Method for treating a state of blood loss

Abstract

Aspects of the present disclosure provide compositions and methods for treating a subject having a state of blood loss, the method comprising administering to the subject a hemodjuvelin (HJV) antagonist (e.g., an anti-HJV antibody).

Description

Technical Field

[0001] Related Art This application claims the benefit of U.S. Provisional Application No. 63 / 350,766, filed Jun. 9, 2022, the entire contents of which are incorporated herein by reference.

[0002] Reference to Electronic Sequence Listing The contents of the electronic sequence listing (D084270007WO00-SEQ-LJG.xml; size: 202,362 bytes; created on Jun. 7, 2023) are incorporated herein by reference in their entirety.

Background Art

[0003] Iron is an important component of oxygen-carrying storage molecules such as hemoglobin and myoglobin. Blood loss conditions cause iron deficiency. Hepcidin is an important peptide hormone that controls systemic iron homeostasis. It exerts its regulatory function by binding to the transmembrane protein ferroportin, which is present in hepatocytes, enterocytes of the duodenum, macrophages, and adipocytes. The binding of hepcidin promotes the degradation of ferroportin and inhibits the excretion of iron from cells and the release of iron into the plasma.

Summary of the Invention

[0004] Aspects of the present disclosure relate to compositions and methods for treating subjects having a blood loss condition. In some embodiments, the treatments described herein promote hematological recovery, such as recovery to baseline levels of erythropoiesis, reticulocyte hemoglobin (CHr), mean corpuscular hemoglobin (MCH), and / or circulating hemoglobin levels.

[0005] In some aspects, the present disclosure provides a method for treating a subject having a blood loss condition, the method comprising administering a hemojuvelin antagonist to the subject.

[0006] In some embodiments, the hepcidin antagonist is administered in an amount effective to promote hematological recovery. In some embodiments, hematological recovery includes the recovery of erythropoiesis, reticulocyte hemoglobin content (CHr), mean corpuscular hemoglobin (MCH), and / or circulating hemoglobin levels to their baseline levels prior to the blood loss condition. In some embodiments, hematological recovery is achieved within a shorter period compared to the period achieved in control subjects not administered the hepcidin antagonist. In some embodiments, hematological recovery includes the recovery of erythropoiesis, reticulocyte hemoglobin (CHr), mean corpuscular hemoglobin (MCH), and / or circulating hemoglobin levels to their baseline levels within 3 days, 5 days, 1 week, 2 weeks, 3 weeks, or 4 weeks.

[0007] In some embodiments, the blood loss condition includes chronic blood loss. In some embodiments, the blood loss condition includes acute blood loss.

[0008] In some embodiments, the blood loss condition includes iatrogenic blood loss. In some embodiments, the blood loss condition includes venipuncture. In some embodiments, the blood loss condition includes surgery. In some embodiments, the blood loss condition includes blood donation procedures.

[0009] In some embodiments, the blood loss condition includes a wound with bleeding. In some embodiments, the wound with bleeding is a wound with internal bleeding. In some embodiments, the wound with internal bleeding is selected from vascular rupture, organ contusion, organ rupture, and hematoma. In some embodiments, the wound with bleeding is a wound with external bleeding. In some embodiments, the wound with external bleeding is selected from laceration, puncture, incision, avulsion, dissection, and penetration.

[0010] In some embodiments, the blood loss condition includes a disease.

[0011] In some embodiments, the disease is a gastrointestinal (GI) disease. In some embodiments, the GI disease includes bleeding due to esophageal varices, gastritis, gastric ulcer, duodenal ulcer, diverticulosis, Meckel's diverticulum, intestinal polyps, inflammatory bowel disease (IBD), hemorrhoids, celiac disease, or colorectal cancer.

[0012] In some embodiments, the disease is a urogenital disease. In some embodiments, the urogenital disease includes bleeding due to menorrhagia, uterine fibroids, endometriosis, bladder tumors, urinary tract infections (UTIs), or kidney stones.

[0013] In some embodiments, the disease is an infectious disease. In some embodiments, the infectious disease includes bleeding due to viral hemorrhagic fevers selected from dengue fever, Ebola virus disease, Lassa fever, hantavirus pulmonary syndrome, Marburg virus disease, and yellow fever. In some embodiments, the infectious disease includes bleeding due to bacterial infections selected from sepsis, bacterial vaginitis, Lemierre's syndrome, and tuberculosis. In some embodiments, the infectious disease includes bleeding due to parasitic infections selected from malaria, trichuriasis, and schistosomiasis.

[0014] In some embodiments, prior to administration, the subject has a hemoglobin level of at least 6 g / dl. In some embodiments, prior to administration, the subject has a hemoglobin level in the range of 7 - 12 g / dl. In some embodiments, prior to administration, the subject has a hemoglobin level in the range of 7 - 11 g / dl. In some embodiments, prior to administration, the subject has a hemoglobin level in the range of 7 - 10 g / dl. In some embodiments, after administration, the subject's hemoglobin level increases by 1 - 3 g / dl. In some embodiments, within 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, or 6 weeks after administration, the subject's hemoglobin level increases by 1 - 3 g / dl.

[0015] In some embodiments, prior to administration, the subject has ferritin levels in the range of up to 5000 ng / ml. In some embodiments, prior to administration, the subject has ferritin levels in the range of 14 - 150 ng / ml. In some embodiments, after administration, the subject's ferritin level decreases by 15% - 50% compared to the ferritin level prior to administration.

[0016] In some embodiments, prior to administration, the subject has TSAT% levels in the range of 15% - 30%. In some embodiments, after administration, the subject has TSAT% levels in the range of 30% - 50%. In some embodiments, the subject has TSAT% levels in the range of 30 - 50% within 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, or 6 weeks.

[0017] In some embodiments, prior to administration, the subject has reticulocyte hemoglobin (CHr) levels in the range of 20 - 40 pg. In some embodiments, after administration, the subject's CHr level increases by 1% - 5% compared to the CHr level prior to administration. In some embodiments, the subject's CHr level increases by 1% - 5% within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, or 2 weeks.

[0018] In some embodiments, prior to administration, the subject has hepcidin levels in the range of 5 - 75 ng / ml. In some embodiments, after administration, the subject's hepcidin level decreases by 2 - 60 ng / ml compared to the hepcidin level prior to administration.

[0019] In some embodiments, prior to administration, the subject has a red blood cell count in the range of 3×10 12 ~6×10 12 cells / L. In some embodiments, after administration, the subject's red blood cell count increases by at least 0.5×10 12 cells / L.

[0020] In some embodiments, prior to administration, the subject has an MCH level of 15 - 50 pg. In some embodiments, after administration, the subject's MCH level increases by 1% - 5% compared to the MCH level prior to administration.

[0021] In some embodiments, the subject does not have functional iron deficiency prior to administration.

[0022] In some embodiments, the subject does not have anemia associated with inflammation prior to administration. In some embodiments, the subject has anemia associated with inflammation prior to administration.

[0023] In some embodiments, the blood loss condition includes persistent blood loss. In some embodiments, the blood loss condition includes more than one instance of intermittent blood loss at intervals of up to 1 week, up to 2 weeks, or up to 1 month. In some embodiments, the blood loss includes loss of up to 10% of the subject's total blood volume. In some embodiments, the blood loss ranges from 1% to 10% of the subject's total blood volume. In some embodiments, the blood loss condition includes persistent blood loss that occurs within 1 hour, 4 hours, 8 hours, 12 hours, 16 hours, 20 hours, 1 day, 3 days, 5 days, 8 days, 10 days, 2 weeks, 3 weeks, 1 month, 2 months, or 3 months. In some embodiments, the blood loss condition includes persistent blood loss that lasts for at least 1 hour, at least 4 hours, at least 8 hours, at least 12 hours, at least 16 hours, at least 20 hours, at least 1 day, at least 3 days, at least 5 days, at least 8 days, at least 10 days, at least 2 weeks, at least 3 weeks, at least 1 month, at least 2 months, or at least 3 months. In some embodiments, the blood loss condition includes instances of intermittent blood loss where each instance of blood loss includes loss of up to 10% of the subject's total blood volume. In some embodiments, each instance of blood loss occurs at intervals of up to 1 hour, up to 4 hours, up to 8 hours, up to 12 hours, up to 16 hours, up to 20 hours, up to 1 day, up to 3 days, up to 5 days, up to 8 days, up to 10 days, or up to 2 weeks.

[0024] In some embodiments, the subject has a ferritin level of 14 - 80 ng / ml due to blood loss. In some embodiments, the subject has at least 40 μg / dL of serum iron.

[0025] In some embodiments, the hepcidin antagonist is an anti-hepcidin (HJV) antibody, such as the anti-HJV antibodies described herein.

[0026] In some embodiments, the hepcidin antagonist is administered to the subject once a week, twice a month, or once a month.

[0027] In some embodiments, the subject is not identified as requiring a blood transfusion. In some embodiments, the subject is identified as requiring a blood transfusion prior to administration of the hepcidin antagonist.

[0028] In some embodiments, the hepcidin antagonist is administered in combination with oral iron supplementation or iron injection.

[0029] In some embodiments, the hepcidin antagonist is administered while the subject is on a gluten-free diet.

[0030] In some embodiments, the hepcidin antagonist is administered in combination with a therapeutic agent. In some embodiments, the therapeutic agent is EPO. In some embodiments, the therapeutic agent is luspatercept. In some embodiments, the therapeutic agent is HIF-PHI. In some embodiments, the therapeutic agent is for treating a disease associated with blood loss.

[0031] In some embodiments, the hepcidin antagonist is administered subcutaneously. In some embodiments, the hepcidin antagonist is administered intravenously.

[0032] In some embodiments, the subject is administered a hepcidin antagonist on multiple occasions. In some embodiments, the occasions are at monthly intervals.

[0033] Another aspect of the disclosure relates to a method of treating a subject having anemia, the method comprising administering to the subject an effective amount of an anti-hepcidin antibody at monthly intervals. In some embodiments, the anemia is associated with functional iron deficiency. In some embodiments, the anemia is associated with inflammation.

[0034] In some embodiments, the anti-hepcidin antibody is administered subcutaneously. In some embodiments, the anti-hepcidin antibody is administered intravenously.

[0035] In some embodiments, the anti-hepcidin antibody is administered at a dose of from 25 mg to 70 mg. In some embodiments, the anti-hepcidin antibody is administered at a dose of from 35 mg to 65 mg. In some embodiments, the anti-hepcidin antibody is administered at a dose of from 45 mg to 60 mg. In some embodiments, the anti-hepcidin antibody is administered at a dose of 56 mg.

[0036] The foregoing, and other aspects, implementations, acts, functionalities, features, and embodiments of the disclosure can be more fully understood from the following description in conjunction with the accompanying drawings.

[0037] In some embodiments, a subject in need of administration of an anti-HJV antibody (e.g., a subject having a blood loss condition as described herein) is administered an anti-HJV antibody comprising an HC CDR1 comprising an amino acid sequence selected from SEQ ID NO: 1 or 9; an HC CDR2 comprising an amino acid sequence selected from SEQ ID NO: 2 or 10; an HC CDR3 comprising an amino acid sequence selected from SEQ ID NO: 3, 11, 12, or 13; an LC CDR1 comprising an amino acid sequence selected from SEQ ID NO: 4, 14, 15, 16, 17, 50; an LC CDR2 comprising an amino acid sequence selected from SEQ ID NO: 5, 49, 18, 19, 20, 21, 22, or 23; and an LC CDR3 comprising an amino acid sequence selected from SEQ ID NO: 6, 24, 25, 26, 27, 28, or 29. In some embodiments, a subject in need of administration of an anti-HJV antibody (e.g., a subject having a blood loss condition as described herein) is administered an anti-HJV antibody comprising a VH comprising an amino acid sequence selected from SEQ ID NO: 7, 34, 36, 38, 42, or 44; and a VL comprising an amino acid sequence selected from SEQ ID NO: 8, 30, 31, 32, 33, 35, 37, 39, 41, 43, or 45. In some embodiments, a subject in need of administration of an anti-HJV antibody (e.g., a subject having a blood loss condition as described herein) is administered an anti-HJV antibody comprising an HC sequence comprising an amino acid sequence selected from SEQ ID NO: 51, 114, 57, 115, 59, 116, 61, 117, 63, 118, 66, 119, 68, or 120; and an LC comprising an amino acid sequence selected from SEQ ID NO: 52, 53, 54, 55, 56, 58, 60, 62, 65, 67, or 69.

[0038] In some embodiments, a subject in need of administration of an anti-HJV antibody (e.g., a subject having a blood loss condition described herein) is administered an anti-HJV antibody comprising an HC CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 1, an HC CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2, an HC CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 3, an LC CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 17, an LC CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 5, and an LC CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 27. In some embodiments, a subject in need of administration of an anti-HJV antibody (e.g., a subject having a blood loss condition described herein) is administered an anti-HJV antibody comprising a VH comprising the amino acid sequence set forth in SEQ ID NO: 38 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 39. In some embodiments, a subject in need of administration of an anti-HJV antibody is administered an anti-HJV antibody comprising an HC comprising the amino acid sequence set forth in SEQ ID NO: 61 or 117 and an LC comprising the amino acid sequence set forth in SEQ ID NO: 62. In some embodiments, a subject in need of administration of an anti-HJV antibody (e.g., a subject having a blood loss condition described herein) is administered an anti-HJV antibody comprising an HC comprising the amino acid sequence set forth in SEQ ID NO: 63 or 118 and an LC comprising the amino acid sequence set forth in SEQ ID NO: 62.

[0039] In some embodiments, a subject in need of administration of an anti-HJV antibody (e.g., a subject having a blood loss condition as described herein) is administered an anti-HJV antibody comprising an HC CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 1, an HC CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2, an HC CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 3, an LC CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 4, an LC CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 5, and an LC CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 6. In some embodiments, a subject in need of administration of an anti-HJV antibody (e.g., a subject having a blood loss condition as described herein) is administered an anti-HJV antibody comprising a VH comprising the amino acid sequence set forth in SEQ ID NO: 7 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 8. In some embodiments, a subject in need of administration of an anti-HJV antibody (e.g., a subject having a blood loss condition as described herein) is administered an anti-HJV antibody comprising an HC comprising the amino acid sequence set forth in SEQ ID NO: 51 or 114 and an LC comprising the amino acid sequence set forth in SEQ ID NO: 52.

[0040] In some embodiments, a subject in need of administration of an anti-HJV antibody (e.g., a subject having a blood loss condition as described herein) is administered an anti-HJV antibody comprising an HC CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 1, an HC CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2, an HC CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 3, an LC CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 4, an LC CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 49, and an LC CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 24. In some embodiments, a subject in need of administration of an anti-HJV antibody (e.g., a subject having a blood loss condition as described herein) is administered an anti-HJV antibody comprising a VH comprising the amino acid sequence set forth in SEQ ID NO: 7 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 30. In some embodiments, a subject in need of administration of an anti-HJV antibody (e.g., a subject having a blood loss condition as described herein) is administered an anti-HJV antibody comprising an HC comprising the amino acid sequence set forth in SEQ ID NO: 51 or 114 and an LC comprising the amino acid sequence set forth in SEQ ID NO: 53.

[0041] In some embodiments, a subject in need of administration of an anti-HJV antibody (e.g., a subject having a blood loss condition as described herein) is administered an anti-HJV antibody comprising an HC CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 1, an HC CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2, an HC CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 3, an LC CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 4, an LC CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 18, and an LC CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 25. In some embodiments, a subject in need of administration of an anti-HJV antibody (e.g., a subject having a blood loss condition as described herein) is administered an anti-HJV antibody comprising a VH comprising the amino acid sequence set forth in SEQ ID NO: 7 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 31. In some embodiments, a subject in need of administration of an anti-HJV antibody (e.g., a subject having a blood loss condition as described herein) is administered an anti-HJV antibody comprising an HC comprising the amino acid sequence set forth in SEQ ID NO: 51 or 114 and an LC comprising the amino acid sequence set forth in SEQ ID NO: 54.

[0042] In some embodiments, a subject in need of administration of an anti-HJV antibody (e.g., a subject having a blood loss condition described herein) is administered an anti-HJV antibody comprising an HC CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 1, an HC CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2, an HC CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 3, an LC CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 4, an LC CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 49, and an LC CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 24. In some embodiments, a subject in need of administration of an anti-HJV antibody (e.g., a subject having a blood loss condition described herein) is administered an anti-HJV antibody comprising a VH comprising the amino acid sequence set forth in SEQ ID NO: 7 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 30. In some embodiments, a subject in need of administration of an anti-HJV antibody (e.g., a subject having a blood loss condition described herein) is administered an anti-HJV antibody comprising an HC comprising the amino acid sequence set forth in SEQ ID NO: 51 or 114 and an LC comprising the amino acid sequence set forth in SEQ ID NO: 53.

[0043] In some embodiments, a subject in need of administration of an anti-HJV antibody (e.g., a subject having a blood loss condition described herein) is administered an anti-HJV antibody comprising an HC CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 1, an HC CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2, an HC CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 3, an LC CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 14, an LC CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 19, and an LC CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 25. In some embodiments, a subject in need of administration of an anti-HJV antibody (e.g., a subject having a blood loss condition described herein) is administered an anti-HJV antibody comprising a VH comprising the amino acid sequence set forth in SEQ ID NO: 7 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 32. In some embodiments, a subject in need of administration of an anti-HJV antibody (e.g., a subject having a blood loss condition described herein) is administered an anti-HJV antibody comprising an HC comprising the amino acid sequence set forth in SEQ ID NO: 51 or 114 and an LC comprising the amino acid sequence set forth in SEQ ID NO: 55.

[0044] In some embodiments, a subject in need of administration of an anti-HJV antibody (e.g., a subject having a blood loss condition described herein) is administered an anti-HJV antibody comprising an HC CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 1, an HC CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2, an HC CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 3, an LC CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 15, an LC CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 20, and an LC CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 26. In some embodiments, a subject in need of administration of an anti-HJV antibody (e.g., a subject having a blood loss condition described herein) is administered an anti-HJV antibody comprising a VH comprising the amino acid sequence set forth in SEQ ID NO: 7 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 33. In some embodiments, a subject in need of administration of an anti-HJV antibody (e.g., a subject having a blood loss condition described herein) is administered an anti-HJV antibody comprising an HC comprising the amino acid sequence set forth in SEQ ID NO: 51 or 114 and an LC comprising the amino acid sequence set forth in SEQ ID NO: 56.

[0045] In some embodiments, a subject in need of administration of an anti-HJV antibody (e.g., a subject having a blood loss condition described herein) is administered an anti-HJV antibody comprising an HC CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, an HC CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2, an HC CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 3, an LC CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 16, an LC CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 21, and an LC CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 27. In some embodiments, a subject in need of administration of an anti-HJV antibody (e.g., a subject having a blood loss condition described herein) is administered an anti-HJV antibody comprising a VH comprising the amino acid sequence set forth in SEQ ID NO: 34 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 35. In some embodiments, a subject in need of administration of an anti-HJV antibody (e.g., a subject having a blood loss condition described herein) is administered an anti-HJV antibody comprising an HC comprising the amino acid sequence set forth in SEQ ID NO: 57 or 115 and an LC comprising the amino acid sequence set forth in SEQ ID NO: 58.

[0046] In some embodiments, a subject in need of administration of an anti-HJV antibody (e.g., a subject having a blood loss condition described herein) is administered an anti-HJV antibody comprising an HC CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 1, an HC CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, an HC CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 11, an LC CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 17, an LC CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 18, and an LC CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 28. In some embodiments, a subject in need of administration of an anti-HJV antibody (e.g., a subject having a blood loss condition described herein) is administered an anti-HJV antibody comprising a VH comprising the amino acid sequence set forth in SEQ ID NO: 36 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 37. In some embodiments, a subject in need of administration of an anti-HJV antibody (e.g., a subject having a blood loss condition described herein) is administered an anti-HJV antibody comprising an HC comprising the amino acid sequence set forth in SEQ ID NO: 59 or 116 and an LC comprising the amino acid sequence set forth in SEQ ID NO: 60.

[0047] In some embodiments, a subject in need of administration of an anti-HJV antibody (e.g., a subject having a blood loss condition as described herein) is administered an anti-HJV antibody comprising an HC CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 1, an HC CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2, an HC CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 3, an LC CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 50, an LC CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 22, and an LC CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 28. In some embodiments, a subject in need of administration of an anti-HJV antibody (e.g., a subject having a blood loss condition as described herein) is administered an anti-HJV antibody comprising a VH comprising the amino acid sequence set forth in SEQ ID NO: 38 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 41. In some embodiments, a subject in need of administration of an anti-HJV antibody (e.g., a subject having a blood loss condition as described herein) is administered an anti-HJV antibody comprising an HC comprising the amino acid sequence set forth in SEQ ID NO: 61 or 117 and an LC comprising the amino acid sequence set forth in SEQ ID NO: 65.

[0048] In some embodiments, a subject in need of administration of an anti-HJV antibody (e.g., a subject having a blood loss condition described herein) is administered an anti-HJV antibody comprising an HC CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 1, an HC CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2, an HC CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 12, an LC CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 15, an LC CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 23, and an LC CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 27. In some embodiments, a subject in need of administration of an anti-HJV antibody (e.g., a subject having a blood loss condition described herein) is administered an anti-HJV antibody comprising a VH comprising the amino acid sequence set forth in SEQ ID NO: 42 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 43. In some embodiments, a subject in need of administration of an anti-HJV antibody (e.g., a subject having a blood loss condition described herein) is administered an anti-HJV antibody comprising an HC comprising the amino acid sequence set forth in SEQ ID NO: 66 or 119 and an LC comprising the amino acid sequence set forth in SEQ ID NO: 67.

[0049] In some embodiments, a subject in need of administration of an anti-HJV antibody (e.g., a subject having a blood loss condition described herein) is administered an anti-HJV antibody comprising an HC CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 1, an HC CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2, an HC CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 13, an LC CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 16, an LC CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 21, and an LC CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 29. In some embodiments, a subject in need of administration of an anti-HJV antibody (e.g., a subject having a blood loss condition described herein) is administered an anti-HJV antibody comprising a VH comprising the amino acid sequence set forth in SEQ ID NO: 44 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 45. In some embodiments, a subject in need of administration of an anti-HJV antibody (e.g., a subject having a blood loss condition described herein) is administered an anti-HJV antibody comprising an HC comprising the amino acid sequence set forth in SEQ ID NO: 68 or 120 and an LC comprising the amino acid sequence set forth in SEQ ID NO: 69.

Brief Description of the Drawings

[0050] The accompanying drawings incorporated herein and constituting a part thereof illustrate specific embodiments and, together with the description, serve to provide non-limiting examples of specific aspects of the compositions and methods disclosed herein.

[0051]

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[0055]

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[0056] According to some aspects, the present disclosure provides compositions and methods for treating a subject having a blood loss condition, the method comprising administering to the subject a hemojuvelin (HJV) antagonist (e.g., an anti-HJV antibody).

[0057] Further aspects of the present disclosure, including explanations of defined terms, are provided below.

[0058] I. Definitions Administration: As used herein, the term "administering" or "administration" means providing a complex to a subject in a physiologically and / or pharmaceutically useful manner (e.g., for treating a condition of the subject).

[0059] Antibody: As used herein, the term "antibody" refers to a polypeptide that includes at least one immunoglobulin variable domain or at least one antigenic determinant, e.g., a paratope, that specifically binds to an antigen. In some embodiments, the antibody is a full-length antibody. In some embodiments, the antibody is a chimeric antibody. In some embodiments, the antibody is a humanized antibody. However, in some embodiments, the antibody is a Fab fragment, a D(ab’)2 fragment, an Fv fragment, or a scFv fragment. In some embodiments, the antibody is a nanobody derived from a camelid antibody or a nanobody derived from a shark antibody. In some embodiments, the antibody is a diabody. In some embodiments, the antibody includes a framework having human germline sequences. In another embodiment, the antibody includes a heavy chain constant domain selected from the group consisting of IgG, IgG1, IgG2, IgG2A, IgG2B, IgG2C, IgG3, IgG4, IgA1, IgA2, IgD, IgM, and IgE constant domains. In some embodiments, the antibody includes a heavy (H) chain variable region (referred to herein as VH) and / or a light (L) chain variable region (referred to herein as VL). In some embodiments, the antibody includes a constant domain, e.g., an Fc region. An immunoglobulin constant domain refers to a heavy chain constant domain or a light chain constant domain. The amino acid sequences of human IgG heavy and light chain constant domains and their functional variants are known. With respect to the heavy chain, in some embodiments, the heavy chain of the antibody described herein can be an alpha (α), delta (Δ), epsilon (ε), gamma (γ), or mu (μ) heavy chain. In some embodiments, the heavy chain of the antibody described herein can include a human alpha (α), delta (Δ), epsilon (ε), gamma (γ), or mu (μ) heavy chain. In certain embodiments, the antibody described herein includes human gamma1 CH1, CH2, and / or CH3 domains. In some embodiments, V HThe amino acid sequence of the domain includes the amino acid sequence of a human gamma (γ) heavy chain constant region, such as any known in the art. Non-limiting examples of human constant region sequences are described in the art, see, for example, U.S. Patent No. 5,693,780 and Kabat E A et al., (1991) supra. In some embodiments, V HThe domain comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, or at least 99% identical to any of the variable constant regions provided herein. In some embodiments, the antibody is modified, e.g., modified via glycosylation, phosphorylation, SUMOylation, and / or methylation. In some embodiments, the antibody is a glycosylated antibody conjugated to one or more sugar or carbohydrate molecules. In some embodiments, the one or more sugar or carbohydrate molecules are conjugated to the antibody via N-glycosylation, O-glycosylation, C-glycosylation, glypiation (GPI anchor attachment), and / or phosphoglycosylation. In some embodiments, the one or more sugar or carbohydrate molecules are monosaccharides, disaccharides, oligosaccharides, or glycans. In some embodiments, the one or more sugar or carbohydrate molecules are branched oligosaccharides or branched glycans. In some embodiments, the one or more sugar or carbohydrate molecules comprise mannose units, glucose units, N-acetylglucosamine units, or lipid phosphate units. In some embodiments, the antibody is a construct comprising a polypeptide comprising one or more antigen-binding fragments of the present disclosure linked to a linker polypeptide or an immunoglobulin constant domain. The linker polypeptide comprises two or more amino acid residues linked by peptide bonds and is used to link one or more antigen-binding portions. Examples of linker polypeptides have been reported (see, e.g., Holliger, P., et al. (1993) Proc. Natl. Acad. Sci. USA 90:6444-6448; Poljak, R. J., et al. (1994) Structure 2:1121-1123). Additionally, the antibody may be part of a larger immunoadhesion molecule formed by covalent or non-covalent interactions between the antibody or antibody portion and one or more other proteins or peptides.Examples of such immunoadhesin molecules include the use of the streptavidin core region to create tetrameric scFv molecules (Kipriyanov, S. M., et al. (1995) Human Antibodies and Hybridomas 6:93-101), as well as the use of cysteine residues, marker peptides, and C-terminal polyhistidine tags to create divalent biotinylated scFv molecules (Kipriyanov, S. M., et al. (1994) Mol. Immunol. 31:1047-1058).

[0060] Affinity matured antibody: As used herein, an “affinity matured antibody” refers to an antibody having one or more alterations in one or more CDRs, wherein the alteration results in an improvement in the affinity (i.e., KD, kd or ka) of the antibody for its target antigen as compared to the parental antibody that does not have the alteration. Exemplary affinity matured antibodies will have nanomolar or picomolar affinity for their target antigen. A variety of procedures for producing affinity matured antibodies are known in the art, including screening of combinatorial antibody libraries prepared using bio-display. As an example, Marks et al., BioTechnology, 10: 779-783 (1992) describes affinity maturation by VH and VL domain shuffling. Random mutagenesis of CDRs and / or framework residues is described in Barbas et al., Proc. Nat. Acad. Sci. USA, 91: 3809-3813 (1994); Schier et al., Gene, 169: 147-155 (1995); Yelton et al., J. Immunol., 155: 1994-2004 (1995); Jackson et al., J. Immunol., 154(7): 3310-3319 (1995); and Hawkins et al, J. Mol. Biol., 226: 889-896 (1992). Selective mutagenesis at selected mutagenesis positions, and at contact or hypervariable positions of activity-enhancing amino acid residues, is described in U.S. Patent No. 6,914,128 B1.

[0061] Approximately: As used herein, the term "approximately" or "about" when applied to one or more values of interest refers to a value similar to the recited reference value. In certain embodiments, the term "approximately" or "about" refers to a range of values within 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less in either direction (greater than or less than) of the recited reference value, unless otherwise stated or clearly different from the context (except when such a numerical value exceeds 100% of the possible values).

[0062] Baseline level: As used herein, the term "baseline level" refers to a value representing an initial level of a measurable quality (including normal level or disease level) used for comparison with a value representing a response to an intervention (e.g., drug, medical treatment, or control). In some embodiments, the baseline reflects the health state (severity of disease, comorbid conditions, biomarkers (e.g., hematological biomarkers)) present in an individual or group of individuals at the start of a process. In some embodiments, the process is a medical treatment plan. In some embodiments, the process is a prospective study (e.g., a clinical trial). In some embodiments, the baseline value is the last non-missing value before the subject starts a process (e.g., a treatment plan or a clinical trial). In some embodiments, the baseline value is the value before the subject suffers from a condition (e.g., the blood loss condition described herein). In some embodiments, the subject experiences a change in value compared to the baseline value before being administered a drug, and the value returns to the baseline level by treatment with that drug. In some embodiments, treatment with a drug causes the value to return to the baseline level faster compared to a subject not administered the drug.

[0063] Blood loss condition: As used herein, the term "blood loss condition" refers to a condition related to blood loss (including, but not limited to, diseases, disorders, injuries, and / or procedures, such as medical procedures or surgeries) that gives rise to the need for hematological recovery to achieve the homeostatic oxygen-carrying capacity in the blood of a subject. In some embodiments, the blood loss can be actual ongoing blood loss. In some embodiments, the blood loss can be past blood loss. In some embodiments, the blood loss can be anticipated blood loss (e.g., prior to a scheduled surgical procedure or blood donation procedure where blood loss is expected to occur). In some embodiments, the blood loss can be chronic or acute. In some embodiments, the blood loss can be intermittent or persistent.

[0064] Comorbid condition: As used herein, "comorbid condition" refers to one or more conditions or disorders that occur (or co-occur) simultaneously with a primary condition (such as a disease related to a blood loss condition) in an individual.

[0065] Control subject: A subject having characteristics and properties equivalent to those of a subject, such as age, species, health status, and other similar parameters. In some embodiments, the control subject can be a group of subjects having a similar condition (e.g., a blood loss condition) but who are expected to receive or are receiving a treatment different from the treatment described herein (e.g., a treatment using a hemoglobin antagonist). In some embodiments, in an experiment or clinical trial, the control subject can be a group of subjects having characteristics similar to the treatment group but who do not receive the treatment being tested. In some embodiments, the control subject receives a substance or treatment (i.e., a placebo) designed to have no therapeutic effect.

[0066] CDR: As used herein, the term "CDR" refers to the complementarity determining regions within an antibody variable sequence. A typical antibody molecule includes a heavy chain variable region (VH) and a light chain variable region (VL), which are usually involved in antigen binding. The VH and VL regions can be further subdivided into hypervariable regions, also known as "complementary determining regions" ("CDRs"), and more conserved regions known as "framework regions" ("FRs") that are interspersed therebetween. Each VH and VL typically consists of three CDRs and four FRs arranged in the following order from the amino terminus to the carboxy terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The ranges of the framework regions and CDRs can be precisely specified using methodologies known in the art, such as the Kabat definition, the IMGT definition, the Chothia definition, the AbM definition, and / or the contact definition, all of which are well known in the art.For example, see Kabat, E.A., et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242; IMGT (registered trademark), the international ImMunoGeneTics information system (registered trademark) http: / / www.imgt.org, Lefranc, M.-P. et al., Nucleic Acids Res., 27:209-212 (1999); Ruiz, M. et al., Nucleic Acids Res., 28:219-221 (2000); Lefranc, M.-P., Nucleic Acids Res., 29:207-209 (2001); Lefranc, M.-P., Nucleic Acids Res., 31:307-310 (2003); Lefranc, M.-P. et al., In Silico Biol., 5, 0006 (2004) [Epub], 5:45-60 (2005); Lefranc, M.-P. et al., Nucleic Acids Res., 33:D593-597 (2005); Lefranc, M.-P. et al., Nucleic Acids Res., 37:D1006-1012 (2009); Lefranc, M.-P. et al., Nucleic Acids Res., 43:D413-422 (2015); Chothia et al., (1989) Nature 342:877; Chothia, C. et al. (1987) J. Mol. Biol. 196:901-917, Al-lazikani et al (1997) J. Molec. Biol. 273:927-948; and Almagro, J. Mol. Recognit. 17:132-143 (2004). Also see hgmp.mrc.ac.uk and bioinf.org.uk / abs.As used herein, CDR may refer to a CDR defined by any method known in the art. Two antibodies having the same CDR refer to the two antibodies having the same amino acid sequence for the CDR defined by the same method, e.g., the IMGT definition.

[0067] Generally, each of the variable regions of the heavy and light chains has three CDRs, which are named CDR1, CDR2, and CDR3 for each variable region. As used herein, the term "CDR set" refers to the group of three CDRs that occur in a single variable region capable of binding an antigen. The exact boundaries of these CDRs have been defined differently according to different systems. The system described by Kabat (Kabat et al., Sequences of Proteins of Immunological Interest (National Institutes of Health, Bethesda, Md. (1987) and (1991))) not only provides an unambiguous residue numbering system applicable to any variable region of an antibody, but also provides the exact residue boundaries that define the three CDRs. These CDRs may be referred to as Kabat CDRs. Sub-portions of the CDRs may also be called L1, L2, and L3, or H1, H2, and H3, where "L" and "H" refer to the light and heavy chain regions, respectively. These regions may be referred to as Chothia CDRs, which have boundaries that overlap with Kabat CDRs. Other boundaries that define CDRs and overlap with Kabat CDRs have been described by Padlan (FASEB J. 9:133-139 (1995)) and MacCallum (J Mol Biol 262(5):732-45 (1996)). Other CDR boundary definitions may not strictly follow one of the above systems, but may still be shortened or extended in light of predictions or empirical findings that a particular residue or group of residues, or the CDR as a whole, does not significantly affect antigen binding, and will overlap with Kabat CDRs. The methods used herein may utilize CDRs defined according to any of these systems, but in exemplary embodiments, CDRs defined by Kabat or Chothia are used.

[0068] CDR-grafted antibody: The term "CDR-grafted antibody" refers to an antibody that contains heavy and light chain variable region sequences from one species, such as an antibody having mouse heavy and light chain variable regions with one or more (e.g., CDR3) of its mouse CDRs replaced with human CDR sequences, where one or more sequences of the CDR regions of VH and / or VL are replaced with CDR sequences of another species.

[0069] Chimeric antibody: The term "chimeric antibody" refers to an antibody that contains heavy and light chain variable region sequences from one species, as well as constant region sequences from another species, such as an antibody having mouse heavy and light chain variable regions linked to human constant regions.

[0070] Complementary: As used herein, the term "complementary" refers to the ability for exact pairing between two nucleotides or two sets of nucleotides. In particular, complementarity is a term that characterizes the degree of hydrogen bond pairing that results in a bond between two nucleotides or two sets of nucleotides. For example, if the base at a position of an oligonucleotide can hydrogen bond with the base at the corresponding position of a target nucleic acid (e.g., mRNA), the bases are considered to be complementary to each other at that position. Base pairing may include both classical Watson-Crick base pairs and non-Watson-Crick base pairing (e.g., wobble base pairs and Hoogsteen base pairs). For example, in some embodiments, with respect to complementary base pairing, an adenosine-type base (A) is complementary to a thymidine-type base (T) or a uracil-type base (U), a cytosine-type base (C) is complementary to a guanosine-type base (G), and universal bases such as 3-nitropyrrole or 5-nitroindole can hybridize to and are considered complementary to any of A, C, U, or T. Inosine (I) is also considered a universal base in the art and is considered complementary to any of A, C, U, T.

[0071] Conservative Amino Acid Substitutions: As used herein, "conservative amino acid substitutions" refer to amino acid substitutions that do not change the relative charge or size characteristics of the protein in which the amino acid substitution is made. Variants can be prepared according to methods known to those of skill in the art for altering polypeptide sequences, such as those described in references that describe such methods, e.g., Molecular Cloning: A Laboratory Manual, J. Sambrook, et al., eds., Fourth Edition, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, 2012, or Current Protocols in Molecular Biology, F.M. Ausubel, et al., eds., John Wiley & Sons, Inc., New York. Conservative substitutions of amino acids include substitutions made between amino acids within the following groups: (a) M, I, L, V; (b) F, Y, W; (c) K, R, H; (d) A, G; (e) S, T; (f) Q, N; and (g) E, D.

[0072] Cross-reactivity: As used herein, in the context of a target substance (e.g., an antibody), the term "cross-reactivity" refers to the property of a substance that can specifically bind, with similar affinity or binding activity, to more than one antigen of a similar type or class (e.g., antigens of multiple homologs, paralogs, or orthologs). For example, in some embodiments, an antibody that is cross-reactive with human and non-human primate antigens of a similar type or class (e.g., human hemojuvelin and non-human primate hemojuvelin) can bind to its human and non-human primate antigens with similar affinity or binding activity. In some embodiments, the antibody is cross-reactive with human antigens and rodent antigens of a similar type or class. In some embodiments, the antibody is cross-reactive with rodent antigens and non-human primate antigens of a similar type or class. In some embodiments, the antibody is cross-reactive with human antigens, non-human primate antigens, and rodent antigens of a similar type or class.

[0073] Effective amount: As used herein, the term "effective amount" or "effective quantity" refers to the amount of each active substance (e.g., a hemojuvelin antagonist comprising an anti-HJV antibody) necessary to provide a therapeutic effect to a subject (e.g., when treating a related blood loss condition, either alone or in combination with one or more other active substances). In some embodiments, the therapeutic effect is a decrease in hepcidin level or activity, an increase in transferrin saturation (TSAT%), a decrease in circulating transferrin level, a decrease in ferritin, and / or promotion of hematological recovery (e.g., promotion of erythropoiesis, reticulocyte hemoglobin (CHr), mean corpuscular hemoglobin (MCH), and / or circulating hemoglobin level).

[0074] Erythropoiesis: As used herein, the term "erythropoiesis" refers to the process of producing red blood cells (RBCs or erythrocytes). In some embodiments, erythropoiesis includes the development from hematopoietic stem cells to mature red blood cells. For example, in the process of red blood cell maturation, cells generally undergo a series of differentiation steps, which may include the differentiation of hematogones (pluripotent hematopoietic stem cells) in the bone marrow along a pathway including one or more of myeloid common progenitor cells, unipotent stem cells, proerythroblasts, erythroblasts, polychromatic erythroblasts, and orthochromatic erythroblasts. In some embodiments, enucleation occurs through the asymmetric division of orthochromatic erythroblasts at the end of the orthochromatic stage, resulting in reticulocytes, which are immature red blood cells. Reticulocytes are generally released from the bone marrow into the circulation and ultimately become "red blood cells" or mature red blood cells after one or two days. Thus, reticulocytes are mainly present in circulating blood. In some embodiments, at the reticulocyte stage, the cells expel their nuclei but can still produce hemoglobin. In further embodiments, the normal RBC count in a subject is 4.7×10 12 to 6.1×10 12 cells / L, or 4.2×10 12 to 5.4×10 12 cells / L.

[0075] Ferritin: As used herein, the term "ferritin" refers to a protein that stores iron and releases it in a controlled manner. It is the major intracellular iron storage protein in both prokaryotes and eukaryotes and holds iron in a soluble and non-toxic form. In humans, it acts as a buffer against iron deficiency and iron overload. Circulating ferritin is also an indirect marker of the total amount of iron stored in the body, and thus serum ferritin is used as a diagnostic test for iron deficiency anemia.

[0076] Free iron acts as a catalyst to form free radicals from reactive oxygen species via the Fenton reaction and is thus toxic to cells. Therefore, vertebrates have a set of elaborate defense mechanisms for binding iron in various tissue compartments. Ferritin stores iron in a non-toxic form, deposits it in a safe form, and plays a role in transporting it to where it is needed. One trigger for ferritin production is the presence of iron. Under steady-state conditions, the level of ferritin in serum is proportional to the total amount of iron stored in the body, and thus, serum ferritin FR5RI is the most convenient laboratory test for estimating iron stores. Iron is released by ferritin degradation for use, which is mainly carried out by lysosomes.

[0077] Framework: As used herein, the term "framework" or "framework sequence" refers to the remaining sequence after subtracting the CDRs from the variable region. Since the precise definition of the CDR sequences can be determined by different systems, the meaning of the framework sequences is correspondingly subject to different interpretations. Also, the six CDRs (CDR-L1, CDR-L2, and CDR-L3 of the light chain, and CDR-H1, CDR-H2, and CDR-H3 of the heavy chain) divide the framework regions of the light and heavy chains into four subregions (FR1, FR2, FR3, and FR4) in each chain, where CDR1 is located between FR1 and FR2, CDR2 is located between FR2 and FR3, and CDR3 is located between FR3 and FR4. When not specifying a particular subregion such as FR1, FR2, FR3, or FR4, the framework region collectively represents the FRs within the variable region of a single native immunoglobulin chain as referred to by others. As used herein, FR (singular) represents one of the four subregions that make up the framework region, and FR (plural) represents two or more of the four subregions. Human heavy and light chain acceptor sequences are known in the art. In certain embodiments, acceptor sequences known in the art may be used in the antibodies disclosed herein.

[0078] Hemojuvelin (HJV): As used herein, the term "hemojuvelin (HJV)" (also known as repulsive guidance molecule C (RGMc) or hemochromatosis type 2 protein (HFE2)) refers to a membrane-bound soluble form of protein that controls hepcidin production through the bone morphogenetic protein (BMP) / SMAD signaling pathway (Xiao et al., "Bone morphogenic proteins in iron homeostasis." Bone. 2020; 138:115495). The HFE2 gene encodes two known classes of HJV molecules that are anchored and glycosylated by glycosylphosphatidylinositol (GPI), and these follow different fates targeting the membrane. HJV exists as multiple isoforms, including two soluble isoforms and two membrane-associated isoforms. In some embodiments, the dominant membrane-associated isoform is a disulfide-bonded two-chain form composed of N-terminal and C-terminal fragments. In some embodiments, the full-length single-chain isoform associates with the membrane but dissociates from the cell surface and accumulates in the extracellular fluid. In some embodiments, HJV may be of human (NCBI Gene ID 148738), non-human primate (e.g., NCBI Gene ID 698805), or rodent (e.g., NCBI Gene ID 69585 or NCBI Gene ID 310681) origin. In addition to HJV (RGMc), the repulsive guidance molecule family includes repulsive guidance molecule A (RGMa) and repulsive guidance molecule B (RGMb). RGMa and RGMb are expressed in the central nervous system during development and are thought to be involved in axon patterning and control of neuronal survival, while HJV is produced in the liver as well as in cardiac and skeletal muscle.

[0079] Hepcidin: As used herein, "hepcidin" refers to an iron-regulatory peptide hormone encoded by the HAMP gene that is produced primarily in the liver. In some embodiments, hepcidin controls the delivery of iron from iron-absorbing enterocytes, erythrocyte-recycling macrophages, and iron-storing hepatocytes into the plasma. Normal hepcidin levels vary depending on the measurement method, gender, tissue or body fluid in which it is measured, and / or menopausal status. In some embodiments, hepcidin inhibits iron transport by binding to ferroportin, an iron efflux channel located on the basolateral membrane of intestinal enterocytes and the plasma membrane of reticuloendothelial cells (macrophages). In some embodiments, inhibition of ferroportin prevents iron excretion and the iron is sequestered intracellularly. In some embodiments, by inhibiting ferroportin, hepcidin prevents enterocytes from transferring iron to the portal system, thereby reducing iron absorption from the diet. Multiple aspects are involved in hepcidin expression, including, for example, transcription of the HAMP gene, translation of the transcribed mRNA, and post-translational processing of the hepcidin precursor into the bioactive hepcidin-25 peptide (DTHFPICIFCCGCCHRSKCGMCCKT (SEQ ID NO: 129)). In some embodiments, hepcidin expression is regulated via the BMP signaling pathway induced by hemojuvelin. In some embodiments, hepcidin expression is regulated via the IL-6-JAK-STAT signaling pathway.

[0080] Hepcidin antagonist: As used herein, "hepcidin antagonist" refers to a substance that (directly or indirectly) reduces hepcidin expression and / or hepcidin activity. In some embodiments, the hepcidin antagonist inhibits ferroportin degradation induced by hepcidin. Thus, in some embodiments, the hepcidin antagonist indirectly targets the function of hepcidin through the hepcidin-stimulating pathway and reduces hepcidin expression. In some embodiments, the hepcidin antagonist directly targets hepcidin function, for example, by binding to the hepcidin peptide to sequester free hepcidin or by binding to ferroportin to inhibit the hepcidin-ferroportin binding interaction, thereby reducing ferroportin degradation induced by hepcidin. In some embodiments, the hepcidin antagonist is a ferroportin inhibitor that interferes with the ferroportin-hepcidin interaction, such as those disclosed in Ross SL, et al., Identification of Antibody and Small Molecule Antagonists of Ferroportin-Hepcidin Interaction. Front Pharmacol. 2017 Nov 21;8:838; Fung E., et al., High-Throughput Screening of Small Molecules Identifies Hepcidin Antagonists. Molecular Pharmacology March 2013, 83 (3) 681-690; and Angeliki Katsarou and Kostas Pantopoulos, Hepcidin Therapeutics. Pharmaceuticals (Basel). 2018 Dec; 11(4): 127, the relevant contents of each of which are incorporated herein by reference.

[0081] Hematological recovery: As used herein, the term "hematological recovery" refers to the process of changing the oxygen-carrying capacity in the blood of a subject to a state equivalent to (e.g., equal to or within the range of) the baseline value of a normal healthy subject (e.g., a normal healthy control subject). The "typical" range of baseline oxygen levels in the blood of a normal healthy subject is between 95% and 100% oxygen saturation. In some embodiments, hematological recovery may be evaluated by assessing one or more levels of erythropoiesis, circulating hemoglobin levels, reticulocyte hemoglobin (CHr), and mean corpuscular hemoglobin (MCH), which are indicators that the subject has achieved a homeostatic oxygen-carrying capacity.

[0082] Hemoglobin: As used herein, the term "hemoglobin (Hb)" refers to the iron-containing oxygen-transport metalloprotein of red blood cells (erythrocytes). Hemoglobin in the blood transports oxygen from the respiratory organs (e.g., lungs or gills) to other parts of the body (i.e., tissues). There, hemoglobin releases oxygen to enable aerobic respiration and provides energy for the functioning of organ functions in a process called metabolism. A healthy human individual has approximately 12 to 20 g / dL of hemoglobin in the blood. Hemoglobin (Hb) is synthesized in a series of complex steps. The heme portion is synthesized in a series of steps in the mitochondria and the cytoplasm of immature red blood cells, while the globin protein portion is synthesized in the cytoplasm by ribosomes. Iron is an essential element for hemoglobin synthesis, particularly heme synthesis. The final step in heme synthesis is the addition of iron ions by an iron-addition enzyme to protoporphyrin IX, which is a precursor of heme, thereby producing a heme molecule. The production of globin chains occurs in the cytoplasm of red blood cells and is caused by gene transcription and translation. Many studies have shown that the presence of heme induces the production of globin. Heme combines with globin to form hemoglobin.

[0083] Hemojuvelin antagonist: As used herein, the term "hemojuvelin antagonist" refers to a molecule that, for example, by binding to hemojuvelin, reduces hemojuvelin expression or inhibits hemojuvelin activity. In some embodiments, the hemojuvelin antagonist is an antisense oligonucleotide (see, e.g., U.S. Patent No. 7,534,764; U.S. Patent Application Publication No. US2014 / 127325; and International Publication No. WO2016 / 180784, which are incorporated herein by reference). In some embodiments, the hemojuvelin antagonist is an antibody (e.g., the anti-HJV antibodies described herein, or the anti-HJV antibodies described in WO2020086736, which is incorporated herein by reference). In other embodiments, the hemojuvelin antagonist is a small molecule compound that inhibits hemojuvelin, for example, by competitive binding and / or chemical modification of hemojuvelin. In some embodiments, the hemojuvelin antagonist is an HJV fragment (e.g., the HJV fragment described in U.S. Patent No. 8,507,435, which is incorporated herein by reference), or an HJV fusion protein (e.g., the HJV-Fc fusion protein described in U.S. Patent 8,637,023, which is incorporated herein by reference).

[0084] HJV-Induced BMP Signaling: As used herein, "HJV-induced BMP signaling" refers to BMP receptor-mediated signaling induced by hemojuvelin (HJV), which is a membrane-bound coreceptor for bone morphogenetic protein (BMP) signaling. As described in Xia Y, et al., Hemojuvelin regulates hepcidin expression via a selective subset of BMP ligands and receptors independently of neogenin, Blood. 2008 May 15; 111(10): 5195-5204, in hepatocytes, HJV-induced BMP signaling positively regulates hepcidin mRNA expression. In some embodiments, HJV binds to BMP2, BMP4, BMP5, or BMP6 and induces BMP signaling to positively regulate, for example, hepcidin levels in hepatocytes. In some embodiments, cleavage of HJV by matriptase-2 reduces the amount of cell surface HJV that can participate in BMP signaling. In some embodiments, induction of BMP signaling by HJV is neogenin-independent. However, in some embodiments, as described in Zhao et al, Neogenin Facilitates the Induction of Hepcidin Expression by Hemojuvelin in the Liver, J Biol Chem. 2016 Jun 3; 291(23): 12322-12335, neogenin facilitates the induction of BMP signaling by HJV. In some embodiments, BMP6 is responsible for iron-dependent activation of Smad signaling. In some embodiments, BMP6 is secreted from liver sinusoidal endothelial cells and binds to the BMP receptor (BMPR) of hepatocytes, thereby activating the SMAD signaling cascade. In such embodiments, HJV serves as a coreceptor for such BMP6 and positively regulates, for example, hepcidin levels in hepatocytes.In some embodiments, BMP signals by binding to one or a combination of serine / threonine kinase receptors type I and II. BMP type II receptors include BMPRII, ActRIIA, and ActRIIB. BMP type I receptors include ALK3, ALK6, and ALK2. In some embodiments, upon ligand binding, a constitutively active type II receptor phosphorylates the type I receptor, which then phosphorylates intracellular receptor-activated Smads (R-Smads), namely Smad1, Smad5, and / or Smad8. In such embodiments, the activated R-Smads form a complex with the common partner Smad4 and translocate to the nucleus to control gene transcription, for example, inducing hepcidin expression.

[0085] Human antibody: As used herein, the term "human antibody" is intended to include antibodies having variable and constant regions derived from human germline immunoglobulin sequences. The human antibodies of the present disclosure may include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations caused by random or site-directed mutagenesis in vitro or somatic mutations in vivo), for example, in CDRs, particularly CDR3. However, the term "human antibody" as used herein is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, are grafted onto human framework sequences (e.g., CDRs grafted onto a heterologous framework).

[0086] Humanized antibody: The term "humanized antibody" refers to an antibody that includes heavy and light chain variable region sequences of a non-human species (e.g., mouse), but in which at least a portion of the V H and / or V L sequences has been changed to be more "human-like", i.e., more similar to human germline variable sequences. One type of humanized antibody is an antibody in which human CDR sequences are grafted onto non-human V H and V LA CDR-grafted antibody that has been introduced into an array and has a corresponding non-human CDR array replaced. In certain embodiments, a humanized anti-hemojuvelin antibody and antigen-binding portion are provided. Such antibodies may be generated by obtaining a mouse anti-hemojuvelin monoclonal antibody using traditional hybridoma technology, followed by humanization using in vitro genetic manipulation, such as that disclosed in Kasaian et al.'s PCT application publication WO2005 / 123126A2.

[0087] Iatrogenic blood loss: The term "iatrogenic blood loss" as used herein refers to the condition of a human having a blood loss condition resulting from a medical intervention (including, but not limited to, blood loss due to medical procedures such as venipuncture, surgery, and dilution of blood by intravenous infusion). In some embodiments, iatrogenic blood loss includes venipuncture. In some embodiments, the subject has or is expected to undergo repeated venipuncture for repeated monitoring of blood parameters. In some embodiments, a subject having or expected to undergo repeated venipuncture is suspected of having a blood loss condition. In some embodiments, the subject has or is expected to undergo a blood donation procedure (e.g., blood donation by venipuncture). In some embodiments, iatrogenic blood loss includes surgery.

[0088] Isolated antibody: As used herein, the term "isolated antibody" is intended to refer to an antibody that is substantially free of other antibodies having different antigen specificities (e.g., an isolated antibody that specifically binds to hemojuvelin is substantially free of antibodies that specifically bind to antigens other than hemojuvelin). However, an isolated antibody that specifically binds to hemojuvelin may have cross-reactivity with other antigens, such as other repulsive guidance molecule (RGM) proteins (e.g., RGMa and / or RGMb). Additionally, an isolated antibody may be substantially free of other cell-derived substances and / or chemical substances.

[0089] Kabat numbering: The terms "Kabat numbering", "Kabat definition", and "Kabat labeling" are used interchangeably herein. These terms, as recognized in the art, refer to a system for numbering amino acid residues in the heavy and light chain variable regions of an antibody or its antigen-binding portion that are more variable (i.e., hypervariable) than other amino acid residues (Kabat et al. (1971) Ann. NY Acad, Sci. 190:382-391 and, Kabat, E. A., et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242). For the heavy chain variable region, the hypervariable regions are in the range of amino acid positions 31 to 35 as CDR1, 50 to 65 as CDR2, and 95 to 102 as CDR3. In the light chain variable region, the hypervariable regions are in the range of amino acid positions 24 to 34 as CDR1, 50 to 56 as CDR2, and 89 to 97 as CDR3.

[0090] Mean corpuscular hemoglobin (MCH): As used herein, the term "mean corpuscular hemoglobin" refers to the average mass of hemoglobin per red blood cell (RBC) in a blood sample. This is calculated by dividing the total mass of hemoglobin in a given volume of blood by the number of red blood cells. MCH=(Hb*10) / RBC

[0091] In some embodiments, the normal MCH value in humans is from 27 to 31 picograms (pg) / cell. The amount of hemoglobin per RBC depends on hemoglobin synthesis and the size of the RBC. The mass of the red blood cell is determined by iron (as part of the hemoglobin molecule), and thus the MCH in picogram units is roughly the mass of one red blood cell. In some embodiments, in iron deficiency anemia, the cytoplasmic mass is reduced, and an MCH below 27 pg is a sign of iron deficiency.

[0092] Recombinant antibody: As used herein, the term "recombinant human antibody" refers to an antibody expressed using a recombinant expression vector transfected into a host cell (more specifically described in this disclosure), an antibody isolated from a recombinant, combinatorial human antibody library (Hoogenboom H. R., (1997) TIB Tech. 15:62-70; Azzazy H., and Highsmith W. E., (2002) Clin. Biochem. 35:425-445; Gavilondo J. V., and Larrick J. W. (2002) BioTechniques 29:128-145; Hoogenboom H., and Chames P. (2000) Immunology Today 21:371-378), an antibody isolated from an animal (e.g., mouse) transgenic for human immunoglobulin genes (see, e.g., Taylor, L. D., et al. (1992) Nucl. Acids Res. 20:6287-6295; Kellermann S-A., and Green L. L. (2002) Current Opinion in Biotechnology 13:593-597; Little M. et al (2000) Immunology Today 21:364-370), or any other antibody prepared, expressed, produced or isolated by any other means involving splicing of human immunoglobulin gene sequences to other DNA sequences, and is intended to include all human antibodies prepared, expressed, produced, or isolated by recombinant means. Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. However, in certain embodiments, such recombinant human antibodies are subjected to in vitro mutagenesis (or, if an animal transgenic for human Ig sequences is used, in vivo somatic mutagenesis), and thus the amino acid sequences of the V H and V L regions of the recombinant antibody are different from the human germline V H and V LOn the one hand, it is derived from and related to an array, and may not naturally exist in the human antibody germline repertoire in vivo. In certain embodiments of the present disclosure, a fully human antibody that can bind to human hemojuvelin can be generated using techniques well known in the art, such as, but not limited to, using a human Ig phage library such as that disclosed in PCT Application No. WO2005 / 007699A2 by Jermutus et al.

[0093] Reticulocyte hemoglobin content (CHr): As used herein, "reticulocyte hemoglobin content (CHr)" refers to the hemoglobin level in reticulocytes, which are immature red blood cells in circulation. Erythrocyte hemoglobin content reflects the amount of iron available for hemoglobin production in the bone marrow. Reticulocyte hemoglobin content provides an indirect measure of the functional iron available for new erythrocyte production over the previous few days (e.g., 3 - 4 days). In some embodiments, reticulocyte hemoglobin equivalent (Ret - He) is used in place of CHr (Toki et al., "Usefulness of Reticulocyte Hemoglobin Equivalent for Diagnosis of Iron Deficiency." Blood. 2016; 128(22):3621).

[0094] Selective: As used herein, the term "selective" or "selectively" refers to the ability of a molecule to have an effect in relation to its target molecule as compared to a reference molecule. For example, a molecule that selectively inhibits its target molecule means that this molecule can inhibit its target molecule to an extent that it can be distinguished from the reference molecule in an inhibition assay or other inhibitory context. For example, with respect to an inhibitor, the term "selectively inhibits" as described herein refers to the ability of the inhibitor to inhibit its target molecule to an extent that it can be distinguished from a reference molecule that is not substantially inhibited in an inhibition assay, for example, to an extent that enables selective inhibition of the target molecule. For example, the 50% inhibitory concentration (IC50) for a target molecule and / or a reference molecule can be tested in a kinase potency assay as described in Asshoff, M. et al., Momelotinib inhibits ACVR1 / ALK2, decreases hepcidin production, and ameliorates anemia of chronic disease in rodents. Blood. 2017 Mar 30; 129(13): 1823-1830 (for example, a kinase potency assay by Carna Biosciences). In this assay, an inhibitor solution (for example, a solution containing the selective inhibitor being tested) / kinase substrate is mixed with a target molecule solution (for example, ALK2) or a reference molecule solution (for example, JAK1 or JAK2) and incubated at room temperature for 1 hour. When the reaction is terminated, the signal generated by the enzyme activity against the substrate can be measured. The 50% inhibitory concentration for the target molecule and the reference molecule can be calculated. In some embodiments, the molecules described herein selectively bind to the target molecule. In some embodiments, the molecules described herein selectively inhibit the target molecule. In some embodiments, the molecules described herein selectively antagonize the target molecule. In some embodiments, the molecules described herein selectively neutralize the target molecule.

[0095] Specifically bind: As used herein, the term "specifically bind" refers to the ability of a molecule to bind to a binding partner with a degree of affinity or binding activity that enables the molecule to distinguish the binding partner from appropriate controls in a binding assay or other binding context. With respect to an antibody, the term "specifically bind" as described herein refers to the ability of the antibody to bind to a specific antigen with a degree of affinity or binding activity that enables the antibody to distinguish the specific antigen from other antigens, for example, to preferentially target a specific cell such as a muscle cell, to the extent possible through binding to the antigen. In some embodiments, the antibody has a K of at least about 10 -4 M, 10 -5 M, 10 -6 M, 10 -7 M, 10 -8 M, 10 -9 M, 10 -10 M, 10 -11 M, 10 -12 M, 10 -13 M, or less for its target. In some embodiments, the antibody specifically binds to hemojuvelin. D Subject: As used herein, the term "subject" refers to a mammal. In some embodiments, the subject is a non-human primate or a rodent. In some embodiments, the subject is a human. In some embodiments, the subject is a patient, for example, a human patient having or suspected of having a disease. In some embodiments, the subject is a human patient having or suspected of having a state of blood loss.

[0096]

[0097] ​Transferrin saturation (TSAT%): As used herein, the term "transferrin saturation (TSAT%)" refers to the percentage value obtained by dividing serum iron by the total iron binding capacity of transferrin (the main protein that binds iron in the blood). This value indicates how much serum iron is bound to transferrin. For example, a value of 15% means that 15% of the iron-binding sites on transferrin are occupied by iron. Low transferrin saturation is a common indicator of iron deficiency, while high transferrin saturation may indicate iron overload or hemochromatosis. Transferrin saturation is also referred to as transferrin saturation index (TSI) or transferrin saturation percent (TS%).

[0098] Treatment: As used herein, the term "treating" or "treatment" refers to the application or administration of a composition comprising one or more active agents to a subject having a target disease or disorder, symptoms of the disease / disorder, or a predisposition to the disease / disorder, with the aim of curing, restoring, alleviating, mitigating, altering, treating, remitting, improving, or affecting the disorder, symptoms of the disease, or predisposition to the disease or disorder. Reduction of the target disease / disorder includes delaying or preventing the onset or progression of the disease, or reducing the severity of the disease.

[0099] II. Methods for treating a state of blood loss The present disclosure provides, at least in part, compositions and methods for treating a subject having a state of blood loss, the method comprising administering a hemodulin antagonist to the subject. In some embodiments, the hemodulin antagonist is administered in an amount effective to promote hematological recovery. In some embodiments, the state of blood loss causes loss of red blood cells (RBCs) in the subject. In some embodiments, when blood is lost, the body tries to keep the blood vessels filled and draws water from the tissues into the bloodstream. As a result, the blood is diluted and the hematocrit (the percentage of red blood cells relative to the total volume or blood volume in the body) decreases. Eventually, increased production of red blood cells by the bone marrow may normalize the state of blood loss. However, over time, bleeding reduces the amount of iron in the body and the bone marrow is unable to increase the production of new red blood cells to replace the lost red blood cells. In some embodiments, the loss of red blood cells and iron due to bleeding reduces the oxygen-carrying capacity of the subject. In such cases, additional treatment may be required to promote hematological recovery in these subjects. Accordingly, aspects of the present disclosure relate to methods for treating a subject having a state of blood loss by administering a hemodulin antagonist in an amount effective to promote hematological recovery. In some embodiments, hematological recovery includes recovery of erythropoiesis, reticulocyte hemoglobin content (CHr), mean corpuscular hemoglobin (MCH), and / or circulating hemoglobin levels to baseline levels.

[0100] In some embodiments, hematological recovery is achieved in a shorter period compared to the period achieved by control subjects that did not receive a hepcidin antagonist (e.g., an anti-HJV antibody) in subjects treated with a hepcidin antagonist (e.g., an anti-HJV antibody). In some embodiments, hematological recovery is achieved within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 2 years, or 3 years in subjects treated with a hepcidin antagonist (e.g., an anti-HJV antibody). In some embodiments, hematological recovery is achieved in a period that is 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 1 year shorter compared to the period achieved by control subjects that did not receive a hepcidin antagonist (e.g., an anti-HJV antibody) in subjects treated with a hepcidin antagonist (e.g., an anti-HJV antibody).

[0101] In some embodiments, administering a hepcidin antagonist (e.g., an anti-HJV antibody) to a subject having a blood loss condition promotes recovery of erythropoiesis. In some embodiments, recovery of erythropoiesis results in an increase in the RBC count to baseline levels. In some embodiments, recovery of erythropoiesis results in an increase in the RBC count to baseline levels within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 2 years, or 3 years.

[0102] In some embodiments, administering a hemojuvelin antagonist (e.g., an anti-HJV antibody) to a subject having a blood loss condition promotes the recovery of erythrocyte hemoglobin content (CHr). In some embodiments, the recovery of CHr results in an increase in CHr to the baseline level. In some embodiments, the recovery of CHr results in an increase in CHr to the baseline level within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 2 years, or 3 years.

[0103] In some embodiments, administering a hemojuvelin antagonist (e.g., an anti-HJV antibody) to a subject having a blood loss condition promotes the recovery of mean corpuscular hemoglobin (MCH). In some embodiments, the recovery of MCH results in an increase in MCH to the baseline level. In some embodiments, the recovery of MCH results in an increase in MCH to the baseline level within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 2 years, or 3 years.

[0104] In some embodiments, administering a hemojuvelin antagonist (e.g., an anti-HJV antibody) to a subject having a blood loss condition promotes the recovery of circulating hemoglobin levels. In some embodiments, the recovery of circulating hemoglobin levels results in an increase in circulating hemoglobin levels to the baseline level. In some embodiments, the recovery of circulating hemoglobin levels results in an increase in circulating hemoglobin levels to the baseline level within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 2 years, or 3 years.

[0105] In some embodiments, the blood loss condition includes acute blood loss. In some embodiments, acute blood loss due to injury, surgery, childbirth, or blood vessel rupture can suddenly cause a large loss of blood. In some embodiments, transfusion is required for acute blood loss of 30% to 40% of the total blood volume, and there is a life crisis for acute blood loss exceeding 40% of the total blood volume, and rapid transfusion is required. In some embodiments, the subject is identified as having an acute blood loss condition in which more than 30% (e.g., 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, or more) of the total blood volume has been lost and transfusion is needed. In some embodiments, a subject having an acute blood loss condition resulting in a blood loss of less than 30% (e.g., less than 30%, less than 25%, less than 20%, less than 15%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%) of the total blood volume does not require transfusion and can be treated with a hemoglobin antagonist (e.g., an anti-HJV antibody).In some embodiments, a subject in an acute blood loss state who has lost blood in the range of 1% to 30% of the total blood volume (e.g., 1% to 30%, 1% to 25%, 1% to 20%, 1% to 15%, 1% to 10%, 1% to 9%, 1% to 8%, 1% to 7%, 1% to 6%, 1% to 5%, 1% to 4%, 1% to 3%, 1% to 2%, 2% to 30%, 2% to 25%, 2% to 20%, 2% to 15%, 2% to 10%, 2% to 9%, 2% to 8%, 2% to 7%, 2% to 6%, 2% to 5%, 2% to 4%, 2% to 3%, 3% to 30%, 3% to 25%, 3% to 20%, 3% to 15%, 3% to 10%, 3% to 9%, 3% to 8%, 3% to 7%, 3% to 6%, 3% to 5%, 3% to 4%, 4% to 30%, 4% to 25%, 4% to 20%, 4% to 15%, 4% to 10%, 4% to 9%, 4% to 8%, 4% to 7%, 4% to 6%, 4% to 5%, 5% to 30%, 5% to 25%, 5% to 20%, 5% to 15%, 5% to 10%, 5% to 9%, 5% to 8%, 5% to 7%, 5% to 6%, 6% to 30%, 6% to 25%, 6% to 20%, 6% to 15%, 6% to 10%, 6% to 9%, 6% to 8%, 6% to 7%, 7% to 30%, 7% to 25%, 7% to 20%, 7% to 15%, 7% to 10%, 7% to 9%, 7% to 8%, 8% to 30%, 8% to 25%, 8% to 20%, 8% to 15%, 8% to 10%, 8% to 9%, 9% to 30%, 9% to 25%, 9% to 20%, 9% to 15%, 9% to 10%, 10% to 30%, 10% to 25%, 10% to 20%, 10% to 15%, 15% to 30%, 15% to 25%, 15% to 20%, 20% to 30%, 20% to 25%, 25% to 30%) does not require blood transfusion and can be treated with a hemojuvelin antagonist (e.g., an anti-HJV antibody). In some embodiments, a subject in an acute blood loss state who has lost blood in the range of 1 to 10% of the total blood volume does not require blood transfusion and can be treated with a hemojuvelin antagonist (e.g., an anti-HJV antibody).

[0106] In some embodiments, the subject has an acute blood loss condition and has a hemoglobin level of less than 7 g / dL (e.g., less than 7 g / dL, less than 6.5 g / dL, less than 6 g / dL, less than 5.5 g / dL, less than 5 g / dL, less than 4.5 g / dL, less than 5.5 g / dL, less than 5 g / dL, less than 4.5 g / dL, less than 4 g / dL, less than 3.5 g / dL, less than 3 g / dL, less than 2.5 g / dL, or less than 2 g / dL), and it is determined that the subject requires a blood transfusion. In some embodiments, the blood transfusion raises the subject's hemoglobin level to at least 7 g / dL. In some embodiments, the blood transfusion raises the subject's hemoglobin level to a range of 7 - 10 g / dL (e.g., 7 - 8 g / dL, 7 - 9 g / dL, 7.5 - 8.5 g / dL, 7.5 - 9.5 g / dL, 7 - 7.5 g / dL, 7 - 8.5 g / dL, 7 - 9.5 g / dL, 7.5 - 8 g / dL, 7.5 - 9 g / dL, 7.5 - 10 g / dL, 8 - 8.5 g / dL, 8 - 9 g / dL, 8 - 9.5 g / dL, 8 - 10 g / dL, 9 - 9.5 g / dL, or 9 - 10 g / dL), and the subject can be treated with a hepcidin antagonist (e.g., an anti-HJV antibody) to promote further hematological recovery. In some embodiments, the subject has an acute blood loss condition and has a hemoglobin level greater than 7 g / dL, and it is determined that the subject does not require a blood transfusion. In some embodiments, the subject has an acute blood loss condition and has a hemoglobin level in the range of 7 - 10 g / dL (e.g., 7 - 8 g / dL, 7 - 9 g / dL, 7.5 - 8.5 g / dL, 7.5 - 9.5 g / dL, 7 - 7.5 g / dL, 7 - 8.5 g / dL, 7 - 9.5 g / dL, 7.5 - 8 g / dL, 7.5 - 9 g / dL, 7.5 - 10 g / dL, 8 - 8.5 g / dL, 8 - 9 g / dL, 8 - 9.5 g / dL, 8 - 10 g / dL, 9 - 9.5 g / dL, or 9 - 10 g / dL), and it is determined that the subject does not require a blood transfusion, and the subject can be treated with a hepcidin antagonist (e.g., an anti-HJV antibody) to promote hematological recovery.

[0107] In some embodiments, the blood loss condition includes chronic blood loss (e.g., blood loss that occurs over a long period of time). Chronic blood loss can occur in various parts of the body. In some embodiments, the chronic blood loss is obvious and significant (e.g., nosebleeds, hemorrhoids, upper gastrointestinal bleeding). In some embodiments, the chronic blood loss is not significant due to the small amount of blood loss, but a significant amount of blood is lost over time. In some embodiments, a subject having chronic blood loss of more than 30% of the total blood volume (e.g., 30% - 35%, 30% - 40%, 30% - 45%, 30% - 50%, 30% - 55%, 30% - 60%, 40% - 45%, 40% - 50%, 40% - 55%, 40% - 60%, 50% - 55%, 50% - 60%, or 55% - 40%) may experience only mild symptoms (e.g., fatigue, weakness, black stools, blood in the urine), and the subject may not require a blood transfusion and may be treated with a hemoferrin antagonist (e.g., an anti-HJV antibody). In some embodiments, a subject having a chronic blood loss condition that results in blood loss of less than 30% of the total blood volume (e.g., less than 30%, less than 25%, less than 20%, less than 15%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%) does not require a blood transfusion and may be treated with a hemoferrin antagonist (e.g., an anti-HJV antibody).In some embodiments, a subject having chronic blood loss with blood loss in the range of 1% to 30% of the total blood volume (e.g., 1% to 30%, 1% to 25%, 1% to 20%, 1% to 15%, 1% to 10%, 1% to 9%, 1% to 8%, 1% to 7%, 1% to 6%, 1% to 5%, 1% to 4%, 1% to 3%, 1% to 2%, 2% to 30%, 2% to 25%, 2% to 20%, 2% to 15%, 2% to 10%, 2% to 9%, 2% to 8%, 2% to 7%, 2% to 6%, 2% to 5%, 2% to 4%, 2% to 3%, 3% to 30%, 3% to 25%, 3% to 20%, 3% to 15%, 3% to 10%, 3% to 9%, 3% to 8%, 3% to 7%, 3% to 6%, 3% to 5%, 3% to 4%, 4% to 30%, 4% to 25%, 4% to 20%, 4% to 15%, 4% to 10%, 4% to 9%, 4% to 8%, 4% to 7%, 4% to 6%, 4% to 5%, 5% to 30%, 5% to 25%, 5% to 20%, 5% to 15%, 5% to 10%, 5% to 9%, 5% to 8%, 5% to 7%, 5% to 6%, 6% to 30%, 6% to 25%, 6% to 20%, 6% to 15%, 6% to 10%, 6% to 9%, 6% to 8%, 6% to 7%, 7% to 30%, 7% to 25%, 7% to 20%, 7% to 15%, 7% to 10%, 7% to 9%, 7% to 8%, 8% to 30%, 8% to 25%, 8% to 20%, 8% to 15%, 8% to 10%, 8% to 9%, 9% to 30%, 9% to 25%, 9% to 20%, 9% to 15%, 9% to 10%, 10% to 30%, 10% to 25%, 10% to 20%, 10% to 15%, 15% to 30%, 15% to 25%, 15% to 20%, 20% to 30%, 20% to 25%, 25% to 30%) does not require a blood transfusion and can be treated with a hemoferrin antagonist (e.g., an anti-HJV antibody). In some embodiments, a subject having chronic blood loss with blood loss in the range of 1% to 10% of the total blood volume does not require a blood transfusion and can be treated with a hemoferrin antagonist (e.g., an anti-HJV antibody).

[0108] Non-limiting examples of diseases that can result in chronic blood loss include gastrointestinal (GI) diseases (e.g., esophageal varices, gastritis, gastric ulcer, duodenal ulcer, diverticulosis, Meckel's diverticulum, intestinal polyps, inflammatory bowel disease (IBD), celiac disease, or colorectal cancer), genitourinary diseases (e.g., menorrhagia, uterine fibroids, endometriosis, bladder tumors, or kidney stones), infectious diseases (e.g., dengue fever, Ebola virus disease, Lassa fever, Marburg virus disease, yellow fever, sepsis, bacterial vaginitis, Lemierre's syndrome, and tuberculosis, malaria, whipworm infection, or schistosomiasis). In some embodiments, a subject having a chronic blood loss condition can be treated with a hemodjuvelin antagonist (e.g., an anti-HJV antibody) to promote hematological recovery.

[0109] In some embodiments, the blood loss condition includes iatrogenic blood loss. In some embodiments, the blood loss condition (e.g., iatrogenic blood loss) includes venipuncture procedures. As used herein, a venipuncture procedure includes any procedure in which a needle is used to draw blood from a vein. In some embodiments, the blood loss condition (e.g., iatrogenic blood loss) includes transfusion procedures. In some embodiments, the blood loss condition (e.g., iatrogenic blood loss) includes blood donation procedures. As used herein, a blood donation procedure includes any procedure in which a subject voluntarily donates blood for use in a medical procedure such as a transfusion. In some embodiments, the blood loss condition (e.g., iatrogenic blood loss) includes surgical procedures. As used herein, a surgical procedure includes any medical procedure involving an incision with an instrument.

[0110] In some embodiments, the blood loss condition includes a wound with bleeding. A wound is one type of injury or breach to tissue (e.g., external or internal tissue).

[0111] In some embodiments, a wound with bleeding is a wound with internal bleeding. In some embodiments, a wound with internal bleeding includes a blood vessel rupture, an organ contusion, or a hematoma. In some embodiments, internal bleeding includes, but is not limited to, blood vessel ruptures such as those caused by aneurysms, strokes, subarachnoid hemorrhages, arterial ruptures, venous ruptures, or capillary ruptures due to aneurysms, or aortic ruptures. In some embodiments, internal bleeding includes an organ contusion. An organ contusion refers to a bruise in an internal organ (e.g., the lung, kidney, heart, bone, spleen, intestine, brain, or muscle). In some embodiments, an organ contusion causes bleeding in the damaged organ. In some embodiments, internal bleeding includes a hematoma. In some embodiments, a hematoma may be a collection (or retention) of blood outside of a blood vessel. In some embodiments, hematomas include, but are not limited to, subdural hematomas, spinal cord hematomas, subungual hematomas, or hepatic hematomas.

[0112] In some embodiments, a wound with bleeding is a wound with external bleeding. An external wound is an injury or breakage on the surface of the skin. A wound with external bleeding includes, but is not limited to, cuts, stabs, punctures, abrasions, incisions, and penetrations caused by, for example, a knife, a gun, a needle, a lancet, external force, or a motor vehicle accident.

[0113] One of ordinary skill in the art will be able to determine whether a subject having a wound with internal bleeding and / or a wound with external bleeding requires a blood transfusion before being administered a hemojuvelin antagonist (e.g., an anti-HJV antibody) based on existing techniques for assessing the subject's condition (e.g., the amount of blood loss of the subject and / or hemoglobin level).

[0114] In some embodiments, the blood loss condition includes a disease. In some embodiments, the disease is a gastrointestinal (GI) disease. As used herein, a GI disease is any disease / disorder that affects normal GI function. Examples of GI diseases include, but are not limited to, esophageal varices, gastritis, gastric ulcer, duodenal ulcer, diverticulosis, Meckel's diverticulum, intestinal polyps, inflammatory bowel disease (IBD), hematoma, celiac disease, and colorectal cancer. Gastrointestinal (GI) diseases may typically present with GI bleeding due to a disorder of the subject's digestive tract. In some embodiments, the blood often appears in the feces (e.g., bright red blood in the stool or black tarry stool) or in the vomit (e.g., bright red vomit or dark brown vomit). In some embodiments, the blood is not visible. The level of bleeding can range from mild to severe and can be life-threatening. In some embodiments, the GI disease includes blood loss due to upper GI bleeding. In some embodiments, upper GI bleeding includes esophageal varices, gastric ulcer, duodenal ulcer, esophagitis, Mallory-Weiss tear. In some embodiments, the GI disease includes blood loss due to lower GI bleeding. In some embodiments, lower GI bleeding includes diverticulosis, diverticulitis, Meckel's diverticulum, intestinal polyps, inflammatory bowel disease (IBD), celiac disease, colorectal cancer, anal fissure, or proctitis. In some embodiments, a subject having a blood loss condition including a GI disease is identified as in need of a blood transfusion and then receives treatment with a hemojuvelin antagonist (e.g., an anti-HJV antibody) (e.g., to promote hematological recovery). In some embodiments, a subject having a blood loss condition including a GI disease is not identified as in need of a blood transfusion and is treated with a hemojuvelin antagonist (e.g., an anti-HJV antibody) (e.g., to promote hematological recovery). The determination of whether a subject needs a blood transfusion may be made by any method known in the art and commonly practiced in a hospital (e.g., see Zomorrodi et al., 「Determining the Need for Blood Transfusion.」 In: StatPearls. Treasure Island (FL): StatPearls Publishing; October 17, 2022).

[0115] In some embodiments, the bleeding condition includes urogenital diseases, which are diseases of the genital and urinary systems. In some embodiments, the disease is a urinary tract disease and blood appears in the urine. In some embodiments, the urinary tract disease includes bladder tumors, urinary tract infections (UTIs), urinary tract lacerations, or kidney stones. In some embodiments, the disease is a genital disease. In some embodiments, the genital disease includes menorrhagia, uterine fibroids, bleeding during pregnancy, ectopic pregnancy, miscarriage, endometrial hyperplasia, or endometriosis.

[0116] In some embodiments, the bleeding condition includes infectious diseases. As used herein, infectious diseases include any disease, disorder, or illness caused by bacteria, fungi, parasites, or viruses. In some embodiments, the infectious disease includes blood loss due to viral hemorrhagic fever (VHF), which is a group of infectious diseases caused by viruses. These infections can damage blood vessels and cause dangerous bleeding in organs throughout the body. In some embodiments, viral hemorrhagic fever (VHF) includes, but is not limited to, dengue fever, Ebola virus disease, Lassa fever, hantavirus pulmonary syndrome, Marburg virus disease, or yellow fever. In some embodiments, the infectious disease includes blood loss due to bacterial infections. In some embodiments, the bacterial infection includes sepsis, bacterial vaginitis, Lemierre's syndrome, or tuberculosis. In some embodiments, the infectious disease includes blood loss due to parasitic infections. In some embodiments, the parasitic infection includes malaria, trichuriasis, and schistosomiasis.

[0117] In some embodiments, the blood loss condition includes persistent blood loss. Persistent blood loss refers to a steady blood loss that does not stop over a long period (e.g., 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 1 year, 2 years, 3 years, 4 years, 5 years, or more). In some embodiments, the persistent blood loss causes the subject to lose 1 - 30% of the total blood volume (e.g., 1% - 30%, 1% - 25%, 1% - 20%, 1% - 15%, 1% - 10%, 1% - 9%, 1% - 8%, 1% - 7%, 1% - 6%, 1% - 5%, 1% - 4%, 1% - 3%, 1% - 2%, 2% - 30%, 2% - 25%, 2% - 20%, 2% - 15%, 2% - 10%, 2% - 9%, 2% - 8%, 2% - 7%, 2% - 6%, 2% - 5%, 2% - 4%, 2% - 3%, 3% - 30%, 3% - 25%, 3% - 20%, 3% - 15%, 3% - 10%, 3% - 9%, 3% - 8%, 3% - 7%, 3% - 6%, 3% - 5%, 3% - 4%, 4% - 30%, 4% - 25%, 4% - 20%, 4% - 15%, 4% - 10%, 4% - 9%, 4% - 8%, 4% - 7%, 4% - 6%, 4% - 5%, 5% - 30%, 5% - 25%, 5% - 20%, 5% - 15%, 5% - 10%, 5% - 9%, 5% - 8%, 5% - 7%, 5% - 6%, 6% - 30%, 6% - 25%, 6% - 20%, 6% - 15%, 6% - 10%, 6% - 9%, 6% - 8%, 6% - 7%, 7% - 30%, 7% - 25%, 7% - 20%, 7% - 15%, 7% - 10%, 7% - 9%, 7% - 8%, 8% - 30%, 8% - 25%, 8% - 20%, 8% - 15%, 8% - 10%, 8% - 9%, 9% - 30%, 9% - 25%, 9% - 20%, 9% - 15%, 9% - 10%, 10% - 30%, 10% - 25%, 10% - 20%, 10% - 15%, 15% - 30%, 15% - 25%, 15% - 20%, 20% - 30%, 20% - 25%, 25% - 30%) of blood, and the subject does not require a blood transfusion and can be treated with a hemoferrin antagonist (e.g., an anti - HJV antibody).

[0118] In some embodiments, the blood loss condition includes intermittent blood loss. Intermittent blood loss refers to blood loss that occurs at intervals. In some embodiments, the intermittent blood loss occurs at equal intervals (e.g., at most 1 hour, at most 4 hours, at most 8 hours, at most 12 hours, at most 16 hours, at most 20 hours, at most 1 day interval, at most 2 day intervals, at most 3 day intervals, at most 5 day intervals, at most 1 week interval, at most 2 week intervals, at most 1 month interval). In some embodiments, the intermittent blood loss occurs at irregular intervals (e.g., the first and second bleeding events are 1 day apart, while the second and third bleeding events are 1 week apart). In some embodiments, the intermittent blood loss causes the subject to lose 1-30% of the total blood volume (e.g., 1% - 30%, 1% - 25%, 1% - 20%, 1% - 15%, 1% - 10%, 1% - 9%, 1% - 8%, 1% - 7%, 1% - 6%, 1% - 5%, 1% - 4%, 1% - 3%, 1% - 2%, 2% - 30%, 2% - 25%, 2% - 20%, 2% - 15%, 2% - 10%, 2% - 9%, 2% - 8%, 2% - 7%, 2% - 6%, 2% - 5%, 2% - 4%, 2% - 3%, 3% - 30%, 3% - 25%, 3% - 20%, 3% - 15%, 3% - 10%, 3% - 9%, 3% - 8%, 3% - 7%, 3% - 6%, 3% - 5%, 3% - 4%, 4% - 30%, 4% - 25%, 4% - 20%, 4% - 15%, 4% - 10%, 4% - 9%, 4% - 8%, 4% - 7%, 4% - 6%, 4% - 5%, 5% - 30%, 5% - 25%, 5% - 20%, 5% - 15%, 5% - 10%, 5% - 9%, 5% - 8%, 5% - 7%, 5% - 6%, 6% - 30%, 6% - 25%, 6% - 20%, 6% - 15%, 6% - 10%, 6% - 9%, 6% - 8%, 6% - 7%, 7% - 30%, 7% - 25%, 7% - 20%, 7% - 15%, 7% - 10%, 7% - 9%, 7% - 8%, 8% - 30%, 8% - 25%, 8% - 20%, 8% - 15%, 8% - 10%, 8% - 9%, 9% - 30%, 9% - 25%, 9% - 20%, 9% - 15%, 9% - 10%, 10% - 30%, 10% - 25%, 10% - 20%, 10% - 15%, 15% - 30%, 15% - 25%, 15% - 20%, 20% - 30%, 20% - 25%, 25% - 30%) of the blood in each bleeding event, and the subject does not require a blood transfusion and can be treated with a hemojuvelin antagonist (e.g., an anti-HJV antibody).

[0119] In some aspects, the present disclosure relates to compositions and methods for treating a subject having a state of blood loss. In some embodiments, the state of blood loss suitable for treatment with a hemojuvelin antagonist (e.g., an HJV antibody) may be characterized by one or more of the hematological criteria described herein. In some embodiments, the state of blood loss may be characterized as a mild to moderate state of blood loss or a severe state of blood loss according to appropriate diagnostic threshold parameters.

[0120] In some embodiments, the blood loss state is characterized based on the level of circulating hemoglobin (Hgb), where the severity of the blood loss state increases with a decrease in the level of circulating Hgb. In some embodiments, the circulating hemoglobin level of the subject is determined (e.g., before treatment with an HJV antagonist (e.g., an anti-HJV antibody) or in other states where no treatment with an HJV antagonist (e.g., an anti-HJV antibody and its composition) has been made at the time of determination) and compared to the circulating hemoglobin level of the subject after treatment. In some embodiments, prior to administration, the subject has not been identified as in need of a blood transfusion, and the blood loss state suitable for a hemodjuvelin antagonist (e.g., an anti-HJV antibody) is related to a circulating hemoglobin level of at least 6 g / dL (e.g., at least 6 g / dL, at least 6.5 g / dL, at least 7 g / dL, at least 7.5 g / dL, at least 8 g / dL, at least 8.5 g / dL, at least 9 g / dL, at least 9.5 g / dL, at least 10 g / dL, at least 10.5 g / dL, at least 11 g / dL, at least 11.5 g / dL, at least 12 g / dL, at least 12.5 g / dL, or at least 13 g / dL). In some embodiments, prior to administration, the subject has not been identified as in need of a blood transfusion, and the blood loss state suitable for a hemodjuvelin antagonist (e.g., an anti-HJV antibody) is 6 - 13 g / dL, 7 - 13 g / dL, 7 - 12.5 g / dL, 7 - 12 g / dL, 7 - 11.5 g / dL, 7 - 11 g / dL, 7 - 10.5 g / dL, 7 - 10 g / dL, 7 - 9.5 g / dL, 7 - 9 g / dL, 7 - 8.5 g / dL, 7 - 8 g / dL, 7 - 7.5 g / dL, 7.5 - 13 g / dL, 7.5 - 12.5 g / dL, 7.5 - 12 g / dL, 7.5 - 11.5 g / dL, 7.5 - 11 g / dL, 7.5 - 10.5 g / dL, 7.5 - 10 g / dL, 7.5 - 9.5 g / dL, 7.5 - 9 g / dL, 7.5 - 8.5 g / dL, 7.5 - 8 g / dL, 8 - 13 g / dL, 8 - 12.5 g / dL, 8 - 12 g / dL, 8 - 11.5 g / dL, 8 - 11 g / dL, 8 - 10.5 g / dL, 8 - 10 g / dL, 8 - 9.5 g / dL, 8 - 9 g / dL, 8 - 8.5 g / dL, 8.5 - 13 g / dL, 8.5 - 12.5 g / dL, 8.5 - 12 g / dL, 8.Related to circulating hemoglobin levels in the range of 5 to 11.5 g / dL, 8.5 to 11 g / dL, 8.5 to 10.5 g / dL, 8.5 to 10 g / dL, 8.5 to 9.5 g / dL, 8.5 to 9 g / dL, 9 to 13 g / dL, 9 to 12.5 g / dL, 9 to 12 g / dL, 9 to 11.5 g / dL, 9 to 11 g / dL, 9 to 10.5 g / dL, 9 to 10 g / dL, 9 to 9.5 g / dL, 10 to 13 g / dL, 10 to 12.5 g / dL, 10 to 12 g / dL, 10 to 11.5 g / dL, 10 to 11 g / dL, 10 to 10.5 g / dL, 10.5 to 13 g / dL, 10.5 to 12.5 g / dL, 10.5 to 12 g / dL, 10.5 to 11.5 g / dL, 10.5 to 11 g / dL, 11 to 13 g / dL, 11 to 12.5 g / dL, 11 to 12 g / dL, 11 to 11.5 g / dL, 11.5 to 13 g / dL, 11.5 to 12.5 g / dL, 11.5 to 12 g / dL, 12 to 13 g / dL, 12 to 12.5 g / dL, 12.5 to 13 g / dL, 6.5 to 13 g / dL, 6.5 to 12.5 g / dL, 6.5 to 12 g / dL, 6.5 to 11.5 g / dL, 6.5 to 11 g / dL, 6.5 to 10.5 g / dL, 6.5 to 10 g / dL, 6.5 to 9.5 g / dL, 6.5 to 9 g / dL, 6.5 to 8.5 g / dL, 6.5 to 8 g / dL, 6.5 to 7.5 g / dL, 6.5 to 7 g / dL, 6 to 13 g / dL, 6 to 12.5 g / dL, 6 to 12 g / dL, 6 to 11.5 g / dL, 6 to 11 g / dL, 6 to 10.5 g / dL, 6 to 10 g / dL, 6 to 9.5 g / dL, 6 to 9 g / dL, 6 to 8.5 g / dL, 6 to 8 g / dL, 6 to 7.5 g / dL, 6 to 7 g / dL, or 6 to 6.5 g / dL. In some embodiments, prior to administration, the subject has a hemoglobin level of at least 6 g / dL (e.g., at least 6 g / dL, at least 6.5 g / dL, at least 7 g / dL, at least 7.5 g / dL, at least 8 g / dL, at least 8.5 g / dL, at least 9 g / dL, at least 9.5 g / dL, at least 10 g / dL, at least 10.5 g / dL, at least 11 g / dL, at least 11.5 g / dL, at least 12 g / dL, at least 12.5 g / dL, at least 13 g / dL, 6 to 13 g / dL, 7 to 13 g / dL, 7 to 12.5 g / dL, 7 to 12 g / dL, 7 to 11.5 g / dL, 7 - 11 g / dL, 7 - 10.5 g / dL, 7 - 10 g / dL, 7 - 9.5 g / dL, 7 - 9 g / dL, 7 - 8.5 g / dL, 7 - 8 g / dL, 7 - 7.5 g / dL, 7.5 - 13 g / dL, 7.5 - 12.5 g / dL, 7.5 - 12 g / dL, 7.5 - 11.5 g / dL, 7.5 - 11 g / dL, 7.5 - 10.5 g / dL, 7.5 - 10 g / dL, 7.5 - 9.5 g / dL, 7.5 - 9 g / dL, 7.5 - 8.5 g / dL, 7.5 - 8 g / dL, 8 - 13 g / dL, 8 - 12.5 g / dL, 8 - 12 g / dL, 8 - 11.5 g / dL, 8 - 11 g / dL, 8 - 10.5 g / dL, 8 - 10 g / dL, 8 - 9.5 g / dL, 8 - 9 g / dL, 8 - 8.5 g / dL, 8.5 - 13 g / dL, 8.5 - 12.5 g / dL, 8.5 - 12 g / dL, 8.5 - 11.5 g / dL, 8.5 - 11 g / dL, 8.5 - 10.5 g / dL, 8.5 - 10 g / dL, 8.5 - 9.5 g / dL, 8.5 - 9 g / dL, 9 - 13 g / dL, 9 - 12.5 g / dL, 9 - 12 g / dL, 9 - 11.5 g / dL, 9 - 11 g / dL, 9 - 10.5 g / dL, 9 - 10 g / dL, 9 - 9.5 g / dL, 10 - 13 g / dL, 10 - 12.5 g / dL, 10 - 12 g / dL, 10 - 11.5 g / dL, 10 - 11 g / dL, 10 - 10.5 g / dL, 10.5 - 13 g / dL, 10.5 - 12.5 g / dL, 10.5 - 12 g / dL, 10.5 - 11.5 g / dL, 10.5 - 11 g / dL, 11 - 13 g / dL, 11 - 12.5 g / dL, 11 - 12 g / dL, 11 - 11.5 g / dL, 11.5 - 13 g / dL, 11.5 - 12.5 g / dL, 11.5 - 12 g / dL, 12 - 13 g / dL, 12 - 12.5 g / dL, 12.5 - 13 g / dL, 6.5 - 13 g / dL, 6.5 - 12.5 g / dL, 6.5 - 12 g / dL, 6.5 - 11.5 g / dL, 6.5 - 11 g / dL, 6.5 - 10.5 g / dL, 6.5 - 10 g / dL, 6.5 - 9.5 g / dL, 6.5 - 9 g / dL, 6.5 - 8.5 g / dL, 6.5 - 8 g / dL, 6.5 - 7.5 g / dL, 6.5 - 7 g / dL, 6 - 13 g / dL, 6 - 12.5 g / dL, 6 - 12 g / dL, 6 - 11.5 g / dL, 6 - 11 g / dL, 6 - 10.5 g / dL, 6 - 10 g / dL, 6 - 9.5 g / dL, 6 - 9 g / dL, 6 - 8.5 g / dL, 6 - 8 g / dL, 6 - 7.Transfusion is determined to be necessary according to the circulating hemoglobin levels described anywhere in this specification such that it rises to a range of 5 g / dL, 6 - 7 g / dL, or 6 - 6.5 g / dL, and the subject can then be treated with a hemodjuvelin antagonist (e.g., an anti-HJV antibody) to promote hematological recovery.

[0121] In some embodiments, after administration of a hemojuvelin antagonist (e.g., an anti-HJV antibody), the circulating hemoglobin level of the subject increases. In some embodiments, after administration of a hemojuvelin antagonist (e.g., an anti-HJV antibody), the circulating hemoglobin level of the subject increases to the baseline level before the blood loss state. In some embodiments, after administration of a hemojuvelin antagonist (e.g., an anti-HJV antibody), the circulating hemoglobin level of the subject increases by 1-5 g / dL, 1-4.5 g / dL, 1-4 g / dL, 1-3.5 g / dL, 1-3 g / dL, 1-2.5 g / dL, 1-2 g / dL, 1-1.5 g / dL, 1.5-5 g / dL, 1.5-4.5 g / dL, 1.5-4 g / dL, 1.5-3.5 g / dL, 1.5-3 g / dL, 1.5-2.5 g / dL, 1.5-2 g / dL, 2-5 g / dL, 2-4.5 g / dL, 2-4 g / dL, 2-3.5 g / dL, 2-3 g / dL, 2-2.5 g / dL, 2.5-5 g / dL, 2.5-4.5 g / dL, 2.5-4 g / dL, 2.5-3.5 g / dL, 2.5-3 g / dL, 3-5 g / dL, 3-4.5 g / dL, 3-4 g / dL, 3-3.5 g / dL, 3.5-5 g / dL, 3.5-4.5 g / dL, 3.5-4 g / dL, 4-5 g / dL, 4-4.5 g / dL, or 4.5-5 g / dL.In some embodiments, after administration of a hemojuvelin antagonist (e.g., an anti-HJV antibody), the circulating hemoglobin level of a subject increases by 1-5 g / dL, 1-4.5 g / dL, 1-4 g / dL, 1-3.5 g / dL, 1-3 g / dL, 1-2.5 g / dL, 1-2 g / dL, 1-1.5 g / dL, 1.5-5 g / dL, 1.5-4.5 g / dL, 1.5-4 g / dL, 1.5-3.5 g / dL, 1.5-3 g / dL, 1.5-2.5 g / dL, 1.5-2 g / dL, 2-5 g / dL, 2-4.5 g / dL, 2-4 g / dL, 2-3.5 g / dL, 2-3 g / dL, 2-2.5 g / dL, 2.5-5 g / dL, 2.5-4.5 g / dL, 2.5-4 g / dL, 2.5-3.5 g / dL, 2.5-3 g / dL, 3-5 g / dL, 3-4.5 g / dL, 3-4 g / dL, 3-3.5 g / dL, 3.5-5 g / dL, 3.5-4.5 g / dL, 3.5-4 g / dL, 4-5 g / dL, 4-4.5 g / dL, or 4.5-5 g / dL within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, or 6 months. In some embodiments, the increase in circulating hemoglobin level in a subject administered a hemojuvelin antagonist (e.g., an anti-HJV antibody) is achieved in a shorter period of time than is achieved in a control subject not administered a hemojuvelin antagonist (e.g., an anti-HJV antibody).In some embodiments, the increase in circulating hemoglobin levels in a subject administered a hemojuvelin antagonist (e.g., an anti-HJV antibody) is achieved earlier by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks than in a control subject not administered a hemojuvelin antagonist (e.g., an anti-HJV antibody).

[0122] In some embodiments, the blood loss state is characterized based on the level of circulating ferritin. Ferritin is a blood protein that contains iron, and its level indicates how much iron the body has stored. In some embodiments, the circulating ferritin level of the subject is determined (e.g., before treatment with an HJV antagonist (e.g., an anti-HJV antibody), or in other states where no HJV antagonist (e.g., an anti-HJV antibody and its composition) treatment has been performed at the time of determination) and compared to the circulating ferritin level of the subject after treatment. In some embodiments, the subject is slightly iron-deficient due to blood loss presenting as a circulating ferritin level of 14 - 80 ng / ml. In some embodiments, prior to administration, a subject having a blood loss state suitable for a hemodjuvelin antagonist (e.g., an anti-HJV antibody) has a circulating ferritin level of up to 5000 ng / ml. In some embodiments, prior to administration, a subject having a blood loss state suitable for a hemodjuvelin antagonist (e.g., an anti-HJV antibody) has a circulating ferritin level of 10 - 5000 ng / ml, 50 - 4000 ng / ml, 100 - 3000 ng / ml, 200 - 2000 ng / ml, 300 - 1000 ng / ml, 500 - 750 ng / ml, 14 - 150 ng / ml, 14 - 140 ng / ml, 14 - 130 ng / ml, 14 - 120 ng / ml, 14 - 110 ng / ml, 14 - 100 ng / ml, 14 - 90 ng / ml, 14 - 80 ng / ml, 14 - 70 ng / ml, 14 - 60 ng / ml, 14 - 50 ng / ml, 14 - 40 ng / ml, 14 - 30 ng / ml, 14 - 20 ng / ml, 15 - 150 ng / ml, 15 - 140 ng / ml, 15 - 130 ng / ml, 15 - 120 ng / ml, 15 - 110 ng / ml, 15 - 100 ng / ml, 15 - 90 ng / ml, 15 - 80 ng / ml, 15 - 70 ng / ml, 15 - 60 ng / ml, 15 - 50 ng / ml, 15 - 40 ng / ml, 15 - 30 ng / ml, 15 - 20 ng / ml, 20 - 150 ng / ml, 20 - 140 ng / ml, 20 - 130 ng / ml, 20 - 120 ng / ml, 20 - 110 ng / ml, 20 - 100 ng / ml, 20 - 90 ng / ml, 20 - 80 ng / ml, 20 - 70 ng / ml, 20 - 60 ng / ml, 20 - 50 ng / ml, 20 - 40 ng / ml,20 - 30 ng / ml, 20 - 25 ng / ml, 30 - 150 ng / ml, 30 - 140 ng / ml, 30 - 130 ng / ml, 30 - 120 ng / ml, 30 - 110 ng / ml, 30 - 100 ng / ml, 30 - 90 ng / ml, 30 - 80 ng / ml, 30 - 70 ng / ml, 30 - 60 ng / ml, 30 - 50 ng / ml, 30 - 40 ng / ml, 40 - 150 ng / ml, 40 - 140 ng / ml, 40 - 130 ng / ml, 40 - 120 ng / ml, 40 - 110 ng / ml, 40 - 100 ng / ml, 40 - 90 ng / ml, 40 - 80 ng / ml, 40 - 70 ng / ml, 40 - 60 ng / ml, 40 - 50 ng / ml, 50 - 150 ng / ml, 50 - 140 ng / ml, 50 - 130 ng / ml, 50 - 120 ng / ml, 50 - 110 ng / ml, 50 - 100 ng / ml, 50 - 90 ng / ml, 50 - 80 ng / ml, 50 - 70 ng / ml, 50 - 60 ng / ml, 60 - 150 ng / ml, 60 - 140 ng / ml, 60 - 130 ng / ml, 60 - 120 ng / ml, 60 - 110 ng / ml, 60 - 100 ng / ml, 60 - 90 ng / ml, 60 - 80 ng / ml, 60 - 70 ng / ml, 70 - 150 ng / ml, 70 - 140 ng / ml, 70 - 130 ng / ml, 70 - 120 ng / ml, 70 - 110 ng / ml, 70 - 100 ng / ml, 70 - 90 ng / ml, 70 - 80 ng / ml, 80 - 150 ng / ml, 80 - 140 ng / ml, 80 - 130 ng / ml, 80 - 120 ng / ml, 80 - 110 ng / ml, 80 - 100 ng / ml, 80 - 90 ng / ml, 90 - 150 ng / ml, 90 - 140 ng / ml, 90 - 130 ng / ml, 90 - 120 ng / ml, 90 - 110 ng / ml, 90 - 100 ng / ml, 100 - 150 ng / ml, 100 - 140 ng / ml, 100 - 130 ng / ml, 100 - 120 ng / ml, 100 - 110 ng / ml, 110 - 150 ng / ml, 110 - 140 ng / ml, 110 - 130 ng / ml, 110 - 120 ng / ml, 120 - 150 ng / ml, 120 - 140 ng / ml, 120 - 130 ng / ml, 140 - 150 ng / ml, 100 - 5000 ng / ml, 200 - 5000 ng / ml, 300 - 5000 ng / ml, 400 - 5000 ng / ml, 500 - 5000 ng / mlwith circulating ferritin levels in the range of 600 - 5000 ng / ml, 700 - 5000 ng / ml, 800 - 5000 ng / ml, 900 - 5000 ng / ml, 1000 - 5000 ng / ml, 1500 - 5000 ng / ml, 2000 - 5000 ng / ml, 2500 - 5000 ng / ml, 3000 - 5000 ng / ml, 3500 - 5000 ng / ml, 4000 - 5000 ng / ml, 4500 - 5000 ng / ml, 100 - 4000 ng / ml, 200 - 4000 ng / ml, 300 - 4000 ng / ml, 400 - 4000 ng / ml, 500 - 4000 ng / ml, 600 - 4000 ng / ml, 700 - 4000 ng / ml, 800 - 4000 ng / ml, 900 - 4000 ng / ml, 1000 - 4000 ng / ml, 1500 - 4000 ng / ml, 2000 - 4000 ng / ml, 2500 - 4000 ng / ml, 3000 - 4000 ng / ml, 3500 - 4000 ng / ml, 100 - 3000 ng / ml, 200 - 3000 ng / ml, 300 - 3000 ng / ml, 400 - 3000 ng / ml, 500 - 3000 ng / ml, 600 - 3000 ng / ml, 700 - 3000 ng / ml, 800 - 3000 ng / ml, 900 - 3000 ng / ml, 1000 - 3000 ng / ml, 1500 - 3000 ng / ml, 2000 - 3000 ng / ml, 2500 - 3000 ng / ml, 100 - 2000 ng / ml, 200 - 2000 ng / ml, 300 - 2000 ng / ml, 400 - 2000 ng / ml, 500 - 2000 ng / ml, 600 - 2000 ng / ml, 700 - 2000 ng / ml, 800 - 2000 ng / ml, 900 - 2000 ng / ml, 1000 - 2000 ng / ml, 1500 - 2000 ng / ml, 100 - 1000 ng / ml, 200 - 1000 ng / ml, 300 - 1000 ng / ml, 400 - 1000 ng / ml, 500 - 1000 ng / ml, 600 - 1000 ng / ml, 700 - 1000 ng / ml, 800 - 1000 ng / ml, or 900 - 1000 ng / ml. In some embodiments, prior to administration, a subject having a blood loss state suitable for a hemojuvelin antagonist (e.g., an anti-HJV antibody) has circulating ferritin levels in the range of 14 - 150 ng / ml.,

[0123] In some embodiments, after administration of a hepcidin antagonist (e.g., an anti-HJV antibody), the circulating ferritin level of a subject decreases. In some embodiments, the decrease in ferritin level suggests that stored iron is released into the circulation and becomes available for RBC production. In some embodiments, after administration of a hepcidin antagonist (e.g., an anti-HJV antibody), the circulating ferritin level of a subject decreases by 10% - 70%, 15% - 70%, 20% - 70%, 25% - 70%, 30% - 70%, 35% - 70%, 40% - 70%, 45% - 70%, 50% - 70%, 55% - 70%, 60% - 70%, 65% - 70%, 10% - 60%, 15% - 60%, 20% - 60%, 25% - 60%, 30% - 60%, 35% - 60%, 40% - 60%, 45% - 60%, 50% - 60%, 55% - 60%, 10% - 50%, 15% - 50%, 20% - 50%, 25% - 50%, 30% - 50%, 35% - 50%, 40% - 50%, 45% - 50%, 10% - 40%, 15% - 40%, 20% - 40%, 25% - 40%, 30% - 40%, 35% - 40%, 10% - 30%, 15% - 30%, 20% - 30%, 25% - 30%, 10% - 20%, or 15% - 20% compared to the circulating ferritin level before administration.In some embodiments, after administration of a hepcidin antagonist (e.g., an anti-HJV antibody), the circulating ferritin levels of the subject decrease by 10% - 70%, 15% - 70%, 20% - 70%, 25% - 70%, 30% - 70%, 35% - 70%, 40% - 70%, 45% - 70%, 50% - 70%, 55% - 70%, 60% - 70%, 65% - 70%, 10% - 60%, 15% - 60%, 20% - 60%, 25% - 60%, 30% - 60%, 35% - 60%, 40% - 60%, 45% - 60%, 50% - 60%, 55% - 60%, 10% - 50%, 15% - 50%, 20% - 50%, 25% - 50%, 30% - 50%, 35% - 50%, 40% - 50%, 45% - 50%, 10% - 40%, 15% - 40%, 20% - 40%, 25% - 40%, 30% - 40%, 35% - 40%, 10% - 30%, 15% - 30%, 20% - 30%, 25% - 30%, 10% - 20%, or 15% - 20% within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, or 6 months. In some embodiments, the decrease in circulating ferritin levels in a subject administered a hepcidin antagonist (e.g., an anti-HJV antibody) is achieved in a shorter period of time than is achieved in a control subject not administered a hepcidin antagonist (e.g., an anti-HJV antibody). In some embodiments, the decrease in circulating ferritin levels in a subject administered a hepcidin antagonist (e.g., an anti-HJV antibody) is achieved 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks earlier than is achieved in a control subject not administered a hepcidin antagonist (e.g., an anti-HJV antibody).

[0124] In some embodiments, the blood loss condition is characterized based on the level of serum iron. In some embodiments, the serum iron level of a subject is determined (e.g., before treatment with an HJV antagonist (e.g., an anti-HJV antibody) or in other conditions where no treatment with an HJV antagonist (e.g., an anti-HJV antibody and compositions thereof) has been made at the time of determination) and compared to the serum iron level of the subject after treatment. In some embodiments, the subject is in a slightly iron-deficient state due to blood loss presenting as a serum iron level of at least 40 μg / dL. In some embodiments, the subject is in a slightly iron-deficient state due to blood loss presenting as a serum iron level in the range of 40 - 60 μg / dL. In some embodiments, prior to administration, a subject having a blood loss condition suitable for a hemodjuvelin antagonist (e.g., an anti-HJV antibody) has a serum iron level in the range of 20 - 80 μg / dL, 20 - 70 μg / dL, 20 - 60 μg / dL, 20 - 50 μg / dL, 20 - 40 μg / dL, 20 - 30 μg / dL, 25 - 80 μg / dL, 25 - 70 μg / dL, 25 - 60 μg / dL, 25 - 50 μg / dL, 25 - 40 μg / dL, 25 - 30 μg / dL, 30 - 80 μg / dL, 30 - 70 μg / dL, 30 - 60 μg / dL, 30 - 50 μg / dL, 30 - 40 μg / dL, 35 - 80 μg / dL, 35 - 70 μg / dL, 35 - 60 μg / dL, 35 - 50 μg / dL, 35 - 40 μg / dL, 40 - 80 μg / dL, 40 - 70 μg / dL, 40 - 60 μg / dL, 40 - 50 μg / dL, 45 - 80 μg / dL, 45 - 70 μg / dL, 45 - 60 μg / dL, 45 - 50 μg / dL, 50 - 80 μg / dL, 50 - 70 μg / dL, 50 - 60 μg / dL, 60 - 80 μg / dL, 60 - 70 μg / dL, or 70 - 80 μg / dL.

[0125] In some embodiments, after administration of a hepcidin antagonist (e.g., an anti-HJV antibody), the serum iron level of a subject increases. In some embodiments, the increase in serum iron level suggests that more iron is available for RBC production. In some embodiments, after administration of a hepcidin antagonist (e.g., an anti-HJV antibody), the serum iron level of a subject is in the range of 45 - 200 μg / dL, 45 - 180 μg / dL, 45 - 160 μg / dL, 45 - 140 μg / dL, 45 - 120 μg / dL, 45 - 100 μg / dL, 45 - 80 μg / dL, 45 - 60 μg / dL, 60 - 200 μg / dL, 60 - 180 μg / dL, 60 - 160 μg / dL, 60 - 140 μg / dL, 60 - 120 μg / dL, 60 - 100 μg / dL, 60 - 80 μg / dL, 70 - 200 μg / dL, 70 - 180 μg / dL, 70 - 160 μg / dL, 70 - 140 μg / dL, 70 - 120 μg / dL, 70 - 100 μg / dL, 70 - 80 μg / dL, 80 - 200 μg / dL, 80 - 180 μg / dL, 80 - 160 μg / dL, 80 - 140 μg / dL, 80 - 120 μg / dL, 80 - 100 μg / dL, 90 - 200 μg / dL, 90 - 180 μg / dL, 90 - 160 μg / dL, 90 - 140 μg / dL, 90 - 120 μg / dL, 90 - 100 μg / dL, 100 - 200 μg / dL, 100 - 180 μg / dL, 100 - 160 μg / dL, 100 - 140 μg / dL, 100 - 120 μg / dL, 120 - 200 μg / dL, 120 - 180 μg / dL, 120 - 160 μg / dL, 120 - 140 μg / dL, 140 - 200 μg / dL, 140 - 180 μg / dL, 140 - 160 μg / dL, 160 - 200 μg / dL, 160 - 180 μg / dL, 160 - 180 μg / dL, or 180 - 200 μg / dL.In some embodiments, after administration of a hepcidin antagonist (e.g., an anti-HJV antibody), the serum iron level of the subject reaches the range of 45 - 200 μg / dL, 45 - 180 μg / dL, 45 - 160 μg / dL, 45 - 140 μg / dL, 45 - 120 μg / dL, 45 - 100 μg / dL, 45 - 80 μg / dL, 45 - 60 μg / dL, 60 - 200 μg / dL, 60 - 180 μg / dL, 60 - 160 μg / dL, 60 - 140 μg / dL, 60 - 120 μg / dL, 60 - 100 μg / dL, 60 - 80 μg / dL, 70 - 200 μg / dL, 70 - 180 μg / dL, 70 - 160 μg / dL, 70 - 140 μg / dL, 70 - 120 μg / dL, 70 - 100 μg / dL, 70 - 80 μg / dL, 80 - 200 μg / dL, 80 - 180 μg / dL, 80 - 160 μg / dL, 80 - 140 μg / dL, 80 - 120 μg / dL, 80 - 100 μg / dL, 90 - 200 μg / dL, 90 - 180 μg / dL, 90 - 160 μg / dL, 90 - 140 μg / dL, 90 - 120 μg / dL, 90 - 100 μg / dL, 100 - 200 μg / dL, 100 - 180 μg / dL, 100 - 160 μg / dL, 100 - 140 μg / dL, 100 - 120 μg / dL, 120 - 200 μg / dL, 120 - 180 μg / dL, 120 - 160 μg / dL, 120 - 140 μg / dL, 140 - 200 μg / dL, 140 - 180 μg / dL, 140 - 160 μg / dL, 160 - 200 μg / dL, 160 - 180 μg / dL, 160 - 180 μg / dL, or 180 - 200 μg / dL within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, or 6 months. In some embodiments, the increase in serum iron level in a subject administered a hepcidin antagonist (e.g., an anti-HJV antibody) is achieved in a shorter period of time than is achieved in a control subject not administered a hepcidin antagonist (e.g., an anti-HJV antibody).In some embodiments, the increase in serum iron levels in a subject administered a hepcidin antagonist (e.g., an anti-HJV antibody) is achieved 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks earlier than is achieved in a control subject not administered a hepcidin antagonist (e.g., an anti-HJV antibody).

[0126] In some embodiments, the state of blood loss is characterized based on the level of reticulocyte hemoglobin content (RET-He or CHr). In some embodiments, the CHr level of a subject is determined (e.g., before treatment with an HJV antagonist (e.g., an anti-HJV antibody), or in other states where no treatment with an HJV antagonist (e.g., an anti-HJV antibody and its compositions) has been made at the time of determination) and compared to the CHr level of the subject after treatment. In some embodiments, prior to treatment, a subject having a state of blood loss suitable for a hemojuvelin antagonist (e.g., an anti-HJV antibody) has a CHr in the range of 10-60 pg, 10-55 pg, 10-50 pg, 10-45 pg, 10-40 pg, 10-35 pg, 10-30 pg, 10-25 pg, 10-20 pg, 10-15 pg, 15-60 pg, 15-55 pg, 15-50 pg, 15-45 pg, 15-40 pg, 15-35 pg, 15-30 pg, 15-25 pg, 15-20 pg, 20-60 pg, 20-55 pg, 20-50 pg, 20-45 pg, 20-40 pg, 20-35 pg, 20-30 pg, 20-25 pg, 25-60 pg, 25-55 pg, 25-50 pg, 25-45 pg, 25-40 pg, 25-35 pg, 25-30 pg, 30-60 pg, 30-55 pg, 30-50 pg, 30-45 pg, 30-40 pg, 30-35 pg, 35-60 pg, 35-55 pg, 35-50 pg, 35-45 pg, 35-40 pg, 40-60 pg, 40-55 pg, 40-50 pg, 40-45 pg, 45-60 pg, 45-55 pg, 45-50 pg, 50-60 pg, 50-55 pg, or 50-60 pg. In some embodiments, a subject having a state of blood loss suitable for a hemojuvelin antagonist (e.g., an anti-HJV antibody) has a CHr in the range of 20-40 pg.

[0127] In some embodiments, after administration of a hemojuvelin antagonist (e.g., an anti-HJV antibody), the CHr level of the subject increases. In some embodiments, after administration of a hemojuvelin antagonist (e.g., an anti-HJV antibody), the CHr level of the subject increases by 1% to 10%, 1% to 9%, 1% to 8%, 1% to 7%, 1% to 6%, 1% to 5%, 1% to 4%, 1% to 3%, 1% to 2%, 2% to 10%, 2% to 9%, 2% to 8%, 2% to 7%, 2% to 6%, 2% to 5%, 2% to 4%, 2% to 3%, 3% to 10%, 3% to 9%, 3% to 8%, 3% to 7%, 3% to 6%, 3% to 5%, 3% to 4%, 4% to 10%, 4% to 9%, 4% to 8%, 4% to 7%, 4% to 6%, 4% to 5%, 5% to 10%, 5% to 9%, 5% to 8%, 5% to 7%, 5% to 6%, 6% to 10%, 6% to 9%, 6% to 8%, 6% to 7%, 7% to 10%, 7% to 9%, 7% to 8%, 8% to 10%, 8% to 9%, or 9% to 10% compared to the CHr level before administration. In some embodiments, after administration of a hemojuvelin antagonist (e.g., an anti-HJV antibody), the CHr level of the subject increases by 1% to 10%, 1% to 9%, 1% to 8%, 1% to 7%, 1% to 6%, 1% to 5%, 1% to 4%, 1% to 3%, 1% to 2%, 2% to 10%, 2% to 9%, 2% to 8%, 2% to 7%, 2% to 6%, 2% to 5%, 2% to 4%, 2% to 3%, 3% to 10%, 3% to 9%, 3% to 8%, 3% to 7%, 3% to 6%, 3% to 5%, 3% to 4%, 4% to 10%, 4% to 9%, 4% to 8%, 4% to 7%, 4% to 6%, 4% to 5%, 5% to 10%, 5% to 9%, 5% to 8%, 5% to 7%, 5% to 6%, 6% to 10%, 6% to 9%, 6% to 8%, 6% to 7%, 7% to 10%, 7% to 9%, 7% to 8%, 8% to 10%, 8% to 9%, or 9% to 10% within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, or 6 months.In some embodiments, the increase in CHr level in a subject administered a hemojuvelin antagonist (e.g., an anti-HJV antibody) is achieved in a shorter period of time than is achieved by control subjects not administered a hemojuvelin antagonist (e.g., an anti-HJV antibody). In some embodiments, the increase in CHr level in a subject administered a hemojuvelin antagonist (e.g., an anti-HJV antibody) is achieved 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks earlier than is achieved by control subjects not administered a hemojuvelin antagonist (e.g., an anti-HJV antibody).

[0128] In some embodiments, the state of blood loss is characterized based on the level of transferrin saturation (TSAT%). In some embodiments, the TSAT% level of a subject is determined (e.g., before treatment with an HJV antagonist (e.g., an anti-HJV antibody), or in other states where no HJV antagonist (e.g., an anti-HJV antibody and its compositions) treatment has been made at the time of determination) and compared to the TSAT% level of the subject after treatment. In some embodiments, prior to administration, a subject having a state of blood loss suitable for a hemojuvelin antagonist (e.g., an anti-HJV antibody) has a TSAT% level in the range of 10% - 40%, 10% - 35%, 10% - 30%, 10% - 25%, 10% - 20%, 10% - 15%, 15% - 40%, 15% - 35%, 15% - 30%, 15% - 25%, 15% - 20%, 20% - 40%, 20% - 35%, 20% - 30%, 20% - 25%, 25% - 40%, 25% - 35%, 25% - 30%, 30% - 40%, 30% - 35%, 35% - 40%. In some embodiments, a subject having a state of blood loss suitable for a hemojuvelin antagonist (e.g., an anti-HJV antibody) has a TSAT% in the range of 15% - 30%.

[0129] In some embodiments, after administration of a hepcidin antagonist (e.g., an anti-HJV antibody), the TSAT% level of the subject increases. In some embodiments, after administration of a hepcidin antagonist (e.g., an anti-HJV antibody), the TSAT% level of the subject increases to a range of 25% - 55%, 25% - 50%, 25% - 45%, 25% - 40%, 25% - 35%, 25% - 30%, 30% - 55%, 30% - 50%, 30% - 45%, 30% - 40%, 30% - 35%, 35% - 55%, 35% - 50%, 35% - 45%, 35% - 40%, 40% - 55%, 40% - 50%, 40% - 45%, 45% - 55%, 45% - 50%, or 50% - 55% compared to the TSAT% level before administration. In some embodiments, after administration of a hepcidin antagonist (e.g., an anti-HJV antibody), the TSAT% level of the subject increases to a range of 25% - 55%, 25% - 50%, 25% - 45%, 25% - 40%, 25% - 35%, 25% - 30%, 30% - 55%, 30% - 50%, 30% - 45%, 30% - 40%, 30% - 35%, 35% - 55%, 35% - 50%, 35% - 45%, 35% - 40%, 40% - 55%, 40% - 50%, 40% - 45%, 45% - 55%, 45% - 50%, or 50% - 55% within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, or 6 months. In some embodiments, the increase in the TSAT% level of a subject administered a hepcidin antagonist (e.g., an anti-HJV antibody) is achieved in a shorter period of time than is achieved in a control subject not administered the hepcidin antagonist (e.g., an anti-HJV antibody).In some embodiments, the increase in the TSAT% level in a subject administered a hepcidin antagonist (e.g., an anti-HJV antibody) is achieved 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks earlier than is achieved in a control subject not administered a hepcidin antagonist (e.g., an anti-HJV antibody).

[0130] In some embodiments, the state of blood loss is characterized based on the level of circulating hepcidin (e.g., hepcidin-25). In some embodiments, the circulating hepcidin (e.g., hepcidin-25) level of a subject is determined (e.g., before treatment with an HJV antagonist (e.g., an anti-HJV antibody) or in other states where no HJV antagonist (e.g., an anti-HJV antibody and its composition) treatment has been performed at the time of determination) and compared to the circulating hepcidin (e.g., hepcidin-25) level of the subject after treatment. In some embodiments, prior to administration, a subject having a state of blood loss suitable for a hemojuvelin antagonist (e.g., an anti-HJV antibody) has a level of 2 to 100 ng / ml, 2 to 95 ng / ml, 2 to 90 ng / ml, 2 to 85 ng / ml, 2 to 80 ng / ml, 2 to 75 ng / ml, 2 to 70 ng / ml, 2 to 65 ng / ml, 2 to 60 ng / ml, 2 to 55 ng / ml, 2 to 50 ng / ml, 2 to 45 ng / ml, 2 to 40 ng / ml, 2 to 35 ng / ml, 2 to 30 ng / ml, 2 to 25 ng / ml, 2 to 20 ng / ml, 2 to 15 ng / ml, 2 to 10 ng / ml, 5 to 100 ng / ml, 5 to 95 ng / ml, 5 to 90 ng / ml, 5 to 85 ng / ml, 5 to 80 ng / ml, 5 to 75 ng / ml, 5 to 70 ng / ml, 5 to 65 ng / ml, 5 to 60 ng / ml, 5 to 55 ng / ml, 5 to 50 ng / ml, 5 to 45 ng / ml, 5 to 40 ng / ml, 5 to 35 ng / ml, 5 to 30 ng / ml, 5 to 25 ng / ml, 5 to 20 ng / ml, 5 to 15 ng / ml, 5 to 10 ng / ml, 10 to 100 ng / ml, 10 to 95 ng / ml, 10 to 90 ng / ml, 10 to 85 ng / ml, 10 to 80 ng / ml, 10 to 75 ng / ml, 10 to 70 ng / ml, 10 to 65 ng / ml, 10 to 60 ng / ml, 10 to 55 ng / ml, 10 to 50 ng / ml, 10 to 45 ng / ml, 10 to 40 ng / ml, 10 to 35 ng / ml, 10 to 30 ng / ml, 10 to 25 ng / ml, 10 to 20 ng / ml, 10 to 15 ng / ml, 20 to 100 ng / ml, 20 to 95 ng / ml, 20 to 90 ng / ml, 20 to 85 ng / ml, 20 to 80 ng / ml, 20 to 75 ng / ml, 20 to 70 ng / ml, 20 to 65 ng / ml, 20 to 60 ng / ml, 20 to 55 ng / ml, 20 to 50 ng / ml,With circulating hepcidin (e.g., hepcidin-25) levels in the range of 20-45 ng / ml, 20-40 ng / ml, 20-35 ng / ml, 20-30 ng / ml, 20-25 ng / ml, 30-100 ng / ml, 30-95 ng / ml, 30-90 ng / ml, 30-85 ng / ml, 30-80 ng / ml, 30-75 ng / ml, 30-70 ng / ml, 30-65 ng / ml, 30-60 ng / ml, 30-55 ng / ml, 30-50 ng / ml, 30-45 ng / ml, 30-40 ng / ml, 30-35 ng / ml, 40-100 ng / ml, 40-95 ng / ml, 40-90 ng / ml, 40-85 ng / ml, 40-80 ng / ml, 40-75 ng / ml, 40-70 ng / ml, 40-65 ng / ml, 40-60 ng / ml, 40-55 ng / ml, 40-50 ng / ml, 40-45 ng / ml, 50-100 ng / ml, 50-95 ng / ml, 50-90 ng / ml, 50-85 ng / ml, 50-80 ng / ml, 50-75 ng / ml, 50-70 ng / ml, 50-65 ng / ml, 50-60 ng / ml, 50-55 ng / ml, 60-100 ng / ml, 60-95 ng / ml, 60-90 ng / ml, 60-85 ng / ml, 60-80 ng / ml, 60-75 ng / ml, 60-70 ng / ml, 60-65 ng / ml, 70-100 ng / ml, 70-95 ng / ml, 70-90 ng / ml, 70-85 ng / ml, 70-80 ng / ml, 70-75 ng / ml, 80-100 ng / ml, 80-95 ng / ml, 80-90 ng / ml, 80-85 ng / ml, 90-100 ng / ml, 90-95 ng / ml, or 95-100 ng / ml. In some embodiments, prior to administration, a subject having a bleeding state suitable for a hemojuvelin antagonist (e.g., an anti-HJV antibody) has circulating hepcidin (e.g., hepcidin-25) levels in the range of 5-75 ng / ml., In some embodiments, after administration of a hepcidin antagonist, the circulating hepcidin (e.g., hepcidin-25) level of a subject decreases. In some embodiments, after administration of a hepcidin antagonist (e.g., an anti-HJV antibody), the circulating hepcidin (e.g., hepcidin-25) level of a subject decreases by 2 - 60 ng / ml, 2 - 55 ng / ml, 2 - 50 ng / ml, 2 - 45 ng / ml, 2 - 40 ng / ml, 2 - 35 ng / ml, 2 - 30 ng / ml, 2 - 25 ng / ml, 2 - 20 ng / ml, 2 - 15 ng / ml, 2 - 10 ng / ml, 2 - 5 ng / ml, 5 - 60 ng / ml, 5 - 55 ng / ml, 5 - 50 ng / ml, 5 - 45 ng / ml, 5 - 40 ng / ml, 5 - 35 ng / ml, 5 - 30 ng / ml, 5 - 25 ng / ml, 5 - 20 ng / ml, 5 - 15 ng / ml, 5 - 10 ng / ml, 10 - 60 ng / ml, 10 - 55 ng / ml, 10 - 50 ng / ml, 10 - 45 ng / ml, 10 - 40 ng / ml, 10 - 35 ng / ml, 10 - 30 ng / ml, 10 - 25 ng / ml, 10 - 20 ng / ml, 10 - 15 ng / ml, 20 - 60 ng / ml, 20 - 55 ng / ml, 20 - 50 ng / ml, 20 - 45 ng / ml, 20 - 40 ng / ml, 20 - 35 ng / ml, 20 - 30 ng / ml, 20 - 25 ng / ml, 30 - 60 ng / ml, 30 - 55 ng / ml, 30 - 50 ng / ml, 30 - 45 ng / ml, 30 - 40 ng / ml, 30 - 35 ng / ml, 40 - 60 ng / ml, 40 - 55 ng / ml, 40 - 50 ng / ml, 40 - 45 ng / ml, 50 - 60 ng / ml, or 50 - 55 ng / ml as compared to the circulating hepcidin (e.g., hepcidin-25) level before administration.In some embodiments, after administration of a hemojuvelin antagonist (e.g., an anti-HJV antibody), the circulating hepcidin (e.g., hepcidin-25) level of a subject decreases by 2 - 60 ng / ml, 2 - 55 ng / ml, 2 - 50 ng / ml, 2 - 45 ng / ml, 2 - 40 ng / ml, 2 - 35 ng / ml, 2 - 30 ng / ml, 2 - 25 ng / ml, 2 - 20 ng / ml, 2 - 15 ng / ml, 2 - 10 ng / ml, 2 - 5 ng / ml, 5 - 60 ng / ml, 5 - 55 ng / ml, 5 - 50 ng / ml, 5 - 45 ng / ml, 5 - 40 ng / ml, 5 - 35 ng / ml, 5 - 30 ng / ml, 5 - 25 ng / ml, 5 - 20 ng / ml, 5 - 15 ng / ml, 5 - 10 ng / ml, 10 - 60 ng / ml, 10 - 55 ng / ml, 10 - 50 ng / ml, 10 - 45 ng / ml, 10 - 40 ng / ml, 10 - 35 ng / ml, 10 - 30 ng / ml, 10 - 25 ng / ml, 10 - 20 ng / ml, 10 - 15 ng / ml, 20 - 60 ng / ml, 20 - 55 ng / ml, 20 - 50 ng / ml, 20 - 45 ng / ml, 20 - 40 ng / ml, 20 - 35 ng / ml, 20 - 30 ng / ml, 20 - 25 ng / ml, 30 - 60 ng / ml, 30 - 55 ng / ml, 30 - 50 ng / ml, 30 - 45 ng / ml, 30 - 40 ng / ml, 30 - 35 ng / ml, 40 - 60 ng / ml, 40 - 55 ng / ml, 40 - 50 ng / ml, 40 - 45 ng / ml, 50 - 60 ng / ml, or 50 - 55 ng / ml within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, or 6 months. In some embodiments, the decrease in the circulating hepcidin (e.g., hepcidin-25) level of a subject administered a hemojuvelin antagonist (e.g., an anti-HJV antibody) is achieved within a shorter period of time than is achieved in control subjects not administered a hemojuvelin antagonist (e.g., an anti-HJV antibody).In some embodiments, the decrease in circulating hepcidin (e.g., hepcidin-25) levels in a subject administered a hemojuvelin antagonist (e.g., an anti-HJV antibody) is achieved 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks earlier than in control subjects not administered a hemojuvelin antagonist (e.g., an anti-HJV antibody).

[0131] In some embodiments, the state of blood loss is characterized based on the level of mean corpuscular hemoglobin (MCH) level. In some embodiments, the MCH level of the subject is determined (e.g., before treatment with an HJV antagonist (e.g., an anti-HJV antibody), or in other states where no HJV antagonist (e.g., an anti-HJV antibody and its composition) treatment has been made at the time of determination) and compared to the MCH level of the subject after treatment. In some embodiments, after administration, a subject having a state of blood loss suitable for a hemojuvelin antagonist (e.g., an anti-HJV antibody) has an MCH level in the range of 15-50 pg, 15-45 pg, 15-40 pg, 15-35 pg, 15-30 pg, 15-25 pg, 15-20 pg, 20-50 pg, 20-45 pg, 20-40 pg, 20-35 pg, 20-30 pg, 20-25 pg, 25-50 pg, 25-45 pg, 25-40 pg, 25-35 pg, 25-30 pg, 30-50 pg, 30-45 pg, 30-40 pg, 30-35 pg, 35-50 pg, 35-45 pg, 35-40 pg, 40-50 pg, 40-45 pg, or 45-50 pg. In some embodiments, a subject having a state of blood loss suitable for a hemojuvelin antagonist (e.g., an anti-HJV antibody) has an MCH level in the range of 15-50 pg.

[0132] In some embodiments, after administration of a hepcidin antagonist (e.g., an anti-HJV antibody), the MCH level of a subject increases. In some embodiments, after administration of a hepcidin antagonist (e.g., an anti-HJV antibody), the MCH level of a subject increases by 1% to 5%, 1% to 4%, 1% to 3%, 1% to 2%, 2% to 5%, 2% to 4%, 2% to 3%, 3% to 5%, 3% to 4%, or 4% to 5% compared to the MCH level before administration. In some embodiments, after administration of a hepcidin antagonist (e.g., an anti-HJV antibody), the MCH level of a subject increases by 1% to 5%, 1% to 4%, 1% to 3%, 1% to 2%, 2% to 5%, 2% to 4%, 2% to 3%, 3% to 5%, 3% to 4%, or 4% to 5% within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, or 6 months. In some embodiments, the increase in MCH level in a subject administered a hepcidin antagonist (e.g., an anti-HJV antibody) is achieved in a shorter period of time than is achieved in a control subject not administered a hepcidin antagonist (e.g., an anti-HJV antibody). In some embodiments, the increase in MCH level in a subject administered a hepcidin antagonist (e.g., an anti-HJV antibody) is achieved 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks earlier than is achieved in a control subject not administered a hepcidin antagonist (e.g., an anti-HJV antibody).

[0133] In some embodiments, the blood loss state is characterized based on the circulating red blood cell (RBC) count. In some embodiments, the RBC count of the subject is determined (e.g., before treatment with an HJV antagonist (e.g., an anti-HJV antibody), or in other states where no HJV antagonist (e.g., an anti-HJV antibody and its composition) treatment has been performed at the time of determination) and compared to the RBC count of the subject after treatment. In some embodiments, prior to administration, a subject having a blood loss state suitable for a hemojuvelin antagonist (e.g., an anti-HJV antibody) has from 2x10 12 to 8x10 12 cells / L, from 2x10 12 to 7x10 12 cells / L, from 2x10 12 to 6x10 12 cells / L, from 2x10 12 to 5x10 12 cells / L, from 2x10 12 to 4x10 12 cells / L, from 2x10 12 to 3x10 12 cells / L, from 3x10 12 to 8x10 12 cells / L, from 3x10 12 to 7x10 12 cells / L, from 3x10 12 to 6x10 12 cells / L, from 3x10 12 to 5x10 12 cells / L, from 3x10 12 to 4x10 12 cells / L, from 4x10 12 to 8x10 12 cells / L, from 4x10 12 to 7x10 12 cells / L, from 4x10 12 to 6x10 12 cells / L, from 4x10 12 to 5x10 12 cells / L, from 5x10 12 to 8x10 12 cells / L, from 5x10 12 to 7x10 12 cells / L, from 5x10 12 to 6x10 12 cells / L, from 6x10 12 to 8x1012 cells / L, or 7x10 12 to 8x10 12 with an RBC count in the range of cells / L. In some embodiments, a subject having a blood loss condition suitable for a hepcidin antagonist (e.g., an anti-HJV antibody) has an RBC count in the range of 3x10 12 to 6x10 12 cells / L.

[0134] In some embodiments, after administration of a hepcidin antagonist (e.g., an anti-HJV antibody), the RBC count of the subject increases. In some embodiments, after administration of a hepcidin antagonist (e.g., an anti-HJV antibody), the RBC count of the subject is at least 0.5x10 12 cells / L, at least 0.6x10 12 cells / L, at least 0.7x10 12 cells / L, at least 0.8x10 12 cells / L, at least 0.9x10 12 cells / L, at least 1.0x10 12 cells / L, at least 1.1x10 12 cells / L, at least 1.2x10 12 cells / L, at least 1.3x10 12 cells / L, at least 1.4x10 12 cells / L, at least 1.5x10 12 cells / L, at least 1.6x10 12 cells / L, at least 1.7x10 12 cells / L, at least 1.8x10 12 cells / L, at least 1.9x10 12 cells / L, at least 2.0x10 12 cells / L, at least 2.1x10 12 cells / L, at least 2.2x10 12 cells / L, at least 2.3x10 12 cells / L, at least 2.4x10 12 cells / L, or at least 2.5x10 12The cells / L increases. In some embodiments, after administration of a hemojuvelin antagonist (e.g., an anti-HJV antibody), the RBC count of the subject is at least 0.5x10 12 cells / L, at least 0.6x10 12 cells / L, at least 0.7x10 12 cells / L, at least 0.8x10 12 cells / L, at least 0.9x10 12 cells / L, at least 1.0x10 12 cells / L, at least 1.1x10 12 cells / L, at least 1.2x10 12 cells / L, at least 1.3x10 12 cells / L, at least 1.4x10 12 cells / L, at least 1.5x10 12 cells / L, at least 1.6x10 12 cells / L, at least 1.7x10 12 cells / L, at least 1.8x10 12 cells / L, at least 1.9x10 12 cells / L, at least 2.0x10 12 cells / L, at least 2.1x10 12 cells / L, at least 2.2x10 12 cells / L, at least 2.3x10 12 cells / L, at least 2.4x10 12 cells / L, or at least 2.5x10 12The number of cells / L increases. In some embodiments, the increase in the number of RBCs in a subject administered a hemojuvelin antagonist (e.g., an anti-HJV antibody) is achieved in a shorter period of time than is achieved in a control subject not administered a hemojuvelin antagonist (e.g., an anti-HJV antibody). In some embodiments, the increase in the number of RBCs in a subject administered a hemojuvelin antagonist (e.g., an anti-HJV antibody) is achieved 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks earlier than is achieved in a control subject not administered a hemojuvelin antagonist (e.g., an anti-HJV antibody).

[0135] In some embodiments, the subject does not have functional iron deficiency (FID) prior to administration of the hemojuvelin antagonist (e.g., an anti-HJV antibody). FID represents a state of iron-restricted erythropoiesis characterized by an imbalance between iron requirements and serum iron readily available for effective erythropoiesis. In FID, iron is sequestered and unavailable for erythropoiesis even when the body has sufficient or increased iron stores. In some embodiments, a subject with a state of blood loss does not have functional iron deficiency prior to treatment with a hemojuvelin antagonist (e.g., an anti-HJV antibody). In some embodiments, upregulation of inflammatory cytokines in the subject's bone marrow is also accompanied by upregulation of circulating hepcidin, which causes anemia. In some embodiments, the subject does not have anemia associated with inflammation prior to administration of the hemojuvelin antagonist (e.g., an anti-HJV antibody). In some embodiments, the subject has anemia associated with inflammation prior to administration of the hemojuvelin antagonist (e.g., an anti-HJV antibody).

[0136] Based on the disclosure provided herein, it will be apparent to those skilled in the art whether a certain amount of HJV antagonist has achieved a therapeutic effect. As recognized by those skilled in the art, the effective amount will vary depending on factors within the knowledge and expertise of medical practitioners, including the particular condition being treated, the severity of that condition, the age, physical condition, size, gender, and weight of the individual patient, the duration of treatment, (where applicable) the nature of concurrent treatments, the specific route of administration, etc. These factors are well known to those skilled in the art and can be addressed with only routine experimentation. The specific dosing regimens, i.e., dosage, timing, and repetition, used in the methods described herein will depend on the particular subject being discussed and that subject's treatment history.

[0137] Another aspect of the disclosure relates to treating a subject having anemia, the method comprising administering to the subject an effective amount of an anti-hemoduvillin antibody at monthly intervals. In some embodiments, the anemia is associated with functional iron deficiency. In some embodiments, the anemia is associated with inflammation.

[0138] Empirical considerations such as time to maximum effect, half-life, and / or time above a particular concentration may be useful in determining the dosage of a hemoduvillin antagonist (e.g., an anti-HJV antibody) used in the methods described herein (e.g., treatment of a subject having a bleeding disorder or anemia). In some embodiments, the dosage of the HJV antagonist described herein may be determined empirically in an individual who has received one or more administrations of the HJV antagonist (e.g., an anti-HJV antibody). The individual receives escalating doses of the HJV antagonist (e.g., an anti-HJV antibody). To evaluate the effectiveness of the HJV antagonist (e.g., an anti-HJV antibody), indicators of the disease / disorder may be tracked.

[0139] The dosing frequency may vary according to the methods described herein (e.g., treatment of a subject having a bleeding condition and / or anemia). In some embodiments, the hepcidin antagonist (e.g., anti-HJV antibody) or a composition thereof is administered once. In some embodiments, the hepcidin antagonist (e.g., anti-HJV antibody) or a composition thereof is administered multiple times. In some embodiments, the hepcidin antagonist (e.g., anti-HJV antibody) or a composition thereof is administered once a month. In some embodiments, the dosing frequency is once a week, every two weeks, every three weeks, every four weeks, every five weeks, every six weeks, every seven weeks, every eight weeks, every nine weeks, or every ten weeks, or once a month, every two months, or every three months, or more. In some embodiments, the hepcidin antagonist (e.g., anti-HJV antibody) or a composition thereof is administered daily, every other week, weekly, every other month, monthly, quarterly, or at any time interval that provides appropriate (e.g., maximal) efficacy while minimizing the safety risk to the subject. Generally, efficacy and treatment and safety risk may be monitored throughout the course of the treatment.

[0140] In some embodiments, the subject may be administered a hemojuvelin antagonist (e.g., an anti-HJV antibody) or a composition thereof one or more times at intervals over a period of time. In some cases, the periods during which the subject is administered the composition at intervals may be separated by periods during which the subject is not administered the composition. In some embodiments, the relative lengths of each period may depend on the response of the subject to the treatment or the severity of the disease, or both, and / or may be determined based on the judgment of the physician performing the treatment. For example, in some embodiments, during a one-year period, the subject may be administered the composition weekly, bi-weekly, or monthly over a period of two months, after which administration is stopped for ten months. In some embodiments, during a one-year period, the subject may be administered the composition weekly, bi-weekly, or monthly over a period of three months, after which administration is stopped for nine months. In some embodiments, during a one-year period, the subject may be administered the composition weekly, bi-weekly, or monthly over a period of four months, after which administration is stopped for eight months. In some embodiments, during a one-year period, the subject may be administered the composition weekly, bi-weekly, or monthly over a period of five months, after which administration is stopped for seven months. In some embodiments, during a one-year period, the subject may be administered the composition weekly, bi-weekly, or monthly over a period of six months, after which administration is stopped for six months. In some embodiments, during a one-year period, the subject may be administered the composition weekly, bi-weekly, or monthly over a period of seven months, after which administration is stopped for five months. In some embodiments, during a one-year period, the subject may be administered the composition weekly, bi-weekly, or monthly over a period of eight months, after which administration is stopped for four months. In some embodiments, during a one-year period, the subject may be administered the composition weekly, bi-weekly, or monthly over a period of nine months, after which administration is stopped for three months. In some embodiments, during a one-year period, the subject may be administered the composition weekly, bi-weekly, or monthly over a period of ten months, after which administration is stopped for two months.In some embodiments, during a one-year period, the subject is administered the composition weekly, bi-weekly, or monthly for 2 months followed by a 2-month drug holiday; or for 3 months followed by a 3-month drug holiday; or for 4 months followed by a 4-month drug holiday. In some embodiments, during a one-year period, the subject may be administered the composition quarterly (i.e., 4 times) for the entire year. In some embodiments, during a one-year period, the subject may be administered the composition 2 or 3 times per quarter, but not 4 times.

[0141] In some embodiments, the hemo-juvillin antagonist (e.g., anti-HJV antibody) used in the methods described herein (e.g., treating a subject having a blood loss condition and / or anemia) is the anti-HJV antibody described herein. Generally, for any administration of an anti-HJV antibody described herein, the dosage may be about 0.01 mg / kg, 0.05 mg / kg, 0.1 mg / kg, 0.2 mg / kg, 0.3 mg / kg, 0.4 mg / kg, 0.5 mg / kg, 0.6 mg / kg, 0.7 mg / kg, 0.8 mg / kg, 0.9 mg / kg, 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, or 5 mg / kg.

[0142] In some embodiments, the dosage of the anti-HJV antibody is up to 0.01 mg / kg, up to 0.05 mg / kg, up to 0.1 mg / kg, up to 0.2 mg / kg, up to 0.3 mg / kg, up to 0.4 mg / kg, up to 0.5 mg / kg, up to 0.6 mg / kg, up to 0.7 mg / kg, up to 0.8 mg / kg, up to 0.9 mg / kg, up to 1 mg / kg, mg / kg, up to 2 mg / kg, up to 3 mg / kg, up to 4 mg / kg, up to 5 g / kg, or more.

[0143] In some embodiments, the dosage of the anti-HJV antibody is from 0.01 mg / kg to 5 mg / kg, from 0.01 mg / kg to 4 mg / kg, from 0.01 mg / kg to 3 mg / kg, from 0.01 mg / kg to 2 mg / kg, from 0.01 mg / kg to 1 mg / kg, from 0.01 mg / kg to 0.9 mg / kg, from 0.01 mg / kg to 0.8 mg / kg, from 0.01 mg / kg to 0.7 mg / kg, from 0.01 mg / kg to 0.6 mg / kg, from 0.01 mg / kg to 0.5 mg / kg, from 0.01 mg / kg to 0.4 mg / kg, from 0.01 mg / kg to 0.3 mg / kg, from 0.01 mg / kg to 0.1 mg / kg, from 0.01 mg / kg to 0.05 mg / kg, from 0.01 mg / kg to 0.02 mg / kg, from 0.05 mg / kg to 5 mg / kg, from 0.05 mg / kg to 4 mg / kg, from 0.05 mg / kg to 3 mg / kg, from 0.05 mg / kg to 2 mg / kg, from 0.05 mg / kg to 1 mg / kg, from 0.05 mg / kg to 0.9 mg / kg, from 0.05 mg / kg to 0.8 mg / kg, from 0.05 mg / kg to 0.7 mg / kg, from 0.05 mg / kg to 0.6 mg / kg, from 0.05 mg / kg to 0.5 mg / kg, from 0.05 mg / kg to 0.4 mg / kg, from 0.05 mg / kg to 0.3 mg / kg, from 0.05 mg / kg to 0.1 mg / kg, from 0.1 mg / kg to 5 mg / kg, from 0.1 mg / kg to 4 mg / kg, from 0.1 mg / kg to 3 mg / kg, from 0.1 mg / kg to 2 mg / kg, from 0.1 mg / kg to 1 mg / kg, from 0.1 mg / kg to 0.9 mg / kg, from 0.1 mg / kg to 0.8 mg / kg, from 0.1 mg / kg to 0.7 mg / kg, from 0.1 mg / kg to 0.6 mg / kg, from 0.1 mg / kg to 0.5 mg / kg, from 0.1 mg / kg to 0.4 mg / kg, from 0.1 mg / kg to 0.3 mg / kg, from 0.5 mg / kg to 5 mg / kg, from 0.5 mg / kg to 4 mg / kg, from 0.5 mg / kg to 3 mg / kg, from 0.5 mg / kg to 2 mg / kg, from 0.5 mg / kg to 1 mg / kg, from 0.5 mg / kg to 0.9 mg / kg, from 0.5 mg / kg to 0.8 mg / kg, from 0.5 mg / kg to 0.7 mg / kg, from 0.5 mg / kg to 0.It can be in the range of 6 mg / kg, from 1 mg / kg to 5 mg / kg, from 1 mg / kg to 4 mg / kg, from 1 mg / kg to 3 mg / kg, from 1 mg / kg to 2 mg / kg, from 2 mg / kg to 5 mg / kg, from 2 mg / kg to 4 mg / kg, from 2 mg / kg to 3 mg / kg, from 3 mg / kg to 4 mg / kg, or from 4 mg / kg to 5 mg / kg.

[0144] In some embodiments, the dosage of the anti-HJV antibody is 5 to 100 mg, 5 to 95 mg, 5 to 90 mg, 5 to 85 mg, 5 to 80 mg, 5 to 75 mg, 5 to 70 mg, 5 to 65 mg, 5 to 60 mg, 5 to 55 mg, 5 to 50 mg, 5 to 45 mg, 5 to 40 mg, 5 to 35 mg, 5 to 30 mg, 5 to 25 mg, 5 to 20 mg, 5 to 15 mg, 5 to 10 mg, 7 to 100 mg, 7 to 95 mg, 7 to 90 mg, 7 to 85 mg, 7 to 80 mg, 7 to 75 mg, 7 to 70 mg, 7 to 65 mg, 7 to 60 mg, 7 to 55 mg, 7 to 50 mg, 7 to 45 mg, 7 to 40 mg, 7 to 35 mg, 7 to 30 mg, 7 to 25 mg, 7 to 20 mg, 7 to 15 mg, 7 to 10 mg, 10 to 100 mg, 10 to 95 mg, 10 to 90 mg, 10 to 85 mg, 10 to 80 mg, 10 to 75 mg, 10 to 70 mg, 10 to 65 mg, 10 to 60 mg, 10 to 55 mg, 10 to 50 mg, 10 to 45 mg, 10 to 40 mg, 10 to 35 mg, 10 to 30 mg, 10 to 25 mg, 10 to 20 mg, 10 to 15 mg, 20 to 100 mg, 20 to 95 mg, 20 to 90 mg, 20 to 85 mg, 20 to 80 mg, 20 to 75 mg, 20 to 70 mg, 20 to 65 mg, 20 to 60 mg, 20 to 55 mg, 20 to 50 mg, 20 to 45 mg, 20 to 40 mg, 20 to 35 mg, 20 to 30 mg, 25 to 100 mg, 25 to 95 mg, 25 to 90 mg, 25 to 85 mg, 25 to 80 mg, 25 to 75 mg, 25 to 70 mg, 25 to 65 mg, 25 to 60 mg, 25 to 55 mg, 25 to 50 mg, 25 to 45 mg, 25 to 40 mg, 25 to 35 mg, 25 to 30 mg, 30 to 100 mg, 30 to 95 mg, 30 to 90 mg, 30 to 85 mg, 30 to 80 mg, 30 to 75 mg, 30 to 70 mg, 30 to 65 mg, 30 to 60 mg, 30 to 55 mg, 30 to 50 mg, 30 to 45 mg, 30 to 40 mg, 30 to 35 mg, 35 to 100 mg, 35 to 95 mg, 35 to 90 mg, 35 to 85 mg, 35 to 80 mg, 35 to 75 mg, 35 to 70 mg, 35 to 65 mg, 35 to 60 mg, 35 to 55 mg, 35 to 50 mg, 35 to 45 mg, 35 to 40 mg, 40 to 100 mg, 40 to 95 mg, 40 to 90 mg, 40 to 85 mg, 40 to 80 mg, 40 to 75 mg, 40 to 70 mg, 40 to 65 mg, 40 to 60 mg, 40 to 55 mg, 40 to 50 mg,It can be in the range of 40 - 45 mg, 45 - 100 mg, 45 - 95 mg, 45 - 90 mg, 45 - 85 mg, 45 - 80 mg, 45 - 75 mg, 45 - 70 mg, 45 - 65 mg, 45 - 60 mg, 45 - 55 mg, 45 - 50 mg, 50 - 100 mg, 50 - 95 mg, 50 - 90 mg, 50 - 85 mg, 50 - 80 mg, 50 - 75 mg, 50 - 70 mg, 50 - 65 mg, 50 - 60 mg, 50 - 55 mg, 55 - 100 mg, 55 - 95 mg, 55 - 90 mg, 55 - 85 mg, 55 - 80 mg, 55 - 75 mg, 55 - 70 mg, 55 - 65 mg, 55 - 60 mg, 60 - 100 mg, 60 - 95 mg, 60 - 90 mg, 60 - 85 mg, 60 - 80 mg, 60 - 75 mg, 60 - 70 mg, 60 - 65 mg, 65 - 100 mg, 65 - 95 mg, 65 - 90 mg, 65 - 85 mg, 65 - 80 mg, 65 - 75 mg, 65 - 70 mg, 70 - 100 mg, 70 - 95 mg, 70 - 90 mg, 70 - 85 mg, 70 - 80 mg, 70 - 75 mg, 80 - 100 mg, 80 - 95 mg, 80 - 90 mg, 80 - 85 mg, 90 - 100 mg, 90 - 95 mg, or 95 - 100 mg. In some embodiments, the dose of anti-HJV replacement can be in the range of 25 - 70 mg. In some embodiments, the dose of the anti-HJV antibody can be in the range of 35 - 65 mg. In some embodiments, the dose of the anti-HJV antibody can be in the range of 45 - 60 mg. In some embodiments, the dose of the anti-HJV antibody is 56 mg. In some embodiments, the dose of the anti-HJV antibody is 7 mg. In some embodiments, the dose of the anti-HJV antibody is 14 mg. In some embodiments, the dose of the anti-HJV antibody is 28 mg. In some embodiments, the subject is administered 56 mg of the anti-HJV antibody monthly.,

[0145] In some embodiments, the antibodies described herein are administered to a subject in need thereof in an amount sufficient to inhibit in vivo at least 20% (e.g., 30%, 40%, 50%, 60%, 70%, 80%, 90%, or more) of the activity of the target antigen (e.g., an amount sufficient to inhibit BMP signaling induced by HJV). In other embodiments, the antibody is administered in an amount effective to reduce the activity level of the target antigen by at least 20% (e.g., 30%, 40%, 50%, 60%, 70%, 80%, 90%, or more).

[0146] In some embodiments, a hemojuvelin antagonist (e.g., an anti-HJV antibody) can be administered parenterally. For example, the composition for parenteral administration may be administered by subcutaneous, intradermal, intravenous, intraperitoneal, intratumoral, intramuscular, intra-articular, intra-arterial, or infusion techniques. In addition, this can be administered to the subject via an injectable depot administration route such as an injectable depot for 1, 3, or 6 months, or via biodegradable materials and methods.

[0147] In some embodiments, a hemojuvelin antagonist (e.g., an anti-HJV antibody) is administered intravenously. In some embodiments, a hemojuvelin antagonist (e.g., an anti-HJV antibody) is administered subcutaneously. In some embodiments, subcutaneous administration of a hemojuvelin antagonist (e.g., an anti-HJV antibody) results in a similar bioavailability compared to intravenous administration of the same antibody at the same dose. In some embodiments, the anti-HJV antibody is administered subcutaneously at 56 mg. In some embodiments, the anti-HJV antibody is administered intravenously at 7 mg. In some embodiments, the anti-HJV antibody is administered subcutaneously at 14 mg. In some embodiments, the anti-HJV antibody is administered subcutaneously at 28 mg.

[0148] In some embodiments, subcutaneous administration of a hemojuvelin antagonist (e.g., an anti-HJV antibody) results in a lower maximum concentration (C max) resulting in comparable pharmacodynamic effects (e.g., decreased circulating hepcidin-25 levels, increased TSAT%, increased CHr, decreased ferritin, increased MCH, increased RBC count, and / or increased circulating hemoglobin). max is the maximum (or maximal) serum concentration of the drug (e.g., a hemojuvelin antagonist (e.g., an anti-HJV antibody)) after the drug is administered and before a second administration. In some embodiments, a low C is observed shortly (e.g., within 12 hours, within 24 hours, etc.) after administration of the hemojuvelin antagonist (e.g., an anti-HJV antibody). max By achieving this, undesirable elevations in serum iron response are minimized and / or potential off-target effects of the hemojuvelin antagonist (e.g., anti-HJV antibody) (e.g., binding to RGMa). In some embodiments, subcutaneous administration of a hemojuvelin antagonist (e.g., anti-HJV antibody) reduces C max By gradual administration of hemojuvelin antagonist (e.g., anti-HJV antibody), an undesirable steep rise in serum iron response is avoided. max By smoothing the C, off-target effects of the hemojuvelin antagonist (e.g., anti-HJV antibody) are reduced. In some embodiments, the C achieved by subcutaneous administration of the hemojuvelin antagonist (e.g., anti-HJV antibody) is max is delivered by intravenous administration max at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% lower.

[0149] For intravenous administration, water-soluble molecules (such as hemojuvelin antagonists like anti-HJV antibodies) can be administered by the drip method, where a pharmaceutical formulation containing the molecule and a physiologically acceptable excipient are dripped. Physiologically acceptable excipients may include, for example, 5% dextrose, 0.9% saline, Ringer's solution, or other suitable excipients. Other injectable compositions may contain various carriers such as vegetable oils, dimethylacetamide, dimethylformamide, ethyl lactate, ethyl carbonate, isopropyl myristate, ethanol, and polyols (such as glycerol, propylene glycol, liquid polyethylene glycol, etc.). In some cases, a sterile formulation of an appropriate soluble salt form of a formulation, such as an antibody, can be dissolved in a pharmaceutical excipient such as water for injection, 0.9% saline, or 5% glucose solution and administered.

[0150] In certain embodiments, a hemojuvelin antagonist (such as an anti-HJV antibody) is administered via a site-specific or targeted local delivery technique. Examples of site-specific or targeted local delivery techniques include various implantable depot sources of the antibody, or local delivery catheters such as drip catheters, indwelling catheters, or needle catheters, synthetic grafts, adventitial wraps, shunts and stents, or other implantable devices, site-specific carriers, direct injection, or direct administration. See, for example, PCT International Publication No. WO2000 / 53211 and U.S. Patent No. 5,981,568.

[0151] In some embodiments, one or more antibodies, or a combination of an antibody and another suitable therapeutic agent, may be administered to a subject in need of treatment. Also, the antibody can be used in combination with other substances that enhance and / or supplement the effectiveness of the substance. The effectiveness of the treatment for the target disease / disorder can be evaluated by methods well known in the art.

[0152] The hepcidin antagonists (e.g., anti-HJV antibodies) described in the present disclosure and methods of treatment involving the same may be used in combination with other types of treatment for the target diseases or disorders disclosed herein. In this context, the hepcidin antagonist (e.g., anti-HJV antibody) compositions and therapeutics may be administered either simultaneously or sequentially. Examples include chemotherapy, immunotherapy (e.g., treatment involving other HJV antagonists), surgery, radiation therapy, gene therapy, etc., or anti-infective therapy. Such treatments may be provided simultaneously or sequentially (in any order) with the treatment according to the present disclosure.

[0153] In some embodiments, the combination therapy may include a hepcidin antagonist (e.g., anti-HJV antibody) and a pharmaceutical composition described herein, formulated and / or administered together with at least one additional therapeutic agent described herein. Such combination therapy may advantageously utilize relatively low doses of the therapeutic agents being administered, thereby preventing toxicities or complications that may occur in relation to various monotherapies. Additionally, the additional therapeutic agents disclosed herein may act on additional or alternative pathways relative to the hepcidin / BMP pathway, thereby enhancing the effect of the hepcidin antagonist (e.g., anti-HJV antibody) and / or acting synergistically therewith.

[0154] In some embodiments, the combination therapy includes a hepcidin antagonist (e.g., anti-HJV antibody) and a pharmaceutical composition described herein, which may be formulated in a composition separate from at least one additional therapeutic agent described herein, and the separate compositions may be administered simultaneously or sequentially.

[0155] In some embodiments, the hepcidin antagonist (e.g., anti-HJV antibody) is administered to a subject in combination with an erythropoietin-stimulating agent. In some embodiments, the erythropoietin-stimulating agent is selected from the group consisting of danazol, prednisone, thalidomide, lenalidomide, and pomalidomide.

[0156] In some embodiments, a hepcidin antagonist (e.g., an anti-HJV antibody) is administered to a subject in combination with erythropoietin (EPO). Erythropoietin (EPO) is a glycoprotein hormone that stimulates red blood cell production and is naturally produced by cells around the renal tubules of the kidney. Recombinant EPO, such as epoetin alfa (Epogen / Procrit), darbepoetin alfa (Aranesp), methoxy polyethylene glycol epoetin beta (Mircera), epoetin alfa-epbx (Retacrit), or a biosimilar of Epogen / Procrit, has been previously described.

[0157] In some embodiments, a hepcidin antagonist (e.g., an anti-HJV antibody) is administered to a subject in combination with a growth factor ligand trap. In some embodiments, the growth factor ligand trap is a transforming growth factor beta (TGF-β) ligand trap. In some embodiments, the TGF-β ligand trap is a GDF trap such as sotatercept or ruspatertcept. See U.S. Patent No. 8,216,997, the contents of each of which are incorporated herein by reference.

[0158] In some embodiments, a subject in need of treatment according to the present disclosure continues to receive a therapeutic treatment for an underlying disease that causes a blood loss condition. Thus, the present disclosure provides, in some aspects, compositions and methods for treating a blood loss condition and / or one or more conditions resulting from the cause of the blood loss condition by administering to a subject in need of treatment a hepcidin antagonist (e.g., an anti-HJV antibody) in combination with one or more therapeutic treatments for a disease that causes the blood loss condition described herein.

[0159] In some embodiments, any of the disclosed hepcidin antagonists (e.g., anti-HJV antibodies) may be administered as combination therapy with a therapeutic agent selected from oral iron, IV iron, HIF-PHIs, and red blood cell transfusions. In some embodiments, any of the disclosed hepcidin antagonists (e.g., anti-HJV antibodies) may be administered in combination with a diet being ingested by the subject. For example, a subject having a bleeding disorder associated with celiac disease may ingest a gluten-free diet while being administered a hepcidin antagonist (e.g., anti-HJV antibody).

[0160] In some embodiments, the hepcidin antagonist (e.g., anti-HJV antibody) is administered to a subject in combination with an IV iron therapy such as iron isomaltoside (MonoFerric (登録商標) ). Additional exemplary IV iron therapies include, but are not limited to, iron sucrose (Venofer (登録商標) ), ferric carboxymaltose (Ferrinject (登録商標) or Injectofer (登録商標) ), ferumoxytol (Ferraheme (登録商標) ), iron dextran (Imferon (登録商標) ), and sodium ferric gluconate in sucrose solution (Ferrlecit (登録商標) ).

[0161] In some embodiments, the hepcidin antagonist (e.g., anti-HJV antibody) is administered to a subject in combination with an oral iron therapy. In some embodiments, the hepcidin antagonists provided herein (e.g., anti-HJV antibodies) may be combined with an oral iron therapy to promote recovery of iron levels and / or to treat anemic subjects who may experience intolerance to oral iron or have an inadequate response to oral iron. Examples of oral iron therapies include ferrous sulfate, ferrous maltol (Accrufer (登録商標)) include, but are not limited to, ferric gluconate, ferric succinate, iron polymaltose, polysaccharide-iron complex, and ferric sulfate. In other cases, iron may be administered intramuscularly (e.g., as iron sorbitol citrate).

[0162] In some embodiments, a hepcidin antagonist (e.g., an anti-HJV antibody) is administered to a subject in combination with an HIF-PHI such as daprodustat, roxadustat, and vadadustat. In some embodiments, the additional therapeutic agent is roxadustat.

[0163] III. Hepcidin (HJV) Antagonist In some embodiments, a hepcidin antagonist is provided for treating the blood loss conditions described herein in a subject in need thereof by inhibiting BMP-SMAD signaling to reduce hepcidin expression and / or the function of hepcidin, such as regulating iron available for erythropoiesis. In some embodiments, such methods are based on the recognition that increased serum or tissue iron triggers transcriptional induction of hepcidin via the BMD-SMAD signaling pathway. In some embodiments, HJV acts as a BMP coreceptor that positively regulates hepcidin levels. In certain cells, such as hepatocytes, BMP signaling induced by HJV positively regulates hepcidin mRNA expression. In such embodiments, HJV binds to BMP2, BMP4, BMP5, and / or BMP6 to mediate BMP signaling and positively regulate hepcidin levels, for example, in hepatocytes. In some embodiments, BMP signals by binding to one or a combination of serine / threonine kinase receptor types I and II. In some embodiments, upon ligand binding, the constitutively active type II receptor phosphorylates the type I receptor, which then phosphorylates the intracellular receptor-activated Smads (R-Smads), namely Smad1, Smad5, and / or Smad8. In such embodiments, the activated R-Smad forms a complex with the common partner Smad4 and translocates to the nucleus to control gene transcription, for example, inducing hepcidin expression.

[0164] In some embodiments, the hepcidin antagonist binds to one or more proteins of the repulsive guidance molecule (RGM) family, including RGMa, RGMb, and RGMc (HJV). In some embodiments, the hepcidin antagonist selectively binds to hepcidin (RGMc) as compared to RGMa and RGMb.

[0165] In some embodiments, the hemojuvelin antagonist binds to one or more proteins of the repulsive guidance molecule (RGM) family, including RGMa, RGMb, and RGMc (HJV). In some embodiments, the hemojuvelin antagonist selectively binds to hemojuvelin (RGMc) as compared to RGMa and RGMb. In some embodiments, the hemojuvelin antagonist is an antisense oligonucleotide that reduces the expression of hemojuvelin (see, e.g., US7534764, published May 19, 2009, entitled "Competitive regulation of hepcidin mRNA by soluble and cell-associated hemojuvelin"; US2014127325, published May 19, 2009, entitled "Competitive regulation of hepcidin mRNA by soluble and cell-associated hemojuvelin"; and WO2016180784, published November 17, 2016, entitled "Improved treatments using oligonucleotides", each of which is incorporated herein by reference). In some embodiments, the hemojuvelin antagonist is a small molecule compound that inhibits hemojuvelin, for example, by competitive binding and / or chemical modification of hemojuvelin.

[0166] In some embodiments, the HJV antagonist is soluble HJV. In some embodiments, the soluble HJV is a soluble HJV-Fc fusion protein. In some embodiments, the soluble HJV is the soluble HJV disclosed in US8318167B2, entitled "Methods and compositions for regulating iron homeostasis by modulation of BMP-6", published November 27, 2012; US9708379B2, entitled "COMPOSITIONS FOR REGULATING IRON HOMEOSTASIS AND METHODS OF USING SAME", published June 18, 2017; US10273273B2, entitled "COMPOSITIONS AND REGULATING IRON HOMEOSTASIS AND METHODS OF USING SAME", published April 30, 2019; US7968091B2, entitled "METHODS AND COMPOSITIONS TO REGULATE IRON METABOLISM", published June 28, 2011; US8637023B2, entitled "HEMOJUVELIN FUSION PROTEINS", published January 28, 2014; US8865168B2, entitled "METHODS AND COMPOSITIONS TO REGULATE HEPCIDIN EXPRESSION", published October 21, 2014; US9556251B2, entitled "METHODS AND COMPOSITIONS TO REGULATE HEPCIDIN EXPRESSION", published January 31, 2017; US8895002B2, entitled "Hemojuvelin fusion proteins and uses thereof", published November 25, 2014; US7511018B2, entitled "Juvenile hemochromatosis gene (HFE2A) cleavage products and uses thereof", published March 31, 2009, the contents of each of which are incorporated herein by reference. In some embodiments, the sHJV-Fc fusion protein is Ferruxmax.In some embodiments, the sHJV-Fc fusion protein is FMX-8.

[0167] In some embodiments, the hemojuvelin antagonist is an antibody specific for hemojuvelin and / or one or more proteins of the RGM protein family (e.g., RGMa, RGMb). In some embodiments, the antibodies specific for hemojuvelin and / or one or more RGM proteins are US10118958, entitled "Composition and method for the diagnosis and treatment of iron-related disorders", published November 6, 2018; US9636398, entitled "Composition and method for the diagnosis and treatment of iron-related disorders", published May 2, 2017; and US8507435, entitled "Juvenile hemochromatosis gene (HFE2A) cleavage products and uses thereof", published August 13, 2013; US10118958, entitled "Composition and method for the diagnosis and treatment of iron-related disorders", published November 6, 2018; US2010 / 0322941, entitled "Bone morphogenetic protein (BMP)-binding domains of proteins of the repulsive guidance molecule (RGM) protein family and functional fragments thereof, and use of same", published December 23, 2010; US9040052, entitled "Precision Medicine By Targeting Rare Human PCSK9 Variants for Cholesterol Treatment", published May 26, 2015; and US2017 / 0029499, entitled "Methods for treating hepcidin-mediated disorders", published February 2, 2017, the contents of each of which are incorporated herein by reference.and the anti-HJV antibodies and / or one or more RGM proteins disclosed in International Publication WO2007039256, entitled "Binding domains of proteins of the repulsive guidance molecule (rgm) protein family and functional fragments thereof, and their use", published on April 12, 2017; WO2015171691, entitled "Compositions and methods for growth factor modulation", published on November 12, 2015; WO2018 / 009624, entitled "Tgf-beta superfamily heteromultimers and uses thereof", published on January 11, 2018; and WO2020 / 086736, entitled "Rgmc-selective inhibitors and use thereof", published on April 30, 2020;

[0168] In some embodiments, the hepcidin antagonist is an antibody (e.g., hHA-001 to hHA-012) specific for hepcidin and / or one or more proteins of the RGM protein family (e.g., RGMa, RGMb) described in Table 1 herein. Suitable antibodies specific for hepcidin or one or more RGM proteins that may be useful in the particular methods provided herein are, for example, U.S. Patent No. 10,118,958; and 8,507,435; U.S. Patent Application Publication US2013 / 330343; US2015 / 166672; and US2017 / 029499; and International Publications WO2015 / 171691; and WO2018 / 009624, which are incorporated herein by reference.

[0169] In one aspect, provided herein are antibodies that bind to human hemojuvelin (HJV) with high specificity and affinity. In some embodiments, the anti-HJV antibodies described herein specifically bind to any extracellular epitope of HJV, or an epitope that is exposed to the antibody. In some embodiments, the anti-HJV antibodies provided herein specifically bind to HJV in humans, non-human primates, mice, rats, etc. In some embodiments, the anti-HJV antibodies provided herein bind to human HJV. In some embodiments, the anti-HJV antibodies described herein bind to an amino acid segment of human or non-human primate HJV.

[0170] In some embodiments, the anti-HJV antibodies described herein specifically bind to an epitope on human HJV. Human HJV is a 426-amino acid protein and is predicted to have a 31-amino acid N-terminal signal peptide and a 45-amino acid C-terminal GPI attachment signal. An exemplary human HJV amino acid sequence is represented by SEQ ID NO: 128: MGEPGQSPSPRSSHGSPPTLSTLTLLLLLCGHAHSQCKILRCNAEYVSSTLSLRGGGSSGALRGGGGGGRGGGVGSGGLCRALRSYALCTRRTARTCRGDLAFHSAVHGIEDLMIQHNCSRQGPTAPPPPRGPALPGAGSGLPAPDPCDYEGRFSRLHGRPPGFLHCASFGDPHVRSFHHHFHTCRVQGAWPLLDNDFLFVQATSSPMALGANATATRKLTIIFKNMQECIDQKVYQAEVDNLPVAFEDGSINGGDRPGGSSLSIQTANPGNHVEIQAAYIGTTIIIRQTAGQLSFSIKVAEDVAMAFSAEQDLQLCVGGCPPSQRLSRSERNRRGAITIDTARRLCKEGLPVEDAYFHSCVFDVLISGDPNFTVAAQAALEDARAFLPDLEKLHLFPSDAGVPLSSATLLAPLLSGLFVLWLCIQ (SEQ ID NO: 128)

[0171] In some embodiments, the anti-HJV antibodies described herein may bind to a fragment of human HJV. The HJV fragment may be about 5 to about 425 amino acids in length, about 10 to about 400 amino acids, about 50 to about 350 amino acids, about 100 to about 300 amino acids, about 150 to about 250 amino acids, about 200 to about 300 amino acids, or about 75 to about 150 amino acids. The fragment may include several consecutive amino acids of RGMc. An exemplary amino acid sequence of the HJV fragment is represented by SEQ ID NO: 123: QCKILRCNAEYVSSTLSLRGGGSSGALRGGGGGGRGGGVGSGGLCRALRSYALCTRRTARTCRGDLAFHSAVHGIEDLMIQHNCSRQGPTAPPPPRGPALPGAGSGLPAPDPCDYEGRFSRLHGRPPGFLHCASFGDPHVRSFHHHFHTCRVQGAWPLLDNDFLFVQATSSPMALGANATATRKLTIIFKNMQECIDQKVYQAEVDNLPVAFEDGSINGGDRPGGSSLSIQTANPGNHVEIQAAYIGTTIIIRQTAGQLSFSIKVAEDVAMAFSAEQDLQLCVGGCPPSQRLSRSERNRRGAITIDTARRLCKEGLPVEDAYFHSCVFDVLISGDPNFTVAAQAALEDARAFLPDLEKLHLFPSD (SEQ ID NO: 123)

[0172] In some embodiments, the anti-HJV antibodies described herein bind to different epitopes within human HJV or a human HJV fragment.

[0173] In some embodiments, the anti-HJV antibody interacts with an epitope within amino acids 160-190 of SEQ ID NO: 123. In some embodiments, the anti-HJV antibody interacts with an epitope having the amino acid sequence of amino acids 170-183 of SEQ ID NO: 123. In some embodiments, the anti-HJV antibody interacts with an epitope having the amino acid sequence SSPMALGANATATR (SEQ ID NO: 121). In some embodiments, the anti-HJV antibody interacts with different segments within SSPMALGANATATR (SEQ ID NO: 121). In some embodiments, the anti-HJV antibody interacts with amino acids 170-171, amino acids 171-180, amino acids 180-182, and amino acids 182-183 of SEQ ID NO: 123. In some embodiments, the antibody interacts with amino acids 170(S), 171(S), 180(T), 182(T), and 183(R) of SEQ ID NO: 123. In some embodiments, hHA-008 interacts with the epitope SSPMALGANATATR (SEQ ID NO: 121). In some embodiments, hHA-008 interacts with amino acids 170(S), 171(S), 180(T), 182(T) and 183(R) of SEQ ID NO: 123.

[0174] In some embodiments, the anti-HJV antibody interacts with epitopes within amino acids 160-190 of SEQ ID NO: 123 and / or amino acids 280-310 of SEQ ID NO: 123. In some embodiments, the anti-HJV antibody interacts with epitopes within amino acids 169-182 of SEQ ID NO: 123 and / or amino acids 289-300 of SEQ ID NO: 123. In some embodiments, the anti-HJV antibody interacts with epitopes within amino acids 169-182 of SEQ ID NO: 123 and amino acids 289-300 of SEQ ID NO: 123. In some embodiments, the anti-HJV antibody interacts with epitopes having the amino acid sequences TSSPMALGANATAT (SEQ ID NO: 122) and SQRLSRSERNRR (SEQ ID NO: 127). In some embodiments, the anti-HJV antibody interacts with different segments within TSSPMALGANATAT (SEQ ID NO: 122) and SQRLSRSERNRR (SEQ ID NO: 127). In some embodiments, the anti-HJV antibody interacts with amino acids 169-171, amino acids 171-180, and amino acids 180-182 of SEQ ID NO: 123, and amino acids 289-293, amino acids 293-294, amino acids 294-295, amino acids 295-297, and amino acids 297-300 of SEQ ID NO: 123. In some embodiments, the antibody interacts with amino acids 169 (T), 170 (S), 171 (S), 180 (T), 182 (T), 289 (S), 293 (S), 294 (R), 295 (S), 297 (R), and 300 (R) of SEQ ID NO: 123. In some embodiments, hHA-008-QL interacts with different segments within TSSPMALGANATAT (SEQ ID NO: 122) and SQRLSRSERNRR (SEQ ID NO: 127). In some embodiments, hHA-008-QL interacts with amino acids 169 (T), 170 (S), 171 (S), 180 (T), 182 (T), 289 (S), 293 (S), 294 (R), 295 (S), 297 (R), and 300 (R) of SEQ ID NO: 123.

[0175] In some embodiments, the anti-HJV antibodies described herein are affinity matured clones. In some embodiments, the anti-HJV antibodies have a binding affinity of at least about 10 -4 M, 10 -5 M, 10 -6 M, 10 -7 M, 10 -8 M, 10 -9 M, 10 -10 M, 10 -11 M, 10 -12 M, 10 -13 M, or less, and specifically bind to HJV (e.g., human or non-human primate HJV) (e.g., as indicated by K D ). For example, the anti-HJV antibodies of the disclosure can bind to hemojuvelin protein (e.g., human hemojuvelin) with an affinity between 5 pM and 500 nM, such as between 50 pM and 100 nM, such as between 500 pM and 50 nM. Also, the disclosure includes antibodies that compete with any of the antibodies described herein with respect to binding to hemojuvelin protein (e.g., human hemojuvelin) and have an affinity of 100 nM or less (e.g., 80 nM or less, 50 nM or less, 20 nM or less, 10 nM or less, 500 pM or less, 50 pM or less, or 5 pM or less). The affinity and binding kinetics of the anti-HJV antibodies can be tested using any suitable method, including but not limited to biosensor technology (e.g., OCTET or BIACORE). In some embodiments, the anti-HJV antibodies described herein bind to HJV with a K D in the sub-nanomolar range. In some embodiments, the anti-HJV antibodies described herein selectively bind to RGMc but do not bind to RGMa or RGMb.

[0176] Binding affinity (or binding specificity) can be determined by various methods, including equilibrium dialysis, equilibrium binding, gel filtration, ELISA, surface plasmon resonance (SPR), fluorescence-activated cell sorting (FACS), or spectroscopy (e.g., those using fluorescence assays). Exemplary conditions for evaluating binding affinity are in HBS-P buffer (10 mM HEPES pH 7.4, 150 mM NaCl, 0.005% (v / v) surfactant P20) and PBS buffer (10 mM PO4-3, 137 mM NaCl, and 2.7 mM KCl). These techniques can be used to measure the concentration of the bound protein as a function of the target protein concentration. The concentration of the bound protein ([bound]) generally has the following relationship to the concentration of the free target protein ([free]): [bound]=[free] / (Kd+[free])

[0177] K A An exact determination of K is not always necessary, and a quantitative measurement of affinity may be sufficient in some cases. For example, the affinity determined using methods such as ELISA or FACS is proportional to K A and can thus be used, for comparison, to obtain a quantitative measurement of affinity or an estimate of affinity, for example, to determine whether a higher affinity is, for example, twice as high, by the activity in a functional assay in an in vitro or in vivo assay.

[0178] Non-limiting examples of heavy chain (HC) and light chain (LC) sequences, heavy chain variable domains (VH) and light chain variable domains (VL), CDR sequences, and heavy chain and light chain constant region sequences of anti-HJV antibodies are provided in Table 1.

Table 1-1

Table 1-2

Table 1-3

Table 1-4

Table 1-5

Table 1-6

Table 1-7

Table 1-8

Table 1-9

Table 1-10

Table 1-11

Table 1-12

Table 1-13

Table 1-14

[0179] In some embodiments, the N-terminus of the heavy chain of the anti-HJV antibodies described herein is glutamic acid (E). In some embodiments, this glutamic acid can spontaneously cyclize to pyroglutamic acid by post-translational modification. The spontaneous cyclization from glutamic acid to pyroglutamic acid has been previously described, for example, in Chelius et al., Formation of Pyroglutamic Acid From N-terminal Glutamic Acid in Immunoglobulin Gamma Antibodies, Anal Chem. 2006;78(7):2370‐2376. In some embodiments, the N-terminus of the heavy chain of the anti-HJV antibodies described herein is pyroglutamic acid. In some embodiments, anti-HJV antibodies having N-terminal pyroglutamic acid are impurities in the population of anti-HJV antibodies (e.g., less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.1%, less than 0.05%, or less than 0.01%). In some embodiments, the population of anti-HJV antibodies comprises a mixture of anti-HJV antibodies having glutamic acid or pyroglutamic acid at the N-terminus of the heavy chain.

[0180] In some embodiments, the anti-HJV antibodies of the disclosure comprise one or more of the HC CDR (e.g., HC CDR1, HC CDR2, or HC CDR3) amino acid sequences from any one of the anti-HJV antibodies selected from Table 1. In some embodiments, the anti-HJV antibodies of the disclosure comprise HC CDR1, HC CDR2, and HC CDR3 as defined for any one of the antibodies selected from Table 1. In some embodiments, the anti-HJV antibodies of the disclosure comprise one or more of the LC CDR (e.g., LC CDR1, LC CDR2, or LC CDR3) amino acid sequences from any one of the anti-HJV antibodies selected from Table 1. In some embodiments, the anti-HJV antibodies of the disclosure comprise LC CDR1, LC CDR2, and LC CDR3 as defined for any one of the anti-HJV antibodies selected from Table 1.

[0181] In some embodiments, the anti-HJV antibodies of the present disclosure comprise HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 as defined for any one of the anti-HJV antibodies selected from Table 1. In some embodiments, the antibody heavy and light chain CDR3 domains may play a particularly important role in the binding specificity / affinity of the antibody for the antigen. Thus, the anti-HJV antibodies of the present disclosure may comprise at least the heavy chain and / or light chain CDR3 of any one of the anti-HJV antibodies selected from Table 1.

[0182] In some embodiments, the isolated anti-HJV antibody comprises a heavy chain variable region comprising heavy chain CDR1 (HC CDR1), heavy chain CDR2 (HC CDR2), and heavy chain CDR3 (HC CDR3).

[0183] In some embodiments, according to the Kabat definition, HC CDR1 may comprise the amino acid sequence of X1YGMN (SEQ ID NO: 105), where X1 can be N or Y. Alternatively or additionally, HC CDR2 may comprise the amino acid sequence of MIYYDSSX2KHYADSVKG (SEQ ID NO: 106), where X2 can be E or D. Alternatively or additionally, HC CDR3 may comprise the amino acid sequence of GX3TPDX4 (SEQ ID NO: 107), where X3 can be T or S, and X4 can be Y, V, or K.

[0184] In some embodiments, according to the Kabat definition, the anti-HJV antibody may comprise a light chain variable region comprising light chain CDR1 (LC CDR1), light chain CDR2 (LC CDR2), and light chain CDR3 (LC CDR3). In some embodiments, LC CDR1 may comprise the amino acid sequence of RSSQSLX5X6SDGX7TFLX8 (SEQ ID NO: 108), where X5 can be A or E, X6 can be T, S, E, or D, X7 can be D, Y, or G, and X8 can be E or H. Alternatively or additionally, LC CDR2 is X9VSX 10It may contain the amino acid sequence of RFS (SEQ ID NO: 109), where X9 can be E, D, or A, and X 10 can be N, S, T, E, or H. Alternatively or additionally, LC CDR3 is X 11 QX 12 TX 13 DPX 14 X 15 (SEQ ID NO: 110), and here X 11 can be F or M, X 12 can be V or A, X 13 can be H or Y, X 14 can be M, L, or V, and X 15 can be T or S.

[0185] Any functional variant of the exemplary anti-HJV antibodies disclosed herein is also within the scope of the present disclosure. The functional variant contains one or more amino acid residue mutations in one or more of V H and / or V L or one or more of the HC CDRs and / or one or more of the LC CDRs, while retaining binding activity and biological activity substantially similar to that of the reference antibody (e.g., substantially similar binding affinity, binding specificity, inhibitory activity, anti-inflammatory activity, or a combination thereof).

[0186] In some embodiments, any of the anti-HJV antibodies of the present disclosure has one or more CDR (e.g., HC CDR or LC CDR) sequences that are substantially similar to any of the HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and / or LC CDR3 sequences of one of the anti-HJV antibodies selected from Table 1. In some embodiments, the position of one or more CDRs along the VH (e.g., HC CDR1, HC CDR2, or HC CDR3) and / or VL (e.g., LC CDR1, LC CDR2, or LC CDR3) regions of the antibodies described herein can vary by 1, 2, 3, 4, 5, or 6 amino acid positions as long as immunospecific binding to hemojuvelin (e.g., human hemojuvelin) is maintained (e.g., substantially maintained, e.g., at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95% of the binding of the original antibody from which it is derived). For example, in some embodiments, the position defining the CDR of any of the antibodies described herein can vary by moving the N-terminal and / or C-terminal boundaries of the CDR by 1, 2, 3, 4, 5, or 6 amino acids compared to the CDR position of any one of the antibodies described herein as long as immunospecific binding to hemojuvelin (e.g., human hemojuvelin) is maintained (e.g., substantially maintained, e.g., at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95% of the binding of the original antibody from which it is derived). In another embodiment, the length of one or more CDRs along the VH (e.g., HC CDR1, HC CDR2, or HC CDR3) and / or VL (e.g., LC CDR1, LC CDR2, or LC CDR3) regions of the antibodies described herein can vary by 1, 2, 3, 4, 5, or more amino acids (e.g., shorter or longer) as long as immunospecific binding to hemojuvelin (e.g., human hemojuvelin) is maintained (e.g., substantially maintained, e.g., at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95% of the binding of the original antibody from which it is derived).

[0187] Thus, in some embodiments, the HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and / or LC CDR3 described herein may be 1, 2, 3, 4, 5 amino acids, or more, shorter than one or more of the CDRs described herein (e.g., any CDR of an anti-HJV antibody selected from Table 1), so long as immunospecific binding to hemojuvelin (e.g., human hemojuvelin) is maintained (e.g., substantially maintained, e.g., at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95% of the binding of the original antibody from which it is derived). In some embodiments, the HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and / or LC CDR3 described herein may be 1, 2, 3, 4, 5 amino acids, or more, longer than one or more of the CDRs described herein (e.g., any CDR of an anti-HJV antibody selected from Table 1), so long as immunospecific binding to hemojuvelin (e.g., human hemojuvelin) is maintained (e.g., substantially maintained, e.g., at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95% of the binding of the original antibody from which it is derived). In some embodiments, the amino portion of the HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and / or LC CDR3 described herein may be extended by 1, 2, 3, 4, 5 amino acids, or more, compared to one or more of the CDRs described herein (e.g., any CDR of an anti-HJV antibody selected from Table 1), so long as immunospecific binding to hemojuvelin (e.g., human hemojuvelin) is maintained (e.g., substantially maintained, e.g., at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95% of the binding of the original antibody from which it is derived).In some embodiments, the carboxy portion of the HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and / or LC CDR3 described herein can be extended by 1, 2, 3, 4, 5 amino acids, or more, compared to one or more of the CDRs described herein (e.g., any CDR of an anti-HJV antibody selected from Table 1), as long as immunospecific binding to hemojuvelin (e.g., human hemojuvelin) is maintained (e.g., substantially maintained, e.g., at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95% of the binding of the original antibody from which it is derived). In some embodiments, the amino portion of the HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and / or LC CDR3 described herein can be shortened by 1, 2, 3, 4, 5 amino acids, or more, compared to one or more of the CDRs described herein (e.g., any CDR of an anti-HJV antibody selected from Table 1), as long as immunospecific binding to hemojuvelin (e.g., human hemojuvelin) is maintained (e.g., substantially maintained, e.g., at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95% of the binding of the original antibody from which it is derived). In some embodiments, the carboxy portion of the HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and / or LC CDR3 described herein can be shortened by 1, 2, 3, 4, 5 amino acids, or more, compared to one or more of the CDRs described herein (e.g., any CDR of an anti-HJV antibody selected from Table 1), as long as immunospecific binding to hemojuvelin (e.g., human hemojuvelin) is maintained (e.g., substantially maintained, e.g., at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95% of the binding of the original antibody from which it is derived). To ascertain whether immunospecific binding to hemojuvelin (e.g., human hemojuvelin) is maintained, any method can be used, such as using binding assays and conditions described in the art.

[0188] In some examples, any of the anti-HJV antibodies of the present disclosure has one or more CDR (e.g., HC CDR or LC CDR) sequences that are substantially similar to any one of the anti-HJV antibodies selected from Table 1. For example, this antibody may contain one or more CDR sequences of any one of the anti-HJV antibodies selected from Table 1 that contain mutations of 5, 4, 3, 2, or 1 amino acid residue compared to one or more of the CDRs described herein (e.g., the CDRs of any of the anti-HJV antibodies selected from Table 1), as long as immunospecific binding to hemojuvelin (e.g., human hemojuvelin) is maintained (e.g., substantially maintained, e.g., at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95% of the binding of the original antibody from which it is derived). In some embodiments, any of the amino acid mutations in any of the CDRs provided herein may be conservative mutations. Conservative mutations can be introduced into the CDR at positions where the residue is considered not to be involved in the interaction with the hemojuvelin protein (e.g., human hemojuvelin protein), as determined, for example, based on the crystal structure. Some aspects of the present disclosure provide anti-HJV antibodies that include one or more of the heavy chain variable (VH) domains and / or light chain variable (VL) domains provided herein. In some embodiments, any of the VH domains provided herein includes one or more of the HC CDR sequences (e.g., HC CDR1, HC CDR2, and HC CDR3) provided herein, such as any of the CDR-H sequences provided in any one of the anti-HJV antibodies selected from Table 1. In some embodiments, any of the VL domains provided herein includes one or more of the CDR-L sequences (e.g., LC CDR1, LC CDR2, and LC CDR3) provided herein, such as any of the LC CDR sequences provided in any one of the anti-HJV antibodies selected from Table 1.

[0189] In some embodiments, the anti-HJV antibodies of the present disclosure include any antibody comprising the heavy chain variable domain and / or the light chain variable domain of any one anti-HJV antibody selected from Table 1, and variants thereof. In some embodiments, the anti-HJV antibodies of the present disclosure include any antibody comprising the heavy chain variable and light chain variable pair of any anti-HJV antibody selected from Table 1.

[0190] Aspects of the present disclosure provide anti-HJV antibodies having heavy chain variable (VH) and / or light chain variable (VL) domain amino acid sequences that are homologous to any of those described herein. In some embodiments, the anti-HJV antibody comprises a heavy chain variable sequence and / or a light chain variable sequence that is at least 75% (e.g., 80%, 85%, 90%, 95%, 98%, or 99%) identical to any one of the heavy chain variable sequences and / or any one of the light chain variable sequences of the anti-HJV antibodies selected from Table 1. In some embodiments, the homologous heavy chain variable and / or light chain variable amino acid sequences do not vary within the CDR sequences provided herein. For example, in some embodiments, a certain degree of sequence variation (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) may occur within the heavy chain variable and / or light chain variable sequences excluding the CDR sequences provided herein. In some embodiments, any of the anti-HJV antibodies provided herein comprises a heavy chain variable sequence and a light chain variable sequence comprising a framework sequence that is at least 75%, 80%, 85%, 90%, 95%, 98%, or 99% identical to the framework sequence of any one of the anti-HJV antibodies selected from Table 1. In some embodiments, any of the anti-HJV antibodies provided herein comprises a heavy chain variable sequence comprising a framework sequence having 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations relative to the framework sequence of any one of the VH of the anti-HJV antibodies selected from Table 1, and / or a light chain variable sequence comprising a framework sequence having 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations relative to the framework sequence of any one of the VL of the anti-HJV antibodies selected from Table 1.

[0191] In some embodiments, the anti-HJV antibodies of the present disclosure are humanized antibodies (e.g., humanized variants containing one or more of the CDRs in Table 1). In some embodiments, the anti-HJV antibodies of the present disclosure include HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 that are identical to those shown in Table 1, and include a humanized heavy chain variable region and / or a humanized light chain variable region. In some embodiments, the amino acid sequences of the humanized heavy chain variable and / or humanized light chain variable regions do not vary within the CDR sequences provided herein. For example, in some embodiments, a certain degree of sequence variation (e.g., at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) may occur within the heavy chain variable and / or light chain variable sequences excluding the CDR sequences provided herein. In some embodiments, the humanized anti-HJV antibodies provided herein include heavy chain variable sequences and light chain variable sequences that include a framework sequence that is at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the framework sequence of any anti-HJV antibody selected from Table 1. In some embodiments, the amino acid sequences of the humanized heavy chain variable and / or humanized light chain variable regions do not vary within any of the CDR sequences provided herein. For example, in some embodiments, a certain number of amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) may occur within the heavy chain variable and / or light chain variable sequences excluding the CDR sequences provided herein.In some embodiments, the humanized anti-HJV antibody provided herein comprises a heavy chain variable sequence comprising a framework sequence containing 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations relative to the framework sequence of any one VH of the anti-HJV antibodies selected from Table 1, and / or a light chain variable sequence comprising a framework sequence containing 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations relative to the framework sequence of any one VL of the anti-HJV antibodies selected from Table 1.

[0192] A humanized antibody is one in which the residues of the complementarity determining regions (CDRs) of a human immunoglobulin (recipient antibody) are replaced by the residues of the CDRs (donor antibody) of a non-human species such as a mouse, rat, or rabbit having the desired specificity, affinity, and capacity. In some embodiments, the Fv framework region (FR) residues of the human immunoglobulin are replaced by the corresponding non-human residues. Further, a humanized antibody may contain residues that are not present in the CDR or framework sequences introduced into the recipient antibody, but are included to further refine and optimize the performance of the antibody. Generally, a humanized antibody will comprise at least one, typically two variable domains, substantially the entire CDR region of which corresponds to that of a non-human immunoglobulin and substantially the entire FR region of which corresponds to that of a human immunoglobulin consensus sequence. Also, a humanized antibody will most desirably include at least a portion of the immunoglobulin constant region or constant domain (Fc), typically that of a human immunoglobulin. The antibody may comprise an Fc region modified as described in WO99 / 58572. Other forms of humanized antibodies have one or more CDRs (1, 2, 3, 4, 5, 6) changed from the original antibody, which may also be referred to as one or more CDRs derived from one or more CDRs of the original antibody. Also, affinity maturation may be involved in humanized antibodies.

[0193] In some embodiments, humanization is achieved by grafting the CDRs (such as those shown in Table 1) into human variable domains (such as the IGKV-NL1*01 and IGHV1-3*01 human variable domains). In some embodiments, the anti-HJV antibodies of the present disclosure are humanized variants that include one or more amino acid substitutions (e.g., within the VH framework region) compared to any one of the VHs listed in Table 1 and / or one or more amino acid substitutions (e.g., within the VL framework region) compared to any one of the VLs listed in Table 1.

[0194] In some embodiments, the anti-HJV antibodies of the present disclosure are humanized antibodies that include a VH containing 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to any one of the VHs of the anti-HJV antibodies listed in Table 1. Alternatively or additionally, the anti-HJV antibodies of the present disclosure are humanized antibodies that include a VL containing 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to any one of the VLs of the anti-HJV antibodies listed in Table 1.

[0195] In some embodiments, the anti-HJV antibodies of the present disclosure include HC CDR1, HC CDR2, and HC CDR3 of the heavy chain variable domain having the amino acid sequence of SEQ ID NO: 7. Alternatively or additionally, the anti-HJV antibodies of the present disclosure include LC CDR1, LC CDR2, and LC CDR3 of the light chain variable domain having the amino acid sequence of SEQ ID NO: 8.

[0196] In some embodiments, according to the Kabat definition system, the anti-HJV antibodies of the present disclosure include an HC CDR1 having the amino acid sequence of SEQ ID NO: 1, an HC CDR2 having the amino acid sequence of SEQ ID NO: 2, an HC CDR3 having the amino acid sequence of SEQ ID NO: 3, an LC CDR1 having the amino acid sequence of SEQ ID NO: 4, an LC CDR2 having the amino acid sequence of SEQ ID NO: 5, and an LC CDR3 having the amino acid sequence of SEQ ID NO: 6.

[0197] In some embodiments, the anti-HJV antibodies of the present disclosure include HC CDR1, HC CDR2, and HC CDR3, which, when compared to an HC CDR1 having the amino acid sequence of SEQ ID NO: 1, an HC CDR2 having the amino acid sequence of SEQ ID NO: 2, and an HC CDR3 having the amino acid sequence of SEQ ID NO: 3, contain a total of 5 or fewer amino acid mutations (e.g., 5, 4, 3, 2, or 1 or fewer amino acid mutations) in combination. As used anywhere in the present disclosure, "in combination" means that the total number of amino acid mutations in all three heavy chain CDRs is within the defined range. Alternatively or additionally, the anti-HJV antibodies of the present disclosure include LC CDR1, LC CDR2, and LC CDR3, which, when compared to an LC CDR1 having the amino acid sequence of SEQ ID NO: 4, an LC CDR2 having the amino acid sequence of SEQ ID NO: 5, and an LC CDR3 having the amino acid sequence of SEQ ID NO: 6, contain a total of 5 or fewer amino acid mutations (e.g., 5, 4, 3, 2, or 1 or fewer amino acid mutations) in combination.

[0198] In some embodiments, the anti-HJV antibodies of the present disclosure comprise HC CDR1 having the amino acid sequence of SEQ ID NO: 1, HC CDR2 having the amino acid sequence of SEQ ID NO: 2, and HC CDR3 having the amino acid sequence of SEQ ID NO: 3, which are together at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to HC CDR1, HC CDR2, and HC CDR3. Alternatively or additionally, the anti-HJV antibodies of the present disclosure comprise LC CDR1 having the amino acid sequence of SEQ ID NO: 4, LC CDR2 having the amino acid sequence of SEQ ID NO: 5, and LC CDR3 having the amino acid sequence of SEQ ID NO: 6, which are together at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to LC CDR1, LC CDR2, and LC CDR3.

[0199] In some embodiments, the anti-HJV antibodies of the present disclosure include: an HC CDR1 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to the amino acid sequence of SEQ ID NO: 1; an HC CDR2 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to the amino acid sequence of SEQ ID NO: 2; and / or an HC CDR3 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to the amino acid sequence of SEQ ID NO: 3. Alternatively or additionally, the anti-HJV antibodies of the present disclosure include: an LC CDR1 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to the amino acid sequence of SEQ ID NO: 4; an LC CDR2 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to the amino acid sequence of SEQ ID NO: 5; and / or an LC CDR3 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to the amino acid sequence of SEQ ID NO: 6.

[0200] In some embodiments, the anti-HJV antibodies of the present disclosure include a VH comprising the amino acid sequence of SEQ ID NO: 7. Alternatively or additionally, the anti-HJV antibodies of the present disclosure include a VL comprising the sequence of SEQ ID NO: 8.

[0201] In some embodiments, the anti-HJV antibodies of the present disclosure include a VH containing 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the VH represented by SEQ ID NO: 7. Alternatively or additionally, the anti-HJV antibodies of the present disclosure include a VL containing 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the VL represented by SEQ ID NO: 8.

[0202] In some embodiments, the anti-HJV antibodies of the present disclosure comprise a VH having an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the VH represented by SEQ ID NO: 7. Alternatively or additionally, the anti-HJV antibodies of the present disclosure comprise a VL having an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the VL represented by SEQ ID NO: 8.

[0203] In some embodiments, the anti-HJV antibodies of the present disclosure comprise HC CDR1, HC CDR2, and HC CDR3 of a heavy chain variable domain having the amino acid sequence of SEQ ID NO: 7. Alternatively or additionally, the anti-HJV antibodies of the present disclosure comprise LC CDR1, LC CDR2, and LC CDR3 of a light chain variable domain having the amino acid sequence of SEQ ID NO: 30.

[0204] In some embodiments, according to the Kabat definition system, the anti-HJV antibodies of the present disclosure comprise HC CDR1 having the amino acid sequence of SEQ ID NO: 1, HC CDR2 having the amino acid sequence of SEQ ID NO: 2, HC CDR3 having the amino acid sequence of SEQ ID NO: 3, LC CDR1 having the amino acid sequence of SEQ ID NO: 4, LC CDR2 having the amino acid sequence of SEQ ID NO: 49, and LC CDR3 having the amino acid sequence of SEQ ID NO: 24.

[0205] In some embodiments, the anti-HJV antibodies of the present disclosure include HC CDR1, HC CDR2, and HC CDR3, which together contain 5 or fewer amino acid mutations (e.g., 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to HC CDR1 having the amino acid sequence of SEQ ID NO: 1, HC CDR2 having the amino acid sequence of SEQ ID NO: 2, and HC CDR3 having the amino acid sequence of SEQ ID NO: 3. As used anywhere in the present disclosure, "in total" means that the total number of amino acid mutations in all three heavy chain CDRs is within the defined range. Alternatively or additionally, the anti-HJV antibodies of the present disclosure include LC CDR1, LC CDR2, and LC CDR3, which together contain 5 or fewer amino acid mutations (e.g., 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to LC CDR1 having the amino acid sequence of SEQ ID NO: 4, LC CDR2 having the amino acid sequence of SEQ ID NO: 49, and LC CDR3 having the amino acid sequence of SEQ ID NO: 24.

[0206] In some embodiments, the anti-HJV antibodies of the present disclosure comprise HC CDR1 having the amino acid sequence of SEQ ID NO: 1, HC CDR2 having the amino acid sequence of SEQ ID NO: 2, and HC CDR3 having the amino acid sequence of SEQ ID NO: 3, which are together at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical. Alternatively or additionally, the anti-HJV antibodies of the present disclosure comprise LC CDR1 having the amino acid sequence of SEQ ID NO: 4, LC CDR2 having the amino acid sequence of SEQ ID NO: 49, and LC CDR3 having the amino acid sequence of SEQ ID NO: 24, which are together at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical.

[0207] In some embodiments, the anti-HJV antibodies of the present disclosure include: an HC CDR1 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to the amino acid sequence of SEQ ID NO: 1; an HC CDR2 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to the amino acid sequence of SEQ ID NO: 2; and / or an HC CDR3 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to the amino acid sequence of SEQ ID NO: 3. Alternatively or additionally, the anti-HJV antibodies of the present disclosure include: an LC CDR1 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to the amino acid sequence of SEQ ID NO: 4; an LC CDR2 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to the amino acid sequence of SEQ ID NO: 49; and / or an LC CDR3 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to the amino acid sequence of SEQ ID NO: 24.

[0208] In some embodiments, the anti-HJV antibodies of the present disclosure include a VH comprising the amino acid sequence of SEQ ID NO: 7. Alternatively or additionally, the anti-HJV antibodies of the present disclosure include a VL comprising the amino acid sequence of SEQ ID NO: 30.

[0209] In some embodiments, the anti-HJV antibodies of the present disclosure include a VH containing 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the VH represented by SEQ ID NO: 7. Alternatively or additionally, the anti-HJV antibodies of the present disclosure include a VL containing 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the VL represented by SEQ ID NO: 30.

[0210] In some embodiments, the anti-HJV antibodies of the present disclosure comprise a VH having an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the VH represented by SEQ ID NO: 7. Alternatively or additionally, the anti-HJV antibodies of the present disclosure comprise a VL having an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the VL represented by SEQ ID NO: 30.

[0211] In some embodiments, the anti-HJV antibodies of the present disclosure comprise HC CDR1, HC CDR2, and HC CDR3 of a heavy chain variable domain having the amino acid sequence of SEQ ID NO: 7. Alternatively or additionally, the anti-HJV antibodies of the present disclosure comprise LC CDR1, LC CDR2, and LC CDR3 of a light chain variable domain having the amino acid sequence of SEQ ID NO: 31.

[0212] In some embodiments, according to the Kabat definition system, the anti-HJV antibodies of the present disclosure comprise HC CDR1 having the amino acid sequence of SEQ ID NO: 1, HC CDR2 having the amino acid sequence of SEQ ID NO: 2, HC CDR3 having the amino acid sequence of SEQ ID NO: 3, LC CDR1 having the amino acid sequence of SEQ ID NO: 4, LC CDR2 having the amino acid sequence of SEQ ID NO: 18, and LC CDR3 having the amino acid sequence of SEQ ID NO: 25.

[0213] In some embodiments, the anti-HJV antibodies of the present disclosure include HC CDR1, HC CDR2, and HC CDR3, which together contain 5 or fewer amino acid mutations (e.g., 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to HC CDR1 having the amino acid sequence of SEQ ID NO: 1, HC CDR2 having the amino acid sequence of SEQ ID NO: 2, and HC CDR3 having the amino acid sequence of SEQ ID NO: 3. As used anywhere in the present disclosure, "in total" means that the total number of amino acid mutations in all three heavy chain CDRs is within the defined range. Alternatively or additionally, the anti-HJV antibodies of the present disclosure include LC CDR1, LC CDR2, and LC CDR3, which together contain 5 or fewer amino acid mutations (e.g., 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to LC CDR1 having the amino acid sequence of SEQ ID NO: 4, LC CDR2 having the amino acid sequence of SEQ ID NO: 18, and LC CDR3 having the amino acid sequence of SEQ ID NO: 25.

[0214] In some embodiments, the anti-HJV antibodies of the present disclosure include HC CDR1 having the amino acid sequence of SEQ ID NO: 1, HC CDR2 having the amino acid sequence of SEQ ID NO: 2, and HC CDR3 having the amino acid sequence of SEQ ID NO: 3, which are together at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the HC CDR1, HC CDR2, and HC CDR3. Alternatively or additionally, the anti-HJV antibodies of the present disclosure include LC CDR1 having the amino acid sequence of SEQ ID NO: 4, LC CDR2 having the amino acid sequence of SEQ ID NO: 18, and LC CDR3 having the amino acid sequence of SEQ ID NO: 25, which are together at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the LC CDR1, LC CDR2, and LC CDR3.

[0215] In some embodiments, the anti-HJV antibodies of the present disclosure include: an HC CDR1 having no more than 3 amino acid mutations (e.g., no more than 3, 2, or 1 amino acid mutations) compared to the amino acid sequence of SEQ ID NO: 1; an HC CDR2 having no more than 3 amino acid mutations (e.g., no more than 3, 2, or 1 amino acid mutations) compared to the amino acid sequence of SEQ ID NO: 2; and / or an HC CDR3 having no more than 3 amino acid mutations (e.g., no more than 3, 2, or 1 amino acid mutations) compared to the amino acid sequence of SEQ ID NO: 3. Alternatively or additionally, the anti-HJV antibodies of the present disclosure include: an LC CDR1 having no more than 3 amino acid mutations (e.g., no more than 3, 2, or 1 amino acid mutations) compared to the amino acid sequence of SEQ ID NO: 4; an LC CDR2 having no more than 3 amino acid mutations (e.g., no more than 3, 2, or 1 amino acid mutations) compared to the amino acid sequence of SEQ ID NO: 18; and / or an LC CDR3 having no more than 3 amino acid mutations (e.g., no more than 3, 2, or 1 amino acid mutations) compared to the amino acid sequence of SEQ ID NO: 25.

[0216] In some embodiments, the anti-HJV antibodies of the present disclosure include a VH comprising the amino acid sequence of SEQ ID NO: 7. Alternatively or additionally, the anti-HJV antibodies of the present disclosure include a VL comprising the amino acid sequence of SEQ ID NO: 31.

[0217] In some embodiments, the anti-HJV antibodies of the present disclosure include a VH having no more than 20 amino acid mutations (e.g., no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid mutations) compared to the VH represented by SEQ ID NO: 7. Alternatively or additionally, the anti-HJV antibodies of the present disclosure include a VL having no more than 20 amino acid mutations (e.g., no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid mutations) compared to the VL represented by SEQ ID NO: 31.

[0218] In some embodiments, the anti-HJV antibodies of the present disclosure include a VH having an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the VH represented by SEQ ID NO: 7. Alternatively or additionally, the anti-HJV antibodies of the present disclosure include a VL having an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the VL represented by SEQ ID NO: 31.

[0219] In some embodiments, the anti-HJV antibodies of the present disclosure include HC CDR1, HC CDR2, and HC CDR3 of a heavy chain variable domain having the amino acid sequence of SEQ ID NO: 7. Alternatively or additionally, the anti-HJV antibodies of the present disclosure include LC CDR1, LC CDR2, and LC CDR3 of a light chain variable domain having the amino acid sequence of SEQ ID NO: 32.

[0220] In some embodiments, according to the Kabat definition system, the anti-HJV antibodies of the present disclosure include HC CDR1 having the amino acid sequence of SEQ ID NO: 1, HC CDR2 having the amino acid sequence of SEQ ID NO: 2, HC CDR3 having the amino acid sequence of SEQ ID NO: 3, LC CDR1 having the amino acid sequence of SEQ ID NO: 14, LC CDR2 having the amino acid sequence of SEQ ID NO: 19, and LC CDR3 having the amino acid sequence of SEQ ID NO: 25.

[0221] In some embodiments, the anti-HJV antibodies of the present disclosure include HC CDR1, HC CDR2, and HC CDR3, which, when compared to HC CDR1 having the amino acid sequence of SEQ ID NO: 1, HC CDR2 having the amino acid sequence of SEQ ID NO: 2, and HC CDR3 having the amino acid sequence of SEQ ID NO: 3, contain a total of 5 or fewer amino acid mutations (e.g., 5, 4, 3, 2, or 1 or fewer amino acid mutations). As used anywhere in the present disclosure, "in total" means that the total number of amino acid mutations in all three heavy chain CDRs is within the defined range. Alternatively or additionally, the anti-HJV antibodies of the present disclosure include LC CDR1, LC CDR2, and LC CDR3, which, when compared to LC CDR1 having the amino acid sequence of SEQ ID NO: 14, LC CDR2 having the amino acid sequence of SEQ ID NO: 19, and LC CDR3 having the amino acid sequence of SEQ ID NO: 25, contain a total of 5 or fewer amino acid mutations (e.g., 5, 4, 3, 2, or 1 or fewer amino acid mutations).

[0222] In some embodiments, the anti-HJV antibodies of the present disclosure include HC CDR1 having the amino acid sequence of SEQ ID NO: 1, HC CDR2 having the amino acid sequence of SEQ ID NO: 2, and HC CDR3 having the amino acid sequence of SEQ ID NO: 3, which are together at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to HC CDR1, HC CDR2, and HC CDR3. Alternatively or additionally, the anti-HJV antibodies of the present disclosure include LC CDR1 having the amino acid sequence of SEQ ID NO: 14, LC CDR2 having the amino acid sequence of SEQ ID NO: 19, and LC CDR3 having the amino acid sequence of SEQ ID NO: 25, which are together at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to LC CDR1, LC CDR2, and LC CDR3.

[0223] In some embodiments, the anti-HJV antibodies of the present disclosure include: an HC CDR1 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to the amino acid sequence of SEQ ID NO: 1; an HC CDR2 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to the amino acid sequence of SEQ ID NO: 2; and / or an HC CDR3 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to the amino acid sequence of SEQ ID NO: 3. Alternatively or additionally, the anti-HJV antibodies of the present disclosure include: an LC CDR1 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to the amino acid sequence of SEQ ID NO: 14; an LC CDR2 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to the amino acid sequence of SEQ ID NO: 19; and / or an LC CDR3 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to the amino acid sequence of SEQ ID NO: 25.

[0224] In some embodiments, the anti-HJV antibodies of the present disclosure include a VH comprising the amino acid sequence of SEQ ID NO: 7. Alternatively or additionally, the anti-HJV antibodies of the present disclosure include a VL comprising the amino acid sequence of SEQ ID NO: 32.

[0225] In some embodiments, the anti-HJV antibodies of the present disclosure include a VH having 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the VH represented by SEQ ID NO: 7. Alternatively or additionally, the anti-HJV antibodies of the present disclosure include a VL having 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the VL represented by SEQ ID NO: 32.

[0226] In some embodiments, the anti-HJV antibodies of the present disclosure comprise a VH having an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the VH represented by SEQ ID NO: 7. Alternatively or additionally, the anti-HJV antibodies of the present disclosure comprise a VL having an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the VL represented by SEQ ID NO: 32.

[0227] In some embodiments, the anti-HJV antibodies of the present disclosure comprise HC CDR1, HC CDR2, and HC CDR3 of a heavy chain variable domain having the amino acid sequence of SEQ ID NO: 7. Alternatively or additionally, the anti-HJV antibodies of the present disclosure comprise LC CDR1, LC CDR2, and LC CDR3 of a light chain variable domain having the amino acid sequence of SEQ ID NO: 33.

[0228] In some embodiments, according to the Kabat definition system, the anti-HJV antibodies of the present disclosure comprise HC CDR1 having the amino acid sequence of SEQ ID NO: 1, HC CDR2 having the amino acid sequence of SEQ ID NO: 2, HC CDR3 having the amino acid sequence of SEQ ID NO: 3, LC CDR1 having the amino acid sequence of SEQ ID NO: 15, LC CDR2 having the amino acid sequence of SEQ ID NO: 20, and LC CDR3 having the amino acid sequence of SEQ ID NO: 26.

[0229] In some embodiments, the anti-HJV antibodies of the present disclosure include HC CDR1, HC CDR2, and HC CDR3, which, when compared to HC CDR1 having the amino acid sequence of SEQ ID NO: 1, HC CDR2 having the amino acid sequence of SEQ ID NO: 2, and HC CDR3 having the amino acid sequence of SEQ ID NO: 3, contain a total of 5 or fewer amino acid mutations (e.g., 5, 4, 3, 2, or 1 or fewer amino acid mutations) in combination. As used anywhere in the present disclosure, "in total" means that the total number of amino acid mutations in all three heavy chain CDRs is within the defined range. Alternatively or additionally, the anti-HJV antibodies of the present disclosure include LC CDR1, LC CDR2, and LC CDR3, which, when compared to LC CDR1 having the amino acid sequence of SEQ ID NO: 15, LC CDR2 having the amino acid sequence of SEQ ID NO: 20, and LC CDR3 having the amino acid sequence of SEQ ID NO: 26, contain a total of 5 or fewer amino acid mutations (e.g., 5, 4, 3, 2, or 1 or fewer amino acid mutations) in combination.

[0230] In some embodiments, the anti-HJV antibodies of the present disclosure include HC CDR1 having the amino acid sequence of SEQ ID NO: 1, HC CDR2 having the amino acid sequence of SEQ ID NO: 2, and HC CDR3 having the amino acid sequence of SEQ ID NO: 3, which are together at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical. Alternatively or additionally, the anti-HJV antibodies of the present disclosure include LC CDR1 having the amino acid sequence of SEQ ID NO: 15, LC CDR2 having the amino acid sequence of SEQ ID NO: 20, and LC CDR3 having the amino acid sequence of SEQ ID NO: 26, which are together at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical.

[0231] In some embodiments, the anti-HJV antibodies of the present disclosure include: an HC CDR1 having no more than 3 amino acid mutations (e.g., no more than 3, 2, or 1 amino acid mutations) compared to the amino acid sequence of SEQ ID NO: 1; an HC CDR2 having no more than 3 amino acid mutations (e.g., no more than 3, 2, or 1 amino acid mutations) compared to the amino acid sequence of SEQ ID NO: 2; and / or an HC CDR3 having no more than 3 amino acid mutations (e.g., no more than 3, 2, or 1 amino acid mutations) compared to the amino acid sequence of SEQ ID NO: 3. Alternatively or additionally, the anti-HJV antibodies of the present disclosure include: an LC CDR1 having no more than 3 amino acid mutations (e.g., no more than 3, 2, or 1 amino acid mutations) compared to the amino acid sequence of SEQ ID NO: 15; an LC CDR2 having no more than 3 amino acid mutations (e.g., no more than 3, 2, or 1 amino acid mutations) compared to the amino acid sequence of SEQ ID NO: 20; and / or an LC CDR3 having no more than 3 amino acid mutations (e.g., no more than 3, 2, or 1 amino acid mutations) compared to the amino acid sequence of SEQ ID NO: 26.

[0232] In some embodiments, the anti-HJV antibodies of the present disclosure include a VH comprising the amino acid sequence of SEQ ID NO: 7. Alternatively or additionally, the anti-HJV antibodies of the present disclosure include a VL comprising the amino acid sequence of SEQ ID NO: 33.

[0233] In some embodiments, the anti-HJV antibodies of the present disclosure include a VH having no more than 20 amino acid mutations (e.g., no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid mutations) compared to the VH represented by SEQ ID NO: 7. Alternatively or additionally, the anti-HJV antibodies of the present disclosure include a VL having no more than 20 amino acid mutations (e.g., no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid mutations) compared to the VL represented by SEQ ID NO: 33.

[0234] In some embodiments, the anti-HJV antibodies of the present disclosure include a VH comprising an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the VH represented by SEQ ID NO: 7. Alternatively or additionally, the anti-HJV antibodies of the present disclosure include a VL comprising an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the VL represented by SEQ ID NO: 33.

[0235] In some embodiments, the anti-HJV antibodies of the present disclosure include HC CDR1, HC CDR2, and HC CDR3 of a heavy chain variable domain having the amino acid sequence of SEQ ID NO: 34. Alternatively or additionally, the anti-HJV antibodies of the present disclosure include LC CDR1, LC CDR2, and LC CDR3 of a light chain variable domain having the amino acid sequence of SEQ ID NO: 35.

[0236] In some embodiments, according to the Kabat definition system, the anti-HJV antibodies of the present disclosure include HC CDR1 having the amino acid sequence of SEQ ID NO: 9, HC CDR2 having the amino acid sequence of SEQ ID NO: 2, HC CDR3 having the amino acid sequence of SEQ ID NO: 3, LC CDR1 having the amino acid sequence of SEQ ID NO: 16, LC CDR2 having the amino acid sequence of SEQ ID NO: 21, and LC CDR3 having the amino acid sequence of SEQ ID NO: 27.

[0237] In some embodiments, the anti-HJV antibodies of the present disclosure include HC CDR1, HC CDR2, and HC CDR3, which together contain 5 or fewer amino acid mutations (e.g., 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to HC CDR1 having the amino acid sequence of SEQ ID NO: 9, HC CDR2 having the amino acid sequence of SEQ ID NO: 2, and HC CDR3 having the amino acid sequence of SEQ ID NO: 3. As used anywhere in the present disclosure, "in total" means that the total number of amino acid mutations in all three heavy chain CDRs is within the defined range. Alternatively or additionally, the anti-HJV antibodies of the present disclosure include LC CDR1, LC CDR2, and LC CDR3, which together contain 5 or fewer amino acid mutations (e.g., 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to LC CDR1 having the amino acid sequence of SEQ ID NO: 16, LC CDR2 having the amino acid sequence of SEQ ID NO: 21, and LC CDR3 having the amino acid sequence of SEQ ID NO: 27.

[0238] In some embodiments, the anti-HJV antibodies of the present disclosure include HC CDR1 having the amino acid sequence of SEQ ID NO: 9, HC CDR2 having the amino acid sequence of SEQ ID NO: 2, and HC CDR3 having the amino acid sequence of SEQ ID NO: 3, which are collectively at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to HC CDR1, HC CDR2, and HC CDR3. Alternatively or additionally, the anti-HJV antibodies of the present disclosure include LC CDR1 having the amino acid sequence of SEQ ID NO: 16, LC CDR2 having the amino acid sequence of SEQ ID NO: 21, and LC CDR3 having the amino acid sequence of SEQ ID NO: 27, which are collectively at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to LC CDR1, LC CDR2, and LC CDR3.

[0239] In some embodiments, the anti-HJV antibodies of the present disclosure include: an HC CDR1 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to the HC CDR1 having the amino acid sequence of SEQ ID NO: 9; an HC CDR2 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to the HC CDR2 having the amino acid sequence of SEQ ID NO: 2; and / or an HC CDR3 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to the HC CDR3 having the amino acid sequence of SEQ ID NO: 3. Alternatively or additionally, the anti-HJV antibodies of the present disclosure include: an LC CDR1 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to the LC CDR1 having the amino acid sequence of SEQ ID NO: 16; an LC CDR2 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to the LC CDR2 having the amino acid sequence of SEQ ID NO: 21; and / or an LC CDR3 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to the LC CDR3 having the amino acid sequence of SEQ ID NO: 27.

[0240] In some embodiments, the anti-HJV antibodies of the present disclosure include a VH comprising the amino acid sequence of SEQ ID NO: 34. Alternatively or additionally, the anti-HJV antibodies of the present disclosure include a VL comprising the amino acid sequence of SEQ ID NO: 35.

[0241] In some embodiments, the anti-HJV antibodies of the present disclosure include a VH containing 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the VH represented by SEQ ID NO: 34. Alternatively or additionally, the anti-HJV antibodies of the present disclosure include a VL containing 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the VL represented by SEQ ID NO: 35.

[0242] In some embodiments, the anti-HJV antibodies of the present disclosure include a VH having an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the VH represented by SEQ ID NO: 34. Alternatively or additionally, the anti-HJV antibodies of the present disclosure include a VL having an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the VL represented by SEQ ID NO: 35.

[0243] In some embodiments, the anti-HJV antibodies of the present disclosure include HC CDR1, HC CDR2, and HC CDR3 of a heavy chain variable domain having the amino acid sequence of SEQ ID NO: 36. Alternatively or additionally, the anti-HJV antibodies of the present disclosure include LC CDR1, LC CDR2, and LC CDR3 of a light chain variable domain having the amino acid sequence of SEQ ID NO: 37.

[0244] In some embodiments, according to the Kabat definition system, the anti-HJV antibodies of the present disclosure include HC CDR1 having the amino acid sequence of SEQ ID NO: 1, HC CDR2 having the amino acid sequence of SEQ ID NO: 10, HC CDR3 having the amino acid sequence of SEQ ID NO: 11, LC CDR1 having the amino acid sequence of SEQ ID NO: 17, LC CDR2 having the amino acid sequence of SEQ ID NO: 18, and LC CDR3 having the amino acid sequence of SEQ ID NO: 28.

[0245] In some embodiments, the anti-HJV antibodies of the present disclosure include HC CDR1, HC CDR2, and HC CDR3, which, when compared to HC CDR1 having the amino acid sequence of SEQ ID NO: 1, HC CDR2 having the amino acid sequence of SEQ ID NO: 10, and HC CDR3 having the amino acid sequence of SEQ ID NO: 11, contain a total of 5 or fewer amino acid mutations (e.g., 5, 4, 3, 2, or 1 or fewer amino acid mutations). As used anywhere in the present disclosure, "in total" means that the total number of amino acid mutations in all three heavy chain CDRs is within the defined range. Alternatively or additionally, the anti-HJV antibodies of the present disclosure include LC CDR1, LC CDR2, and LC CDR3, which, when compared to LC CDR1 having the amino acid sequence of SEQ ID NO: 17, LC CDR2 having the amino acid sequence of SEQ ID NO: 18, and LC CDR3 having the amino acid sequence of SEQ ID NO: 28, contain a total of 5 or fewer amino acid mutations (e.g., 5, 4, 3, 2, or 1 or fewer amino acid mutations).

[0246] In some embodiments, the anti-HJV antibodies of the present disclosure include HC CDR1 having the amino acid sequence of SEQ ID NO: 1, HC CDR2 having the amino acid sequence of SEQ ID NO: 10, and HC CDR3 having the amino acid sequence of SEQ ID NO: 11, which are in total at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the corresponding sequences. Alternatively or additionally, the anti-HJV antibodies of the present disclosure include LC CDR1 having the amino acid sequence of SEQ ID NO: 17, LC CDR2 having the amino acid sequence of SEQ ID NO: 18, and LC CDR3 having the amino acid sequence of SEQ ID NO: 28, which are in total at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the corresponding sequences.

[0247] In some embodiments, the anti-HJV antibodies of the present disclosure include: an HC CDR1 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to the amino acid sequence of SEQ ID NO: 1; an HC CDR2 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to the amino acid sequence of SEQ ID NO: 10; and / or an HC CDR3 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to the amino acid sequence of SEQ ID NO: 11. Alternatively or additionally, the anti-HJV antibodies of the present disclosure include: an LC CDR1 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to the amino acid sequence of SEQ ID NO: 17; an LC CDR2 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to the amino acid sequence of SEQ ID NO: 18; and / or an LC CDR3 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to the amino acid sequence of SEQ ID NO: 28.

[0248] In some embodiments, the anti-HJV antibodies of the present disclosure include a VH comprising the amino acid sequence of SEQ ID NO: 36. Alternatively or additionally, the anti-HJV antibodies of the present disclosure include a VL comprising the amino acid sequence of SEQ ID NO: 37.

[0249] In some embodiments, the anti-HJV antibodies of the present disclosure include a VH having 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the VH represented by SEQ ID NO: 36. Alternatively or additionally, the anti-HJV antibodies of the present disclosure include a VL having 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the VL represented by SEQ ID NO: 37.

[0250] In some embodiments, the anti-HJV antibodies of the present disclosure comprise a VH comprising an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the VH represented by SEQ ID NO: 36. Alternatively or additionally, the anti-HJV antibodies of the present disclosure comprise a VL comprising an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the VL represented by SEQ ID NO: 37.

[0251] In some embodiments, the anti-HJV antibodies of the present disclosure comprise HC CDR1, HC CDR2, and HC CDR3 of a heavy chain variable domain having the amino acid sequence of SEQ ID NO: 38. Alternatively or additionally, the anti-HJV antibodies of the present disclosure comprise LC CDR1, LC CDR2, and LC CDR3 of a light chain variable domain having the amino acid sequence of SEQ ID NO: 39.

[0252] In some embodiments, according to the Kabat definition system, the anti-HJV antibodies of the present disclosure comprise HC CDR1 having the amino acid sequence of SEQ ID NO: 1, HC CDR2 having the amino acid sequence of SEQ ID NO: 2, HC CDR3 having the amino acid sequence of SEQ ID NO: 3, LC CDR1 having the amino acid sequence of SEQ ID NO: 17, LC CDR2 having the amino acid sequence of SEQ ID NO: 5, and LC CDR3 having the amino acid sequence of SEQ ID NO: 27.

[0253] In some embodiments, the anti-HJV antibodies of the present disclosure include HC CDR1, HC CDR2, and HC CDR3, which together contain 5 or fewer amino acid mutations (e.g., 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to HC CDR1 having the amino acid sequence of SEQ ID NO: 1, HC CDR2 having the amino acid sequence of SEQ ID NO: 2, and HC CDR3 having the amino acid sequence of SEQ ID NO: 3. As used anywhere in the present disclosure, "in total" means that the total number of amino acid mutations in all three heavy chain CDRs is within the defined range. Alternatively or additionally, the anti-HJV antibodies of the present disclosure include LC CDR1, LC CDR2, and LC CDR3, which together contain 5 or fewer amino acid mutations (e.g., 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to LC CDR1 having the amino acid sequence of SEQ ID NO: 17, LC CDR2 having the amino acid sequence of SEQ ID NO: 5, and LC CDR3 having the amino acid sequence of SEQ ID NO: 27.

[0254] In some embodiments, the anti-HJV antibodies of the present disclosure include HC CDR1 having the amino acid sequence of SEQ ID NO: 1, HC CDR2 having the amino acid sequence of SEQ ID NO: 2, and HC CDR3 having the amino acid sequence of SEQ ID NO: 3, which are collectively at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical. Alternatively or additionally, the anti-HJV antibodies of the present disclosure include LC CDR1 having the amino acid sequence of SEQ ID NO: 17, LC CDR2 having the amino acid sequence of SEQ ID NO: 5, and LC CDR3 having the amino acid sequence of SEQ ID NO: 27, which are collectively at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical.

[0255] In some embodiments, the anti-HJV antibodies of the present disclosure include: an HC CDR1 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to the amino acid sequence of SEQ ID NO: 1; an HC CDR2 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to the amino acid sequence of SEQ ID NO: 2; and / or an HC CDR3 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to the amino acid sequence of SEQ ID NO: 3. Alternatively or additionally, the anti-HJV antibodies of the present disclosure include: an LC CDR1 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to the amino acid sequence of SEQ ID NO: 17; an LC CDR2 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to the amino acid sequence of SEQ ID NO: 5; and / or an LC CDR3 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to the amino acid sequence of SEQ ID NO: 27.

[0256] In some embodiments, the anti-HJV antibodies of the present disclosure include a VH comprising the amino acid sequence of SEQ ID NO: 38. Alternatively or additionally, the HJV antibodies of the present disclosure include a VL comprising the amino acid sequence of SEQ ID NO: 39.

[0257] In some embodiments, the anti-HJV antibodies of the present disclosure include a VH containing 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the VH represented by SEQ ID NO: 38. Alternatively or additionally, the anti-HJV antibodies of the present disclosure include a VL containing 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the VL represented by SEQ ID NO: 39.

[0258] In some embodiments, the anti-HJV antibodies of the present disclosure comprise a VH having an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the VH represented by SEQ ID NO: 38. Alternatively or additionally, the anti-HJV antibodies of the present disclosure comprise a VL having an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the VL represented by SEQ ID NO: 39.

[0259] In some embodiments, the anti-HJV antibodies of the present disclosure comprise HC CDR1, HC CDR2, and HC CDR3 of a heavy chain variable domain having the amino acid sequence of SEQ ID NO: 38. Alternatively or additionally, the anti-HJV antibodies of the present disclosure comprise LC CDR1, LC CDR2, and LC CDR3 of a light chain variable domain having the amino acid sequence of SEQ ID NO: 41.

[0260] In some embodiments, according to the Kabat definition system, the anti-HJV antibodies of the present disclosure comprise HC CDR1 having the amino acid sequence of SEQ ID NO: 1, HC CDR2 having the amino acid sequence of SEQ ID NO: 2, HC CDR3 having the amino acid sequence of SEQ ID NO: 3, LC CDR1 having the amino acid sequence of SEQ ID NO: 50, LC CDR2 having the amino acid sequence of SEQ ID NO: 22, and LC CDR3 having the amino acid sequence of SEQ ID NO: 28.

[0261] In some embodiments, the anti-HJV antibodies of the present disclosure include HC CDR1, HC CDR2, and HC CDR3, which, when compared to HC CDR1 having the amino acid sequence of SEQ ID NO: 1, HC CDR2 having the amino acid sequence of SEQ ID NO: 2, and HC CDR3 having the amino acid sequence of SEQ ID NO: 3, contain a total of 5 or fewer amino acid mutations (e.g., 5, 4, 3, 2, or 1 or fewer amino acid mutations) in combination. As used anywhere in the present disclosure, "in total" means that the total number of amino acid mutations in all three heavy chain CDRs is within the defined range. Alternatively or additionally, the anti-HJV antibodies of the present disclosure include LC CDR1, LC CDR2, and LC CDR3, which, when compared to LC CDR1 having the amino acid sequence of SEQ ID NO: 50, LC CDR2 having the amino acid sequence of SEQ ID NO: 22, and LC CDR3 having the amino acid sequence of SEQ ID NO: 28, contain a total of 5 or fewer amino acid mutations (e.g., 5, 4, 3, 2, or 1 or fewer amino acid mutations) in combination.

[0262] In some embodiments, the anti-HJV antibodies of the present disclosure comprise HC CDR1 having the amino acid sequence of SEQ ID NO: 1, HC CDR2 having the amino acid sequence of SEQ ID NO: 2, and HC CDR3 having the amino acid sequence of SEQ ID NO: 3, which are together at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to HC CDR1, HC CDR2, and HC CDR3. Alternatively or additionally, the anti-HJV antibodies of the present disclosure comprise LC CDR1 having the amino acid sequence of SEQ ID NO: 50, LC CDR2 having the amino acid sequence of SEQ ID NO: 22, and LC CDR3 having the amino acid sequence of SEQ ID NO: 28, which are together at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to LC CDR1, LC CDR2, and LC CDR3.

[0263] In some embodiments, the anti-HJV antibodies of the present disclosure include: an HC CDR1 having no more than 3 amino acid mutations (e.g., no more than 3, 2, or 1 amino acid mutations) compared to the amino acid sequence of SEQ ID NO: 1; an HC CDR2 having no more than 3 amino acid mutations (e.g., no more than 3, 2, or 1 amino acid mutations) compared to the amino acid sequence of SEQ ID NO: 2; and / or an HC CDR3 having no more than 3 amino acid mutations (e.g., no more than 3, 2, or 1 amino acid mutations) compared to the amino acid sequence of SEQ ID NO: 3. Alternatively or additionally, the anti-HJV antibodies of the present disclosure include: an LC CDR1 having no more than 3 amino acid mutations (e.g., no more than 3, 2, or 1 amino acid mutations) compared to the amino acid sequence of SEQ ID NO: 50; an LC CDR2 having no more than 3 amino acid mutations (e.g., no more than 3, 2, or 1 amino acid mutations) compared to the amino acid sequence of SEQ ID NO: 22; and / or an LC CDR3 having no more than 3 amino acid mutations (e.g., no more than 3, 2, or 1 amino acid mutations) compared to the amino acid sequence of SEQ ID NO: 28.

[0264] In some embodiments, the anti-HJV antibodies of the present disclosure include a VH comprising the amino acid sequence of SEQ ID NO: 38. Alternatively or additionally, the anti-HJV antibodies of the present disclosure include a VL comprising the amino acid sequence of SEQ ID NO: 41.

[0265] In some embodiments, the anti-HJV antibodies of the present disclosure include a VH having no more than 20 amino acid mutations (e.g., no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid mutations) compared to the VH represented by SEQ ID NO: 38. Alternatively or additionally, the anti-HJV antibodies of the present disclosure include a VL having no more than 20 amino acid mutations (e.g., no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid mutations) compared to the VL represented by SEQ ID NO: 41.

[0266] In some embodiments, the anti-HJV antibodies of the present disclosure comprise a VH having an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the VH represented by SEQ ID NO: 38. Alternatively or additionally, the anti-HJV antibodies of the present disclosure comprise a VL having an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the VL represented by SEQ ID NO: 41.

[0267] In some embodiments, the anti-HJV antibodies of the present disclosure comprise HC CDR1, HC CDR2, and HC CDR3 of the heavy chain variable domain having the amino acid sequence of SEQ ID NO: 42. Alternatively or additionally, the anti-HJV antibodies of the present disclosure comprise LC CDR1, LC CDR2, and LC CDR3 of the light chain variable domain having the amino acid sequence of SEQ ID NO: 43.

[0268] In some embodiments, according to the Kabat definition system, the anti-HJV antibodies of the present disclosure comprise HC CDR1 having the amino acid sequence of SEQ ID NO: 1, HC CDR2 having the amino acid sequence of SEQ ID NO: 2, HC CDR3 having the amino acid sequence of SEQ ID NO: 12, LC CDR1 having the amino acid sequence of SEQ ID NO: 15, LC CDR2 having the amino acid sequence of SEQ ID NO: 23, and LC CDR3 having the amino acid sequence of SEQ ID NO: 27.

[0269] In some embodiments, the anti-HJV antibodies of the disclosure include HC CDR1, HC CDR2, and HC CDR3, which together contain 5 or fewer amino acid mutations (e.g., 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to HC CDR1 having the amino acid sequence of SEQ ID NO: 1, HC CDR2 having the amino acid sequence of SEQ ID NO: 2, and HC CDR3 having the amino acid sequence of SEQ ID NO: 12. As used anywhere in the disclosure, "in total" means that the total number of amino acid mutations in all three heavy chain CDRs is within the defined range. Alternatively or additionally, the anti-HJV antibodies of the disclosure include LC CDR1, LC CDR2, and LC CDR3, which together contain 5 or fewer amino acid mutations (e.g., 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to LC CDR1 having the amino acid sequence of SEQ ID NO: 15, LC CDR2 having the amino acid sequence of SEQ ID NO: 23, and LC CDR3 having the amino acid sequence of SEQ ID NO: 27.

[0270] In some embodiments, the anti-HJV antibodies of the present disclosure comprise HC CDR1 having the amino acid sequence of SEQ ID NO: 1, HC CDR2 having the amino acid sequence of SEQ ID NO: 2, and HC CDR3 having the amino acid sequence of SEQ ID NO: 12, which are together at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to HC CDR1, HC CDR2, and HC CDR3. Alternatively or additionally, the anti-HJV antibodies of the present disclosure comprise LC CDR1 having the amino acid sequence of SEQ ID NO: 15, LC CDR2 having the amino acid sequence of SEQ ID NO: 23, and LC CDR3 having the amino acid sequence of SEQ ID NO: 27, which are together at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to LC CDR1, LC CDR2, and LC CDR3.

[0271] In some embodiments, the anti-HJV antibodies of the present disclosure include: an HC CDR1 having no more than 3 amino acid mutations (e.g., no more than 3, 2, or 1 amino acid mutations) compared to the amino acid sequence of SEQ ID NO: 1; an HC CDR2 having no more than 3 amino acid mutations (e.g., no more than 3, 2, or 1 amino acid mutations) compared to the amino acid sequence of SEQ ID NO: 2; and / or an HC CDR3 having no more than 3 amino acid mutations (e.g., no more than 3, 2, or 1 amino acid mutations) compared to the amino acid sequence of SEQ ID NO: 12. Alternatively or additionally, the anti-HJV antibodies of the present disclosure include: an LC CDR1 having no more than 3 amino acid mutations (e.g., no more than 3, 2, or 1 amino acid mutations) compared to the amino acid sequence of SEQ ID NO: 15; an LC CDR2 having no more than 3 amino acid mutations (e.g., no more than 3, 2, or 1 amino acid mutations) compared to the amino acid sequence of SEQ ID NO: 23; and / or an LC CDR3 having no more than 3 amino acid mutations (e.g., no more than 3, 2, or 1 amino acid mutations) compared to the amino acid sequence of SEQ ID NO: 27.

[0272] In some embodiments, the anti-HJV antibodies of the present disclosure include a VH comprising the amino acid sequence of SEQ ID NO: 42. Alternatively or additionally, the anti-HJV antibodies of the present disclosure include a VL comprising the amino acid sequence of SEQ ID NO: 43.

[0273] In some embodiments, the anti-HJV antibodies of the present disclosure include a VH having no more than 20 amino acid mutations (e.g., no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid mutations) compared to the VH represented by SEQ ID NO: 42. Alternatively or additionally, the anti-HJV antibodies of the present disclosure include a VL having no more than 20 amino acid mutations (e.g., no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid mutations) compared to the VL represented by SEQ ID NO: 43.

[0274] In some embodiments, the anti-HJV antibodies of the present disclosure comprise a VH having an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the VH represented by SEQ ID NO: 42. Alternatively or additionally, the anti-HJV antibodies of the present disclosure comprise a VL having an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the VL represented by SEQ ID NO: 43.

[0275] In some embodiments, the anti-HJV antibodies of the present disclosure comprise HC CDR1, HC CDR2, and HC CDR3 of a heavy chain variable domain having the amino acid sequence of SEQ ID NO: 44. Alternatively or additionally, the anti-HJV antibodies of the present disclosure comprise LC CDR1, LC CDR2, and LC CDR3 of a light chain variable domain having the amino acid sequence of SEQ ID NO: 45.

[0276] In some embodiments, according to the Kabat definition system, the anti-HJV antibodies of the present disclosure comprise HC CDR1 having the amino acid sequence of SEQ ID NO: 1, HC CDR2 having the amino acid sequence of SEQ ID NO: 2, HC CDR3 having the amino acid sequence of SEQ ID NO: 13, LC CDR1 having the amino acid sequence of SEQ ID NO: 16, LC CDR2 having the amino acid sequence of SEQ ID NO: 21, and LC CDR3 having the amino acid sequence of SEQ ID NO: 29.

[0277] In some embodiments, the anti-HJV antibodies of the present disclosure include HC CDR1, HC CDR2, and HC CDR3, which together contain 5 or fewer amino acid mutations (e.g., 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to HC CDR1 having the amino acid sequence of SEQ ID NO: 1, HC CDR2 having the amino acid sequence of SEQ ID NO: 2, and HC CDR3 having the amino acid sequence of SEQ ID NO: 13. As used anywhere in the present disclosure, "in total" means that the total number of amino acid mutations in all three heavy chain CDRs is within the defined range. Alternatively or additionally, the anti-HJV antibodies of the present disclosure include LC CDR1, LC CDR2, and LC CDR3, which together contain 5 or fewer amino acid mutations (e.g., 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to LC CDR1 having the amino acid sequence of SEQ ID NO: 16, LC CDR2 having the amino acid sequence of SEQ ID NO: 21, and LC CDR3 having the amino acid sequence of SEQ ID NO: 29.

[0278] In some embodiments, the anti-HJV antibodies of the present disclosure comprise HC CDR1 having the amino acid sequence of SEQ ID NO: 1, HC CDR2 having the amino acid sequence of SEQ ID NO: 2, and HC CDR3 having the amino acid sequence of SEQ ID NO: 13, which are together at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical. Alternatively or additionally, the anti-HJV antibodies of the present disclosure comprise LC CDR1 having the amino acid sequence of SEQ ID NO: 16, LC CDR2 having the amino acid sequence of SEQ ID NO: 21, and LC CDR3 having the amino acid sequence of SEQ ID NO: 29, which are together at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical.

[0279] In some embodiments, the anti-HJV antibodies of the present disclosure include: an HC CDR1 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to the amino acid sequence of SEQ ID NO: 1; an HC CDR2 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to the amino acid sequence of SEQ ID NO: 2; and / or an HC CDR3 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to the amino acid sequence of SEQ ID NO: 13. Alternatively or additionally, the anti-HJV antibodies of the present disclosure include: an LC CDR1 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to the amino acid sequence of SEQ ID NO: 16; an LC CDR2 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to the amino acid sequence of SEQ ID NO: 21; and / or an LC CDR3 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to the amino acid sequence of SEQ ID NO: 29.

[0280] In some embodiments, the anti-HJV antibodies of the present disclosure include a VH comprising the amino acid sequence of SEQ ID NO: 44. Alternatively or additionally, the anti-HJV antibodies of the present disclosure include a VL comprising the amino acid sequence of SEQ ID NO: 45.

[0281] In some embodiments, the anti-HJV antibodies of the present disclosure include a VH containing 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the VH represented by SEQ ID NO: 44. Alternatively or additionally, the anti-HJV antibodies of the present disclosure include a VL containing 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the VL represented by SEQ ID NO: 45.

[0282] In some embodiments, the anti-HJV antibodies of the present disclosure comprise a VH comprising an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the VH represented by SEQ ID NO: 44. Alternatively or additionally, the anti-HJV antibodies of the present disclosure comprise a VL comprising an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the VL represented by SEQ ID NO: 45.

[0283] When different definition systems are used (e.g., IMGT definition, Kabat definition, or Chothia definition), the CDRs of an antibody may have different amino acid sequences. The definition system annotates each amino acid in a given antibody sequence (e.g., VH or VL sequence) with a number, and the numbers corresponding to the heavy and light chain CDRs are provided in Table 2. The CDRs listed in Table 1 are defined according to the Kabat definition. One of ordinary skill in the art can derive the CDR sequences for the anti-HJV antibodies provided in Table 1 using different numbering systems.

Table 2

[0284] In some embodiments, the anti-HJV antibodies of the present disclosure are chimeric antibodies, which may include the heavy chain constant region and the light chain constant region of a human antibody. A chimeric antibody refers to an antibody having a variable region or a portion of the variable region from a first species and a constant region from a second species. Typically, in these chimeric antibodies, the variable regions of both the light chain and the heavy chain mimic the variable regions of antibodies derived from a mammalian species (e.g., a non-human mammalian species such as a mouse, rabbit, and rat), while the constant portion is homologous to the sequence of an antibody derived from another mammalian species such as a human. In some embodiments, amino acid modifications may be made to the variable region and / or the constant region.

[0285] In some embodiments, the anti-HJV antibodies described herein are chimeric antibodies, which may include the heavy chain constant region and the light chain constant region of a human antibody. A chimeric antibody refers to an antibody having a variable region or a portion of the variable region from a first species and a constant region from a second species. Typically, in these chimeric antibodies, the variable regions of both the light chain and the heavy chain mimic the variable regions of antibodies derived from a mammalian species (e.g., a non-human mammalian species such as a mouse, rabbit, and rat), while the constant portion is homologous to the sequence of an antibody derived from another mammalian species such as a human. In some embodiments, amino acid modifications may be made to the variable region and / or the constant region.

[0286] In some embodiments, the anti-HJV antibodies of the present disclosure include the VL domain and / or the VH domain of any one of the anti-HJV antibodies selected from Table 1, and include a constant region including the amino acid sequence of the constant region of an IgG, IgE, IgM, IgD, IgA, or IgY immunoglobulin molecule of any class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2) or any subclass (e.g., IgG2a and IgG2b) of an immunoglobulin molecule. Non-limiting examples of human constant regions are described in the art: see, e.g., Kabat E A et al., (1991) supra. Examples of human IgG constant regions are shown below:

Chemical formula

[0287] In some embodiments, the heavy chain of any of the anti-HJV antibodies described herein comprises a mutant human IgG constant region. For example, introduction of the LALA mutation (a variant derived from mAb b12 mutated such that the lower hinge residues Leu234 and Leu235 are replaced by Ala234 and Ala235) in the CH2 domain of human IgG1 is known to reduce Fcg receptor binding (Bruhns, P., et al. (2009) and Xu, D. et al. (2000)). The following mutant human IgG1 constant region is provided (mutations are in bold (bonded) and underlined):

Chemical formula

[0288] In some embodiments, the heavy chain of any of the anti-HJV antibodies described herein further comprises a mutation in the human IgG1 constant region. For example, introduction of the T250Q and M248L substitutions. In some embodiments, such substitutions may affect FcRn binding and serum half-life (WO2005047307 and WO2013063110). An exemplary IgG1 constant region containing the LALA and QL mutations is provided below (mutations are in bold and underlined):

Chemical formula

[0289] In some embodiments, it may be preferred that the lysine at the C-terminus of the heavy chain is cleaved during antibody production, particularly by Chinese hamster ovary (CHO) cells. Thus, the human IgG1 constant region in the secreted antibody may be:

Chemical formula

[0290] In some embodiments, the mutant human IgG1 containing the LALA mutation in the secreted antibody can be as follows: [Chemical formula]

[0291] In some embodiments, the mutant human IgG1 containing the LALA mutation and the QL mutation can be as follows: [Chemical formula]

[0292] In some embodiments, the light chain of the anti-HJV antibody described herein may further include a light chain constant region (CL), which can be any CL known in the art. In some embodiments, the CL is a kappa light chain. In other examples, the CL is a lambda light chain. In some embodiments, the CL is a kappa light chain, and its sequence is provided below: RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 47)

[0293] Other antibody heavy and light chain constant regions are well known in the art and are provided, for example, by the IMGT database (www.imgt.org) or www.vbase2.org / vbstat.php, both of which are incorporated herein by reference.

[0294] In some embodiments, the anti-HJV antibodies described herein comprise a heavy chain that comprises any one of the VHs listed in Table 1 or a variant thereof, and a heavy chain constant region that is at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to SEQ ID NO: 46, SEQ ID NO: 48, SEQ ID NO: 112, or SEQ ID NO: 113. In some embodiments, the anti-HJV antibodies described herein comprise a heavy chain that comprises any one of the VHs listed in Table 1 or any variant thereof, and a heavy chain constant region that contains 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to SEQ ID NO: 46, SEQ ID NO: 48, SEQ ID NO: 112, or SEQ ID NO: 113. In some embodiments, the anti-HJV antibodies described herein comprise a heavy chain that comprises any one of the VHs listed in Table 1 or any variant thereof, and a heavy chain constant region represented by SEQ ID NO: 46. In some embodiments, the anti-HJV antibodies described herein comprise a heavy chain that comprises any one of the VHs listed in Table 1 or any variant thereof, and a heavy chain constant region represented by SEQ ID NO: 48. In some embodiments, the anti-HJV antibodies described herein comprise a heavy chain that comprises any one of the VHs listed in Table 1 or any variant thereof, and a heavy chain constant region represented by SEQ ID NO: 112. In some embodiments, the anti-HJV antibodies described herein comprise a heavy chain that comprises any one of the VHs listed in Table 1 or any variant thereof, and a heavy chain constant region represented by SEQ ID NO: 113.

[0295] In some embodiments, the anti-HJV antibodies described herein include a light chain that includes any one of the VLs listed in Table 1 or any variant thereof, and a light chain constant region that is at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to SEQ ID NO: 47. In some embodiments, the anti-HJV antibodies described herein include a light chain that includes any one of the VLs listed in Table 1 or any variant thereof, and a light chain constant region that contains 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to SEQ ID NO: 47. In some embodiments, the anti-HJV antibodies described herein include a light chain that includes any one of the VLs listed in Table 1 or any variant thereof, and a light chain constant region represented by SEQ ID NO: 47.

[0296] Examples of the IgG heavy and light chain amino acid sequences of the anti-HJV antibodies described are provided in Table 1 above.

[0297] In some embodiments, the anti-HJV antibodies of the present disclosure include a heavy chain that contains 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the heavy chain represented by any one of SEQ ID NOs: 51, 57, 59, 61, 63, 66, 68, 114, 115, 116, 117, 118, 119, or 120. Alternatively or additionally, the anti-HJV antibodies of the present disclosure include a light chain that contains 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the light chain represented by any one of SEQ ID NOs: 52, 53, 54, 55, 56, 58, 60, 62, 65, 67, or 69. In some embodiments, the anti-HJV antibodies described herein include a heavy chain that includes an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to any one of SEQ ID NOs: 51, 57, 59, 61, 63, 66, 68, 114, 115, 116, 117, 118, 119, or 120. Alternatively or additionally, the anti-HJV antibodies described herein include a light chain that includes an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to any one of SEQ ID NOs: 52, 53, 54, 55, 56, 58, 60, 62, 65, 67, or 69. In some embodiments, the anti-HJV antibodies described herein include a heavy chain that includes the amino acid sequence of any one of SEQ ID NOs: 51, 57, 59, 61, 63, 66, 68, 114, 115, 116, 117, 118, 119, or 120.Alternatively or in addition, the anti-HJV antibodies described herein include a light chain comprising any one of the amino acid sequences of SEQ ID NOs: 52, 53, 54, 55, 56, 58, 60, 62, 65, 67, or 69.

[0298] In some embodiments, the anti-HJV antibodies of the disclosure include a heavy chain having 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the heavy chain represented by any one of SEQ ID NOs: 51 or 114. Alternatively or in addition, the anti-HJV antibodies of the disclosure include a light chain having 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the light chain represented by any one of SEQ ID NOs: 52. In some embodiments, the anti-HJV antibodies described herein include a heavy chain comprising an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to any one of SEQ ID NOs: 51 or 114. Alternatively or in addition, the anti-HJV antibodies described herein include a light chain comprising an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to any one of SEQ ID NOs: 52. In some embodiments, the anti-HJV antibodies described herein include a heavy chain comprising the amino acid sequence of any one of SEQ ID NOs: 51 or 114. Alternatively or in addition, the anti-HJV antibodies described herein include a light chain comprising the amino acid sequence of any one of SEQ ID NOs: 52.

[0299] In some embodiments, the anti-HJV antibodies of the present disclosure include a heavy chain that contains 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the heavy chain represented by any one of SEQ ID NO: 51 or 114. Alternatively or additionally, the anti-HJV antibodies of the present disclosure include a light chain that contains 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the light chain represented by any one of SEQ ID NO: 53. In some embodiments, the anti-HJV antibodies described herein include a heavy chain that comprises an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to any one of SEQ ID NO: 51 or 114. Alternatively or additionally, the anti-HJV antibodies described herein include a light chain that comprises an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to any one of SEQ ID NO: 53. In some embodiments, the anti-HJV antibodies described herein include a heavy chain that comprises the amino acid sequence of any one of SEQ ID NO: 51 or 114. Alternatively or additionally, the anti-HJV antibodies described herein include a light chain that comprises the amino acid sequence of any one of SEQ ID NO: 53.

[0300] In some embodiments, the anti-HJV antibodies of the present disclosure include a heavy chain that contains 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the heavy chain represented by any one of SEQ ID NO: 51 or 114. Alternatively or additionally, the anti-HJV antibodies of the present disclosure include a light chain that contains 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the light chain represented by any one of SEQ ID NO: 54. In some embodiments, the anti-HJV antibodies described herein include a heavy chain that includes an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to any one of SEQ ID NO: 51 or 114. Alternatively or additionally, the anti-HJV antibodies described herein include a light chain that includes an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to any one of SEQ ID NO: 54. In some embodiments, the anti-HJV antibodies described herein include a heavy chain that includes the amino acid sequence of any one of SEQ ID NO: 51 or 114. Alternatively or additionally, the anti-HJV antibodies described herein include a light chain that includes the amino acid sequence of any one of SEQ ID NO: 54.

[0301] In some embodiments, the anti-HJV antibodies of the present disclosure include a heavy chain that contains 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the heavy chain represented by any one of SEQ ID NO: 51 or 114. Alternatively or additionally, the anti-HJV antibodies of the present disclosure include a light chain that contains 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the light chain represented by any one of SEQ ID NO: 55. In some embodiments, the anti-HJV antibodies described herein include a heavy chain that includes an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to any one of SEQ ID NO: 51 or 114. Alternatively or additionally, the anti-HJV antibodies described herein include a light chain that includes an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to any one of SEQ ID NO: 55. In some embodiments, the anti-HJV antibodies described herein include a heavy chain that includes the amino acid sequence of any one of SEQ ID NO: 51 or 114. Alternatively or additionally, the anti-HJV antibodies described herein include a light chain that includes the amino acid sequence of any one of SEQ ID NO: 55.

[0302] In some embodiments, the anti-HJV antibodies of the present disclosure include a heavy chain containing 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the heavy chain represented by any one of SEQ ID NO: 51 or 114. Alternatively or additionally, the anti-HJV antibodies of the present disclosure include a light chain containing 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the light chain represented by any one of SEQ ID NO: 56. In some embodiments, the anti-HJV antibodies described herein include a heavy chain comprising an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to any one of SEQ ID NO: 51 or 114. Alternatively or additionally, the anti-HJV antibodies described herein include a light chain comprising an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to any one of SEQ ID NO: 56. In some embodiments, the anti-HJV antibodies described herein include a heavy chain comprising the amino acid sequence of any one of SEQ ID NO: 51 or 114. Alternatively or additionally, the anti-HJV antibodies described herein include a light chain comprising the amino acid sequence of any one of SEQ ID NO: 56.

[0303] In some embodiments, the anti-HJV antibodies of the present disclosure include a heavy chain that contains 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the heavy chain represented by any one of SEQ ID NO: 57 or 115. Alternatively or additionally, the anti-HJV antibodies of the present disclosure include a light chain that contains 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the light chain represented by any one of SEQ ID NO: 58. In some embodiments, the anti-HJV antibodies described herein include a heavy chain that includes an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to any one of SEQ ID NO: 57 or 115. Alternatively or additionally, the anti-HJV antibodies described herein include a light chain that includes an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to any one of SEQ ID NO: 58. In some embodiments, the anti-HJV antibodies described herein include a heavy chain that includes the amino acid sequence of any one of SEQ ID NO: 57 or 115. Alternatively or additionally, the anti-HJV antibodies described herein include a light chain that includes the amino acid sequence of any one of SEQ ID NO: 58.

[0304] In some embodiments, the anti-HJV antibodies of the present disclosure include a heavy chain containing 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the heavy chain represented by any one of SEQ ID NO: 59 or 116. Alternatively or additionally, the anti-HJV antibodies of the present disclosure include a light chain containing 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the light chain represented by any one of SEQ ID NO: 60. In some embodiments, the anti-HJV antibodies described herein include a heavy chain comprising an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to any one of SEQ ID NO: 59 or 116. Alternatively or additionally, the anti-HJV antibodies described herein include a light chain comprising an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to any one of SEQ ID NO: 60. In some embodiments, the anti-HJV antibodies described herein include a heavy chain comprising the amino acid sequence of any one of SEQ ID NO: 59 or 116. Alternatively or additionally, the anti-HJV antibodies described herein include a light chain comprising the amino acid sequence of any one of SEQ ID NO: 60.

[0305] In some embodiments, the anti-HJV antibodies of the present disclosure include a heavy chain that contains 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the heavy chain represented by any one of SEQ ID NO: 61 or 117. Alternatively or additionally, the anti-HJV antibodies of the present disclosure include a light chain that contains 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the light chain represented by any one of SEQ ID NO: 62. In some embodiments, the anti-HJV antibodies described herein include a heavy chain that comprises an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to any one of SEQ ID NO: 61 or 117. Alternatively or additionally, the anti-HJV antibodies described herein include a light chain that comprises an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to any one of SEQ ID NO: 62. In some embodiments, the anti-HJV antibodies described herein include a heavy chain that comprises the amino acid sequence of any one of SEQ ID NO: 61 or 117. Alternatively or additionally, the anti-HJV antibodies described herein include a light chain that comprises the amino acid sequence of any one of SEQ ID NO: 62.

[0306] In some embodiments, the anti-HJV antibodies of the present disclosure include a heavy chain that contains 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the heavy chain represented by any one of SEQ ID NO: 63 or 118. Alternatively or additionally, the anti-HJV antibodies of the present disclosure include a light chain that contains 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the light chain represented by any one of SEQ ID NO: 62. In some embodiments, the anti-HJV antibodies described herein include a heavy chain that includes an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to any one of SEQ ID NO: 63 or 118. Alternatively or additionally, the anti-HJV antibodies described herein include a light chain that includes an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to any one of SEQ ID NO: 62. In some embodiments, the anti-HJV antibodies described herein include a heavy chain that includes the amino acid sequence of any one of SEQ ID NO: 63 or 118. Alternatively or additionally, the anti-HJV antibodies described herein include a light chain that includes the amino acid sequence of any one of SEQ ID NO: 62.

[0307] In some embodiments, the anti-HJV antibodies of the present disclosure comprise a heavy chain having 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the heavy chain represented by any one of SEQ ID NO: 61 or 117. Alternatively or additionally, the anti-HJV antibodies of the present disclosure comprise a light chain having 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the light chain represented by any one of SEQ ID NO: 65. In some embodiments, the anti-HJV antibodies described herein comprise a heavy chain comprising an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to any one of SEQ ID NO: 61 or 117. Alternatively or additionally, the anti-HJV antibodies described herein comprise a light chain comprising an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to any one of SEQ ID NO: 65. In some embodiments, the anti-HJV antibodies described herein comprise a heavy chain comprising the amino acid sequence of any one of SEQ ID NO: 61 or 117. Alternatively or additionally, the anti-HJV antibodies described herein comprise a light chain comprising the amino acid sequence of any one of SEQ ID NO: 65.

[0308] In some embodiments, the anti-HJV antibodies of the present disclosure include a heavy chain containing 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the heavy chain represented by any one of SEQ ID NO: 66 or 119. Alternatively or additionally, the anti-HJV antibodies of the present disclosure include a light chain containing 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the light chain represented by any one of SEQ ID NO: 67. In some embodiments, the anti-HJV antibodies described herein include a heavy chain comprising an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to any one of SEQ ID NO: 66 or 119. Alternatively or additionally, the anti-HJV antibodies described herein include a light chain comprising an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to any one of SEQ ID NO: 67. In some embodiments, the anti-HJV antibodies described herein include a heavy chain comprising the amino acid sequence of any one of SEQ ID NO: 66 or 119. Alternatively or additionally, the anti-HJV antibodies described herein include a light chain comprising the amino acid sequence of any one of SEQ ID NO: 67.

[0309] In some embodiments, the anti-HJV antibodies of the present disclosure include a heavy chain that contains 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the heavy chain represented by any one of SEQ ID NO: 68 or 120. Alternatively or additionally, the anti-HJV antibodies of the present disclosure include a light chain that contains 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the light chain represented by any one of SEQ ID NO: 69. In some embodiments, the anti-HJV antibodies described herein include a heavy chain that comprises an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to any one of SEQ ID NO: 68 or 120. Alternatively or additionally, the anti-HJV antibodies described herein include a light chain that comprises an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to any one of SEQ ID NO: 69. In some embodiments, the anti-HJV antibodies described herein include a heavy chain that comprises the amino acid sequence of any one of SEQ ID NO: 68 or 120. Alternatively or additionally, the anti-HJV antibodies described herein include a light chain that comprises the amino acid sequence of any one of SEQ ID NO: 69.

[0310] The anti-HJV antibodies described herein can be in any antibody form, including but not limited to intact (i.e., full-length) antibodies, antigen-binding fragments thereof (Fab, F(ab’), F(ab’)2, Fv, etc.), single-chain antibodies, bispecific antibodies, or nanobodies. In some embodiments, the anti-HJV antibodies described herein are scFv. In some embodiments, the anti-HJV antibodies described herein are scFv-Fab (e.g., scFv fused to a portion of the constant region).

[0311] In some embodiments, conservative mutations can be introduced into the antibody sequence (e.g., CDR or framework sequences) at positions that are not thought to be involved in the interaction with the target antigen (e.g., hemojuvelin), such as those determined based on the crystal structure. In some embodiments, one or more functional properties of the antibody, such as serum half-life, complement binding, Fc receptor binding, and / or antibody-dependent cell cytotoxicity, are altered by introducing one, two, or more mutations (e.g., amino acid substitutions) into the Fc region of the anti-HJV antibodies described herein (e.g., numbering according to the Kabat numbering system (e.g., Kabat's EU index), CH2 domain (residues 231-340 of human IgG1) and / or CH3 domain (residues 341-447 of human IgG1) and / or hinge region).

[0312] In some embodiments, one, two, or more mutations (e.g., amino acid substitutions) are introduced into the hinge region of the Fc region (CH1 domain) such that the number of cysteine residues in the hinge region is changed (e.g., increased or decreased), as described, for example, in U.S. Patent No. 5,677,425. The number of cysteine residues in the hinge region of the CH1 domain can be altered, for example, to facilitate light and heavy chain association, or to change the stability of the antibody (e.g., increase or decrease it), or to facilitate linker conjugation.

[0313] In some embodiments, to increase or decrease the affinity of an antibody for an Fc receptor (e.g., an activating Fc receptor) on the surface of an effector cell, one, two, or more mutations (e.g., amino acid substitutions) are introduced into the Fc region of the muscle-targeting antibodies described herein (e.g., numbered according to the Kabat numbering system (e.g., the EU index of Kabat), the CH2 domain (residues 231-340 of human IgG1) and / or the CH3 domain (residues 341-447 of human IgG1) and / or the hinge region). Mutations in the Fc region of an antibody that decrease or increase the affinity of the antibody for an Fc receptor, and methods for introducing such mutations into an Fc receptor or a fragment thereof, are known to those of skill in the art. Examples of mutations in an antibody's Fc receptor that can be made to change the affinity of the antibody for the Fc receptor are described, for example, in Smith P et al., (2012) PNAS 109: 6181-6186, which is incorporated herein by reference; U.S. Patent No. 6,737,056; International Publication No. WO02 / 060919; WO98 / 23289; and WO97 / 34631, which are incorporated herein by reference.

[0314] In some embodiments, to change (e.g., decrease or increase) the half-life of an antibody in vivo, one, two, or more amino acid mutations (i.e., substitutions, insertions, or deletions) are introduced into the IgG constant domain or an FcRn-binding fragment thereof (e.g., an Fc or hinge-Fc domain fragment). Examples of mutations that change (e.g., decrease or increase) the half-life of an antibody in vivo can be found, for example, in International Publications WO02 / 060919; WO98 / 23289; and WO97 / 34631; and U.S. Patent Nos. 5,869,046; 6,121,022; 6,277,375; and 6,165,745.

[0315] In some embodiments, to reduce the half-life of an anti-HJV antibody in vivo, one, two, or more amino acid mutations (i.e., substitutions, insertions, or deletions) are introduced into the IgG constant domain or its FcRn-binding fragment (e.g., Fc or hinge-Fc domain fragment). In some embodiments, to increase the half-life of an antibody in vivo, one, two, or more amino acid mutations (i.e., substitutions, insertions, or deletions) are introduced into the IgG constant region or its FcRn-binding fragment (e.g., Fc or hinge-Fc domain fragment). In some embodiments, the antibody may have one or more ami...

Claims

1. A pharmaceutical composition for treating a blood loss condition in a subject, comprising an anti-hemoduvelin (HJV) antibody.

2. The pharmaceutical composition according to claim 1, wherein the anti-HJV antibody is administered in an effective amount to promote hematological recovery.

3. (i) Hematological recovery includes recovery of erythropoiesis, reticulocyte hemoglobin content (CHr), mean corpuscular hemoglobin (MCH), and / or circulating hemoglobin levels to baseline levels prior to the state of blood loss; (ii) Hematological recovery is achieved within a shorter timeframe than that achieved in control subjects who were not administered anti-HJV antibodies; and / or (iii) Hematological recovery including recovery of erythrocyte production, reticulocyte hemoglobin (CHr), mean corpuscular hemoglobin (MCH), and / or circulating hemoglobin levels to baseline levels within 3, 5, 1, 2, 3, or 4 weeks, The pharmaceutical composition according to claim 2.

4. The pharmaceutical composition according to claim 1, wherein the blood loss condition includes chronic blood loss, acute blood loss, iatrogenic blood loss, venous puncture, surgical procedure, blood donation procedure, bleeding wound, or disease.

5. A wound accompanied by bleeding, (a) a wound with internal bleeding, ruptured blood vessel, organ contusion, organ rupture, or hematoma; or (b) A wound, cut, puncture, dissection, incision, or penetration accompanied by external bleeding, The pharmaceutical composition according to claim 4.

6. The disease is (i) blood loss resulting from gastrointestinal (GI) disease, inflammatory bowel disease (IBD), esophageal varices, gastritis, gastric ulcer, duodenal ulcer, diverticulosis, Meckel's diverticulum, intestinal polyps, hemorrhoids, celiac disease, or colorectal cancer; (ii) blood loss resulting from genitourinary disorders, menorrhagia, uterine fibroids, endometriosis, bladder tumors, urinary tract infections (UTIs), or kidney stones; or (iii) It is an infectious disease, or (a) Viral hemorrhagic fever selected from dengue fever, Ebola virus disease, Lassa fever, hantavirus pulmonary syndrome, Marburg virus disease, and yellow fever, (b) A bacterial infection selected from sepsis, bacterial vaginosis, Lemière's syndrome, and tuberculosis, or (c) Parasitic infections selected from malaria, whipworm disease, and schistosomiasis This is blood loss caused by The pharmaceutical composition according to claim 4.

7. Before administration, the subject, (i) a hemoglobin level of at least 6 g / dl; and / or (ii) Hemoglobin levels in the range of 7 to 12 g / dl; and / or (iii) Hemoglobin levels in the range of 7 to 11 g / dl; and / or (iv) Hemoglobin levels in the range of 7-10 g / dl A pharmaceutical composition according to claim 1, having the following characteristics.

8. After administration, (a) The subject's hemoglobin level increases by 1 to 3 g / dl; or (b) The target hemoglobin level increases by 1 to 3 g / dl within one, two, three, four, five, or six weeks. The pharmaceutical composition according to claim 1.

9. Before administration, the subject (i) Ferritin levels up to 5000 ng / ml; and / or (ii) Ferritin levels in the range of 14–150 ng / ml A pharmaceutical composition according to claim 1, having the following characteristics.

10. The pharmaceutical composition according to claim 1, wherein, after administration, the target ferritin level decreases by 15% to 50% compared to the ferritin level before administration.

11. Before administration, the subject (a) Transferrin saturation (TSAT) levels in the range of 15% to 30%; and / or (b) Reticulocyte hemoglobin (CHr) levels in the range of 20–40 pg; and / or (c) Hepcidin levels in the range of 5 to 75 ng / ml; and / or (d) Red blood cell count in the range of 3 × 10¹² to 6 × 10¹² cells / L; and / or (e) Mean corpuscular hemoglobin (MCH) level of 15-50 pg A pharmaceutical composition according to claim 1, having the following characteristics.

12. After administration, (a) The subject is, (i) Having a TSAT% level in the range of 30% to 50%, or (ii) Having a TSAT% level in the range of 30% to 50% within one, two, three, four, five, or six weeks; (b) The CHr level of the subject is (i) CHr levels increase by 1% to 5% compared to the level before administration, (ii) It rises by 1% to 5% within 1, 2, 3, 4, 5, 6 days, 1 week, or 2 weeks; (c) The subject's hepcidin level decreases by 2 to 60 ng / ml compared to the hepcidin level before administration; (d) The target red blood cell count increases by at least 0.5 × 10¹² cells / L compared to the red blood cell count before administration; or (e) The target MCH level increases by 1% to 5% compared to the MCH level before administration. The pharmaceutical composition according to claim 1.

13. (i) The subject does not have functional iron deficiency prior to administration; (ii) The subject does not have inflammation-related anemia prior to administration; or (iii) The subject has inflammation-related anemia prior to administration, The pharmaceutical composition according to claim 1.

14. The state of blood loss is (i) Persistent blood loss; or (ii) More than one instance of intermittent blood loss at intervals of up to one week, up to two weeks, or up to one month; or (iii) Loss of up to 10% of the target's total blood volume A pharmaceutical composition according to claim 1, comprising:

15. (i) The blood loss is in the range of 1 to 10% of the total blood volume of the subject; (ii) including persistent blood loss, in which the state of blood loss lasts for at least 1 hour, at least 4 hours, at least 8 hours, at least 12 hours, at least 16 hours, at least 20 hours, at least 1 day, at least 3 days, at least 5 days, at least 8 days, at least 10 days, at least 2 weeks, at least 3 weeks, at least 1 month, at least 2 months, or at least 3 months; (iii) The blood loss condition includes intermittent blood loss cases in which each instance of blood loss involves a loss of up to 10% of the total blood volume of the subject; (iv) The blood loss condition includes intermittent blood loss, where each blood loss occurs at intervals of up to 1 hour, up to 4 hours, up to 8 hours, up to 12 hours, up to 16 hours, up to 20 hours, up to 1 day, up to 3 days, up to 5 days, up to 8 days, up to 10 days, or up to 2 weeks; (v) The subject has a ferritin level of 14-80 ng / ml due to blood loss; (vi) The subject has serum iron of at least 40 μg / dL, The pharmaceutical composition according to claim 1.

16. The pharmaceutical composition according to claim 1, which is administered to the subject once a week, twice a month, once a month, or every four weeks.

17. The object is, (i) Not identified as needing a blood transfusion; or (ii) It has been identified that a blood transfusion is required before administration of the pharmaceutical composition. The pharmaceutical composition according to claim 1.

18. (i) administered in combination with oral iron supplementation or iron injection; (ii) administered while the subject is on a gluten-free diet; and / or (iii) Therapeutic drugs, erythropoietin (EPO), ruspatercept, and hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHI) are administered in combination. The pharmaceutical composition according to claim 1.

19. (i) administered subcutaneously; or (ii) It is administered intravenously. The pharmaceutical composition according to claim 1.

20. (i) It is administered on multiple occasions; or (ii) It is administered once a month or every four weeks. The pharmaceutical composition according to claim 1.

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