg / ml, about 0.64 pg / ml, about 0.65 pg / ml, about 0.66 pg / ml, about 0.67 pg / ml, about 0.68 pg / ml, about 0.69 pg / ml, about 0.7 pg / ml, about 0.71 pg / ml, about 0.72 pg / ml, about 0.73 pg / ml, about 0.74 pg / ml, about 0.75 pg / ml, about 0.76 pg / ml, about 0.77 pg / ml about 0.78 pg / ml, about 0.79 pg / ml, about 0.8 pg / ml, about 0.81 pg / ml, about 0.82 pg / ml, about 0.83 pg / ml, about 0.84 pg / ml, about 0.85 pg / ml, about 0.86 pg / ml, about 0.87 pg / ml, about 0.88 pg / ml, about 0.89 pg / ml, about 0.9 pg / ml, about 0.91 pg / ml, about 0.92 pg / ml, about 0.93 pg / ml, about 0.94 pg / ml, about 0.95 pg / ml, about 0.96 pg / ml, about 0.97 pg / ml, about 0.98 pg / ml, about 0.99 pg / ml, or about 1.0 pg / ml.

[0067] The D-dimer levels following administration of the Protein S antibody may be about 1.0 pg / ml, about 1.01 pg / ml, about 1.02 pg / ml, about 1.03 pg / ml, about 1.04 pg / ml, about 1.05 pg / ml, about 1.06 pg / ml, about 1.07 pg / ml, about 1.08 pg / ml, about 1.09 pg / ml, about 1.1 pg / ml, about 1.12 pg / ml, about 1.13 pg / ml, about 1.14 pg / ml, about 1.15 pg / ml, about 1.16gg / ml, about 1.17 gg / ml, about 1.18 gg / ml, about 1.19 gg / ml, about 1.2 gg / ml, about 1.21 gg / ml, about 1.22 gg / ml, about 1.23 gg / ml, about 1.24 gg / ml, about 1.25 gg / ml, about 1.26 gg / ml, about 1.27 gg / ml, about 1.28 gg / ml, about 1.29 gg / ml, about 1.3 gg / ml, about 1.31 gg / ml, about 1.32 gg / ml, about 1.33 gg / ml, about 1.34 gg / ml, about 1.35 gg / ml, about 1.36 gg / ml, about 1.37 gg / ml, about 1.38 gg / ml, about 1.39 gg / ml, about 1.4 gg / ml, about 1.41 gg / ml, about 1.42 gg / ml, about 1.43 gg / ml, about 1.44 gg / ml, about 1.45 gg / ml, about 1.46 gg / ml, about 1.47 gg / ml, about 1.48 gg / ml, about 1.49 gg / ml, about 1.5 gg / ml, about 1.51 gg / ml, about 1.52 gg / ml, about 1.53 gg / ml, about 1.54 gg / ml, about 1.55 gg / ml, about 1.56 gg / ml, about 1.57 gg / ml, about 1.58 gg / ml, about 1.6 gg / ml, about 1.61 gg / ml, about 1.62 gg / ml, about 1.63 gg / ml, about 1.64 gg / ml, about 1.65 gg / ml, about 1.66 gg / ml, about 1.67 gg / ml, about 1.68 gg / ml, about 1.69 gg / ml, about 1.7 gg / ml, about 1.71 gg / ml, about 1.72 gg / ml, about 1.73 gg / ml, about 1.74 gg / ml, about 1.75 gg / ml, about 1.76 gg / ml, about 1.77 gg / ml about 1.78 gg / ml, about 1.79 gg / ml, about 1.8 gg / ml, about 1.81 gg / ml, about 1.82 gg / ml, about 1.83 gg / ml, about 1.84 gg / ml, about 1.85 gg / ml, about 1.86 gg / ml, about 1.87 gg / ml, about 1.88 gg / ml, about 1.89 gg / ml, about 1.9 gg / ml, about 1.91 gg / ml, about 1.92 gg / ml, about 1.93 gg / ml, about 1.94 gg / ml, about 1.95 gg / ml, about 1.96 gg / ml, about 1.97 gg / ml, about 1.98 gg / ml, about 1.99 gg / ml, about 2.0 gg / ml, about 2.01 gg / ml, about 2.02 gg / ml, about 2.03 gg / ml, about 2.04 gg / ml, about 2.05 gg / ml, about 2.06 gg / ml, about 2.07 gg / ml, about 2.08 gg / ml, about 2.09 gg / ml, about 2.1 gg / ml, about 2.12 gg / ml, about 2.13 gg / ml, about 2.14 gg / ml, about 2.15 gg / ml, about 2.16 gg / ml, about 2.17 gg / ml, about 2.18 gg / ml, about 2.19 gg / ml, about 2.2 gg / ml, about 2.21 gg / ml, about 2.22 gg / ml, about 2.23 gg / ml, about 2.24 gg / ml, about 2.25 gg / ml, about 2.26 gg / ml, about 2.27 gg / ml, about 2.28 gg / ml, about 2.29 gg / ml, about 2.3 gg / ml, about 2.31 gg / ml, about 2.32 gg / ml, about 2.33 gg / ml, about 2.34 gg / ml, about 2.35 gg / ml, about 2.36 gg / ml, about 2.37 gg / ml, about 2.38 gg / ml, about 2.39 gg / ml, about 2.4 gg / ml, about 2.41 gg / ml, about 2.42 gg / ml, about 2.43 gg / ml, about 2.44 gg / ml, about 2.45 gg / ml, about 2.46 gg / ml, about 2.47 gg / ml, about 2.48 gg / ml, about 2.49 gg / ml, or about 2.5 gg / ml.

[0068] In some embodiments, D-dimer levels following administration of the Protein S antibody may be from about 2.5 gg / ml to about 5.0 gg / ml. In some embodiments, D-dimer levels following administration of the Protein S antibody may be about 2.5 gg / ml, about 2.6 gg / ml, about 2.7 gg / ml, about 2.8 gg / ml, about 2.9 gg / ml, about 3.0 gg / ml, about 3.1 gg / ml,about 3.2 pg / ml, about 3.3 pg / ml, about 3.4 pg / ml, about 3.5 pg / ml, about 3.6 pg / ml, about 3.7 pg / ml, about 3.8 pg / ml, about 3.9 pg / ml, about 4.0 pg / ml, about 4.1 pg / ml, about 4.2 pg / ml, about 4.3 pg / ml, about 4.4 pg / ml, about 4.5 pg / ml, about 4.6 pg / ml, about 4.7 pg / ml, about 4.8 pg / ml, about 4.9 pg / ml, or about 5.0 pg / ml.

[0069] In some embodiments, D-dimer levels following administration of the Protein S antibody may be from about 5.0 pg / ml to about 7.5 pg / ml. In some embodiments, D-dimer levels following administration of the Protein S antibody may be about 5.0 pg / ml, about 5.1 pg / ml, about 5.2 pg / ml, about 5.3 pg / ml, about 5.4 pg / ml, about 5.5 pg / ml, about 5.6 pg / ml, about 5.7 pg / ml, about 5.8 pg / ml, about 5.9 pg / ml, about 6.0 pg / ml, about 6.1 pg / ml, about 6.2 pg / ml, about 6.3 pg / ml, about 6.4 pg / ml, about 6.5 pg / ml, about 6.6 pg / ml, about 6.7 pg / ml, about 6.8 pg / ml, about 6.9 pg / ml, about 7.0 pg / ml, about 7.1 pg / ml, about 7.2 pg / ml, about 7.3 pg / ml, about 7.4 pg / ml, or about 7.5 pg / ml.

[0070] In some embodiments, D-dimer levels following administration of the Protein S antibody may be from about 7.5 pg / ml to about 10.0 pg / ml. In some embodiments, D-dimer levels following administration of the Protein S antibody may be about 7.5 pg / ml, about 7.6 pg / ml, about 7.7 pg / ml, about 7.8 pg / ml, about 7.9 pg / ml, about 8.0 pg / ml, about 8.1 pg / ml, about 8.2 pg / ml, about 8.3 pg / ml, about 8.4 pg / ml, about 8.5 pg / ml, about 8.6 pg / ml, about 8.7 pg / ml, about 8.8 pg / ml, about 8.9 pg / ml, about 9.0 pg / ml, about 9.1 pg / ml, about 9.2 pg / ml, about 9.3 pg / ml, about 9.4 pg / ml, about 9.5 pg / ml, about 9.6 pg / ml, about 9.7 pg / ml, about 9.8 pg / ml, about 9.9 pg / ml, or about 10.0 pg / ml.

[0071] In some embodiments, the percent increase of D-Dimer levels in the subject following administration of the antibody may be in the range of about 1% to about 10%, about 10% to about 20%, about 10% to about 30%, about 10% to about 40%, about 10% to about 50%, about 10% to about 60%, about 10% to about 70%, about 10% to about 80%, about 10% to about 90%, about 10% to about 100%, about 100% to about 1000%, or the like. In some embodiments, the percent increase may be about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 11%, at least about 12%, at least about 13%, at least about 14%, at least about 15%, at least about 16%, at least about 17%, at least about 18%, at least about 19%, at least about 20%, at least about 21%, at least about 22%, at least about 23%, at least about24%, at least about 25%, at last about 26%, at least about 27%, at least about 28%, at least about 29%, at least about 30%, at least about 31%, at least about 32%, at least about 33%, at least about 34%, at least about 35%, at least about 36%, at least about 37%, at least about 38%, at least about 39%, at least about 40%, at least about 41%, at least about 42%, at least about 43%, at least about 44%, at least about 45%, at least about 46%, at least about 47%, at least about 48%, at least about 49%, or at least about 50%.

[0072] In some embodiments, the percent increase of D-Dimer levels in the subject following administration of the antibody may be at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 100%, at least about 150%, at least about 200%, at least about 250%, at least about 300%, at least about 350%, at least about 400%, at least about 450%, at least about 500%, at least about 550%, at least about 600%, at least about 650%, at least about 700%, at least about 750%, at least about 800%, at least about 850%, at least about 900%, at least about 950%, or at least about 1000%.

[0073] In some embodiments, the administration of the Protein S antibody to the subject may result in an increase in Prothrombin Fl +2 (e.g., mean % change from baseline) compared to Prothrombin Fl +2 levels before administration of the Protein S antibody to the subject (baseline Prothrombin Fl +2 levels). In some embodiments, the increase in Prothrombin Fl+2 levels from baseline may be in the range of about 1% to about 10%, about 1% to about 20%, about 1% to about 30%, about 1% to about 40%, about 1% to about 50%, about 1% to about 60%, about 1% to about 70%, about 1% to about 80%, about 1% to about 90%, about 1% to about 100%, about 100% to about 1000%. In some embodiments, the increase in Prothrombin Fl+2 levels may be at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 11%, at least about 12%, at least about 13%, at least about 14%, at least about 15%, at least about 16%, at least about 17%, at least about 18%, at least about 19%, at least about 20%, at least about 21%, at least about 22%, at least about 23%, at least about 24%, at least about 25%, at last about 26%, at least about 27%, at least about 28%, at least about 29%, at least about 30%, at least about 31%, at least about 32%, at least about 33%, at least about 34%, at least about 35%, at least about 36%, at least about 37%, at least about 38%, at least about 39%, at least about 40%, at least about 41%, at least about 42%, at least about 43%, at least about44%, at least about 45%, at least about 46%, at least about 47%, at least about 48%, at least about 49%, or at least about 50%.

[0074] In some embodiments, the increase in Prothrombin Fl +2 levels may be at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 100%, at least about 150%, at least about 200%, at least about 250%, at least about 300%, at least about 350%, at least about 400%, at least about 450%, at least about 500%, at least about 550%, at least about 600%, at least about 650%, at least about 700%, at least about 750%, at least about 800%, at least about 850%, at least about 900%, at least about 950%, or at least about 1000%.Combination Therapies

[0075] The administration of any one of the Protein S antibodies provided herein to a subject in need thereof may be a monotherapy, or may be in combination with any other known drugs or treatments for diseases or conditions. In some embodiments, the other known drugs or treatments are useful for treating disorders, diseases, or conditions associated with reduced or impaired clotting including VWD. In some embodiments, the disorder, condition is a bleeding disorder. In some embodiments, the disorder, disease, or condition is a bleeding disorder or a platelet disorder.

[0076] In some embodiments, the administration of any of the Protein S antibodies provided herein may be in combination with a factor replacement therapy. In some embodiments, the administration of any of the Protein S antibodies provided herein may be in combination with the administration of a recombinant Factor VII. In some embodiments, the administration of any of the Protein S antibodies provided herein may be in combination with an agent used to treat a breakthrough bleed.B. Protein S Antibodies

[0077] Provided herein are therapeutically effective Protein S antibodies. It is noted that the term “antibody” as used herein throughout is used a broad sense and includes a monoclonal antibody, human antibody, humanized antibody, a monovalent antibody, or an antigen-binding fragment (e.g., a Fab fragment, a Fab’2 fragment, an scFv), and other antibody fragments that retain specificity for and binding of Protein S. In some embodiments, the antibodies are monoclonal antibodies.

[0078] The Protein S antibodies of the disclosure specifically bind to Protein S and are capable of inhibiting its cofactor activity for TFPI and / or APC, and are useful in the treatment of VWD, other bleeding disorders, or other related diseases by promoting clot formation. The Protein S antibodies provided herein, bind a conformational epitope, including a thrombin sensitive (TSR) domain, and / or a Gia domain of Protein S. The Protein S antibodies of the disclosure are capable of binding human Protein S, and certain non-human primate forms for Protein S, including but not limited to cynomolgus monkey Protein S.

[0079] The amino acid sequence of human Protein S, targeted by antibodies of the disclosure, is shown below as SEQ ID. NO: 1.MRVLGGRCGA LLACLLLVLP VSEANFLSKQ QASQVLVRKR RANSLLEETK QGNLERECIE ELCNKEEARE VFENDPETDY FYPKYLVCLR SFQTGLFTAA RQSTNAYPDL RSCVNAIPDQ CSPLPCNEDG YMSCKDGKAS FTCTCKPGWQ GEKCEFDINE CKDPSNINGG CSQICDNTPG SYHCSCKNGF VMLSNKKDCK DVDECSLKPS ICGTAVCKNI PGDFECECPE GYRYNLKSKS CEDIDECSEN MCAQLCVNYP GGYTCYCDGK KGFKLAQDQK SCEVVSVCLP LNLDTKYELL YLAEQFAGVV LYLKFRLPEI SRFSAEFDFR TYDSEGVILY AESIDHSAWL LIALRGGKIE VQLKNEHTSK ITTGGDVINN GLWNMVSVEE LEHSISIKIA KEAVMDINKP GPLFKPENGL LETKVYFAGF PRKVESELIK PINPRLDGCI RSWNLMKQGA SGIKEIIQEK QNKHCLVTVE KGSYYPGSGI AQFHIDYNNV SSAEGWHVNV TLNIRPSTGT GVMLALVSGN NTVPFAVSLV DSTSEKSQDI LLSVENTVIY RIQALSLCSD QQSHLEFRVN RNNLELSTPL KIETISHEDL QRQLAVLDKA MKAKVATYLG GLPDVPFSAT PVNAFYNGCM EVNINGVQLD LDEAISKHND IRAHSCPSVW KKTKNS ( SEQ ID . NO : 1 ) i. Exemplary Protein S Antibodies - Complementarity Determining Region(CDR) Sequences

[0080] Provided herein are sequences for the exemplary Protein S antibodies of the disclosure. As referred below, a light chain variable (VL) region CDR1 region is referred to as CDR-L1; a VL CDR2 region is referred to as CDR-L2; a VL CDR3 region is referred to as CDR-L3; a heavy chain variable (VH) domain CDR1 region is referred to as CDR-H1; a VH CDR2 region is referred to as CDR-H2; and a VH CDR3 region is referred to as CDR-H3.

[0081] Table 1 provides the CDR triplet sequences for an exemplary antibody of the disclosure. The CDRs can be identified using standard antibody numbering schemes including, but not limited to, IMGT, Kabat, Chothia, and / or hybrid or variant schemes thereof. It will beunderstood that the precise boundaries of the CDRs may vary depending on the numbering scheme applied.Table 1 : Exemplary Protein S antibody CDR Combinations

[0082] In some embodiments, the light chain variable region comprises CDR sequences of SEQ ID NO: 4, an amino acid sequence of DAS, and SEQ ID NO: 6, and the heavy chain variable region comprises CDR sequences of SEQ ID NOS: 7, 8, and 9.

[0083] In some embodiments, the light chain variable region comprises CDR sequences of SEQ ID NO: 4, an amino acid sequence of DA, and SEQ ID NO: 6, and the heavy chain variable region comprises CDR sequences of SEQ ID NOS: 20, 21, and 9.

[0084] In some embodiments, the light chain variable region comprises CDR sequences of SEQ ID NOS: 22, 23, and 6, and the heavy chain variable region comprises CDR sequences of SEQ ID NOS: 24, 25, and 26. ii. Exemplary Protein S Antibodies- Variable Region Sequences

[0085] In some embodiments the Protein S antibodies of the disclosure comprise a heavy chain variable region (VH) comprising an amino acid sequence of SEQ ID NO: 10, or an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and comprise a light chain variable region (VL) comprising an amino acid sequence of SEQ ID NO: 11, or an aminoacid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%,92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0086] The term variable region and variable region are used interchangeably and refer to the portions of the light and heavy chains of an antibody that include the complementarity determining regions and framework regions (FRs).

[0087] In some embodiments, the Protein S antibodies of the disclosure comprises the combination of VH / VL variable chain sequences presented in Table 2Table 2: Variable Light Chain and Variable Heavy Chain Amino Acid Sequences

[0088] In some embodiments, provided herein is the exemplary Protein S antibody administered to the subject in need thereof, wherein the heavy chain variable region of the antibody comprises the amino acid sequence of SEQ ID NO: 11 or an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and / or wherein the light chain variable region of the antibody comprises the amino acid sequence of SEQ ID NO: 10, or an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto. In some embodiments, the heavy chain variable region of the antibody comprises the amino acid sequence of SEQ ID NO: 11, and the light chain variable region of the antibody comprises the amino acid sequence of SEQ ID NO: 10. In some embodiments, the light chain variable region comprises CDR sequences of SEQ ID NOS: 4, 5, and 6, and the heavy chain variable region comprises CDR sequences of SEQ ID NOS: 7, 8, and 9. In some embodiments, the light chain variable region comprises CDR sequences of SEQ ID NOS: 4, 19, and 6, and the heavy chain variable region comprises CDR sequences of SEQ ID NOS: 20, 21, and 9. In some embodiments, the light chain variable region comprises CDRsequences of SEQ ID NOS: 22, 23, and 6, and the heavy chain variable region comprises CDR sequences of SEQ ID NOS: 24, 25, and 26. iii. Exemplary Protein S Antibodies - Full Length Sequences

[0089] In some embodiments, the Protein S antibodies of the disclosure comprise a heavy chain amino acid sequence of SEQ ID NO: 12 or an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto and comprise a light chain amino acid sequence of SEQ ID NO: 13 or an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0090] The amino acid sequences of the heavy chain and light chain of VGA039, an exemplary antibody of the disclosure, and used throughout the examples, are shown Table 3.Table 3: Heavy Chain and Light Chain Amino Acid Sequences VGA039

[0091] In some embodiments, the Protein S antibodies of the disclosure comprise a heavy chain encoded by the nucleic acid sequence of SEQ ID NO: 17 or an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto and comprise a light chain encoded by the nucleic acid sequence of SEQ ID NO: 18 or an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0092] The nucleic acid sequences encoding the heavy chain and light chain of VGA039, an exemplary antibody of the disclosure, and used throughout the examples, are shown Table 4.

[0093] Table 4: Exemplary Heavy Chain and Light Chain Nucleic Acid Sequences encodingVGA039

[0094] In some embodiments, the Protein S antibodies of the disclosure comprise a constant region (herein referred to also as a Fc domain, a Fc sequence or simply as a Fc). In some embodiments, the Fc domain comprises a human Fc domain. In some embodiments, the Fc domain of a Protein S antibody is human IgGl, human IgG2, human IgG3, or human IgG4.

[0095] In some embodiments, the Protein S antibody administered to the subject in need thereof contains an Fc domain, and the Fc domain of the antibody is a human IgGl Fc. Exemplary, but non-limiting, human IgGl Fc domain sequences are provided as SEQ ID NOS: 2.1 ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS 61 GLYSLSSWT VPSSSLGTQT YICNVNHKPS NTKVDKKVEP KSCDKTHTCP PCPAPELLGG 121 PSVFLFPPKP KDTLMI SRTP EVTCVWDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN 181 STYRWSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTI S KAKGQPREPQ VYTLPPSRDE 241 LTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW 301 QQGNVFSCSV MHEALHNHYT QKSLSLSPGK ( SEQ ID NO : 2 )

[0096] In some embodiments, the Protein S antibody contains an Fc domain, and the Fc domain of the antibody is a human IgG4 Fc. An exemplary human IgG4 heavy chain Fc domain sequence is provided as SEQ ID NO: 3.ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLG TKTYTCNVDHKPSNTKVDKRVESKYGPPCPSCPAPEFLGGPSVFLFPPKPKDTLMI SRTPEVTCVWDVSQEDPEVQ FNWYVDGVEVHNAKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTI SKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK ( SEQ ID NO : 3 )

[0097] The EU numbering scheme is one of many available antibody numbering schemes based on the residue numbers assigned to a canonical antibody sequence. Accordingly, a skilled artisan would understand that reference to a particular residue using the EU numbering scheme may or may not be exactly the residue in one of the antibodies of the disclosure. For example, if a Protein S antibody of the disclosure comprises a V215A substitution in the Fc, wherein the position number of the amino acid residue is of the EU numbering scheme, the residue may not be the actual residue 215 in that particular Protein S antibody. It may be actual residue number 213, or 214, or 215, or 216. Accordingly, a skilled artisan will understand how to correspond the recited residue using the EU numbering scheme, to the actual residue in a Protein S antibody of the disclosure. The EU numbering system for antibodies is known in the art and is described, for example, at imgt.org / IMGTScientificChart / Numbering / Hu_IGHGnber.html.

[0098] In some embodiments, the Fc domain of a Protein S antibody administered to the subject in need thereof is an IgGl or IgG4 human Fc domain, and Fc variants comprise at least one amino acid substitution at a position selected from the group consisting of: 215, 221, 222, 228, 234, 235, 236, 239, 240, 241, 243, 244, 245, 247, 250, 252, 254, 256, 262, 263, 264, 265, 266, 267, 268, 269, 270, 292, 296, 297, 298, 299, 300, 305, 313, 324, 325, 326, 327, 328, 329, 330, 332, 333, 334, 345, 396, 428, 430, 433, 434, and 440, wherein the position numbers of the amino acid residues are of the EU numbering scheme. In some embodiments, the amino acid substitutions with the Fc domain of the Protein S antibody may result in one or more of the following: changes in FcRn binding, changes in effector function, changes in FcgR and Clq binding, changes in half-life of the antibody, and changes in Fab arm exchange. In some embodiments, the changes in each of FcRn binding, effector function, changes in FcgR and Clq binding, half-life of the antibody and Fab arm exchange includes increases or decreases, as will be described in more detail herein.

[0099] In some embodiments, the Fc domain of a Protein S antibody administered to a subject in need thereof is a human IgGl, and substitutions are introduced to reduce effector function, including N297A, N297Q, N297G, L235E, L234A, and L235A, wherein the position numbers of the amino acid residues are of the EU numbering scheme. In some embodiments, the Fcdomain of a full-length Protein S antibody is human IgG4, and substitutions are introduced to reduce effector function, including L235E, and F234A / L235A, wherein the position numbers of the amino acid residues are of the EU numbering scheme. In some embodiments, the Fc domain of a full-length Protein S antibody is human IgG2, and substitutions are introduced to reduce effector function, including H268Q / V309L / A330S / P33 IS and V234A / G237A / P238S / H268A / V309L / A330S / P331S, wherein the position numbers of the amino acid residues are of the EU numbering scheme.

[0100] In some embodiments, the Fc domain of a Protein S antibody administered to a subject in need thereof is an IgG4 human Fc domain, and the antibody is prone to the dynamic process of Fab-arm exchange. Accordingly, in some embodiments the IgG4 Fc domain comprises a S228P substitution, resulting in the reduction of this process, wherein the position number of the amino acid residues are of the EU numbering scheme.

[0101] In some embodiments, the Fc domain of a Protein S antibody administered to a subject in need thereof is an IgG4 human Fc domain, and the antibody is prone to FcyR and Clq binding. Accordingly, in some embodiments, the IgG4 Fc domain comprises a L235E substitution, resulting in a reduction of this process, wherein the position number of the amino acid residues are of the EU numbering scheme.

[0102] In some embodiments, the Fc domain of a Protein S antibody administered to a subject in need thereof is an IgG4 human Fc domain, and the antibody is prone to reduced FcRn binding. Accordingly, in some embodiments, the IgG4 Fc domain comprises either a M428L substitution, N434S substitution, or both M428L and N434S substitutions, resulting in an increased FcRn binding including at a pH=6.0, wherein the position numbers of the amino acid residues are of the EU numbering scheme.

[0103] In some embodiments, the Fc domain of the Protein S antibody administered to a subject in need thereof is an IgG4 human Fc domain and comprises the S228P substitution, the L235E substitution, and each of the M428L substitution and the N434S substation, wherein the position numbers of the amino acid residues are of the EU numbering scheme. These substitutions may be identified in Table 3 as being underlined and in bold.

[0104] In other embodiments, the Fc domain of a Protein S antibody administered to a subject in need thereof is altered to increase its serum half-life. Such alterations include substitutions of a human IgGl (e.g., SEQ ID NO: 2) such as T250Q / M428L, M252Y / S254T / T256E, M428L / N434S, S267E / L328F, N325S / L328F, and H433K / N434F, wherein the position number of the amino acid residues are of the EU numbering scheme.

[0105] In other embodiments, the Fc domain of a Protein S antibody administered to a subject in need thereof is altered to increase its serum half-life. Such alterations include substitutions of a human IgG4 (e.g., SEQ ID NO: 3) such as T250Q / M428L, M252Y / S254T / T256E, M428L / N434S, S267E / L328F, N325S / L328F, and H433K / N434F, wherein the position number of the amino acid residues are of the EU numbering scheme.C. Pharmaceutical Compositions

[0106] The disclosure also provides pharmaceutical compositions suitable for administration to a human subjects, comprising the Protein S antibodies disclosed herein, and optionally a pharmaceutically acceptable excipient or carrier. In some embodiments, the pharmaceutical composition is sterile. The pharmaceutical compositions may be formulated to be compatible with their intended routes of administration, e.g. subcutaneous or intravenous. .Enumerated Embodiments

[0107] The following non-limiting enumerated embodiments are provided as exemplary.

[0108] Embodiment 1-1. A method of treating Von Willebrand Disease (VWD) in a human subject in need thereof, comprising administering to the subject a therapeutically effective amount of a Protein S antibody, wherein an antibody plasma concentration of about Ipg / ml to about 200 pg / ml is reached upon administration of the antibody.

[0109] Embodiment 1-2. A method of treating Von Willebrand Disease (VWD) in a human subject in need thereof, comprising administering to the subject a therapeutically effective amount of a Protein S antibody using a body weight-based regimen, wherein the antibody is administered at one or more doses of about 0.1 mg / kg to about 10 mg / kg each.

[0110] Embodiment 1-3. A method of treating Von Willebrand Disease (VWD) in a human subject in need thereof, comprising administering to the subject a therapeutically effective amount of a Protein S antibody using a non-body weight-based regimen, wherein the antibody is administered at one or more doses of about 100 mg / dose to about 1000 mg / dose each.[OHl] Embodiment 1-4. The method of any one of Embodiment I- 1 -Embodiment 1-3, wherein the antibody is specific for a Thrombin Sensitive Region (TSR) domain and / or a Gia domain of Protein S.

[0112] Embodiment 1-5. The method of any one of Embodiment I- 1 -Embodiment 1-4, wherein the antibody comprises:

[0113] a. a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 11 or an amino acid sequence with at least 80% sequence identity thereto; and

[0114] b.a light chain variable region (VL) of the antibody comprising the amino acid sequence of SEQ ID NO: 10, or an amino acid sequence with at least 80% sequence identity thereto.

[0115] Embodiment 1-6. The method of any one of Embodiment I- 1 -Embodiment 1-5, wherein the antibody comprises complementarity determining region (CDR) sequences of:

[0116] a. SEQ ID NO: 4, an amino acid sequence of DAS, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, and SEQ ID NO: 9;

[0117] b.SEQ ID NO: 4, an amino acid sequence of DA, SEQ ID NO: 6, SEQ ID NO: 20, SEQ ID NO: 21, and SEQ ID NO: 9; or

[0118] c. SEQ ID NO: 22, SEQ ID NO: 23, and SEQ ID NO: 6, SEQ ID NO: 24, SEQ ID NO: 25, and SEQ ID NO: 26.

[0119] Embodiment 1-7. The method of any one of Embodiment I- 1 -Embodiment 1-6, wherein the antibody comprises a Fc domain.

[0120] Embodiment 1-8. The method of Embodiment 1-7, wherein the Fc domain exhibits a reduced FcRn binding.

[0121] Embodiment 1-9. The method of Embodiment 1-7, wherein the Fc domain exhibits a reduced effector function.

[0122] Embodiment 1-10. The method of Embodiment 1-7, wherein the Fc domain is engineered to increase the half-life of the antibody.

[0123] Embodiment 1-11. The method of any one of Embodiment I-7-Embodiment 1-10, wherein the Fc domain is selected from the group consisting of human IgGl, IgG2, IgG3, and IgG4.

[0124] Embodiment 1-12. The method of Embodiment 1-11, wherein the Fc domain of the antibody is a human IgG4, and comprises at least one amino acid substitution relative to SEQ ID NO: 3, wherein the position numbers of the amino acid residues are of the EU numbering scheme.

[0125] Embodiment 1-13. The method of Embodiment 1-12, wherein the Fc domain of the antibody is a human IgG4, and comprises substitutions S228P, L235E, M428L, and N434S, relative to SEQ ID NO: 3, wherein the position numbers of the amino acid residues are of the EU numbering scheme.

[0126] Embodiment 1-14. The method of any one of Embodiment I- 1 -Embodiment 1-13, wherein the antibody comprises:

[0127] a. a heavy chain comprising the amino acid sequence of SEQ ID NO: 12, or an amino acid sequence with at least 80% sequence identity thereto; and

[0128] b.a light chain comprising the amino acid sequence of SEQ ID NO: 13, or an amino acid sequence with at least 80% sequence identity thereto.

[0129] Embodiment 1-15. The method of any one of Embodiment I- 1 -Embodiment 1-14, wherein the antibody comprises:

[0130] a. a heavy chain encoded by the nucleic acid sequence of SEQ ID NO: 17, or a nucleic acid sequence with at least 80% sequence identity thereto; and

[0131] b.a light chain encoded by the nucleic acid sequence of SEQ ID NO: 18, or a nucleic acid sequence with at least 80% sequence identity thereto.

[0132] Embodiment 1-16. The method of any one of Embodiment I- 1 -Embodiment 1-15, wherein the antibody is administered to the subject subcutaneously.

[0133] Embodiment 1-17. The method of any one of Embodiment I- 1 -Embodiment 1-15, wherein the antibody is administered to the subject intravenously.

[0134] Embodiment 1-18. The method of any one of Embodiment I- 1 -Embodiment 1-17, wherein the antibody is administered to the subject daily.

[0135] Embodiment 1-19. The method of any one of Embodiment I- 1 -Embodiment 1-17, wherein the antibody is administered to the subject once weekly.

[0136] Embodiment 1-20. The method of any one of Embodiment I- 1 -Embodiment 1-17, wherein the antibody is administered to the subject once about every two weeks.

[0137] Embodiment 1-21. The method of any one of Embodiment I- 1 -Embodiment 1-17, wherein the antibody is administered to the subject once every about three weeks.

[0138] Embodiment 1-22. The method of any one of Embodiment I- 1 -Embodiment 1-17, wherein the antibody is administered to the subject once about every four weeks.

[0139] Embodiment 1-23. The method of any one of Embodiment I- 1 -Embodiment 1-17, wherein the treatment comprises the administration of a plurality of doses.

[0140] Embodiment 1-24. The method of any one of Embodiment I- 1 -Embodiment 1-23, wherein the treatment comprises one or more loading doses.

[0141] Embodiment 1-25. The method of any one of Embodiment I- 1 -Embodiment 1-24, wherein the treatment comprises one or more loading doses and one or more maintenance doses.

[0142] Embodiment 1-26. The method of Embodiment 1-25, wherein the loading dose is administered on Day 1 and one or more maintenance doses are administered on Day 8 followed by once every 4 weeks.

[0143] Embodiment 1-27. The method of any one of Embodiment I- 1 -Embodiment 1-26, wherein a plasma concentration of about 1 pg / ml - 10 pg / ml is reached upon administration of the antibody.

[0144] Embodiment 1-28. The method of any one of Embodiment I- 1 -Embodiment 1-26, wherein a plasma concentration of about 10 pg / ml - 100 pg / ml is reached upon administration of the antibody.

[0145] Embodiment 1-29. The method of any one of Embodiment I- 1 -Embodiment 1-26, wherein a plasma concentration of about 10 pg / ml -50 pg / ml is reached upon administration of the antibody.

[0146] Embodiment 1-30. The method of any one of Embodiment I- 1 -Embodiment 1-26, wherein a plasma concentration of about 5 pg / ml -50 pg / ml is reached upon administration of the antibody.

[0147] Embodiment 1-31. The method of any one of Embodiment I- 1 -Embodiment 1-26, wherein a plasma concentration of about 20 pg / ml -25 pg / ml is reached upon administration of the antibody.

[0148] Embodiment 1-32. The method of any one of Embodiment I- 1 -Embodiment 1-26, wherein a plasma concentration of about 50 pg / ml -200 pg / ml is reached upon administration of the antibody.

[0149] Embodiment 1-33. The method of any one of Embodiment I- 1 -Embodiment 1-26, wherein a plasma concentration of about 75 pg / ml -200 pg / ml is reached upon administration of the antibody.

[0150] Embodiment 1-34. The method of any one of Embodiment I- 1 -Embodiment 1-26, wherein a plasma concentration of about 100 pg / ml -200 pg / ml is reached upon administration of the antibody.

[0151] Embodiment 1-35. The method of any one of Embodiment 1-1, 3, 4-32, wherein the one or more doses is selected from the group consisting of: 150 mg / dose, 225mg / dose, 300 mg / dose, 450 mg / dose, 600 mg / dose, and 900 mg / dose.

[0152] Embodiment 1-36. The method of any one of Embodiment I- 1 -Embodiment 1-2,Embodiment I-4-Embodiment 1-34, wherein the method comprises administering one or more doses having a concentration of at least about 0.1 mg / kg to about 1.0 mg / kg.

[0153] Embodiment 1-37. The method of any one of Embodiment I- 1 -Embodiment 1-2,Embodiment I-4-Embodiment 1-34, wherein the method comprises one or more doses having a concentration of at least about 1.0 mg / kg to about 10.0 mg / kg.

[0154] Embodiment 1-38. The method of any one of Embodiment I- 1 -Embodiment 1-2,Embodiment I-4-Embodiment 1-34, wherein the method comprises one or more doses having a concentration of at least about 1.0 mg / kg to about 3.0 mg / kg.

[0155] Embodiment 1-39. The method of any one of Embodiment I- 1 -Embodiment 1-38, wherein the VWD subtype is selected from the group consisting of: VWD type 1, VWD type 2A, VWD type 2B, VWD type 2M, VWD type 2N, and VWD type 3.

[0156] Embodiment 1-40. The method of any one of Embodiment I- 1 -Embodiment 1-39, wherein the method results in an increase in thrombin generation of at least 10% from baseline.

[0157] Embodiment 1-41. The method of any one of Embodiment I- 1 -Embodiment 1-40 wherein the method results in an increase in D-dimer of at least 0.3 pg / ml.

[0158] Embodiment 1-42. The method of any one of Embodiment I- 1 -Embodiment 1-41 wherein the method results in an increase in Prothrombin Fl +2 of at least 10% from baseline.

[0159] Embodiment 1-43. The method of any one of 1-40 wherein the method results in a restoration of hemostasis.

[0160] Embodiment 1-44. The method of any one of Embodiment I- 1 -Embodiment 1-43, wherein the method reduces the frequency, duration, and / or severity of a bleed in the subject.

[0161] Embodiment 1-45. The method of any one of Embodiment I- 1 -Embodiment 1-44, wherein the subject is an infant, about 29 days to about 23 months.

[0162] Embodiment 1-46. The method of any one of Embodiment I- 1 -Embodiment 1-44, wherein the subject is a child, about 2 years of age to about 12 years of age.

[0163] Embodiment 1-47. The method of any one of Embodiment I- 1 -Embodiment 1-44, wherein the subject is an adolescent, about 12 years of age to about 17 years of age.

[0164] Embodiment 1-48. The method of any one of Embodiment I- 1 -Embodiment 1-44, wherein the subject is an adult, ages at least 18 years.

[0165] Embodiment 1-49. The method of any one of Embodiment I- 1 -Embodiment 1-48, wherein the subject is a male.

[0166] Embodiment 1-50. The method of any one of Embodiment I- 1 -Embodiment 1-48, wherein the subject is a female.

[0167] Embodiment 1-51. The method of Embodiment 1-50, wherein the method results in a restoration of a normal menstrual bleed in the female subject.

[0168] Embodiment 1-52. The method of any one of Embodiment I- 1 -Embodiment 1-51, wherein the subject is administered a therapeutically effect amount of the Protein S antibody for routine prophylaxis.

[0169] Embodiment 1-53. The method of any one of Embodiment I- 1 -Embodiment 1-51, wherein the subject is administered a therapeutically effect amount of Protein S antibody for on- demand prophylaxis.

[0170] Embodiment 1-54. The method of Embodiment 1-53, wherein the on-demand prophylaxis is for perioperative management of bleeding.

[0171] Embodiment 1-55. The method of Embodiment 1-53, wherein the on-demand prophylaxis is for management of an anticipated trauma.

[0172] Embodiment 1-56. The method of any one of Embodiment I- 1 -Embodiment 1-55, wherein the subject is at risk of suffering from a bleed selected from the group consisting of intercranial hemorrhage, mouth bleeds, epistaxis, hematemesis, pulmonary hemorrhage, gastrointestinal bleeds, joint bleeds, muscle bleeds, hematomas, bruising, menorrhagia, and hematuria.

[0173] Embodiment 1-57. The method of any one of Embodiment I- 1 -Embodiment 1-56, wherein the antibody is administered as part of a pharmaceutical composition comprising the Protein S antibody and a pharmaceutically acceptable excipient or carrier.

[0174] Embodiment 1-58. The method of any one of Embodiment I- 1 -Embodiment 1-57, wherein the subject suffers from at least one additional bleeding disorder selected form the group consisting of hemophilia A, hemophilia B, menorrhagia including menorrhagia due to a congenital or acquired factor deficiency, Factor I deficiency, Factor II deficiency, Factor V deficiency, Factor VII deficiency, Factor X deficiency, Factor XI deficiency (hemophilia C), Factor VIII deficiency (hemophilia A), Factor IX deficiency (hemophilia B), trauma, and hereditary hemorrhagic telangiectasia.

[0175] Embodiment 1-59. Use of a Protein S antibody in the manufacture of a medicament for treating Von Willebrand Disease (VWD) in a human subject in need thereof, comprising administering to the subject a therapeutically effective amount of the antibody, wherein a plasma concentration of about Ipg / ml to about 200 pg / ml is reached upon administration of the antibody.

[0176] Embodiment 1-60. Use of a Protein S antibody in the manufacture of a medicament for treating Von Willebrand Disease (VWD) in a human subject in need thereof, comprising administering to the subject a therapeutically effective amount of the antibody using a body weight-based regimen, wherein the antibody is administered at one or more doses of about 0.1 mg / kg to about 10 mg / kg each.

[0177] Embodiment 1-61. Use of a Protein S antibody in the manufacture of a medicament for treating Von Willebrand Disease (VWD) in a human subject in need thereof, comprising administering to the subject a therapeutically effective amount of the antibody using a non-body weight-based regimen, wherein the antibody is administered at one or more doses of about 100 mg / dose to about 1000 mg / dose each.

[0178] Embodiment 1-62. A Protein S antibody for use in treating Von Willebrand Disease (VWD) in a human subject in need thereof, comprising administering to the subject atherapeutically effective amount of the antibody, wherein a plasma concentration of about Ipg / ml to about 200 pg / ml is reached upon administration of the antibody.

[0179] Embodiment 1-63. A Protein S antibody for use in treating Von Willebrand Disease (VWD) in a human subject in need thereof, comprising administering to the subject a therapeutically effective amount of the antibody using a body weight-based regimen, wherein the antibody is administered at one or more doses of about 0.1 mg / kg to about 10 mg / kg each.

[0180] Embodiment 1-64. A Protein S antibody for use in treating Von Willebrand Disease (VWD) in a human subject in need thereof, comprising administering to the subject a therapeutically effective amount of the antibody using a non-body weight-based regimen, wherein the antibody is administered at one or more doses of about 100 mg / dose to about 1000 mg / dose each.

[0181] Embodiment 1-65. A method of treating Von Willebrand Disease (VWD) in a human subject in need thereof, comprising administering to the subject a therapeutically effective amount of a Protein S antibody, wherein a plasma concentration of about 1 pg / ml to about 200 pg / ml is reached upon administration of the antibody, wherein the antibody comprises a means for binding Protein S.

[0182] Embodiment 1-66. A method of treating Von Willebrand Disease (VWD) in a human subject in need thereof, comprising administering to the subject a therapeutically effective amount of a Protein S antibody using a body weight-based regimen, wherein the antibody is administered at one or more doses of about 0.1 mg / kg to about 10 mg / kg each, wherein the antibody comprises a means for binding Protein S.

[0183] Embodiment 1-67. A method of treating Von Willebrand Disease (VWD) in a human subject in need thereof, comprising administering to the subject a therapeutically effective amount of a Protein S antibody using a non-body weight-based regimen, wherein the antibody is administered at one or more doses of about 100 mg / dose to about 1000 mg / dose each, wherein the antibody comprises a means for binding Protein S.EXAMPLESExample 1: VGA039 Increases Thrombin Generation in Samples from VWD Human Donors Protocol Design and Criteria

[0184] To evaluate the ability of VGA039 to increase thrombin generation in vitro, plasma samples were taken from subjects diagnosed with four different types of VWD, including type 1, type 2A, type 2B, and type 3. The samples were assayed in the absence of added activated protein C (APC) or after addition of APC and addition of increasing concentrations of the exemplary Protein S antibody of the disclosure (from about 0.1 pg / mL to about 1000 pg / mL). Thrombin generation was measured (peak height, in nM) and plotted on the graph depicted in FIG. 3. VGA039 increased thrombin generation in plasma samples from patients regardless of the VWD type.

[0185] It is noted that in this and subsequent examples, VGA039 is evaluated. The same studies may be repeated with any Protein S antibody of disclosure.Example 2: VGA039 demonstrates in vivo hemostatic efficacy in NHP VWD Model

[0186] To examine the effect of administration of VGA039 in vivo using a bleeding disorder model, an experimentally induced, severe VWD model was generated in non-human primates (i.e., cynomolgus monkeys). The methods are described in WO / 2024 / 124136 filed on December 8, 2023, the contents of which are expressly incorporated herein in their entirety. Cynomolgus monkeys were split into two groups: Group 1, or Group 2, with each group having three monkeys therein and were treated with one of the following dosing regimens according to Table El.

[0187] Caplacizumab, an exemplary anti-VWF antibody, was used. Caplacizumab is a bivalent single domain antibody that is specific for the Al domain of Von Willebrand Factor (and currently sold under the name Cablivi®) and comprises the sequence of SEQ ID NO: 14:EVQLVESGGGLVQPGGSLRLSCAASGRTFSYNPMGWFRQAPGKGRELVAAISRTGGSTYYPDSV EGRFTISRDNAKRMVYLQMNSLRAEDTAVYYCAAAGVRAEDGRVRTLPSEYTFWGQGTQVTVSS ( SEQ ID NO : 14 ) .

[0188] Also used was a monoclonal -Factor VIII antibody, that is specific for the C2 domain of Factor VIII and includes: a light chain variable sequence of SEQ ID NO: 15:EIALTQSPGTLSLSPGERATLSGRASQSFSSSYLAWYQQKPGQAPRLLIYGASTATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQKYGTSAITFGQGTRLEIKRAVAAPSVFI F PPSEDQVKSGTVSWCLLNNFYPREASVKWKVDGALKTGNSQESVTEQDSKDNTYSLSSTLTLS STDYQSHNVYACEVTHQGLSSPVTKSFN RGEC ( SEQ ID NO : 15 ) , and a heavy chain variable sequence of SEQ ID NO: 16:QVQLVQSGAEVKKPGASVKVSCKVSGYTLTELPVHWVGQAPGKGLEWVGSFDPESGES IYAREF QGSVTMTADTSTDIAYMELSSLRSDDTAVYYGAVPDPDAFDIWGQGTMVTVSSASTKGPSVFPL APSSRSTSESTAALGCLVKDYFPEPVTVSWNSGSLTSGVHTFPAVLQSSGLYSLSSWTVPSSS LGTQTYVCNVNHKPSNTKVDKRVEIKTCGGGSKPPTCPPCPAPELLGGPSVFLFPPKPKDTLMI SRTPEVTCVWDVSQEDPDVKFNWYVNGAEVHHAQTKPRETQYNSTYRWSVLTVTHQDWLNGK EYTCKVSNKALPAPIQKTISKDKGQPREPQVYTLPPSREELTKNQVSLTGLVKGFYPSDIWEW ESSGQPENTYKTTPPVLDSDGSYFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSVSP ( SEQ ID NO : 16 ) ; or the combination of the two antibodies and VGA039.Table El. Dosing Schedule

[0189] FIGS. 4A-4B depicts the effects of administration of either PBS or VGA039 on mucosal bleeding time and hemoglobin levels in the experimentally induced, severe VWD model in non-human primates.

[0190] For each of FIGS. 4A-4B, vertical dotted lines represent repeated administration of caplacizumab (“Cap”) subcutaneously (5 mg / kg according to Table 3) on Day -4 (-96 hours), Day -3 (-72 hours), Day -2 (-48 hours), Day -1 (-24 hours), Day 1 (0 hours), Day 2 (24 hours), and Day 3 (72 hours) while the single dotted line at Day 1 (0 hours) represents theadministration of anti-FVIII intravenously (0.1 mg / kg according to Table 3). The vertical dashed line at Day 1 (3.5 hours) represents the intravenous administration of either: a vehicle (PBS) or VGA039(10 mg / kg according to Table El).

[0191] As seen in FIG. 4A, administration of VGA039 decreases mucosal bleeding time compared to control, indicating that VGA039 reduces bleed duration. As seen in FIG. 4B, administration of VGA039 maintains hemoglobin levels (e.g., reduces bleed severity) while administration of PBS demonstrates a reduction in hemoglobin levels at later time points.Example 3: VGA039 Dosing Protocol Design and Criteria

[0192] To examine the effects of administration of VGA039 in healthy human subjects, a dosing protocol was designed. FIG. 5 is a schematic of a randomized, double-blind, placebo- controlled single ascending dose protocol. The protocol was used to examine safety, tolerability, pharmacokinetics (PD), and pharmacodynamics (PD) of VGA039.

[0193] The protocol was set up using two different routes of administration (IV and SC) using a single ascending dose in healthy volunteers. Healthy volunteers were split up into 7 cohorts with 4 cohorts being administered the Protein S antibody using the IV route of administration and 3 cohorts being administered VGA039 using the SC route of administration. Within each cohort, healthy volunteers were randomized in a 3:2 ratio (3 volunteers receiving VGA039 and 2 volunteers receiving placebo) and administered a single ascending dose. The starting IV dose was 0.1 mg / kg. The single dose was escalated until the dose escalation stopping criteria was met or if 1 mg / kg IV or 3 mg / kg SC was reached. The dose escalation stopping criteria included measured D-dimer levels greater than upper limit of normal (ULN), or measured D-dimer levels being two-fold greater than baseline, whichever was higher, in two consecutive results separated by at least 24 hours in at least 2 subjects. Based on an assumption of reduced bioavailability with SC versus IV administration, the maximally tolerated or administered dose for intravenous administration was the starting dose for subcutaneous administration. Table E2 shows a description of the cohorts, route of administration and dose for the VGA039 dosing protocol, also seen in FIG. 5.Table E2: Description of Cohorts, Routes of Administration and Dose

[0194] The protocol had key inclusion and exclusion criteria for the healthy volunteers enrolled. Table E3 identifies the key inclusions and exclusions criteria.Table E3: Key Inclusion and Exclusion CriteriaExample 4: Administration of VGA039

[0195] A total of 35 normal healthy volunteers (NHVs) were dosed in 7 cohorts with each cohort having at least 2 NHVs receiving a placebo, as described above. None of the volunteers demonstrated Grade 2 or higher adverse effects related to the administration of VGA039. None of the volunteers demonstrated any remarkable abnormalities in laboratory, PE, or ECG parameters. None of the volunteers demonstrated infusion-related or injection site reactions in either the IV or SC cohorts.

[0196] FIG. 6A is a graph of mean drug concentration in the IV cohorts after administration of VGA039 and FIG. 6B is a graph of mean drug concentration in the SC cohorts after administration of VGA039. Both graphs demonstrate dose-dependent increases in VGA039antibody concentrations. Administration of VGA039 demonstrated an increased thrombin generation at higher doses.

[0197] FIG. 7 is a graph of plasma drug concentrations in subjects administered a single dose of VGA039 at 1 mg / kg IV or 1 mg / kg SC. Administration of VGA039 demonstrated a half-life of about 25 days with SC administration, bioavailability of 101% at Img / kg SC. Drug concentrations over time indicate high bioavailability and sustained SC exposure. Without being held to any theory or mechanism, with the half-life of about 25 days, VGA039 may be dosed weekly or less frequently.Example 5: Evaluation of Biomarkers after Administration of VGA039

[0198] Various biomarkers were measured, before, during and after administration of VGA039 to the subjects. The various biomarkers included thrombin generation, D-dimer concentrations, and Prothrombin Fl +2 concentrations. FIG. 8A shows a thrombin generation graph depicting mean % APC reversal for Cohorts 5, 6, and 7. Dose- and concentrationdependent changes in thrombin generation were observed across Cohorts 5, 6, and 7 for up to 168 hours post administration.

[0199] FIG. 8B depicts a graph of changes in mean D-dimer levels for Cohorts 5, 6, and 7. Dose and concentration-dependent changes were observed across Cohorts 5, 6, and 7 up to 1344 hours post administration. FIG. 8C depicts a graph of Mean % change from baseline for Prothrombin Fl +2 concentrations for Cohorts 5, 6, and 7 for up to 1344 hours post administration. There was no clinical evidence of thromboembolism at any dose tested.Example 6: Additional VGA039 Dosing and Evaluation of Biomarkers

[0200] In order to continue safety, tolerability, pharmacokinetics, and pharmacodynamics studies of SC administered VGA039 in VWD patients, additional dosages were explored. In this openlabel phase I protocol, the key eligibility criteria included: (1) symptomatic VWD of any type or subtype, (2) baseline FVIII activity level <50 ILJ / dL, (3) and no laboratory evidence of thrombophilia or prior history of thromboembolism. Dose escalations were determined based on emerging D-dimer levels, with a dose limiting toxicity (DLT) threshold set at 4 times the upper limit of normal. A total of 10 subjects were dosed with 3.0, 4.5, or 7.0 mg / kg of SC VGA039: 1with Type 1 VWD, 1 with Type 1 VWD + mild hemophilia A, 2 with Type 2A VWD, 2 with Type 2M VWD, 1 with Type 2N VWD, and 3 with Type 3 VWD (see Table E4). There were no drug- related adverse events, changes in coagulation laboratory parameters, thromboembolic events, DLTs, or injection-site reactions reported. No D-dimer elevations >1.0 pg / mL were observed, except in one 7.0 mg / kg, Type 1 subject (1.5 pg / mL) (FIG. 10). VGA039 concentrations predicted to increase prothrombin fragment 1+2 to levels above VWD subjects’ baseline and to increase their thrombin generation to levels measured in HVs at baseline were sustained for >4 weeks following a single, SC >4.5 mg / kg dose (FIGS. 9A-9C). Three evaluable 4.5 mg / kg subjects and one 7.0 mg / kg subject with historical annualized bleeding rates (AB Rs) >50 had reductions of 75% (Type 2M), 85% (Type 3), 87% (Type 2A), and 88% (Type 3) after a single dose of VGA039. One Type 3 subject had resolution of iron deficiency, with recrudescence of bleeding and iron deficiency following washout. Additionally, one Type 2N VWD subject in the 7 mg / kg cohort, who is a professional jet skier, previously suffered a number of traumatic muscle bleeds. On day 16, the subject reported having left calf pain, and an ultrasound of his left lower extremity showed a gastrocnemius muscle tear. Surprisingly there was no associated muscle hematoma, indicating that VGA039 may prevent “hemophilia-like” bleeds as well.Table E4:

[0201] While embodiments of the present invention have been shown and described herein, those skilled in the art will understand that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims

CLAIMSWhat is claimed is:

1. A method of treating Von Willebrand Disease (VWD) in a human subject in need thereof, comprising administering to the subject a therapeutically effective amount of a Protein S antibody, wherein an antibody plasma concentration of about Ipg / ml to about 200 pg / ml is reached upon administration of the antibody.

2. A method of treating Von Willebrand Disease (VWD) in a human subject in need thereof, comprising administering to the subject a therapeutically effective amount of a Protein S antibody using a body weight-based regimen, wherein the antibody is administered at one or more doses of about 0.1 mg / kg to about 10 mg / kg each.

3. A method of treating Von Willebrand Disease (VWD) in a human subject in need thereof, comprising administering to the subject a therapeutically effective amount of a Protein S antibody using a non-body weight-based regimen, wherein the antibody is administered at one or more doses of about 100 mg / dose to about 1000 mg / dose each.

4. The method of any one of claims 1-3, wherein the antibody is specific for a Thrombin Sensitive Region (TSR) domain and / or a Gia domain of Protein S.

5. The method of any one of claims 1-4, wherein the antibody comprises: a. a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 11 or an amino acid sequence with at least 80% sequence identity thereto; and b. a light chain variable region (VL) of the antibody comprising the amino acid sequence of SEQ ID NO: 10, or an amino acid sequence with at least 80% sequence identity thereto.

6. The method of any one of claims 1-5, wherein the antibody comprises complementarity determining region (CDR) sequences of:a. SEQ ID NO: 4, an amino acid sequence of DAS, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, and SEQ ID NO: 9; b. SEQ ID NO: 4, an amino acid sequence of DA, SEQ ID NO: 6, SEQ ID NO: 20, SEQ ID NO: 21, and SEQ ID NO: 9; or c. SEQ ID NO: 22, SEQ ID NO: 23, and SEQ ID NO: 6, SEQ ID NO: 24, SEQ ID NO: 25, and SEQ ID NO: 26.

7. The method of any one of claims 1-6, wherein the antibody comprises a Fc domain.

8. The method of claim 7, wherein the Fc domain exhibits a reduced FcRn binding.

9. The method of claim 7, wherein the Fc domain exhibits a reduced effector function.

10. The method of claim 7, wherein the Fc domain is engineered to increase the half-life of the antibody.

11. The method of any one of claims 7-10, wherein the Fc domain is selected from the group consisting of human IgGl, IgG2, IgG3, and IgG4.

12. The method of claim 11, wherein the Fc domain of the antibody is a human IgG4, and comprises at least one amino acid substitution relative to SEQ ID NO: 3, wherein the position numbers of the amino acid residues are of the EU numbering scheme.

13. The method of claim 12, wherein the Fc domain of the antibody is a human IgG4, and comprises substitutions S228P, L235E, M428L, and N434S, relative to SEQ ID NO: 3, wherein the position numbers of the amino acid residues are of the EU numbering scheme.

14. The method of any one of claims 1-13, wherein the antibody comprises: a. a heavy chain comprising the amino acid sequence of SEQ ID NO: 12, or an amino acid sequence with at least 80% sequence identity thereto; andb. a light chain comprising the amino acid sequence of SEQ ID NO: 13, or an amino acid sequence with at least 80% sequence identity thereto.

15. The method of any one of claims 1-14, wherein the antibody comprises: a. a heavy chain encoded by the nucleic acid sequence of SEQ ID NO: 17, or a nucleic acid sequence with at least 80% sequence identity thereto; and b. a light chain encoded by the nucleic acid sequence of SEQ ID NO: 18, or a nucleic acid sequence with at least 80% sequence identity thereto.

16. The method of any one of claims 1-15, wherein the antibody is administered to the subject subcutaneously.

17. The method of any one of claims 1-15, wherein the antibody is administered to the subject intravenously.

18. The method of any one of claims 1-17, wherein the antibody is administered to the subject daily.

19. The method of any one of claims 1-17, wherein the antibody is administered to the subject once weekly.

20. The method of any one of claims 1-17, wherein the antibody is administered to the subject once about every two weeks.

21. The method of any one of claims 1-17, wherein the antibody is administered to the subject once every about three weeks.

22. The method of any one of claims 1-17, wherein the antibody is administered to the subject once about every four weeks.

23. The method of any one of claims 1-17, wherein the treatment comprises the administration of a plurality of doses.

24. The method of any one of claims 1-23, wherein the treatment comprises one or more loading doses.

25. The method of any one of claims 1-24, wherein the treatment comprises one or more loading doses and one or more maintenance doses.

26. The method of claim 25, wherein the loading dose is administered on Day 1 and one or more maintenance doses are administered on Day 8 followed by once every 4 weeks.

27. The method of any one of claims 1-26, wherein a plasma concentration of about 1 pg / ml - 10 pg / ml is reached upon administration of the antibody.

28. The method of any one of claims 1-26, wherein a plasma concentration of about 10 pg / ml - 100 pg / ml is reached upon administration of the antibody.

29. The method of any one of claims 1-26, wherein a plasma concentration of about 10 pg / ml -50 pg / ml is reached upon administration of the antibody.

30. The method of any one of claims 1-26, wherein a plasma concentration of about 5 pg / ml -50 pg / ml is reached upon administration of the antibody.

31. The method of any one of claims 1-26, wherein a plasma concentration of about 20 pg / ml -25 pg / ml is reached upon administration of the antibody.

32. The method of any one of claims 1-26, wherein a plasma concentration of about 50 pg / ml -200 pg / ml is reached upon administration of the antibody.

33. The method of any one of claims 1-26, wherein a plasma concentration of about 75 pg / ml -200 pg / ml is reached upon administration of the antibody.

34. The method of any one of claims 1-26, wherein a plasma concentration of about 100 pg / ml -200 pg / ml is reached upon administration of the antibody.

35. The method of any one of claims 1, 3, 4-32, wherein the one or more doses is selected from the group consisting of: 150 mg / dose, 225mg / dose, 300 mg / dose, 450 mg / dose, 600 mg / dose, and 900 mg / dose.

36. The method of any one of claims 1-2, 4-34, wherein the method comprises administering one or more doses having a concentration of at least about 0.1 mg / kg to about 1.0 mg / kg.

37. The method of any one of claims 1-2, 4-34, wherein the method comprises one or more doses having a concentration of at least about 1.0 mg / kg to about 10.0 mg / kg.

38. The method of any one of claims 1-2, 4-34, wherein the method comprises one or more doses having a concentration of at least about 1.0 mg / kg to about 3.0 mg / kg.

39. The method of any one of claims 1-38, wherein the VWD subtype is selected from the group consisting of: VWD type 1, VWD type 2A, VWD type 2B, VWD type 2M, VWD type 2N, and VWD type 3.

40. The method of any one of claims 1-39, wherein the method results in an increase in thrombin generation of at least 10% from baseline.

41. The method of any one of claims 1-40 wherein the method results in an increase in D- dimer of at least 0.3 pg / ml.

42. The method of any one of claims 1-41 wherein the method results in an increase in Prothrombin Fl +2 of at least 10% from baseline.

43. The method of any one of claims 1-40 wherein the method results in a restoration of hemostasis.

44. The method of any one of claims 1-43, wherein the method reduces the frequency, duration, and / or severity of a bleed in the subject.

45. The method of any one of claims 1-44, wherein the subject is an infant, about 29 days to about 23 months.

46. The method of any one of claims 1-44, wherein the subject is a child, about 2 years of age to about 12 years of age.

47. The method of any one of claims 1-44, wherein the subject is an adolescent, about 12 years of age to about 17 years of age.

48. The method of any one of claims 1-44, wherein the subject is an adult, ages at least 18 years.

49. The method of any one of claims 1-48, wherein the subject is a male.

50. The method of any one of claims 1-48, wherein the subject is a female.

51. The method of claim 50, wherein the method results in a restoration of a normal menstrual bleed in the female subject.

52. The method of any one of claims 1-51, wherein the subject is administered a therapeutically effect amount of the Protein S antibody for routine prophylaxis.

53. The method of any one of claims 1-51, wherein the subject is administered a therapeutically effect amount of Protein S antibody for on-demand prophylaxis.

54. The method of claim 53, wherein the on-demand prophylaxis is for perioperative management of bleeding.

55. The method of claim 53, wherein the on-demand prophylaxis is for management of an anticipated trauma.

56. The method of any one of claims 1-55, wherein the subject is at risk of suffering from a bleed selected from the group consisting of intercranial hemorrhage, mouth bleeds, epistaxis, hematemesis, pulmonary hemorrhage, gastrointestinal bleeds, joint bleeds, muscle bleeds, hematomas, bruising, menorrhagia, and hematuria.

57. The method of any one of claims 1-56, wherein the antibody is administered as part of a pharmaceutical composition comprising the Protein S antibody and a pharmaceutically acceptable excipient or carrier.

58. The method of any one of claims 1-57, wherein the subject suffers from at least one additional bleeding disorder selected form the group consisting of hemophilia A, hemophilia B, menorrhagia including menorrhagia due to a congenital or acquired factor deficiency, Factor I deficiency, Factor II deficiency, Factor V deficiency, Factor VII deficiency, Factor X deficiency, Factor XI deficiency (hemophilia C), Factor VIIIdeficiency (hemophilia A), Factor IX deficiency (hemophilia B), trauma, and hereditary hemorrhagic telangiectasia.

59. Use of a Protein S antibody in the manufacture of a medicament for treating Von Willebrand Disease (VWD) in a human subject in need thereof, comprising administering to the subject a therapeutically effective amount of the antibody, wherein a plasma concentration of about Ipg / ml to about 200 pg / ml is reached upon administration of the antibody.

60. Use of a Protein S antibody in the manufacture of a medicament for treating Von Willebrand Disease (VWD) in a human subject in need thereof, comprising administering to the subject a therapeutically effective amount of the antibody using a body weight-based regimen, wherein the antibody is administered at one or more doses of about 0.1 mg / kg to about 10 mg / kg each.

61. Use of a Protein S antibody in the manufacture of a medicament for treating Von Willebrand Disease (VWD) in a human subject in need thereof, comprising administering to the subject a therapeutically effective amount of the antibody using a non-body weight-based regimen, wherein the antibody is administered at one or more doses of about 100 mg / dose to about 1000 mg / dose each.

62. A Protein S antibody for use in treating Von Willebrand Disease (VWD) in a human subject in need thereof, comprising administering to the subject a therapeutically effective amount of the antibody, wherein a plasma concentration of about 1 pg / ml to about 200 pg / ml is reached upon administration of the antibody.

63. A Protein S antibody for use in treating Von Willebrand Disease (VWD) in a human subject in need thereof, comprising administering to the subject a therapeutically effective amount of the antibody using a body weight-based regimen, wherein the antibody is administered at one or more doses of about 0.1 mg / kg to about 10 mg / kg each.

64. A Protein S antibody for use in treating Von Willebrand Disease (VWD) in a human subject in need thereof, comprising administering to the subject a therapeuticallyeffective amount of the antibody using a non-body weight-based regimen, wherein the antibody is administered at one or more doses of about 100 mg / dose to about 1000 mg / dose each.

65. A method of treating Von Willebrand Disease (VWD) in a human subject in need thereof, comprising administering to the subject a therapeutically effective amount of a Protein S antibody, wherein a plasma concentration of about 1 pg / ml to about 200 pg / ml is reached upon administration of the antibody, wherein the antibody comprises a means for binding Protein S.

66. A method of treating Von Willebrand Disease (VWD) in a human subject in need thereof, comprising administering to the subject a therapeutically effective amount of a Protein S antibody using a body weight-based regimen, wherein the antibody is administered at one or more doses of about 0.1 mg / kg to about 10 mg / kg each, wherein the antibody comprises a means for binding Protein S.

67. A method of treating Von Willebrand Disease (VWD) in a human subject in need thereof, comprising administering to the subject a therapeutically effective amount of a Protein S antibody using a non-body weight-based regimen, wherein the antibody is administered at one or more doses of about 100 mg / dose to about 1000 mg / dose each, wherein the antibody comprises a means for binding Protein S.

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