Anti-TMPRSS6 antibodies and their uses.

Description

Anti-TMPRSS6 Antibodies and Their Uses Cross-reference to related applications

[001] This request claims priority over Request U.S. Provisional No. 63 / 457,081, filed April 4, 2023, which is incorporated herein by reference in its entirety. Reference to an electronic sequence listing

[002] The contents of the electronic sequence listing (D084270011W000-SEQ-LJG.xml; Size: 95,921 bytes; and Creation date: April 1, 2024) are incorporated herein by reference in their entirety. Background

[003] Transmembrane serine protease 6 (TMPRSS6; also known as Matriptase-2 or MTP-2) is a type II transmembrane serine protease. TMPRSS6 is highly expressed in the liver and plays a role in iron homeostasis by negatively regulating hepcidin expression. TMPRSS6 cleaves BMP coreceptors (e.g., hemojuvelin (HJV)), resulting in decreased hepcidin expression. Decreased hepcidin expression levels lead to iron overload in various conditions. There is a need for improved compositions and methods for the treatment of iron overload disorders. Summary

[004] Certain aspects of the revelation relate to the recognition that iron overload occurs in various conditions (e.g., hemochromatosis, sickle cell disease (SCD), thalassemia, hemolysis, African iron overload, Diamond-Blackfan anemia, myelodysplastic syndrome (MDS), blood transfusion, etc.). In some modalities, methods and related compositions provided herein are useful for treating various diseases and conditions (e.g., hemochromatosis, sickle cell disease (SCD), thalassemia, hemolysis, African iron overload, Diamond-Blackfan anemia, myelodysplastic syndrome). Petition 870250088518, dated 09 / 30 / 2025, page 15 / 245 2 / 213 (MDS), etc.). In some embodiments, methods and related compositions provided herein are useful for inhibiting TMPRSS6 in order to reduce iron overload in diseases and conditions described herein. In some embodiments, reducing iron overload improves disease severity. Aspects of the development provide anti-TMPRSS6 antibodies that have high binding affinity and specificity to TMPRSS6 and that inhibit TMPRSS6 activity. Thus, in some embodiments, the development provides methods and compositions of related anti-TMPRSS6 antibodies to treat diseases and conditions associated with iron overload, such as hemochromatosis, sickle cell disease (SCD), thalassemia, hemolysis, Diamond-Blackfan anemia, African iron overload, myelodysplastic syndrome (MDS), blood transfusion, etc. In some embodiments, the methods provided herein reduce iron overload in an individual.In some modalities, the methods provided here reduce systemic iron levels. In some modalities, the methods provided here reduce the mean corpuscular hemoglobin concentration (MCHC) in an individual.

[005] In some embodiments, the disclosure provides methods for treating sickle cell disease (SCD) by administering an effective amount of an anti-TMPRSS6 antibody to an individual. In some aspects, the present disclosure provides methods and compositions for treating iron overload in an individual with SCD by administering an effective amount of an anti-TMPRSS6 antibody to the individual. In some embodiments, the methods provided herein result in a reduction in the frequency of painful crises (i.e., vaso-occlusive crisis, VOC), severity of VOC (e.g., hospitalization and duration), systemic iron level, mean corpuscular hemoglobin concentration (MCHC), hemoglobin S (HbS) polymerization, blood transfusion, and / or hemolysis in individuals with SCD (e.g., hemoglobin SC disease). In some embodiments, the methods provided herein reduce Petition 870250088518, dated 09 / 30 / 2025, page 16 / 245 3 / 213 the frequency of painful crises (CVO) for hemoglobin SC disease.

[006] In some respects, the present disclosure provides a method for treating sickle cell disease (SCD), the method comprising administering to an individual an effective amount of an anti-serine transmembrane protease 6 (TMPRSS6) antibody comprising: (a) an HC CDR1, HC CDR2 and HC CDR3 of a variable heavy chain domain having the amino acid sequence of SEQ ID NO: 4 9 and an LC CDR1, LC CDR2 and LC CDR3 of a variable light chain domain having the amino acid sequence of SEQ ID NO: 50; (b) an HC CDR1, HC CDR2 and HC CDR3 of a variable heavy chain domain having the amino acid sequence of SEQ ID NO: 7 and an LC CDR1, LC CDR2 and LC CDR3 of a variable light chain domain having the amino acid sequence of SEQ ID NO: 8; (c) an HC CDR1, HC CDR2 and HC CDR3 of a variable heavy chain domain having the amino acid sequence SEQ ID NOs: 19 or 78, and an LC CDR1, LC CDR2 and LC CDR3 of a variable light chain domain having the amino acid sequence SEQ ID NO: 20; (d) an HC CDR1, HC CDR2 and HC CDR3 of a variable heavy chain domain having the amino acid sequence of SEQ ID NO: 30 and an LC CDR1, LC CDR2 and LC CDR3 of a variable light chain domain having the amino acid sequence of SEQ ID NO: 31; (e) an HC CDR1, HC CDR2 and HC CDR3 of a variable heavy chain domain having the amino acid sequence of SEQ ID NO: 37 and an LC CDR1, LC CDR2 and LC CDR3 of a variable light chain domain having the amino acid sequence of SEQ ID NO: 38; or Petition 870250088518, dated 09 / 30 / 2025, p. 17 / 245 4 / 213 (f) an HC CDR1, HC CDR2 and HC CDR3 of a variable heavy chain domain having the amino acid sequence of SEQ ID NO: 44 and an LC CDR1, LC CDR2 and LC CDR3 of a variable light chain domain having the amino acid sequence of SEQ ID NO: 45.

[007] In some embodiments, the anti-TMPRSS6 antibody comprises an HC CDR1, HC CDR2 and HC CDR3 of a variable heavy chain domain having the amino acid sequence of SEQ ID NO: 49, and an LC CDR1, LC CDR2 and LC CDR3 of a variable light chain domain having the amino acid sequence of SEQ ID NO: 50.

[008] In some embodiments, the anti-TMPRSS6 antibody comprises: (a) an HC CDR1 having the amino acid sequence SEQ ID NO: 24, an HC CDR2 having the amino acid sequence SEQ ID NO: 48, an HC CDR3 having the amino acid sequence SEQ ID NO: 26, an LC CDR1 having the amino acid sequence SEQ ID NO: 27, an LC CDR2 having the amino acid sequence WAT and an LC CDR3 having the amino acid sequence SEQ ID NO: 29; (b) 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 RAN and an LC CDR3 having the amino acid sequence of SEQ ID NO: 6; (c) an HC CDR1 having the amino acid sequence of SEQ ID NO: 13, an HC CDR2 having the amino acid sequence of SEQ ID NO: 14, an HC CDR3 having the amino acid sequence of SEQ ID NO: 15, an LC CDR1 having the amino acid sequence of SEQ ID NO: 16, an LC CDR2 having the amino acid sequence of WAF and an LC CDR3 having the amino acid sequence of SEQ ID NO: 18; (d) a CDR1 HC having the amino acid sequence SEQ ID NO: 24, a CDR2 HC having the amino acid sequence SEQ ID NO: 25, a CDR3 HC having the amino acid sequence SEQ Petition 870250088518, dated 09 / 30 / 2025, p. 18 / 245 5 / 213 ID NO: 26, a CDR1 LC having the amino acid sequence of SEQ ID NO: 27, an LC CDR2 having the amino acid sequence of WAT and an LC CDR3 with the amino acid sequence of SEQ ID NO: 29; (e) 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, a CDR3 HC having the amino acid sequence of SEQID NO: 35, a CDR1 LC having the amino acid sequence of SEQID NO: 36, an LC CDR2 having the amino acid sequence of RAN and an LC CDR3 having the amino acid sequence of SEQ ID NO: 6; or (f) an HC CDR1 having the amino acid sequence of SEQ ID NO: 13, an HC CDR2 having the amino acid sequence of SEQ ID NO: 43, an HC CDR3 having the amino acid sequence of SEQ ID NO: 15, a CDR1 LC having the amino acid sequence of SEQ ID NO: 16, an LC CDR2 having the amino acid sequence of WAF and an LC CDR3 having the amino acid sequence of SEQ ID NO: 18.

[009] In some embodiments, the anti-TMPRSS6 antibody comprises a CDR1 HC having the amino acid sequence SEQ ID NO: 24, a CDR2 HC having the amino acid sequence SEQ ID NO: 48, an HC CDR3 having the amino acid sequence of SEQ ID NO: 26, an LC CDR1 having the amino acid sequence of SEQ ID NO: 27, an LC CDR2 having the amino acid sequence of WAT and an LC CDR3 with the amino acid sequence of SEQ ID NO: 29.

[0010] In some embodiments, the anti-TMPRSS6 antibody comprises: (a) a variable heavy chain domain having the amino acid sequence SEQ ID NO: 49 and a variable light chain domain having the amino acid sequence SEQ ID NO: 50; (b) a variable heavy chain domain having the amino acid sequence SEQ ID NO: 7 and a variable light chain domain having the amino acid sequence SEQ ID NO: 8; (c) a variable heavy chain domain having the amino acid sequence SEQ ID NOs: 19 or 78 and a domain Petition 870250088518, dated 09 / 30 / 2025, page 19 / 245 6 / 213 light chain variable having the amino acid sequence SEQ ID NO: 20; (d) a variable heavy chain domain having the amino acid sequence SEQ ID NO: 30 and a variable light chain domain having the amino acid sequence SEQ ID NO: 31; (e) a variable heavy chain domain having the amino acid sequence SEQ ID NO: 37 and a variable light chain domain having the amino acid sequence SEQ ID NO: 38; or (f) a variable heavy chain domain having the amino acid sequence SEQ ID NO: 44 and a variable light chain domain having the amino acid sequence SEQ ID NO: 45;

[0011] In some embodiments, the anti-TMPRSS6 antibody comprises a variable heavy chain domain having the amino acid sequence SEQ ID NO: 49 and a variable light chain domain having the amino acid sequence SEQ ID NO: 50.

[0012] In some embodiments, the anti-TMPRSS6 antibody comprises: (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 52 and a light chain comprising the amino acid sequence of SEQ ID NO: 53; (b) a heavy chain comprising the amino acid sequence of SEQ ID NO: 11 and a light chain comprising the amino acid sequence of SEQ ID NO: 12; (c) a heavy chain comprising the amino acid sequence of SEQ ID NOs: 17 or 22 and a light chain comprising the amino acid sequence of SEQ ID NO: 23; (d) a heavy chain comprising the amino acid sequence of SEQ ID NO: 33 and a light chain comprising the amino acid sequence of SEQ ID NO: 34; Petition 870250088518, dated 09 / 30 / 2025, p. 20 / 245 7 / 213 (e) a heavy chain comprising the amino acid sequence of SEQ ID NO: 41 and a light chain comprising the amino acid sequence of SEQ ID NO: 42; or (f) a heavy chain comprising the amino acid sequence of SEQ ID NO: 46 and a light chain comprising the amino acid sequence of SEQ ID NO: 47.

[0013] In some embodiments, the anti-TMPRSS6 antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 52 and a light chain comprising the amino acid sequence of SEQ ID NO: 53.

[0014] In some modalities, antibody administration reduces iron overload in the individual. In some modalities, antibody administration reduces hemolysis in the individual compared to the individual before administration. In some modalities, the individual has moderate to severe recurrent vaso-occlusive crisis (VOC). In some modalities, antibody administration reduces the frequency of VOC in the individual compared to the individual before administration. In some modalities, administration reduces the severity of VOC compared to the individual before administration. In some modalities, the severity of VOC is measured by the frequency of hospitalization and / or duration of hospitalization.

[0015] In some embodiments, antibody administration reduces systemic iron in the individual prior to administration. In some embodiments, antibody administration reduces mean corpuscular hemoglobin concentration (MCHC) relative to the period prior to administration. In some embodiments, administration reduces hemoglobin S (HbS) polymerization relative to the individual prior to administration. In some embodiments, administration reduces the frequency with which the individual requires blood transfusions relative to the individual prior to administration. In some embodiments, administration reduces inflammation in the individual relative to the individual prior to administration. Petition 870250088518, dated 09 / 30 / 2025, page 21 / 245 8 / 213 administration. In some forms, sickle cell disease is hemoglobin SS disease. In some forms, sickle cell disease is hemoglobin SC disease.

[0016] In some embodiments, the anti-TMPRSS6 antibody is administered as co-therapy in combination with a hemoglobin S polymerization inhibitor (e.g., voxelotor), therapeutic agents to reduce CVO (e.g., hydroxyurea, L-glutamine powder for oral administration, crizanlizumab, selective pyruvate kinase-R (PKR) activator), pain-relieving medications (e.g., narcotics, opioids, gabapentin, cannabis), a blood transfusion, a stem cell transplant, Exagamglogene autotemcel (exacel), LentiGlobin, GMI-1070, VIT-2763 (vamifeport), Ticagrelor, vitamin D, simvastatin, AG-348 (mitapivat sulfate), propranolol, epinephrine, regadenoson, atorvastatin, prasugrel, L-arginine, OTQ923, oxygen therapy or gene therapy.

[0017] In some respects, the present disclosure provides a method for treating a condition associated with iron overload in an individual in need thereof, wherein the individual does not have β-thalassemia intermedia or hemochromatosis type I, the method comprising administering to the individual an effective amount of an anti-serine transmembrane protease 6 antibody (TMPRSS6) comprising: (a) an HC CDR1, HC CDR2 and HC CDR3 of a variable heavy chain domain having the amino acid sequence of SEQ ID NO: 49 and an LC CDR1, LC CDR2 and LC CDR3 of a variable light chain domain having the amino acid sequence of SEQ ID NO: 50; (b) an HC CDR1, HC CDR2 and HC CDR3 of a variable heavy chain domain having the amino acid sequence of SEQ ID NO: 7 and an LC CDR1, LC CDR2 and LC CDR3 of a variable light chain domain having the amino acid sequence of SEQ ID NO: 8; Petition 870250088518, dated 09 / 30 / 2025, p. 22 / 245 9 / 213 (c) an HC CDR1, HC CDR2 and HC CDR3 of a variable heavy chain domain having the amino acid sequence of SEQ ID NOs: 19 or 78, and an LC CDR1, LC CDR2 and LC CDR3 of a variable light chain domain having the amino acid sequence of SEQ ID NO: 20; (d) an HC CDR1, HC CDR2 and HC CDR3 of a variable heavy chain domain having the amino acid sequence of SEQ ID NO: 30 and an LC CDR1, LC CDR2 and LC CDR3 of a variable light chain domain having the amino acid sequence of SEQ ID NO: 31; (e) an HC CDR1, HC CDR2 and HC CDR3 of a variable heavy chain domain having the amino acid sequence of SEQ ID NO: 37 and an LC CDR1, LC CDR2 and LC CDR3 of a variable light chain domain having the amino acid sequence of SEQ ID NO: 38; or (f) an HC CDR1, HC CDR2 and HC CDR3 of a variable heavy chain domain having the amino acid sequence of SEQ ID NO: 44, and an LC CDR1, LC CDR2 and LC CDR3 of a variable light chain domain having the amino acid sequence of SEQ ID NO: 45.

[0018] In some embodiments, the anti-TMPRSS6 antibody comprises an HC CDR1, HC CDR2 and HC CDR3 of a variable heavy chain domain having the amino acid sequence of SEQ ID NO: 49, and an LC CDR1, LC CDR2 and LC CDR3 of a variable light chain domain having the amino acid sequence of SEQ ID NO: 50.

[0019] In some embodiments, the anti-TMPRSS6 antibody comprises: (a) an HC CDR1 having the amino acid sequence SEQ ID NO: 24, an HC CDR2 having the amino acid sequence SEQ ID NO: 48, an HC CDR3 having the amino acid sequence SEQ ID NO: 26, an LC CDR1 having the amino acid sequence SEQ ID NO: 27, an LC CDR2 having the amino acid sequence WAT and an LC CDR3 with the amino acid sequence SEQ ID NO: 29; Petition 870250088518, dated 09 / 30 / 2025, p. 23 / 245 10 / 213 (b) 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 RAN and an LC CDR3 having the amino acid sequence of SEQ ID NO: 6; (c) an HC CDR1 having the amino acid sequence of SEQ ID NO: 13, an HC CDR2 having the amino acid sequence of SEQ ID NO: 14, an HC CDR3 having the amino acid sequence of SEQ ID NO: 15, an LC CDR1 having the amino acid sequence of SEQ ID NO: 16, an LC CDR2 having the amino acid sequence of WAF and an LC CDR3 having the amino acid sequence of SEQ ID NO: 18; (d) an HC CDR1 having the amino acid sequence SEQ ID NO: 24, an HC CDR2 having the amino acid sequence SEQ ID NO: 25, an HC CDR3 having the amino acid sequence SEQ ID NO: 26, an LC CDR1 having the amino acid sequence SEQ ID NO: 27, an LC CDR2 having the amino acid sequence of WAT and an LC CDR3 with the amino acid sequence SEQ ID NO: 29; (e) an HC CDR1 having the amino acid sequence SEQ ID NO: 1, an HC CDR2 having the amino acid sequence SEQ ID NO: 2, an HC CDR3 having the amino acid sequence SEQ ID NO: 35, an LC CDR1 having the amino acid sequence SEQ ID NO: 36, an LC CDR2 having the amino acid sequence RAN and an LC CDR3 having the amino acid sequence SEQ ID NO: 6; or (f) an HC CDR1 having the amino acid sequence SEQ ID NO: 13, an HC CDR2 having the amino acid sequence SEQ ID NO: 43, an HC CDR3 having the amino acid sequence SEQ ID NO: 15, an LC CDR1 having the amino acid sequence SEQ ID NO: 16, an LC CDR2 having the amino acid sequence WAF and an LC CDR3 having the amino acid sequence SEQ ID NO: 18.

[0020] In some embodiments, the anti-TMPRSS6 antibody comprises a CDR1 HC having the amino acid sequence SEQ ID NO: 24, a CDR2 HC having the amino acid sequence SEQ Petition 870250088518, dated 09 / 30 / 2025, p. 24 / 245 11 / 213 ID NO: 48, an HC CDR3 having the amino acid sequence of SEQ ID NO: 26, an LC CDR1 having the amino acid sequence of SEQ ID NO: 27, an LC CDR2 having the amino acid sequence of WAT and an LC CDR3 with the amino acid sequence of SEQ ID NO: 29.

[0021] In some embodiments, the anti-TMPRSS6 antibody comprises: (a) a variable heavy chain domain having the amino acid sequence SEQ ID NO: 49 and a variable light chain domain having the amino acid sequence SEQ ID NO: 50; (b) a variable heavy chain domain having the amino acid sequence SEQ ID NO: 7 and a variable light chain domain having the amino acid sequence SEQ ID NO: 8; (c) a variable heavy chain domain having the amino acid sequence SEQ ID NOs: 19 or 78 and a variable light chain domain having the amino acid sequence SEQ ID NO: 20; (d) a variable heavy chain domain having the amino acid sequence SEQ ID NO: 30 and a variable light chain domain having the amino acid sequence SEQ ID NO: 31; (e) a variable heavy chain domain having the amino acid sequence SEQ ID NO: 37 and a variable light chain domain having the amino acid sequence SEQ ID NO: 38; or (f) a variable heavy chain domain having the amino acid sequence SEQ ID NO: 44 and a variable light chain domain having the amino acid sequence SEQ ID NO: 45;

[0022] In some embodiments, the anti-TMPRSS6 antibody comprises a variable heavy chain domain having the amino acid sequence SEQ ID NO: 49 and a variable light chain domain having the amino acid sequence SEQ ID NO: 50. Petition 870250088518, dated 09 / 30 / 2025, page 25 / 245 12 / 213

[0023] In some embodiments, the anti-TMPRSS6 antibody comprises: (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 52 and a light chain comprising the amino acid sequence of SEQ ID NO: 53; (b) a heavy chain comprising the amino acid sequence of SEQ ID NO: 11 and a light chain comprising the amino acid sequence of SEQ ID NO: 12; (c) a heavy chain comprising the amino acid sequence of SEQ ID NOs: 17 or 22 and a light chain comprising the amino acid sequence of SEQ ID NO: 23; (d) a heavy chain comprising the amino acid sequence of SEQ ID NO: 33 and a light chain comprising the amino acid sequence of SEQ ID NO: 34; (e) a heavy chain comprising the amino acid sequence of SEQ ID NO: 41 and a light chain comprising the amino acid sequence of SEQ ID NO: 42; or (f) a heavy chain comprising the amino acid sequence of SEQ ID NO: 46 and a light chain comprising the amino acid sequence of SEQ ID NO: 47.

[0024] In some embodiments, the anti-TMPRSS6 antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 52 and a light chain comprising the amino acid sequence of SEQ ID NO: 53.

[0025] In some modalities, antibody administration reduces systemic iron in the individual relative to the period prior to administration. In some modalities, antibody administration reduces mean corpuscular hemoglobin concentration (MCHC) relative to the period prior to administration. In some modalities, antibody administration reduces iron overload in the individual relative to the period prior to administration. Petition 870250088518, dated 09 / 30 / 2025, p. 26 / 245 13 / 213

[0026] In some forms, the individual has hereditary hemochromatosis. In some forms, the hereditary hemochromatosis is hereditary hemochromatosis type 3.

[0027] In some forms, the individual has or is suspected of having thalassemia. In some forms, the thalassemia is α-thalassemia. In some forms, the α-thalassemia is α-thalassemia major, α-thalassemia intermedia, or α-thalassemia minor. In some forms, the thalassemia is β-thalassemia. In some forms, the β-thalassemia is β-thalassemia major or β-thalassemia minor.

[0028] In some modalities, the individual has or is suspected of having transfusion-related iron overload. In some modalities, the individual is receiving blood transfusions due to blood loss. In some modalities, the individual is receiving repeated blood transfusions due to anemia.

[0029] In some forms, the individual has hemolytic anemia. In some forms, the individual has transfusion-dependent hemolytic anemia, pyruvate kinase deficiency hemolytic anemia, thalassemia-related hemolytic anemia, or sickle cell disease-related hemolytic anemia.

[0030] In some modalities, the individual has African iron overload.

[0031] In some forms, the individual has Diamond-Blackfan anemia.

[0032] In some forms, the individual has myelodysplastic syndrome (MDS). In some forms, MDS is refractory anemia with ring sideroblasts (ARSA). In some forms, the individual has an SF3B1 mutation.

[0033] The aspects, implementations, acts, functionalities, characteristics and modalities above and others of the present Petition 870250088518, dated 09 / 30 / 2025, page 27 / 245 14 / 213 teachings can be more fully understood from the following description along with the attached drawings. Brief description of the drawings

[0034] FIGS. 1A to 1E demonstrate a dose-dependent effect of treatment of mice with an inhibitory anti-TMPRSS6 antibody. Mice were injected intraperitoneally with 0 (vehicle), 2, 5 or 10 mg / kg of anti-TMPRSS6 antibody and monitored for a period of 10 days. Serum antibody (FIG. 1A), iron (FIG. 1B) and hepcidin (FIG. 1C) concentrations were measured over 10 days after injection. FIG. 1D shows Hamp expression in the liver and FIG. 1E shows the TSAT% of the mice throughout the study.

[0035] FIGS. 2A to 2D show the body, spleen, and liver weights of sickle cell disease mice (Townes model) administered with anti-TMPRSS6 antibody. FIG. 2A shows the progression of total body weight of mice that received 0.3 or 10 mg / kg of anti-TMPRSS6 antibody, stratified into male and female groups (designated M and F, respectively), over 8 weeks. FIG. 2B shows the spleen weight / body weight measurement of male and female mice 56 days after administration of 0.3 or 10 mg / kg of anti-TMPRSS6 antibody. FIG. 2C shows the liver weight / body weight measurement of male and female mice 56 days after administration of 0 or 10 mg / kg of anti-TMPRSS6 antibody. FIG. 2D shows the liver weight / body weight of all mice (male and female mice combined) 56 days after administration of 0 or mg / kg of anti-TMPRSS6 antibody.

[0036] FIGS. 3A to 3C show the reduction of hemolysis markers in sickle cell mice administered with anti-TMPRSS6 antibody. Lactate dehydrogenase (LDH) (FIG. 3A), direct bilirubin (DBili) (FIG. 3B) and total bilirubin (TBili) (FIG. 3C) levels were measured in sickle cell mice 56 Petition 870250088518, dated 09 / 30 / 2025, page 28 / 245 15 / 213 days after administration of 0, 3 or 10 mg / kg of anti-TMPRSS6 antibody.

[0037] FIGS. 4A to 4C show the reduction of systemic inflammation markers in sickle cell mice administered with anti-TMPRSS6 antibody. White blood cell (WBC) levels measured by the peroxidase method (FIG. 4A), neutrophils (FIG. 4B) and lymphocytes (FIG. 4C) were measured in the blood of sickle cell mice 56 days after administration of 0, 3 or 10 mg / kg of anti-TMPRSS6 antibody.

[0038] FIGS. 5A to 5C demonstrate the reduction in HbS polymerization in sickle cell mice treated with anti-TMPRSS6 antibody. HbS (MCHC) levels (FIG. 5A), hypochromic red blood cells (FIG. 5B) and microcytic red blood cells (FIG. 5C) were measured in the blood of sickle cell mice 56 days after administration of 0, 3 or 10 mg / kg of anti-TMPRSS6 antibody. Detailed description

[0039] The present disclosure, at least in part, relates to the recognition that iron overload occurs in various conditions (e.g., hemochromatosis, sickle cell disease, thalassemia, hemolysis, Diamond-Blackfan anemia, African iron overload, myelodysplastic syndrome (MDS), blood transfusion, etc.). In some embodiments, methods and related compositions provided herein are useful for treating various diseases and conditions (e.g., hemochromatosis, sickle cell disease (SCD), thalassemia, hemolysis, African iron overload, Diamond-Blackfan anemia, myelodysplastic syndrome (MDS), etc.). In some embodiments, methods and related compositions are provided that are useful for inhibiting TMPRSS6 in order to reduce iron overload, thereby improving disease severity. Aspects of the disclosure provide anti-TMPRSS6 antibodies that have high binding affinity and specificity to TMPRSS6 and that inhibit TMPRSS6 activity. Thus, in some Petition 870250088518, dated 09 / 30 / 2025, page 29 / 245 In 16 / 213 embodiments, the disclosure provides methods and compositions of related anti-TMPRSS6 antibodies to treat diseases and conditions associated with iron overload, such as hemochromatosis, sickle cell disease (SCD), thalassemia, hemolysis, DiamondBlackfan anemia, African iron overload, myelodysplastic syndrome (MDS), and blood transfusion. In some embodiments, the methods provided here reduce iron overload.

[0040] In some embodiments, the disclosure provides methods for treating sickle cell disease (SCD) by administering to an individual an effective amount of an anti-TMPRSS6 antibody. In some aspects, the present disclosure provides methods and compositions for treating iron overload in an individual with SCD by administering to the individual an effective amount of an anti-TMPRSS6 antibody. In some embodiments, the methods provided herein result in a reduction in the frequency of painful crises (e.g., vaso-occlusive crisis, VOC), severity of VOC (e.g., hospitalization and duration), hemoglobin S (HbS) polymerization, blood transfusion, and / or hemolysis in individuals with SCD (e.g., hemoglobin SC disease). In some embodiments, the methods provided herein reduce the frequency of painful crises (VOC) for hemoglobin C sickle cell disease (SC).

[0041] The aspects, implementations, acts, functionalities, characteristics and modalities above and others of the present teachings can be more fully understood from the following description together with the attached drawings. I. Definitions

[0042] And / or: As used herein, the term “and / or” is to be considered as a specific disclosure of each of the two or more specified features or components, with or without the other. Thus, the term “and / or,” as used in a phrase such as “A and / or B” herein, is intended to include “A and B,” “A or B,” “A” (alone), and “B” (alone). Similarly, the term “and / or,” as used Petition 870250088518, dated 09 / 30 / 2025, p. 30 / 245 17 / 213 in a sentence like “A, B and / or C”, intends to cover each of the following aspects: A, B and C; A, B or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0043] Administration: As used herein, the terms “administer”, “administered”, “administering” or “administration” mean providing an antibody or a composition thereof to an individual in a physiologically and / or pharmacologically useful manner (for example, to treat a condition in the individual).

[0044] Affinity-matured antibody: “Affinity-matured antibody” is used here to refer to an antibody with one or more alterations in one or more CDRs, resulting in an improvement in the antibody's affinity (i.e., KD, kd, or ka) for a target antigen compared to a parental antibody that does not have the alteration(s). Exemplary affinity-matured antibodies will have nanomolar or even picomolar affinities for the target antigen. A variety of procedures for producing affinity-matured antibodies are known in the art, including screening a combinatorial antibody library that has been prepared using bio-display. For example, Marks et al., BioTechnology, 10: 779-783 (1992) describes affinity maturation through shuffling of VH and VL domains. Random mutagenesis of CDR residues and / or the framework is described by 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 mutation at selective mutagenesis positions and contact or hypermutation with an amino acid residue that increases activity is described in US Patent No. 6,914,128 B1. Petition 870250088518, dated 09 / 30 / 2025, p. 31 / 245 18 / 213

[0045] Antibody: As used herein, the term antibody refers to a polypeptide that includes at least one immunoglobulin variable domain or at least one site, for example, a paratope, that specifically binds to an antigen. In some embodiments, an antibody comprises a paratope. In some embodiments, a paratope comprises one or more complementarity-determining regions (CDRs). In some embodiments, an antibody is a full-length antibody. In some embodiments, an antibody is a chimeric antibody. In some embodiments, an antibody is a humanized antibody. However, in some embodiments, an antibody is a Fab fragment, an F(ab')2 fragment, an Fv fragment, or an scFv fragment. In some embodiments, an antibody is a nanobody derived from a camelid antibody or a nanobody derived from a shark antibody. In some embodiments, an antibody is a diabody.In some embodiments, an antibody comprises a framework with a human germline sequence. In another embodiment, an antibody comprises a constant heavy chain domain selected from the group consisting of constant domains of IgG, IgG1, IgG2, IgG2A, IgG2B, IgG2C, IgG3, IgG4, IgA1, IgA2, IgD, IgM, and IgE. In some embodiments, an antibody comprises a variable heavy chain (H) region (abbreviated here as VH) and / or a variable light chain (L) region (abbreviated here as VL). In some embodiments, an antibody comprises a constant domain, for example, an Fc region. An immunoglobulin constant domain refers to a constant heavy or light chain domain. The amino acid sequences of the constant heavy chain and light chain domains of human IgG and their functional variations are known.With respect to the heavy chain, in some embodiments, the heavy chain of an antibody described herein may be an alpha (α), delta (Δ), epsilon (ε), gamma (γ), or mu (μ) heavy chain. In some embodiments, the heavy chain of an antibody described herein may... Petition 870250088518, dated 09 / 30 / 2025, p. 32 / 245 19 / 213 comprise an alpha (α), delta (Δ), epsilon (ε), gamma (γ) or mu (μ) heavy chain. In a specific embodiment, an antibody described herein comprises a human gamma 1 CH1, CH2 and / or CH3 domain. In some embodiments, the amino acid sequence of the VH domain comprises the amino acid sequence of a constant region of the human gamma (γ) heavy chain, such as any known in the art. Non-limiting examples of human constant region sequences have been described in the art, for example, see US Patent No. 5,693,780 and Kabat EA et al., (1991) above. In some embodiments, the VH 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 constant variable chain regions provided herein. In some embodiments, an antibody is modified, for example, modified by glycosylation, phosphorylation, sumoylation, and / or methylation. In some embodiments, an antibody is a glycosylated antibody, which is conjugated to one or more sugar or carbohydrate molecules. In some embodiments, one or more sugar or carbohydrate molecules are conjugated to the antibody by N-glycosylation, O-glycosylation, C-glycosylation, glypiation (GPI anchor attachment), and / or phosphoglycosylation. In some embodiments, one or more sugar or carbohydrate molecules are monosaccharides, disaccharides, oligosaccharides, or glycans. In some embodiments, one or more sugar or carbohydrate molecules are branched oligosaccharides or branched glycans.In some embodiments, one or more sugar or carbohydrate molecules include a mannose unit, a glucose unit, an N-acetylglucosamine unit, or a phospholipid unit. In some embodiments, an antibody is a construct comprising a polypeptide comprising one or more antigen-binding fragments of the developing antibody linked to a connector peptide or to a constant immunoglobulin domain. Connective polypeptides comprise two or more residues of Petition 870250088518, dated 09 / 30 / 2025, page 33 / 245 20 / 213 amino acids linked by peptide bonds and used to bind one or more antigen-binding moieties. Examples of connector polypeptides have been reported (see, for example, Holliger, P., et al. (1993) Proc. Natl. Acad. Sci. USA 90:64446448; Poljak, RJ, et al. (1994) Structure 2:1121-1123). Furthermore, an antibody can be part of a larger immunoadhesion molecule, formed by the covalent or non-covalent association of the antibody or a portion of the antibody with one or more other proteins or peptides. Examples of such immunoadhesion molecules include the use of the central region of streptavidin to produce a tetrameric scFv molecule (Kipriyanov, SM, et al. (1995) Human Antibodies and Hybridomas 6:93-101) and the use of a cysteine ​​residue, a marker peptide, and a C-terminal polyhistidine tag to produce bivalent and biotinylated scFv molecules (Kipriyanov, SM, et al. (1994) Mol. Imunol. 31:1047-1058).

[0046] Approximately: As used herein, the term approximately or “about”, when applied to one or more values ​​of interest, refers to a value that is similar to a stated reference value. In certain embodiments, the term approximately or about refers to a range of values ​​that fall within 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less in any direction (greater or less than) the stated reference value, unless otherwise indicated or evident from the context (except where such a number exceeds 100% of a possible value).

[0047] CDR: As used herein, the term CDR refers to the complementarity-determining region within variable antibody sequences. A typical antibody molecule comprises a variable heavy chain (VH) region and a variable light chain (VL) region, which are generally involved in antigen binding. The VH and VL regions can be subdivided into hypervariable regions, also known as Petition 870250088518, dated 09 / 30 / 2025, page 34 / 245 21 / 213 as “complementar determining regions (CDRs), interspersed with more conserved regions, known as framework regions (FRs). Each VH and VL is typically composed of three CDRs and four FRs, arranged from the amino-terminal to the carboxy-terminal in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The extent of the framework region and CDRs can be precisely identified using methodology known in the art, for example, by the Kabat definition, the IMGT definition, the Chothia definition, the AbM definition and / or the contact definition, all well known in the art. See, for example, Kabat, EA, et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, US Department of Health and Human Services, NIH Publication No. 913242; IMGT®, the international ImMunoGeneTics information system® 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., 31:307310 (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). 17:132-143 (2004). See also hgmp.mrc.ac.uk and bioinf.org.uk / abs. As used herein, a CDR may refer to a CDR defined by any method known in the art. Two antibodies with the same CDR means that the two antibodies have the same amino acid sequence of that CDR, as determined by the same method, for example, the definition of IMGT. Petition 870250088518, dated 09 / 30 / 2025, p. 35 / 245 22 / 213

[0048] In certain embodiments, there are three CDRs in each of the variable regions of a heavy chain and a light chain, which are designated CDR1, CDR2, and CDR3 for each of the variable regions. The term CDR set, as used herein, refers to a group of three CDRs that occur in a single variable region capable of binding to 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 precise residue boundaries that define the three CDRs. These CDRs may be called Kabat CDRs.Subportions of CDRs can be designated as L1, L2, and L3 or H1, H2, and H3, where L and H designate the light chain and heavy chain regions, respectively. These regions can be called Chothia CDRs, which have boundaries that overlap with Kabat CDRs. Other boundaries defining CDRs that 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 definitions of CDR boundaries may not strictly follow one of the above systems, but will still overlap with Kabat CDRs, although they may be shortened or lengthened in light of predictions or experimental findings that specific residues or groups of residues, or even entire CDRs, do not significantly impact antigen binding. The methods used here can employ the CDRs defined according to any of these systems, although preferred embodiments use the CDRs defined by Kabat or Chothia.

[0049] In certain embodiments, the CDRs of an antibody may have different amino acid sequences when different definition systems are used (e.g., the IMGT definition, Petition 870250088518, dated 09 / 30 / 2025, page 36 / 245 23 / 213 the Kabat definition or the Chothia definition). A definition system annotates each amino acid in a given antibody sequence (e.g., VH or VL sequence) with a number, and the corresponding numbers for the heavy chain and light chain CDRs are provided in Table 1. The CDRs listed in Table 2 are defined according to the Kabat definition. A person skilled in the art is able to derive the CDR sequences using the different numbering systems for the anti-TMPRSS6 antibodies provided in Table 2. Table 1. CDR Definitions IMGT1 Kabat2 Chothia3 HC CDR1 27 a 38 31 a 35 26 a 32 HC CDR2 56 a 65 50 a 65 53 a 55 HC CDR3 105 a 116 / 117 95 a 102 96 a 101 LC CDR1 27 a 38 24 a 34 26 a 32 LC CDR2 56 a 65 50 a 56 50 a 52 LC CDR3 105 a 116 / 117 89 a 97 91 a 96 1IMGT®, the international ImMunoGeneTics information system®, imgt.org, Lefranc, M.-P. et al., Nucleic Acids Res., 27:209-212 (1999)2Kabat et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-32423Chothia et al., J. Mol. Biol. 196:901-917 (1987)

[0050] CDR-grafted antibody: The term CDR-grafted antibody refers to antibodies comprising variable heavy and light chain regions sequences of one species, but in which the sequences of one or more VH and / or VL CDR regions are replaced by CDR sequences of another species, such as antibodies that have murine variable heavy and light chain regions in which one or more murine CDRs (e.g., CDR3) have been replaced by human CDR sequences.

[0051] Chimeric antibody: The term chimeric antibody refers to antibodies comprising sequences of variable heavy and light chain regions of one species and sequences of Petition 870250088518, dated 09 / 30 / 2025, p. 37 / 245 24 / 213 constant regions of another species, such as antibodies that have variable murine heavy and light chain regions linked to human constant regions.

[0052] Complementary: As used herein, the term complementary refers to the ability of two nucleotides or two sets of nucleotides to pair precisely. In particular, complementary is a term that characterizes an extension of hydrogen bonding that results in bonding between two nucleotides or two sets of nucleotides. For example, if a base at a position in an oligonucleotide is capable of forming a hydrogen bond with a base at the corresponding position in a target nucleic acid (e.g., mRNA), then the bases are considered complementary to each other at that position. Base pairings can include both canonical Watson-Crick base pairing and non-Watson-Crick pairing (e.g., Wobble base pairing and Hoogsteen base pairing).For example, in some embodiments, for complementary base pairs, adenosine (A)-type bases are complementary to thymidine (T)-type bases or uracil (U)-type bases, cytosine (C)-type bases are complementary to guanosine (G)-type bases, and universal bases such as 3-nitropyrrole or 5-nitroindole can hybridize and are considered complementary to any A, C, U, or T. Inosine (I) has also been considered in the technique as a universal base and is considered complementary to any A, C, U, or T.

[0053] Conservative amino acid substitution: As used herein, a conservative amino acid substitution refers to an amino acid substitution that does not alter the relative charge or size characteristics of the protein in which the amino acid substitution is made. Variants may be prepared according to methods for altering the polypeptide sequence known to a person skilled in the art, such as those found in references compiling such methods, by Petition 870250088518, dated 09 / 30 / 2025, p. 38 / 245 25 / 213 example, 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, FM Ausubel, et al., eds., John Wiley & Sons, Inc., New York. Conservative amino acid substitutions 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.

[0054] Cross-reactivity: As used herein and in the context of a targeting agent (e.g., antibody), the term “cross-reactivity” refers to a property of the agent that is capable of specifically binding to more than one antigen of a similar type or class (e.g., multiple homologous, paralogous, or orthologous antigens) with similar affinity or avidity. For example, in some embodiments, an antibody that cross-reacts against human and non-human primate antigens of a similar type or class (e.g., a human TMPRSS6 and a non-human primate TMPRSS6) is capable of binding to the human antigen and the non-human primate antigens with similar affinity or avidity. In some embodiments, an antibody cross-reacts against a human antigen and a rodent antigen of a similar type or class.In some embodiments, an antibody is cross-reactive against a rodent antigen and a non-human primate antigen of a similar type or class. In some embodiments, an antibody is cross-reactive against a human antigen, a non-human primate antigen, and a rodent antigen of a similar type or class.

[0055] Effective Amount: As used herein, “an effective amount” refers to the amount of each active agent (e.g., anti-TMPRSS6 antibody) required to confer a therapeutic effect on the individual, alone or in combination with one or more other active agents. In some embodiments, the effect Petition 870250088518, dated 09 / 30 / 2025, page 39 / 245 26 / 213 therapeutic is the reduction of the level or activity of TMPRSS6, increase in the level or activity of hepcidin, and / or relief of disease conditions (e.g., iron overload in sickle cell disease, thalassemia, hemochromatosis, etc.).

[0056] Framework: As used herein, the term framework region or framework sequence refers to the remaining sequences of a variable region minus the CDRs. Because the exact definition of a CDR sequence can be determined by different systems, the meaning of a framework sequence is subject to different corresponding interpretations. 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) also divide the framework regions in the light and heavy chains into four sub-regions (FR1, FR2, FR3, and FR4) in each chain, where CDR1 is positioned between FR1 and FR2, CDR2 between FR2 and FR3, and CDR3 between FR3 and FR4. Without specifying specific subregions such as FR1, FR2, FR3, or FR4, a structure region, as referred to by others, represents the combined FRs within the variable region of a single natural immunoglobulin chain.As used herein, a FR represents one of four subregions, and FRs represent two or more of the four subregions that constitute a structural region. Human heavy and light chain receptor sequences are known in the art. In one embodiment, receptor sequences known in the art can be used in the antibodies disclosed herein. In some embodiments, the sequences of the disclosed structural regions may vary by up to 20% (e.g., the sequences are approximately 80% (e.g., 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) identical to the disclosed sequence.

[0057] Human antibody: The term human antibody, as used herein, is intended to include antibodies with variable and constant regions derived from immunoglobulin sequences. Petition 870250088518, dated 09 / 30 / 2025, p. 40 / 245 27 / 213 of the human germline. Human antibodies of revelation may include amino acid residues not encoded by immunoglobulin sequences of the human germline (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo), for example in CDRs and in particular in 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, have been grafted onto human structural sequences.

[0058] Humanized antibody: The term humanized antibody refers to antibodies comprising variable region heavy and light chain sequences from a non-human species (e.g., a mouse), but in which at least a portion of the VH and / or VL sequence has been altered to be more human-like, i.e., more similar to the variable sequences of the human germline. One type of humanized antibody is a CDR-grafted antibody, in which human CDR sequences are introduced into non-human VH and VL sequences to replace the corresponding non-human CDR sequences. In one embodiment, humanized anti-TMPRSS6 antibodies and antigen-binding moieties are provided. Such antibodies can be generated by obtaining murine anti-TMPRSS6 monoclonal antibodies using traditional hybridoma technology followed by humanization using in vitro genetic engineering, such as those disclosed in PCT publication No. WO 2005 / 123126 A2 by Kasaian et al.

[0059] Humanized antibodies are human immunoglobulins (receptor antibody) in which residues of a complementarity-determining region (CDR) of the receptor are replaced by residues of a CDR from a non-human species (donor antibody), such as mouse, rat, or rabbit, with the desired specificity, affinity, and capacity. In some Petition 870250088518, dated 09 / 30 / 2025, page 41 / 245 In 28 / 213 embodiments, residues of the Fv (FR) structural region of human immunoglobulin are replaced by corresponding non-human residues. In addition, the humanized antibody may comprise residues that are not found in either the recipient antibody or the imported CDR or structural sequences, but are included to further refine and optimize antibody performance. In general, the humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all CDR regions correspond to those of a non-human immunoglobulin and all or substantially all FR regions are those of a human immunoglobulin consensus sequence. The humanized antibody will also ideally comprise at least a portion of a constant region or immunoglobulin (Fc) domain, typically that of a human immunoglobulin.Antibodies may have modified Fc regions as described in WO 99 / 58572. Other forms of humanized antibodies have one or more CDRs (one, two, three, four, five, six) that are altered relative to the original antibody, which are also termed one or more CDRs derived from one or more CDRs of the original antibody. Humanized antibodies may also involve affinity maturation.

[0060] In some embodiments, humanization is achieved by grafting CDRs (e.g., as shown in Table 2) onto human variable domains (e.g., human variable domain IGKV1-NL1*01 and IGHV1-3*01). In some embodiments, the present disclosure anti-TMPRSS6 antibody is a humanized variant comprising one or more amino acid substitutions (e.g., in the VH structural region) compared to any of the VHs listed in Table 2, and / or one or more amino acid substitutions (e.g., in the VL structural region) compared to any of the VLs listed in Table 2. Petition 870250088518, dated 09 / 30 / 2025, page 42 / 245 29 / 213

[0061] Isolated antibody: An isolated antibody, as used herein, refers to an antibody that is substantially free of other antibodies with different antigenic specificities (for example, an isolated antibody that specifically binds to TMPRSS6 is substantially free of antibodies that specifically bind to antigens other than TMPRSS6). An isolated antibody that specifically binds to TMPRSS6 may, however, have cross-reactivity with other antigens. In addition, an isolated antibody may be substantially free of other cellular materials and / or chemicals.

[0062] Kabat Numbering: The terms Kabat numbering, Kabat definitions, and Kabat labeling are used interchangeably herein. These terms, which are recognized in the art, refer to a numbering system for amino acid residues that are more variable (i.e., hypervariable) than other amino acid residues in the variable regions of the heavy and light chains of an antibody, or an antigen-binding portion thereof (Kabat et al. (1971) Ann. NY Acad. Sci. 190:382-391 and, Kabat, EA, et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, US Department of Health and Human Services, NIH Publication No. 91-3242). For the variable region of the heavy chain, the hypervariable region ranges from amino acid positions 31 to 35 for CDR1, amino acid positions 50 to 65 for CDR2, and amino acid positions 95 to 102 for CDR3.For the variable region of the light chain, the hypervariable region ranges from amino acid positions 24 to 34 for CDR1, amino acid positions 50 to 56 for CDR2, and amino acid positions 89 to 97 for CDR3.

[0063] Sequence Identity Percentage (%): The terms “Sequence Identity Percentage (%)”, “identity percentage (%)” and “identity percentage (%) with respect to” with respect to a reference polypeptide (or nucleotide) sequence are defined as the percentage of residues of Petition 870250088518, dated 09 / 30 / 2025, page 43 / 245 30 / 213 amino acids (or nucleic acids) in a candidate sequence that are identical to the amino acid (or nucleic acid) residues in the reference polypeptide (or nucleotide) sequence, after sequence alignment and the introduction of gaps, if necessary, to achieve maximum sequence identity percent, and not considering any conservative substitutions as part of the sequence identity. Alignment for the purpose of determining sequence identity percent can be achieved in several ways that are within the art, for example, using publicly available computer software such as BLAST, BLAST-2, ALIGN, or Megalign (DNASTAR). Those skilled in the art can determine appropriate parameters for aligning sequences, including any algorithms necessary to achieve maximum alignment across the entire length of the sequences being compared.For the purposes described herein, however, the amino acid (or nucleic acid) sequence identity % values ​​are generated using the ALIGN-2 sequence comparison computer program. The ALIGN-2 sequence comparison computer program was created by Genentech, Inc., and the source code is filed with the user documentation at the US Copyright Office, Washington DC, 20559, where it is registered under US copyright registration number TXU510087. The ALIGN-2 program is publicly available from Genentech, Inc., South San Francisco, California, or can be compiled from the source code. The ALIGN-2 program must be compiled for use on a UNIX operating system, including Digital UNIX V4.0D. All sequence comparison parameters are defined by the ALIGN-2 program and do not vary.

[0064] Recombinant antibody: The term recombinant antibody, as used herein, is intended to include all antibodies that are prepared, expressed, created or isolated by recombinant means, such as antibodies expressed using a Petition 870250088518, dated 09 / 30 / 2025, page 44 / 245 31 / 213 recombinant expression vector transfected into a host cell (described in more detail in this disclosure), including, for example, antibodies isolated from a recombinant combinatorial human antibody library (Hoogenboom HR, (1997) TIB Tech. 15:62-70; Azzazy H. and Highsmith WE, (2002) Clin. Portuguese Biochem. 35:425-445; Gavilondo JV, and Larrick JW (2002) BioTechniques 29: 128-145; Hoogenboom H., and Chames P. (2000) Immunology Today 21: 371-378), antibodies isolated from an animal (e.g., a mouse) that is transgenic for human immunoglobulin genes (see, for example, Taylor, LD, et al. (1992) Nucl. Acids Res. 20: 6287-6295; Kellermann SA., and Green LL (2002) Current Opinion in Biotechnology 13:593-597; Little M. et al (2000) Immunology Today 21:364-370) or antibodies prepared, expressed, created, or isolated by any other means involving the splicing of human immunoglobulin gene sequences to other DNA sequences. In some embodiments, recombinant human antibodies are provided herein. In certain embodiments, such recombinant human antibodies have variable and constant regions derived from immunoglobulin sequences of the human germline lineage.In certain embodiments, however, such recombinant human antibodies are subjected to in vitro mutagenesis (or, when a transgenic animal for human Ig sequences is used, to in vivo somatic mutagenesis) and thus the amino acid sequences of the VH and VL regions of the recombinant antibodies are sequences that, although derived from and related to the VH and VL sequences of the human germline, may not naturally exist within the repertoire of the human germline antibody in vivo. One embodiment of the development provides fully human antibodies capable of binding to human TMPRSS6 that can be generated using well-known techniques in the art, such as, but not limited to, using human Ig phage libraries, such as those. Petition 870250088518, dated 09 / 30 / 2025, page 45 / 245 32 / 213 revealed in Jermutus et al., PCT publication No. WO 2005 / 007699 A2.

[0065] Selective: As used herein, the term selective or selectively refers to the ability of a molecule to produce an effect (e.g., inhibit, antagonize, agonize, etc.) with respect to its target molecule compared to a reference molecule. For example, a molecule that selectively inhibits its target molecule means that this molecule is able to inhibit its target molecule to a degree that is distinguishable from a reference molecule in an inhibition assay or other inhibitory context. For example, with respect to an inhibitor, the term selectively inhibits refers to the inhibitor's ability to inhibit its target molecule to a degree that is distinguishable from a reference molecule that is not substantially inhibited in an inhibition assay, for example, to an extent that allows selective inhibition of the target molecule as described herein. Once the reaction is complete, the signal produced by the inhibition of the target molecule can be measured.The maximum concentration of the inhibitor for the target molecule and the reference molecule can be calculated. In some embodiments, a molecule described herein selectively binds to a target molecule. In some embodiments, a molecule described herein selectively inhibits a target molecule. In some embodiments, a molecule described herein selectively antagonizes a target molecule.

[0066] Binds specifically: As used herein, the term binds specifically refers to the ability of a molecule to bind to a binding partner with a degree of affinity or avidity that allows the molecule to be used to distinguish the binding partner from an appropriate control in a binding assay or other binding context. With respect to an antibody, the term binds specifically refers to the antibody's ability to bind to a specific antigen with Petition 870250088518, dated 09 / 30 / 2025, p. 46 / 245 33 / 213 a degree of affinity or avidity, compared to one or more appropriate reference antigens, which allows the antibody to be used to distinguish the specific antigen from others, as described herein. In some embodiments, an antibody specifically binds to a target if the antibody has a Kd for target binding 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. In some embodiments, an antibody specifically binds to TMPRSS6.

[0067] Individual: As used herein, the term “individual” refers to a mammal. In some embodiments, the individual is a non-human primate or a rodent. In some embodiments, the individual is a human. In some embodiments, an individual is a patient, for example, a human patient who has or is suspected of having a disease. In some embodiments, the individual is a human patient who has or is suspected of having iron overload and / or one or more conditions resulting from iron overload.

[0068] Treatment: As used herein, the term “treat,” “treated,” “treating,” or “treatment” refers to the application or administration of a composition including one or more active agents (e.g., anti-TMPRSS6 antibodies) to an individual who has a target disease or disorder, a symptom of the disease / disorder, or a predisposition to the disease / disorder, for the purpose of curing, healing, attenuating, relieving, altering, remedying, improving, enhancing, or affecting the disorder, the symptom of the disease, or the predisposition to the disease or disorder. Relieving a target disease / disorder includes delaying or preventing the onset, development, or progression of the disease, or reducing the severity of the disease. In some embodiments, the target disease or disorder of the present disclosure includes, but is not limited to, hemochromatosis, sickle cell disease (SCD), thalassemia, hemolysis, Petition 870250088518, dated 09 / 30 / 2025, p. 47 / 245 34 / 213 African iron overload, Diamond-Blackfan anemia, myelodysplastic syndrome (MDS), and blood transfusion. II. Anti-TMPRSS6 antibodies

[0069] In some embodiments, the anti-TMPRSS6 antibody is a specific antibody for TMPRSS6. Antibodies that bind to human TMPRSS6 with high specificity and affinity are provided herein in some aspects. In some embodiments, the anti-TMPRSS6 antibody described herein binds specifically to any extracellular epitope of a TMPRSS6 or to an epitope that is exposed to an antibody. In some embodiments, the anti-TMPRSS6 antibodies provided herein bind specifically to TMPRSS6 from humans, non-human primates, mice, rats, etc. In some embodiments, the anti-TMPRSS6 antibodies provided herein bind to human TMPRSS6. In some embodiments, the anti-TMPRSS6 antibody described herein binds to an amino acid segment of a human or non-human primate TMPRSS6. In some embodiments, the anti-TMPRSS6 antibody described herein binds specifically to an epitope in human TMPRSS6.

[0070] TMPRSS6, also called Matriptase-2, is a serine protease of the type II transmembrane serine protease (TTSP) family. Enzymes in this family share common structural features, including a serine protease domain, a stem region of variable length comprising a mosaic of structural domains, and a short cytoplasmic tail (Hooper et al., Type II transmembrane serine proteases: Insights into an emerging class of cell surface proteolytic enzymes. J Biol Chem. (2001; 276:857-60). The TTSP protease family comprises several subfamilies, including the matriptase subfamily, which comprises TMPRSS 2-5. TMPRSS6, to which antibodies in some embodiments of the present disclosure specifically bind, is highly conserved across mammalian species. In some embodiments, antibodies in the present disclosure specifically bind to a TMPRSS6 protein encoded by a Petition 870250088518, dated 09 / 30 / 2025, page 48 / 24535 / 213 human TMPRSS6 gene (e.g., GenBank: AAH39082.1, e.g., NCBI Gene ID: 164656). In some embodiments, the antibodies of the present disclosure bind specifically to a TMPRSS6 protein encoded by a mouse TMPRSS6 gene (e.g., GenBank: AAH57674.1, e.g., NCBI Gene ID: 71753). In other embodiments, the antibodies of the present disclosure bind specifically to a TMPRSS6 protein encoded by a non-human primate TMPRSS6 gene (e.g., cynomolgus macaque (i.e., Macaca fascicularis), e.g., NCBI gene ID: 102139590). The TMPRSS6 gene spans 18 exons with 17 intervening introns, with the boundaries of the matriptase-2 protein domain corresponding to the intron / exon junctions of the encoding gene in all species.Structurally, matriptase-2 comprises canonical features of TTSP, such as a short cytoplasmic amino-terminal tail, a transmembrane region, a stem region containing two complement protein subcomponents (C1r / C1s domains, hedgehog embryonic growth factor, and bone morphogenetic protein 1 (CUB)) and three class A low-density lipoprotein receptor (LDLR) domains, as well as a trypsin-like serine protease domain at the carboxy-terminal. All these structural features are rigorously conserved in humans, monkeys, dogs, cows, mice, and rats, with the human protein sharing 95.6%, 91.1%, 85.6%, 80.1%, and... 80.4% identity, respectively, with matriptase-2 of these species (Ramsay et al., The type II transmembrane serine protease matriptase-2—identification, structural characteristics, enzymology, expression pattern and potential roles. Front Biosci. (2008; 13:259-79).

[0071] The proteolytic domain of matriptase-2 comprises a serine protease triad of H, D, and S residues required for catalytic activity, and an SWG motif predicted to be located at the top of the S1 binding pocket of the substrate, Petition 870250088518, dated 09 / 30 / 2025, page 49 / 245 36 / 213 positioning the cleavable substrate bond in the correct orientation. Proteolytic activation of matriptase-2 is predicted to occur within a motif (RIVGG (SEQ ID NO: 80)) at the junction of the pro- and catalytic domains, which is characteristic of serine proteases and conserved across species (Velasco et al., Matriptase-2, a membrane-bound mosaic serine proteinase predominantly expressed in human liver and showing degrading activity against extracellular matrix proteins. J Biol Chem. (2002; 277:37637-46). In human and adult mouse tissues, the main site of matriptase-2 mRNA expression is the liver. Specifically, matriptase-2 mRNA expression has been shown to be restricted to liver hepatocytes.

[0072] Functionally, matriptase-2 acts by cleaving hemojuvelin (HJV), a protein essential in the iron regulation process through its positive regulation of hepcidin expression. Hepcidin is a known negative regulator of iron absorption, release, and recycling. In the absence of matriptase-2, HJV levels increase, leading to increased hepcidin levels and, consequently, inhibition of iron transport. The establishment of matriptase-2 as an essential component of iron homeostasis was based on phenotypes of iron-refractory iron deficiency anemia in human patients with loss-of-function mutations in TMPRSS6 (Cui et al., Iron-refractory iron deficiency anemia: new molecular mechanisms. Kidney Int. 2009; 76(11):1137-1141). Thus, in some embodiments, the antibodies of the present discovery inhibit matriptase-2 activity to regulate iron homeostasis.In some embodiments, the antibodies of the present disclosure inhibit matriptase-2 activity to decrease iron transport by increasing hepcidin activity.

[0073] In some embodiments, the anti-TMPRSS6 antibody described herein can bind to a fragment of a human TMPRSS6. The TMPRSS6 fragment can be between about 5 and about 425 Petition 870250088518, dated 09 / 30 / 2025, p. 50 / 245 37 / 213 amino acids, between about 10 and about 400 amino acids, between about 50 and about 350 amino acids, between about 100 and about 300 amino acids, between about 150 and about 250 amino acids, between about 200 and about 300 amino acids, or between about 75 and about 150 amino acids in length. In some embodiments, the fragment may comprise a contiguous number of TMPRSS6 amino acids. In other embodiments, the fragment may comprise a non-contiguous number of TMPRSS6 amino acids.

[0074] In some embodiments, the anti-TMPRSS6 antibodies disclosed herein bind specifically to mouse TMPRSS6. In some embodiments, the anti-TMPRSS6 antibodies disclosed herein bind specifically to rat TMPRSS6. In some embodiments, the anti-TMPRSS6 antibodies disclosed herein bind specifically to non-human primate TMPRSS6 (e.g., cynomolgus monkey, rhesus monkey, African green monkey, vervet monkey, squirrel monkey, night monkey, pig-tailed macaque, or baboon TMPRSS6). In some embodiments, the anti-TMPRSS6 antibodies disclosed herein bind specifically to human TMPRSS6.

[0075] In some embodiments, the anti-TMPRSS6 antibodies described herein are affinity-matured clones. In some embodiments, an anti-TMPRSS6 antibody specifically binds to a TMPRSS6 (e.g., a human or non-human primate TMPRSS6) with binding affinity (e.g., as indicated by Kd) of at least about 10⁻⁴M, 10⁻⁵M, 10⁻⁶M, 10⁻⁷M, 8⁻⁷M, 6⁻⁷M, 4⁻⁷M, 2⁻⁷M, 10⁻⁸M, 8⁻⁸M, 6⁻⁸M, 4⁻⁸M, 2⁻⁸M, 10⁻⁹M, 10⁻¹⁰M, 10⁻¹¹M, 10⁻¹²M, 10⁻¹³M or less. For example, the anti-TMPRSS6 antibodies of the present discovery can bind to a TMPRSS6 protein (e.g., human TMPRSS6) with an affinity between 5 pM and 750 nM, for example, between 1 nM and 500 nM, for example, between 10 nM and 450 nM, for example, between 50 pM and 100 nM, for example, between 500 pM and 50 nM. The discovery also Petition 870250088518, dated 09 / 30 / 2025, p. 51 / 245 38 / 213 includes antibodies that compete with any of the antibodies described herein for binding to a TMPRSS6 protein (e.g., human TMPRSS6) and that have an affinity of 500 nM or less (e.g., 400 nM or less, 100 nM or less, 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). In some embodiments, the anti-TMPRSS6 antibodies described herein bind to TMPRSS6 with a KD of subnanomolar range.

[0076] The affinity and binding kinetics of anti-TMPRSS6 antibody can be tested using any suitable method, for example, binding affinity (or binding specificity) can be determined by a variety of methods, including but not limited to, biosensor technology (e.g., OCTET or BIACORE), equilibrium dialysis, equilibrium binding, gel filtration, ELISA, surface plasmon resonance (SPR), fluorescence-activated cell sorting (FACS), or spectroscopy (e.g., using a fluorescence assay). Exemplary conditions for assessing 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 bound proteins as a function of the target protein concentration. The concentration of bound protein ([[Bound]]) is generally related to the concentration of free target protein ([[Free]]) by the following equation: [[Limited]] = [[Free]] / (Kd+[[Free]])

[0077] It is not always necessary to make an exact determination of KA, as sometimes it is sufficient to obtain a quantitative measure of affinity, for example, determined using a method such as ELISA or FACS analysis, which is proportional to KA and therefore can be used for comparisons, such as determining whether a higher affinity is, for example, 2 times greater, to obtain a measure Petition 870250088518, dated 09 / 30 / 2025, page 52 / 245 39 / 213 qualitative affinity or to obtain an inference of affinity, for example, by activity in a functional assay, for example, an in vitro or in vivo assay.

[0078] The heavy chain (HC) and light chain (LC) sequences, heavy chain variable domain (VH) and light chain variable domain (VL), CDR sequences, and heavy chain and light chain constant region sequences of non-limiting examples of anti-TMPRSS6 antibodies are provided in Table 2. Table 2. Examples of anti-TMPRSS6 antibodies (CDRs according to Kabat's definition) TMPRSS6 Antibody Sequence SEQ ID NO A1 HC CDR1 GYTFTSYW 1 HC CDR2 IYPGSGST 2 HC CDR3 APYDSDYAMDY 3 LC CDR1 QDINNY 4 LC CDR2 RAN N / A LC CDR3 LQYDEFPLT 6 VH QVQLQQPGAELAKPGASVKMSCKASGYT FTSYWITWVKQRPGQDLEWIGNIYPGSG STYYNEKFKSKATLTVDTSSRTAYMQLS SLTSADSAVYYCAPYDSDYAMDYWGQGT SVTVSS 7 VL DIKMTQSPSSMYASLGERVTITCKASQD INNYLSWFQQKPGKSPKTLIYRANRLVD GVPSRVSGSGSGQDYSLTISSLEYEDVG IYFCLQYDEFPLTFGAGTKLELK 8 Constant Region HC AKTTAPSVYPLAPVCGDTTGSSVTLGCL VKGYFPEPVTLTWNSGSLSSGVHTFPAV LQSDLYTLSSSVTVTSSTWPSQSITCNV AHPASSTKVDKKIEPRGPTIKPCPPCKC PAPNLLGGPSVFIFPPKIKDVLMISLSP IVTCVVVDVSEDDPDVQISWFVNNVEVH 9 Petition 870250088518, dated 09 / 30 / 2025, page 53 / 245 40 / 213 TMPRSS6 Antibody Sequence SEQ ID NO Constant Region LC RADAAPTVSIFPPSSEQLTSGGASVVCF LNNFYPKDINVKWKIDGSERQNGVLNSW TDQDSKDSTYSMSSTLTLTKDEYERHNS YTCEATHKTSTSPIVKSFNRNEC 10 Heavy Chain QVQLQQPGAELAKPGASVKMSCKASGYT 11 FTSYWITWVKQRPGQDLEWIGNIYPGSG STYYNEKFKSKATLTVDTSSRTAYMQLS SLTSADSAVYYCAPYDSDYAMDYWGQGT SVTVSSAKTTAPSVYPLAPVCGDTTGSS VTLGCLVKGYFPEPVTLTWNSGSLSSGV HTFPAVLQSDLYTLSSSVTVTSSTWPSQ SITCNVAHPASSTKVDKKIEPRGPTIKP CPPCKCPAPNLLGGPSVFIFPPKIKDVL MISLSPIVTCVVVDVSEDDPDVQISWFV NNVEVHTAQTQTHREDYNSTLRVVSALP IQHQDWMSGKEFKCKVNNKDLPAPIERT ISKPKGSVRAPQVYVLPPPEEEMTKKQV TLTCMVTDFMPEDIYVEWTNNGKTELNY KNTEPVLDSDGSYFMYSKLRVEKKNWVE RNSYSCSVVHEGLHNHHTTKSFSRTPG Light Chain DIKMTQSPSSMYASLGERVTITCKASQD 12 INNYLSWFQQKPGKSPKTLIYRANRLVD GVPSRVSGSGSGQDYSLTISSLEYEDVG IYFCLQYDEFPLTFGAGTKLELKRADAA PTVSIFPPSSEQLTSGGASVVCFLNNFY PKDINVKWKIDGSERQNGVLNSWTDQDS KDSTYSMSSTLTLTKDEYERHNSYTCEA THKTSTSPIVKSFNRNEC B1 HC CDR1 GFNIKDYY 13 HC CDR2 IDPEDGES 14 HC CDR3 TRGDSMMVTYFDY 15 LC CDR1 QDVSTA 16 LC CDR2 WAF N / A LCCDR3 QQHYRSPWT 18 — VH EVQLQQSGAELVKPGASVKLSCTASGFN IKDYYIHWVKERTEQGLEWFGRIDPEDG ESEYAPKFQGKATLTADTSSNTAYLQLS SLTSEDTAVYYCTRGDSMMVTYFDYWGQ GTTLTVSSE 19 VH EVQLQQSGAELVKPGASVKLSCTASGFN IKDYYIHWVKERTEQGLEWFGRIDPEDG 78 Petition 870250088518, dated 09 / 30 / 2025, page 54 / 245 41 / 213 TMPRSS6 Antibody Sequence SEQ ID NO ESEYAPKFQGKATLTADTSSNTAYLQLS SLTSEDTAVYYCTRGDSMMVTYFDYWGQ GTTLTVSS VL DIVMTQSHKFMSTSVGDRVSITCKASQD VSTAVAWYQQKPGQSPKLLIYWAFTRHT GVPDRFTSTGSGTDYALTISSVQAEDLA LYYCQQHYRSPWTFGGGTKLEIK 20 Constant Region HC KTTPPSVYPLAPGCGDTTGSSVTLGCLV KGYFPESVTVTWNSGSLSSSVHTFPALL QSGLYTMSSSVTVPSSTWPSQTVTCSVA HPASSTTVDKKLEPSGPISTINPCPPCK ECHKCPAPNLEGGPSVFIFPPNIKDVLM ISLTPKVTCVVVDVSEDDPDVQISWFVN NVEVHTAQTQTHREDYNSTIRVVSTLPI QHQDWMSGKEFKCKVNNKDLPSPIERTI SKIKGLVRAPQVYILPPPAEQLSRKDVS LTCLVVGFNPGDISVEWTSNGHTEENYK DTAPVLDSDGSYFIYSKLNMKTSKWEKT DSFSCNVRHEGLKNYYLKKTISRSPGK 21 Constant Region LC RADAAPTVSIFPPSSEQLTSGGASVVCF LNNFYPKDINVKWKIDGSERQNGVLNSW TDQDSKDSTYSMSSTLTLTKDEYERHNS YTCEATHKTSTSPIVKSFNRNEC 10 Heavy Chain EVQLQQSGAELVKPGASVKLSCTASGFN 17 IKDYYIHWVKERTEQGLEWFGRIDPEDG ESEYAPKFQGKATLTADTSSNTAYLQLS SLTSEDTAVYYCTRGDSMMVTYFDYWGQ GTTLTVSSEKTTPPSVYPLAPGCGDTTG SSVTLGCLVKGYFPESVTVTWNSGSLSS SVHTFPALLQSGLYTMSSSVTVPSSTWP SQTVTCSVAHPASSTTVDKKLEPSGPISTINPCPPCKECHKCPAPNLEGGPSVFIF PPNIKDVLMISLTPKVTCVVVDVSEDDP DVQISWFVNNVEVHTAQTQTHREDYNST IRVVSTLPIQHQDWMSGKEFKCKVNNKD LPSPIERTISKIKGLVRAPQVYILPPPA EQLSRKDVSLTCLVVGFNPGDISVEWTS NGHTEENYKDTAPVLDSDGSYFIYSKLN MKTSKWEKTDFSCNVRHEGLKNYYLKK TISRSPGK Petition 870250088518, dated 09 / 30 / 2025, page 55 / 245 42 / 213 Anticorpo da TMPRSS6 Sequência SEQ ID NO Cadeia Pesada EVQLQQSGAELVKPGASVKLSCTASGFN 22 IKDYYIHWVKERTEQGLEWFGRIDPEDG ESEYAPKFQGKATLTADTSSNTAYLQLS SLTSEDTAVYYCTRGDSMMVTYFDYWGQ GTTLTVSSKTTPPSVYPLAPGCGDTTGS SVTLGCLVKGYFPESVTVTWNSGSLSSS VHTFPALLQSGLYTMSSSVTVPSSTWPS QTVTCSVAHPASSTTVDKKLEPSGPIST INPCPPCKECHKCPAPNLEGGPSVFIFP PNIKDVLMISLTPKVTCVVVDVSEDDPD VQISWFVNNVEVHTAQTQTHREDYNSTI RVVSTLPIQHQDWMSGKEFKCKVNNKDL PSPIERTISKIKGLVRAPQVYILPPPAE QLSRKDVSLTCLVVGFNPGDISVEWTSN GHTEENYKDTAPVLDSDGSYFIYSKLNM KTSKWEKTDSFSCNVRHEGLKNYYLKKT ISRSPGK Cadeia Leave DIVMTQSHKFMSTSVGDRVSITCKASQD 23 VSTAVAWYQQKPGQSPKLLIYWAFTRHT GVPDRFTSTGSGTDYALTISSVQAEDLA LYYCQQHYRSPWTFGGGTKLEIKRADAA PTVSIFPPSSEQLTSGGASVVCFLNNFY PKDINVKWKIDGSERQNGVLNSWTDQDS KDSTYSMSSTLTLTKDEYERHNSYTCEA THKTSTSPIVKSFNRNEC C1 HC CDR1 GFNIEDYY 24 HC CDR2 IDPEDGET 25 HC CDR3 ARSIYLDPMDY 26 LC CDR1 QDVTTA 27 LC CDR2 WAT N / A LC CDR3 QQHYSTPYT 29 VH EVQLQQSGAELVKPGASVKLSCTASGFN IEDYYIHWVKERTEQGLEWIGRIDPEDG ettyapqfqgkatiipdtssntaymqlsSLTSEDAAVYYCARSIYLDPMDYWGQGT SVTVSS 30 VL DIVMTQSHKFMSTSVGDRVSITCKASQD VTTAVAWYQQKPGQSPKILIYWATTRHT GVPDRFTGSISGTTYILTISSVQAEDLA LYYCQQHYSTPYTFGGGTKLEIK 31 Petition 870250088518, dated 09 / 30 / 2025, page 56 / 245 43 / 213 TMPRSS6 Antibody Sequence SEQ ID NO Constant Region HC KTTPPSVYPLAPGCGDTTGSSVTLGCLV KGYFPESVTVTWNSGSLSSSVHTFPALL QSGLYTMSSSVTVPSSTWPSQTVTCSVA HPASSTTVDKKLEPSGPISTINPCPPCK ECHKCPAPNLEGGPSVFIFPPNIKDVLM ISLTPKVTCVVVDVSEDDPDVQISWFVN NVEVHTAQTQTHREDYNSTIRVVSTLPI QHQDWMSGKEFKCKVNNKDLPSPIERTI SKIKGLVRAPQVYILPPPAEQLSRKDVS LTCLVVGFNPGDISVEWTSNGHTEENYK DTAPVLDSDGSYFIYSKLNMKTSKWEKT DSFSCNVRHEGLKNYYLKKTISRSPGK 21 Constant Region LC RADAAPTVSIFPPSSEQLTSGGASVVCF LNNFYPKDINVKWKIDGSERQNGVLNSW TDQDSKDSTYSMSSTLTLTKDEYERHNS YTCEATHKTSTSPIVKSFNRNEC 10 Heavy Chain EVQLQQSGAELVKPGASVKLSCTASGFN 33 IEDYYIHWVKERTEQGLEWIGRIDPEDG ETTYAPQFQGKATIIPDTSSNTAYMQLS SLTSEDAAVYYCARSIYLDPMDYWGQGT SVTVSSKTTPPSVYPLAPGCGDTTGSSV TLGCLVKGYFPESVTVTWNSGSLSSSVH TFPALLQSGLYTMSSSVTVPSSTWPSQT VTCSVAHPASSTTVDKKLEPSGPISTIN PCPPCKECHKCPAPNLEGGPSVFIFPPN IKDVLMISLTPKVTCVVVDVSEDDPDVQ ISWFVNNVEVHTAQTQTHREDYNSTIRV VSTLPIQHQDWMSGKEFKCKVNNKDLPS PIERTISKIKGLVRAPQVYILPPPAEQL SRKDVSLTCLVVGFNPGDISVEWTSNGH TEENYKDTAPVLDSDGSYFIYSKLNMKTSKWEKTDSFSCNVRHEGLKNYYLKKTIS RSPGK Light Chain DIVMTQSHKFMSTSVGDRVSITCKASQD 34 VTTAVAWYQQKPGQSPKILIYWATTRHT GVPDRFTGSISGTTYILTISSVQAEDLA LYYCQQHYSTPYTFGGGTKLEIKRADAA PTVSIFPPSSEQLTSGGASVVCFLNNFY PKDINVKWKIDGSERQNGVLNSWTDQDS KDSTYSMSSTLTLTKDEYERHNSYTCEA THKTSTSPIVKSFNRNEC Petition 870250088518, dated 09 / 30 / 2025, page 57 / 245 44 / 213 Anticorpo da TMPRSS6 Sequência SEQ ID NO A2 HC CDR1 GYTFTSYW 1 HC CDR2 IYPGSGST 2 HC CDR3 APYDADYAMDY 35 LC CDR1 QDISNY 36 LC CDR2 RAN N / A LC CDR3 LQYDEFPLT 6 VH EVQLVQSGAEVKKPGASVKVSCKASGYT FTSYWITWVRQAPGQRLEWIGNIYPGSG STYYNEKFKSKATITRDTSSRTAYMELS SLRSEDTAVYYCAPYDADYAMDYWGQGT LVTVSS 37 VL DIQMTQSPSSLSASVGDRVTITCKASQD ISNYLSWFQQKPGKAPKLLIYRANRLVE GVPSRFSGSGSGTDFTLTISSLQPEDFA TYFCLQYDEFPLTFGGGTKVEIK 38 Região Constante HC ASTKGPSVFPLAPSSKSTSGGTAALGCL VKDYFPEPVTVSWNSGALTSGVHTFPAV LQSSGLYSLSSVVTVPSSSLGTQTYICN VNHKPSNTKVDKKVEPKSCDKTHTCPPC PAPELLGGPSVFLFPPKPKDTLMISRTP EVTCVVVDVSHEDPEVKFNWYVDGVEVH NAKTKPREEQYASTYRVVSVLTVLHQDW LNGKEYKCKVSNKALPAPIEKTISKAKG QPREPQVYTLPPSRDELTKNQVSLTCLV KGFYPSDIAVEWESNGQPENNYKTTPPV LDSDGSFFLYSKLTVDKSRWQQGNVFSC SVMHEALHNHYTQKSLSLSPG 39 Região constante LC RTVAAPSVFIFFPPSDEQLKSGTASVVCL LNNFYPREAKVQWKVDNALQSGNSQESV TEQDSKDSTYSLSSTLTLSKADYEKHKV YACEVTHQGLSSPVTKSFNRGEC 40 Cadeia Pesada EVQLVQSGAEVKKPGASVKVSCKASGYT 41 FTSYWITWVRQAPGQRLEWIGNIYPGSGSTYYNEKFKSKATITRDTSSRTAYMELS SLRSEDTAVYYCAPYDADYAMDYWGQGT LVTVSSASTKGPSVFPLAPSSKSTSGGT AALGCLVKDYFPEPVTVSWNSGALTSGV HTFPAVLQSSGLYSLSSVVTVPSSSLGT QTYICNVNHKPSNTKVDKKVEPKSCDKT HTCPPCPAPELLGGPSVFLFPPKPKDTL MISRTPEVTCVVVDVSHEDPEVKFNWYV Petition 870250088518, dated 09 / 30 / 2025, page 58 / 245 45 / 213 Anticorpo da TMPRSS6 Sequência SEQ ID NO DGVEVHNAKTKPREEQYASTYRVVSVLT VLHQDWLNGKEYKCKVSNKALPAPIEKT ISKAKGQPREPQVYTLPPSRDELTKNQV SLTCLVKGFYPSDIAVEWESNGQPENNY KTTPPVLDSDGSFFLYSKLTVDKSRWQQ GNVFSCSVMHEALHNHYTQKSLSLSPG Cadeia Leave DIQMTQSPSSLSASVGDRVTITCKASQD 42 ISNYLSWFQQKPGKAPKLLIYRANRLVE GVPSRFSGSGSGTDFTLTISSLQPEDFA TYFCLQYDEFPLTFGGGTKVEIKRTVAA PSVFIFPPSDEQLKSGTASVVCLLNNFY PREAKVQWKVDNALQSGNSQESVTEQDS KDSTYSLSSTLTLSKADYEKHKVYACEV THQGLSSPVTKSFNRGEC B2 HC CDR1 GFNIKDYY 13 HC CDR2 IDPEDAES 43 HC CDR3 TRGDSMMVTYFDY 15 LC CDR1 QDVSTA 16 LC CDR2 WAF N / A LC CDR3 QQHYRSPWT 18 VH EVQLVQSGAEVKKPGASVKVSCKASGFN IKDYYIHWVRQATGQGLEWMGRIDPEDA ESEYAPKFQGRVTITADTSTDTAYMELS SLRSEDTAVYYCTRGDSMMVTYFDYWGQ GTLVTVSS 44 VL DIQMTQSPSSLSASVGDRVTITCKASQD VSTAVAWYQQKPGKAPKLLIYWAFTRHT GVPSRFSGSGSGTDYALTISSLQPEDFA TYYCQQHYRSPWT FGGGTKVEIK 45 Região Constante HC ASTKGPSVFPLAPSSKSTSGGTAALGCL VKDYFPEPVTVSWNSGALTSGVHTFPAV LQSSGLYSLSSVVTVPSSSLGTQTYICN VNHKPSNTKVDKKVEPKSCDKTHTCPPC PAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVH NAKTKPREEQYASTYRVVSVLTVLHQDW LNGKEYKCKVSNKALPAPIEKTISKAKG QPREPQVYTLPPSRDELTKNQVSLTCLV KGFYPSDIAVEWESNGQPENNYKTTPPV LDSDGSFLYSKLTVDKSRWQQGNVFSC SVMHEALHNHYTQKSLSLSPG 39 Petition 870250088518, dated 09 / 30 / 2025, page 59 / 245 46 / 213 Anticorpo da TMPRSS6 Sequência SEQ ID NO Região constante LC RTVAAPSVFIFPPSDEQLKSGTASVVCL LNNFYPREAKVQWKVDNALQSGNSQESV TEQDSKDSTYSLSSTLTLSKADYEKHKV YACEVTHQGLSSPVTKSFNRGEC 40 Cadeia Pesada EVQLVQSGAEVKKPGASVKVSCKASGFN 46 IKDYYIHWVRQATGQGLEWMGRIDPEDA ESEYAPKFQGRVTITADTSTDTAYMELS SLRSEDTAVYYCTRGDSMMVTYFDYWGQ GTLVTVSSASTKGPSVFPLAPSSKSTSG GTAALGCLVKDYFPEPVTVSWNSGALTS GVHTFPAVLQSSGLYSLSSVVTVPSSSL GTQTYICNVNHKPSNTKVDKKVEPKSCD KTHTCPPCPAPELLGGPSVFLFPPKPKD TLMISRTPEVTCVVVDVSHEDPEVKFNW YVDGVEVHNAKTKPREEQYASTYRVVSV LTVLHQDWLNGKEYKCKVSNKALPAPIE KTISKAKGQPREPQVYTLPPSRDELTKN QVSLTCLVKGFYPSDIAVEWESNGQPEN NYKTTPPVLDSDGSFFLYSKLTVDKSRW QQGNVFSCSVMHEALHNHYTQKSLSLSP G Cadeia Leve DIQMTQSPSSLSASVGDRVTITCKASQD 47 VSTAVAWYQQKPGKAPKLLIYWAFTRHT GVPSRFSGSGSGTDYALTISSLQPEDFA TYYCQQHYRSPWTFGGGTKVEIKRTVAA PSVFIFPPSDEQLKSGTASVVCLLNNFY PREAKVQWKVDNALQSGNSQESVTEQDS KDSTYSLSSTLTLSKADYEKHKVYACEV THQGLSSPVTKSFNRGEC C3 HC CDR1 GFNIEDYY 24 HC CDR2 IDPEDAET 48 HC CDR3 ARSIYLDPMDY 26 LC CDR1 QDVTTA 27 LC CDR2 WAT N / A LCCDR3 QQHYSTPYT 29 VH QVQLVQSGAEVKKPGASVKVSCKASGFN IEDYYMHWVRQAPGQRLEWMGRIDPEDA ettyspkfqgrvtiipdtsantaymels SLRSEDTAVYYCARSIYLDPMDYWGQGT LVTVSS 49 Petition 870250088518, dated 09 / 30 / 2025, page 60 / 245 47 / 213 TMPRSS6 Antibody Sequence SEQ ID NO VL DIQMTQSPKSLSASVGDRVTITCRASQD VTTALAWYQQKPGQSPKLLIYWATTRHS GVPSRFSGSGSGTDFTLTISSLQPEDFA TYYCQQHYSTPYTFGQGTKLEIK 50 Constant Region HC ASTKGPSVFPLAPSSKSTSGGTAALGCL VKDYFPEPVTVSWNSGALTSGVHTFPAV LQSSGLYSLSSVVTVPSSSLGTQTYICN VNHKPSNTKVDKKVEPKSCDKTHTCPPC PAPEAAGGPSVFLFPPKPKDTLMISRTP EVTCVVVDVSHEDPEVKFNWYVDGVEVH NAKTKPREEQYNSTYRVVSVLTVLHQDW LNGKEYKCKVSNKALPAPIEKTISKAKG QPREPQVYTLPPSREEMTKNQVSLTCLV KGFYPSDIAVEWESNGQPENNYKTTPPV LDSDGSFFLYSKLTVDKSRWQQGNVFSC SVMHEALHNHYTQKSLSLSPG 51 Constant Region LC RTVAAPSVFIFPPSDEQLKSGTASVVCL LNNFYPREAKVQWKVDNALQSGNSQESV TEQDSKDSTYSLSSTLTLSKADYEKHKV YACEVTHQGLSSPVTKSFNRGEC 40 Heavy Chain QVQLVQSGAEVKKPGASVKVSCKASGFN 52 IEDYYMHWVRQAPGQRLEWMGRIDPEDA ETTYSPKFQGRVTIIPDTSANTAYMELS SLRSEDTAVYYCARSIYLDPMDYWGQGT LVTVSSASTKGPSVFPLAPSSKSTSGGT AALGCLVKDYFPEPVTVSWNSGALTSGV HTFPAVLQSSGLYSLSSVVTVPSSSLGT QTYICNVNHKPSNTKVDKKVEPKSCDKT HTCPPCPAPEAAGGPSVFLFPPKPKDTL MISRTPEVTCVVVDVSHEDPEVKFNWYV DGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKT ISKAKGQPREPQVYTLPPSREEMTKNQV SLTCLVKGFYPSDIAVEWESNGQPENNY KTTPPVLDSDGSFFLYSKLTVDKSRWQQ GNVFSCSVMHEALHNHYTQKSLSLSPG Light Chain DIQMTQSPKSLSASVGDRVTITCRASQD 53 VTTALAWYQQKPGQSPKLLIYWATTRHS GVPSRFSGSGSGTDFTLTISSLQPEDFA TYYCQQHYSTPYTFGQGTKLEIKRTVAA PSVFIFPPSDEQLKSGTASVVCLLNNFY Petition 870250088518, dated 09 / 30 / 2025, page 61 / 245 48 / 213 TMPRSS6 Antibody Sequence SEQ ID NO PREAKVQWKVDNALQSGNSQESVTEQDS KDSTYSLSSTLTLSKADYEKHKVYACEV THQGLSSPVTKSFNRGEC

[0079] In some embodiments, the anti-TMPRSS6 antibodies of the present disclosure comprise one or more HC CDR amino acid sequences (e.g., HC CDR1, HC CDR2, or HC CDR3) from any of the selected anti-TMPRSS6 antibodies in Table 2. In some embodiments, the anti-TMPRSS6 antibodies of the present disclosure comprise HC CDR1, HC CDR2, and HC CDR3, as provided for any of the selected antibodies in Table 2. In some embodiments, the anti-TMPRSS6 antibodies of the present disclosure comprise one or more LC CDR amino acid sequences (e.g., LC CDR1, LC CDR2, or LC CDR3) from any of the selected anti-TMPRSS6 antibodies in Table 2. In some embodiments, the anti-TMPRSS6 antibodies of the present disclosure comprise LC CDR1, LC CDR2, and LC CDR3, as provided for any of the selected anti-TMPRSS6 antibodies in Table 2. Table 2.

[0080] In some embodiments, the anti-TMPRSS6 antibodies of the present disclosure comprise HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3, as provided for any of the selected anti-TMPRSS6 antibodies from Table 2. In some embodiments, the CDR3 domains of the antibody heavy and light chains may play a particularly important role in the specificity / binding affinity of an antibody for an antigen. Consequently, the anti-TMPRSS6 antibodies of the disclosure may include at least the heavy and / or light chain CDR3s of any of the selected anti-TMPRSS6 antibodies from Table 2.

[0081] In some embodiments, the anti-TMPRSS6 antibody comprises a variable heavy chain region comprising a CDR1 heavy chain (HC CDR1), a CDR2 heavy chain Petition 870250088518, dated 09 / 30 / 2025, page 62 / 245 49 / 213 (HC CDR2) and a heavy chain CDR3 (HC CDR3). In some embodiments, the anti-TMPRSS6 antibody comprises a variable light chain region comprising a light chain CDR1 (LC CDR1), a light chain CDR2 (LC CDR2), and a light chain CDR3 (LC CDR3).

[0082] Also within the scope of the present disclosure are functional variants of any of the exemplary antiTMPRSS6 antibodies, as disclosed herein. A functional variant may contain one or more amino acid residue variations in the VH and / or VL, or in one or more CDRs of the HC and / or one or more CDRs of the LC relative to the reference antibody, while retaining substantially similar biological and binding activities (e.g., binding affinity, binding specificity, inhibitory activity, or a combination thereof) to the reference antibody.

[0083] In some embodiments, any of the anti-TMPRSS6 antibodies of the development has one or more CDR sequences (e.g., HC CDR or LC CDR) 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-TMPRSS6 antibodies selected from Table 2. 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) region of an antibody described herein may vary by one, two, three, four, five, or six amino acid positions, provided that the immunospecific binding to TMPRSS6 (e.g., human TMPRSS6) 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 that defines a CDR of any antibody described here may vary by shifting the N-terminal and / or C-terminal boundary. Petition 870250088518, dated 09 / 30 / 2025, p. 63 / 245 50 / 213 terminal of the CDR at one, two, three, four, five, or six amino acids, relative to the CDR position of any of the antibodies described herein, provided that the immunospecific binding to TMPRSS6 (e.g., human TMPRSS6) 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 region (e.g., HC CDR1, HC CDR2, or HC CDR3) and / or VL region (e.g., LC CDR1, LC CDR2, or LC CDR3) of an antibody described herein may vary (e.g., be shorter or longer) by one, two, three, four, five, or more amino acids, provided that the immunospecific binding to TMPRSS6 (e.g., human TMPRSS6) 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 to the original antibody from which it is derived).

[0084] Thus, in some embodiments, an HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2 and / or LC CDR3 written herein may have one, two, three, four, five or more fewer amino acids than one or more of the CDRs described herein (e.g., CDRs of any of the selected anti-TMPRSS6 antibodies from Table 2), provided that the immunospecific binding to TMPRSS6 (e.g., human TMPRSS6) 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% relative to the binding of the original antibody from which it is derived). In some embodiments, an HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2 and / or LC CDR3 described herein may have one, two, three, four, five or more additional amino acids from one or more of the CDRs described herein (e.g., CDRs from any of the selected anti-TMPRSS6 antibodies from Table 2), provided that the immunospecific binding to TMPRSS6 (e.g., human TMPRSS6) is Petition 870250088518, dated 09 / 30 / 2025, p. 64 / 245 51 / 213 maintained (e.g., substantially maintained, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95% relative to the binding of the original antibody from which it is derived). In some embodiments, the amino portion of an HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2 and / or LC CDR3 described herein may be extended by one, two, three, four, five or more amino acids compared to one or more of the CDRs described herein (e.g., CDRs of any of the selected anti-TMPRSS6 antibodies from Table 2), provided that the immunospecific binding to TMPRSS6 (e.g., human TMPRSS6) 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% relative to the binding of the original antibody from which it is derived).In some embodiments, the carboxy portion of an HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2 and / or LC CDR3 described herein may be extended by one, two, three, four, five or more amino acids compared to one or more of the CDRs described herein (e.g., CDRs of any of the selected anti-TMPRSS6 antibodies from Table 2), provided that the immunospecific binding to TMPRSS6 (e.g., human TMPRSS6) 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% relative to the binding of the original antibody from which it is derived).In some embodiments, the amino portion of an HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2 and / or LC CDR3 described herein may be shortened by one, two, three, four, five or more amino acids compared to one or more of the CDRs described herein (e.g., CDRs of any of the selected anti-TMPRSS6 antibodies from Table 2), provided that the immunospecific binding to TMPRSS6 (e.g., human TMPRSS6) 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% relative). Petition 870250088518, dated 09 / 30 / 2025, p. 65 / 245 52 / 213 to the binding of the original antibody from which it is derived). In some embodiments, the carboxy portion of an HC CDR1, HC CDR2, HC CDR3, The LC CDR1, LC CDR2, and / or LC CDR3 described herein may be shortened by one, two, three, four, five, or more amino acids compared to one or more of the CDRs described herein (e.g., CDRs of any of the selected anti-TMPRSS6 antibodies from Table 2), provided that the immunospecific binding to TMPRSS6 (e.g., human TMPRSS6) 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% relative to the binding of the original antibody from which it is derived). Any method may be used to verify that the immunospecific binding to TMPRSS6 (e.g., human TMPRSS6) is maintained, e.g., using binding assays and conditions described in the technique.

[0085] In some instances, any of the anti-TMPRSS6 antibodies in the discovery have one or more CDR sequences (e.g., HC CDR or LC CDR) substantially similar to any of the selected anti-TMPRSS6 antibodies from Table 2. For example, the antibodies may include one or more CDR sequences from any of the selected anti-TMPRSS6 antibodies from Table 2 containing up to 5, 4, 3, 2, or 1 amino acid residue variation compared to the corresponding CDR region in any of the CDRs provided herein (e.g., CDRs from any of the selected anti-TMPRSS6 antibodies from Table 2), provided that the immunospecific binding to TMPRSS6 (e.g., human TMPRSS6) 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% relative to the original antibody binding of the which is derived).In some modalities, any of the amino acid variations in any of the CDRs provided here may be conservative variations. Conservative variations may... Petition 870250088518, dated 09 / 30 / 2025, p. 66 / 245 53 / 213 to be introduced into CDRs at positions where residues are unlikely to be involved in interaction with a TMPRSS6 protein (e.g., a human TMPRSS6 protein), for example, as determined based on a crystal structure. Some embodiments provide anti-TMPRSS6 antibodies comprising one or more variable heavy chain (VH) and / or variable light chain (VL) domains provided herein. In some embodiments, any of the VH domains provided herein includes one or more sequences of the HC CDR (e.g., HC CDR1, HC CDR2, and HC CDR3) provided herein, for example, any of the CDR-H sequences provided in any of the selected anti-TMPRSS6 antibodies from Table 2. In some embodiments, any of the VL domains provided herein includes one or more sequences of CDR-L (e.g., LC CDR1, LC CDR2, and LC CDR3) provided here, for example, any of the LC CDR sequences provided in any of the selected anti-TMPRSS6 antibodies from Table 2.

[0086] In some embodiments, a breakthrough anti-TMPRSS6 antibody includes any antibody that includes a variable heavy chain domain and / or a variable light chain domain from any of the selected anti-TMPRSS6 antibodies from Table 2 and variants thereof. In some embodiments, breakthrough anti-TMPRSS6 antibodies include any antibody that includes both variable heavy chain and variable light chain pairs from any selected anti-TMPRSS6 antibodies from Table 2.

[0087] Aspects of the revelation provide anti-TMPRSS6 antibodies with a variable heavy chain (VH) and / or variable light chain (VL) domain amino acid sequence homologous to any of those described herein. In some embodiments, the anti-TMPRSS6 antibody comprises a variable heavy chain sequence or a variable light chain sequence that is at least 75% (e.g., at least 80%, at least 85%, Petition 870250088518, dated 09 / 30 / 2025, page 67 / 245 54 / 213 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 variable heavy chain sequence and / or any variable light chain sequence of any of the selected anti-TMPRSS6 antibodies from Table 2. In some embodiments, the amino acid sequences of the variable heavy chain and / or light chain region do not vary in any of the CDR sequences provided here. For example, in some embodiments, the 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 in a variable sequence of the heavy chain and / or light chain, excluding any of the CDR sequences provided herein.In some embodiments, any of the anti-TMPRSS6 antibodies provided herein comprises a variable heavy chain sequence and a variable light chain sequence comprising a structure 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 structure sequence of any anti-TMPRSS6 antibodies selected from Table 2.

[0088] In some embodiments, an anti-TMPRSS6 antibody of the present disclosure is an antibody comprising a VH containing no more than 20 amino acid variations (for example, 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 variation) compared to the VH of any of the anti-TMPRSS6 antibodies listed in Table 2. Alternatively or additionally, the anti-TMPRSS6 antibody of the present disclosure is a humanized antibody comprising a VL ... Petition 870250088518, dated 09 / 30 / 2025, p. 68 / 245 55 / 213 example, 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 variation) compared to the VL of any of the anti-TMPRSS6 antibodies listed in Table 2. In some embodiments, the amino acid sequences of the variable region of the heavy chain and / or light chain do not vary in any of the CDR sequences provided here. For example, in some embodiments, the number of amino acid variations (e.g., not 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 variation) may occur in a variable sequence of the heavy chain and / or light chain, excluding any of the CDR sequences provided herein.In some embodiments, any of the anti-TMPRSS6 antibodies provided herein comprises a variable heavy chain sequence comprising a structural sequence containing 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 variation in the structural sequence of a VH of any of the anti-TMPRSS6 antibodies selected from Table 2 and / or a variable light chain sequence comprising a structural sequence containing 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 variation in the structural sequence of a VL of any of the antibodies anti-TMPRSS6 selected from Table 2.

[0089] In some embodiments, an anti-TMPRSS6 antibody of the present disclosure is a humanized antibody (e.g., a humanized variant containing one or more CDRs from Table 2). In some embodiments, an anti-TMPRSS6 antibody of the present disclosure comprises an HC CDR1, an HC CDR2, an HC CDR3, an LC CDR1, an LC CDR2, and an LC CDR3 that are the same as HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 shown in Table 2, and comprises a humanized heavy chain variable region and / or a humanized light chain variable region. In some embodiments, the amino acid sequences of the chain Petition 870250088518, dated 09 / 30 / 2025, p. 69 / 245 56 / 213 variable heavy chain and / or variable light chain humanized modalities do not exhibit variation in any of the CDR sequences provided here. For example, in some modalities, the 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 in a variable heavy chain and / or light chain sequence, excluding any of the CDR sequences provided here.In some embodiments, a humanized anti-TMPRSS6 antibody provided herein comprises a variable heavy chain sequence and a variable light chain sequence comprising a structure 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 structure sequence of any selected anti-TMPRSS6 antibodies from Table 2. In some embodiments, the humanized variable heavy chain and / or variable light chain amino acid sequences do not exhibit variation in any of the CDR sequences provided herein.For example, in some embodiments, the number of amino acid variations (e.g., not 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 variation) may occur in a variable sequence of the heavy chain and / or light chain, excluding any of the CDR sequences provided herein. In some embodiments, a humanized anti-TMPRSS6 antibody provided herein comprises a variable heavy chain sequence comprising a structure sequence containing 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 variation for the structure sequence of a VH of any of the selected anti-TMPRSS6 antibodies from Table 2 and / or a variable light chain sequence that... Petition 870250088518, dated 09 / 30 / 2025, p. 70 / 245 57 / 213 comprises a structural sequence containing 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 variation for the structural sequence of a VL of any of the anti-TMPRSS6 antibodies selected from Table 2.

[0090] In some embodiments, an anti-TMPRSS6 antibody of the present disclosure comprises an HC CDR1, HC CDR2 and HC CDR3 of a variable heavy chain domain having the amino acid sequence of SEQ ID NO: 7. Alternatively or additionally, the anti-TMPRSS6 antibody of the present disclosure comprises an LC CDR1, LC CDR2 and LC CDR3 of a variable light chain domain having the amino acid sequence of SEQ ID NO: 8.

[0091] In some embodiments, according to Kabat's system of definition, an anti-TMPRSS6 antibody of the present disclosure comprises 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 RAN and an LC CDR3 having the amino acid sequence of SEQ ID NO: 6.

[0092] In some embodiments, an anti-TMPRSS6 antibody of the present disclosure comprises an HC CDR1, an HC CDR2, and an HC CDR3, which collectively contain no more than 5 amino acid variations (e.g., no more than 5, 4, 3, 2, or 1 amino acid variation) 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. “Collectively,” as used anywhere in the present disclosure, means that the total number of amino acid variations in all three heavy chain CDRs is within the defined range. Alternatively or additionally, the anti-TMPRSS6 antibody of the present disclosure Petition 870250088518, dated 09 / 30 / 2025, p. 71 / 245 58 / 213 comprises an LC CDR1, an LC CDR2 and an LC CDR3, which collectively contain no more than 5 amino acid variations (for example, no more than 5, 4, 3, 2 or 1 amino acid variation) compared to LC CDR1 having the amino acid sequence of SEQ ID NO: 4, LC CDR2 having the amino acid sequence of RAN and LC CDR3 having the amino acid sequence of SEQ ID NO: 6.

[0093] In some embodiments, an anti-TMPRSS6 antibody of the present disclosure comprises an HC CDR1, an HC CDR2 and an HC CDR3 that collectively are 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 having the amino acid sequence of SEQ ID NO: 1, for HC CDR2 having the amino acid sequence of SEQ ID NO: and to HC CDR3 having the amino acid sequence SEQ ID NO: 3. Alternatively or additionally, the anti-TMPRSS6 antibody of the present disclosure comprises a CDR1 LC, a CDR2 LC, and an LC. CDR3 that collectively are 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 having the amino acid sequence of SEQ ID NO: 4, to LC CDR2 having the amino acid sequence of RAN and to LC CDR3 having the amino acid sequence SEQ ID NO: 6.

[0094] In some embodiments, an anti-TMPRSS6 antibody of the present disclosure comprises: an HC CDR1 with a maximum of 3 amino acid variations (e.g., a maximum of 3, 2 or 1 amino acid variation) compared to HC CDR1 having the amino acid sequence of SEQ ID NO: 1; an HC CDR2 with a maximum of 3 amino acid variations (e.g., a maximum of 3, 2 or 1 amino acid variation) compared to HC CDR2 having the amino acid sequence of SEQ ID NO: 2; and / or an HC CDR3 with Petition 870250088518, dated 09 / 30 / 2025, p. 72 / 245 59 / 213 with a maximum of 3 amino acid variations (e.g., a maximum of 3, 2, or 1 amino acid variation) compared to HC CDR3 having the amino acid sequence of SEQ ID NO: 3. Alternatively or additionally, the anti-TMPRSS6 antibody of the present disclosure comprises: a CDR1 LC with a maximum of 3 amino acid variations (e.g., a maximum of 3, 2, or 1 amino acid variation) compared to CDR1 LC having the amino acid sequence of SEQ ID NO: 4; a CDR2 LC with a maximum of 3 amino acid variations (e.g., a maximum of 3, 2, or 1 amino acid variation) compared to CDR2 LC having the amino acid sequence of RAN; and / or a CDR3 LC with a maximum of 3 amino acid variations (e.g., a maximum of 3, 2, or 1 amino acid variation) compared to the CDR3 LC having the amino acid sequence SEQ ID NO: 6.

[0095] In some embodiments, an anti-TMPRSS6 antibody of the present disclosure comprises: an HC CDR1 that is at least 80% (for example, 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 that has the amino acid sequence of SEQ ID NO: 1; a HC CDR2 that is at least 80% (for example, 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 CDR2 having the amino acid sequence of SEQ ID NO: 2; and / or an HC CDR3 that is at least 80% (for example, 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 CDR3 having the amino acid sequence of SEQ ID NO: 3. Alternatively or additionally, the anti-TMPRSS6 antibody of the present disclosure comprises: a LC CDR1 that is at least 80% (for example, at least 80%, at least Petition 870250088518, dated 09 / 30 / 2025, p. 73 / 245 60 / 213 less 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 which has the amino acid sequence of SEQ ID NO: 4; an LC CDR2 which 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 LC CDR2 which has the amino acid sequence of RAN; and / or a CDR3 LC that is at least 80% (for example, 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 CDR3 LC having the amino acid sequence of SEQ ID NO: 6.

[0096] In some embodiments, an anti-TMPRSS6 antibody of the present disclosure comprises a VH comprising the amino acid sequence of SEQ ID NO: 7. Alternatively or additionally, the anti-TMPRSS6 antibody of the present disclosure comprises a VL comprising the amino acid sequence of SEQ ID NO: 8.

[0097] In some embodiments, an anti-TMPRSS6 antibody of the present disclosure comprises a VH containing no more than 20 amino acid variations (for example, 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 variation) compared to VH as set forth in SEQ ID NO: 7. Alternatively or additionally, the anti-TMPRSS6 antibody of the present disclosure comprises a VL containing no more than 20 amino acid variations (for example, 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 variation) compared to VL as set forth in SEQ ID NO: 8. In some embodiments, the number of amino acid variations (e.g., not more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, Petition 870250088518, dated 09 / 30 / 2025, p. 74 / 245 61 / 213 7, 6, 5, 4, 3, 2 or 1 amino acid variation) may occur within a VH of SEQ ID NO: 7 and / or a VL of SEQ ID NO: 8 excluding any of the CDR sequences contained therein. In some embodiments, the anti-TMPRSS6 antibodies provided herein comprise a variable heavy chain sequence comprising a structure sequence containing 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 variation for the structure sequence of a VH of SEQ ID NO: 7, and / or a variable light chain sequence comprising a structure sequence containing 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 variation for the structure sequence of a VL of SEQ ID NO: 8.

[0098] In some embodiments, an anti-TMPRSS6 antibody of the present disclosure comprises 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 as set forth in SEQ ID NO: 7. Alternatively or additionally, the anti-TMPRSS6 antibody of the present disclosure comprises 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 as established in SEQ ID NO: 8.In some modalities, the 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 a VH of SEQ ID NO: 7 and / or a VL of SEQ ID NO: 8 excluding any of the CDR sequences contained therein. Petition 870250088518, dated 09 / 30 / 2025, p. 75 / 245 62 / 213 In some embodiments, an anti-TMPRSS6 antibody provided herein comprises a variable heavy chain 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 structural sequence of a VH with SEQ ID NO: 7, and / or a variable light chain sequence comprising a structural 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 structural sequence of a VL of SEQ ID NO: 8.

[0099] In some embodiments, an anti-TMPRSS6 antibody of the present disclosure comprises an HC CDR1, HC CDR2 and HC CDR3 of a variable heavy chain domain having the amino acid sequence of SEQ ID NO: 19 or 78. Alternatively or additionally, the anti-TMPRSS6 antibody of the present disclosure comprises an LC CDR1, LC CDR2 and LC CDR3 of a variable light chain domain having the amino acid sequence of SEQ ID NO: 20.

[00100] In some embodiments, according to Kabat's system of definition, an anti-TMPRSS6 antibody of the present disclosure comprises an HC CDR1 having the amino acid sequence of SEQ ID NO: 13, an HC CDR2 having the amino acid sequence of SEQ ID NO: 14, an HC CDR3 having the amino acid sequence of SEQ ID NO: 15, an LC CDR1 having the amino acid sequence of SEQ ID NO: 16, an LC CDR2 having the amino acid sequence of WAF and an LC CDR3 having the amino acid sequence of SEQ ID NO: 18.

[00101] In some embodiments, an anti-TMPRSS6 antibody of the present disclosure comprises an HC CDR1, an HC CDR2 and an HC CDR3, which collectively contain no more than 5 amino acid variations (for example, no more than 5, 4, 3, 2 or 1 variation). Petition 870250088518, dated 09 / 30 / 2025, p. 76 / 245 63 / 213 amino acid) compared to HC CDR1 having the amino acid sequence of SEQ ID NO: 13, HC CDR2 having the amino acid sequence of SEQ ID NO: 14, and HC CDR3 having the amino acid sequence of SEQ ID NO: 15. Alternatively or additionally, the anti-TMPRSS6 antibody of the present disclosure comprises an LC CDR1, an LC CDR2, and an LC CDR3, which collectively contain no more than 5 amino acid variations (e.g., no more than 5, 4, 3, 2, or 1 amino acid variation) compared to LC CDR1 having the amino acid sequence of SEQ ID NO: 16, LC CDR2 having the amino acid sequence of WAF, and LC CDR3 having the amino acid sequence of SEQ ID NO: 18.

[00102] In some embodiments, an anti-TMPRSS6 antibody of the present disclosure comprises an HC CDR1, an HC CDR2 and an HC CDR3 cells that collectively are at least 80% (for example, 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 cells having the amino acid sequence from SEQ ID NO: 13, for HC CDR2 cells having the amino acid sequence from SEQ ID NO: and to HC CDR3 having the amino acid sequence of SEQ ID NO: 15. Alternatively or additionally, the anti-TMPRSS6 antibody of the present disclosure comprises an LC CDR1, an LC CDR2 and a LC CDR3 that collectively are at least 80% (for example, 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 having the amino acid sequence of SEQ ID NO: 16, to LC CDR2 having the amino acid sequence of WAF, and to LC CDR3 having the amino acid sequence SEQ ID NO: 18.

[00103] In some embodiments, an anti-TMPRSS6 antibody of the present disclosure comprises: an HC CDR1 with a maximum of 3 amino acid variations (for example, a maximum of 3, 2 or 1 amino acid variation) compared to HC CDR1 having the Petition 870250088518, dated 09 / 30 / 2025, p. 77 / 245 64 / 213 amino acid sequence of SEQ ID NO: 13; an HC CDR2 with a maximum of 3 amino acid variations (e.g., a maximum of 3, 2, or 1 amino acid variation) compared to HC CDR2 having the amino acid sequence of SEQ ID NO: 14; and / or an HC CDR3 with a maximum of 3 amino acid variations (e.g., a maximum of 3, 2, or 1 amino acid variation) compared to HC CDR3 having the amino acid sequence of SEQ ID NO: 15.Alternatively or additionally, the anti-TMPRSS6 antibody of the present disclosure comprises: a CDR1 LC with a maximum of 3 amino acid variations (e.g., a maximum of 3, 2, or 1 amino acid variation) compared to a CDR1 LC having the amino acid sequence of SEQ ID NO: 16; a CDR2 LC with a maximum of 3 amino acid variations (e.g., a maximum of 3, 2, or 1 amino acid variation) compared to a CDR2 LC having the amino acid sequence of WAF; and / or a CDR3 LC with a maximum of 3 amino acid variations (e.g., a maximum of 3, 2, or 1 amino acid variation) compared to a CDR3 LC having the amino acid sequence of SEQ ID NO: 18.

[00104] In some embodiments, an anti-TMPRSS6 antibody of the present disclosure comprises: an HC CDR1 that is at least 80% (for example, 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 that has the amino acid sequence of SEQ ID NO: 13; a HC CDR2 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 HC CDR2 having the amino acid sequence of SEQ ID NO: 14; and / or an HC CDR3 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%, or at least 99%) identical to HC CDR2 having the amino acid sequence of SEQ ID NO: 14; Petition 870250088518, dated 09 / 30 / 2025, page 78 / 24565 / 213 less than 98% or at least 99%) identical to HC CDR3 having the amino acid sequence of SEQ ID NO: 15. Alternatively or additionally, the anti-TMPRSS6 antibody of the present disclosure comprises: an LC CDR1 that is at least 80% (for example, 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 that has the amino acid sequence of SEQ ID NO: 16; an LC CDR2 that is at least 80% (for example, 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 CDR2 that has the amino acid sequence of WAF;and / or a CDR3 LC that is at least 80% (for example, 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 CDR3 LC that has the amino acid sequence SEQ ID NO: 18.;

[00105] In some embodiments, an anti-TMPRSS6 antibody of the present disclosure comprises a VH comprising the amino acid sequence of SEQ ID NO: 19 or 78. Alternatively or additionally, the anti-TMPRSS6 antibody of the present disclosure comprises a VL comprising the amino acid sequence of SEQ ID NO: 20.

[00106] In some embodiments, an anti-TMPRSS6 antibody of the present disclosure comprises a VH containing no more than 20 amino acid variations (for example, 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 variation) compared to VH as set forth in SEQ ID NO: 19 or 78. Alternatively or additionally, the anti-TMPRSS6 antibody of the present disclosure comprises a VL containing no more than 20 amino acid variations (for example, no more than 20, 19, 18, 17, 16, Petition 870250088518, dated 09 / 30 / 2025, p. 79 / 245 66 / 213 15, 14, 13, 12, 11, 9, 8, 7, 6, 5, 4, 3, 2 or 1 amino acid variation) compared to VL as established in SEQ ID NO: 20. In some embodiments, the number of amino acid variations (e.g., not 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 variation) may occur within a VH of SEQ ID NO: 19 or 78 and / or a VL of SEQ ID NO: 20 excluding any of the CDR sequences contained therein.In some embodiments, the anti-TMPRSS6 antibodies provided herein comprise a variable heavy chain sequence comprising a structure sequence containing 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 variation for the structure sequence of a VH of SEQ ID NO: 19 or 78, and / or a variable light chain sequence comprising a structure sequence containing 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 variation for the structure sequence of a VL of SEQ ID NO: 20.

[00107] In some embodiments, an anti-TMPRSS6 antibody of the present disclosure comprises 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 as set forth in SEQ ID NO: 19 or 78. Alternatively or additionally, the anti-TMPRSS6 antibody of the present disclosure comprises 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 as established in SEQ ID NO: 20. In some embodiments, the degree of sequence variation (e.g., by Petition 870250088518, dated 09 / 30 / 2025, page 80 / 24567 / 213 less 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 a VH of SEQ ID NO: 19 or 78 and / or a VL of SEQ ID NO: 20 excluding any of the CDR sequences contained therein.In some embodiments, an anti-TMPRSS6 antibody provided herein comprises a variable heavy chain 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 structural sequence of a VH with SEQ ID NO: 19 or 78, and / or a variable light chain sequence comprising a structural 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 Structural sequence of a VL with SEQ ID NO: 20.

[00108] In some embodiments, an anti-TMPRSS6 antibody of the present disclosure comprises an HC CDR1, HC CDR2 and HC CDR3 of a variable heavy chain domain having the amino acid sequence of SEQ ID NO: 30. Alternatively or additionally, the anti-TMPRSS6 antibody of the present disclosure comprises an LC CDR1, LC CDR2 and LC CDR3 of a variable light chain domain having the amino acid sequence of SEQ ID NO: 31.

[00109] In some embodiments, according to Kabat's system of definition, an anti-TMPRSS6 antibody of the present disclosure comprises an HC CDR1 having the amino acid sequence of SEQ ID NO: 24, an HC CDR2 having the amino acid sequence of SEQ ID NO: 25, an HC CDR3 having the amino acid sequence of SEQ ID NO: 26, an LC CDR1 having the amino acid sequence of SEQ ID NO: 27, an LC CDR2 having the amino acid sequence Petition 870250088518, dated 09 / 30 / 2025, p. 81 / 245 68 / 213 of WAT and an LC CDR3 having the amino acid sequence SEQ ID NO: 29.

[00110] In some embodiments, an anti-TMPRSS6 antibody of the present disclosure comprises an HC CDR1, an HC CDR2, and an HC CDR3, which collectively contain no more than 5 amino acid variations (e.g., no more than 5, 4, 3, 2, or 1 amino acid variation) compared to HC CDR1 having the amino acid sequence of SEQ ID NO: 24, HC CDR2 having the amino acid sequence of SEQ ID NO: 25, and HC CDR3 having the amino acid sequence of SEQ ID NO: 26. Alternatively or additionally, the anti-TMPRSS6 antibody of the present disclosure comprises an LC CDR1, an LC CDR2, and an LC CDR3, which collectively contain no more than 5 amino acid variations (e.g., no more than 5, 4, 3, 2, or 1 amino acid variation) compared to LC CDR1 having the amino acid sequence SEQ ID NO: 27, LC CDR2 having the amino acid sequence WAT, and LC CDR3 having the amino acid sequence SEQ ID NO: 29.

[00111] In some embodiments, an anti-TMPRSS6 antibody of the present disclosure comprises an HC CDR1, an HC CDR2 and an HC CDR3 that collectively are at least 80% (for example, 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 having the amino acid sequence from SEQ ID NO: 24, to HC CDR2 having the amino acid sequence from SEQ ID NO: and to HC CDR3 having the amino acid sequence of SEQ ID NO: 26. Alternatively or additionally, the anti-TMPRSS6 antibody of the present disclosure comprises an LC CDR1, an LC CDR2 and a LC CDR3 that collectively are 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 having the amino acid sequence of SEQ ID Petition 870250088518, dated 09 / 30 / 2025, p. 82 / 245 69 / 213 NO: 27, to LC CDR2 having the amino acid sequence of WAT and to LC CDR3 having the amino acid sequence SEQ ID NO: 29.

[00112] In some embodiments, an anti-TMPRSS6 antibody of the present disclosure comprises: an HC CDR1 with a maximum of 3 amino acid variations (e.g., a maximum of 3, 2 or 1 amino acid variation) compared to HC CDR1 having the amino acid sequence of SEQ ID NO: 24; an HC CDR2 with a maximum of 3 amino acid variations (e.g., a maximum of 3, 2 or 1 amino acid variation) compared to HC CDR2 having the amino acid sequence of SEQ ID NO: 25; and / or an HC CDR3 with a maximum of 3 amino acid variations (e.g., a maximum of 3, 2 or 1 amino acid variation) compared to HC CDR3 having the amino acid sequence of SEQ ID NO: 26.Alternatively or additionally, the anti-TMPRSS6 antibody of the present disclosure comprises: a CDR1 LC with a maximum of 3 amino acid variations (e.g., a maximum of 3, 2, or 1 amino acid variation) compared to a CDR1 LC having the amino acid sequence of SEQ ID NO: 27; a CDR2 LC with a maximum of 3 amino acid variations (e.g., a maximum of 3, 2, or 1 amino acid variation) compared to a CDR2 LC having the amino acid sequence WAT; and / or a CDR3 LC with a maximum of 3 amino acid variations (e.g., a maximum of 3, 2, or 1 amino acid variation) compared to a CDR3 LC having the amino acid sequence of SEQ ID NO: 29.

[00113] In some embodiments, an anti-TMPRSS6 antibody of the present disclosure comprises: an HC CDR1 that is at least 80% (for example, 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 that has the amino acid sequence of SEQ ID NO: 24; an HC CDR2 that is at least 80% (for example, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, Petition 870250088518, dated 09 / 30 / 2025, p. 83 / 245 70 / 213 at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical to HC CDR2 having the amino acid sequence of SEQ ID NO: 25; and / or an HC CDR3 that is at least 80% (e.g., at least 80%, at least 85%, at least 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 CDR3 having the amino acid sequence of SEQ ID NO: 26. Alternatively or additionally, the anti-TMPRSS6 antibody of the present disclosure comprises: an LC CDR1 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 LC CDR1 having the amino acid sequence of SEQ ID NO: 27; an LC CDR2 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 CDR2 LC that has the amino acid sequence of WAT; and / or an LC CDR3 that is at least 80% (for example, 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 CDR3 having the amino acid sequence of SEQ ID NO: 29.

[00114] In some embodiments, an anti-TMPRSS6 antibody of the present disclosure comprises a VH comprising the amino acid sequence of SEQ ID NO: 30. Alternatively or additionally, the anti-TMPRSS6 antibody of the present disclosure comprises a VL comprising the amino acid sequence of SEQ ID NO: 31.

[00115] In some embodiments, an anti-TMPRSS6 antibody of the present disclosure comprises a VH containing no more than 20 amino acid variations (e.g., no more than 20, 19, Petition 870250088518, dated 09 / 30 / 2025, p. 84 / 245 71 / 213 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 amino acid variation) compared to VH as set forth in SEQ ID NO: 30. Alternatively or additionally, the anti-TMPRSS6 antibody of the present disclosure comprises a VL containing no more than 20 amino acid variations (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 variation) compared to VL as established in SEQ ID NO: 31. In some embodiments, the number of amino acid variations (e.g., not 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 variation) may occur within a VH of SEQ ID NO: 30 and / or a VL of SEQ ID NO: 31, excluding any of the CDR sequences contained therein. In some embodiments, the anti-TMPRSS6 antibodies provided herein comprise a variable heavy chain sequence comprising a structure sequence containing 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 variation for the structural sequence of a VH with SEQ ID NO: 30, and / or a variable light chain sequence comprising a structural sequence containing 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 variation for the structural sequence of a VL with SEQ ID NO: 31.

[00116] In some embodiments, an anti-TMPRSS6 antibody of the present disclosure comprises a VH comprising an amino acid sequence that is at least 80% (for example, 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 VH as set forth in SEQ ID NO: 30. Alternatively or additionally, the anti-TMPRSS6 antibody of the present disclosure comprises a VL comprising an amino acid sequence that Petition 870250088518, dated 09 / 30 / 2025, page 85 / 245 72 / 213 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 as established in SEQ ID NO: 31. In some embodiments, the 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 a VH of SEQ ID NO: 30 and / or a VL of SEQ ID NO: 31 excluding any of the CDR sequences contained therein.In some embodiments, an anti-TMPRSS6 antibody provided herein comprises a variable heavy chain 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 structural sequence of a VH with SEQ ID NO: 30, and / or a variable light chain sequence comprising a structural 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 structural sequence of a VL of SEQ ID NO: 31.

[00117] In some embodiments, an anti-TMPRSS6 antibody of the present disclosure comprises an HC CDR1, HC CDR2 and HC CDR3 of a variable heavy chain domain having the amino acid sequence of SEQ ID NO: 37. Alternatively or additionally, the anti-TMPRSS6 antibody of the present disclosure comprises an LC CDR1, LC CDR2 and LC CDR3 of a variable light chain domain having the amino acid sequence of SEQ ID NO: 38.

[00118] In some embodiments, according to the Kabat definition system, the anti-TMPRSS6 antibody of the present disclosure comprises an HC CDR1 having the amino acid sequence Petition 870250088518, dated 09 / 30 / 2025, p. 86 / 245 73 / 213 of SEQ ID NO: 1, a HC CDR2 having the amino acid sequence of SEQ ID NO: 2, an HC CDR3 having the amino acid sequence of SEQ ID NO: 35, an LC CDR1 having the amino acid sequence of SEQ ID NO: 36, an LC CDR2 having the amino acid sequence of RAN is an LC CDR3 having the amino acid sequence SEQ ID NO: 6.

[00119] In some embodiments, an anti-TMPRSS6 antibody of the present disclosure comprises an HC CDR1, an HC CDR2, and an HC CDR3, which collectively contain no more than 5 amino acid variations (e.g., no more than 5, 4, 3, 2, or 1 amino acid variation) 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: 35. Alternatively or additionally, an anti-TMPRSS6 antibody of the present disclosure comprises an LC CDR1, an LC CDR2, and an LC CDR3, which collectively contain no more than 5 amino acid variations (e.g., no more than 5, 4, 3, 2, or 1 amino acid variation) compared to LC CDR1 having the amino acid sequence of SEQ ID NO: 36, LC CDR2 having the amino acid sequence of RAN and LC CDR3 having the amino acid sequence of SEQ ID NO: 6.

[00120] In some embodiments, an anti-TMPRSS6 antibody of the present disclosure comprises an HC CDR1, an HC CDR2 and an HC CDR3 that collectively are at least 80% (for example, 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 having the amino acid sequence from SEQ ID NO: 1, to HC CDR2 having the amino acid sequence from SEQ ID NO: and to HC CDR3 having the amino acid sequence of SEQ ID NO: 35. Alternatively or additionally, the anti-TMPRSS6 antibody of the present disclosure comprises an LC CDR1, an LC CDR2 and an LC CDR3 which collectively are at least 80% (e.g., by Petition 870250088518, dated 09 / 30 / 2025, p. 87 / 245 74 / 213 less 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 having the amino acid sequence of SEQ ID NO: 36, to LC CDR2 having the amino acid sequence of RAN and to LC CDR3 having the amino acid sequence SEQ ID NO: 6.

[00121] In some embodiments, an anti-TMPRSS6 antibody of the present disclosure comprises: an HC CDR1 with a maximum of 3 amino acid variations (e.g., a maximum of 3, 2 or 1 amino acid variation) compared to HC CDR1 having the amino acid sequence of SEQ ID NO: 1; an HC CDR2 with a maximum of 3 amino acid variations (e.g., a maximum of 3, 2 or 1 amino acid variation) compared to HC CDR2 having the amino acid sequence of SEQ ID NO: 2; and / or an HC CDR3 with a maximum of 3 amino acid variations (e.g., a maximum of 3, 2, or 1 amino acid variation) compared to the HC CDR3 having the amino acid sequence of SEQ ID NO: 35. Alternatively or additionally, the anti-TMPRSS6 antibody of the present disclosure comprises: an LC CDR1 with a maximum of 3 amino acid variations (e.g., a maximum of 3, 2, or 1 amino acid variation) compared to the LC CDR1 having the amino acid sequence of SEQ ID NO: 36; an LC CDR2 with a maximum of 3 amino acid variations (e.g., a maximum of 3, 2, or 1 amino acid variation) compared to an LC CDR2 having the amino acid sequence of RAN; and / or a CDR3 LC with a maximum of 3 amino acid variations (e.g., a maximum of 3, 2, or 1 amino acid variation) compared to the CDR3 LC having the amino acid sequence SEQ ID NO: 6.

[00122] In some embodiments, an anti-TMPRSS6 antibody of the present disclosure comprises: an HC CDR1 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%) Petition 870250088518, dated 09 / 30 / 2025, p. 88 / 245 75 / 213 or at least 99%) identical to HC CDR1 having the amino acid sequence SEQ ID NO: 1; an HC CDR2 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 HC CDR2 having the amino acid sequence SEQ ID NO: 2; and / or an HC CDR3 that is at least 80% (for example, 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 CDR3 having the amino acid sequence SEQ ID NO: 35. Alternatively or additionally, the anti-TMPRSS6 antibody of the present disclosure comprises: an LC CDR1 that is at least 80% (for example, 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 having the amino acid sequence of SEQ ID NO: 36; an LC CDR2 that is at least 80% (for example, 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 CDR2 which has the amino acid sequence of RAN; and / or an LC CDR3 that is at least 80% (for example, 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 CDR3 having the amino acid sequence of SEQ ID NO: 6.

[00123] In some embodiments, an anti-TMPRSS6 antibody of the present disclosure comprises a VH comprising the amino acid sequence of SEQ ID NO: 37. Alternatively or additionally, the anti-TMPRSS6 antibody of the present disclosure Petition 870250088518, dated 09 / 30 / 2025, p. 89 / 245 76 / 213 comprises a VL comprising the amino acid sequence of SEQ ID NO: 38.

[00124] In some embodiments, an anti-TMPRSS6 antibody of the present disclosure comprises a VH containing no more than 20 amino acid variations (for example, 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 variation) compared to VH as set forth in SEQ ID NO: 37. Alternatively, or additionally, the anti-TMPRSS6 antibody of the present disclosure comprises a VL containing no more than 20 amino acid variations (for example, no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 9, 8, 7, 6, 5, 4, 3, 2 or 1 variation of amino acid) compared to VL as set out in SEQ ID NO: 38. In some embodiments, the number of amino acid variations (e.g., not 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 variation) may occur within a VH of SEQ ID NO: 37 and / or a VL of SEQ ID NO: 38, excluding any of the CDR sequences contained therein.In some embodiments, the anti-TMPRSS6 antibodies provided herein comprise a variable heavy chain sequence comprising a structure sequence containing 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 variation for the structure sequence of a VH of SEQ ID NO: 37, and / or a variable light chain sequence comprising a structure sequence containing 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 variation for the structure sequence of a VL of SEQ ID NO: 38.

[00125] In some embodiments, an anti-TMPRSS6 antibody of the present disclosure comprises 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 Petition 870250088518, dated 09 / 30 / 2025, p. 90 / 245 77 / 213 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 as set forth in SEQ ID NO: 37. Alternatively or additionally, the anti-TMPRSS6 antibody of the present disclosure comprises 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%) of the VL as set forth in SEQ ID NO: 38.In some forms, the 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 a VH of SEQ ID NO: 37 and / or a VL of SEQ ID NO: 38 excluding any of the CDR sequences contained therein.In some embodiments, an anti-TMPRSS6 antibody provided herein comprises a variable heavy chain 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 structural sequence of a VH with SEQ ID NO: 37, and / or a variable light chain sequence comprising a structural 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 structural sequence of a VL of SEQ ID NO: 38.

[00126] In some embodiments, an anti-TMPRSS6 antibody of the present disclosure comprises an HC CDR1, HC CDR2 and HC CDR3 of a variable heavy chain domain having the amino acid sequence of SEQ ID NO: 44. Alternatively or additionally, the anti-TMPRSS6 antibody of the present disclosure comprises an LC Petition 870250088518, dated 09 / 30 / 2025, p. 91 / 245 78 / 213 CDR1, LC CDR2 and LC CDR3 of a variable light chain domain having the amino acid sequence SEQ ID NO: 45.

[00127] In some embodiments, according to Kabat's system of definition, an anti-TMPRSS6 antibody of the present disclosure comprises an HC CDR1 having the amino acid sequence of SEQ ID NO: 13, an HC CDR2 having the amino acid sequence of SEQ ID NO: 43, an HC CDR3 having the amino acid sequence of SEQ ID NO: 15, an LC CDR1 having the amino acid sequence of SEQ ID NO: 16, an LC CDR2 having the amino acid sequence of WAF and an LC CDR3 having the amino acid sequence of SEQ ID NO: 18.

[00128] In some embodiments, an anti-TMPRSS6 antibody of the present disclosure comprises an HC CDR1, an HC CDR2, and an HC CDR3, which collectively contain no more than 5 amino acid variations (e.g., no more than 5, 4, 3, 2, or 1 amino acid variation) compared to HC CDR1 having the amino acid sequence of SEQ ID NO: 13, HC CDR2 having the amino acid sequence of SEQ ID NO: 43, and HC CDR3 having the amino acid sequence of SEQ ID NO: 15. Alternatively or additionally, an anti-TMPRSS6 antibody of the present disclosure comprises an LC CDR1, an LC CDR2, and an LC CDR3, which collectively contain no more than 5 amino acid variations (e.g., no more than 5, 4, 3, 2, or 1 amino acid variation) compared to LC CDR1 having the amino acid sequence of SEQ ID NO: 16, LC CDR2 having the amino acid sequence of WAF and LC CDR3 having the amino acid sequence of SEQ ID NO: 18.

[00129] In some embodiments, an anti-TMPRSS6 antibody of the present disclosure comprises an HC CDR1, an HC CDR2 and an HC CDR3 that collectively are 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 having the amino acid sequence of SEQ ID Petition 870250088518, dated 09 / 30 / 2025, p. 92 / 245 79 / 213 NO: 13, for HC CDR2 having the amino acid sequence of SEQ ID NO: and to HC CDR3 having the amino acid sequence of SEQ ID NO: 15. Alternatively or additionally, the anti-TMPRSS6 antibody of the present disclosure comprises an LC CDR1, an LC CDR2 and a LC CDR3 that collectively are at least 80% (for example, 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 having the amino acid sequence of SEQ ID NO: 16, to LC CDR2 having the amino acid sequence of WAF, and to LC CDR3 having the amino acid sequence SEQ ID NO: 18.

[00130] In some embodiments, an anti-TMPRSS6 antibody of the present disclosure comprises: an HC CDR1 with a maximum of 3 amino acid variations (e.g., a maximum of 3, 2 or 1 amino acid variation) compared to HC CDR1 having the amino acid sequence of SEQ ID NO: 13; an HC CDR2 with a maximum of 3 amino acid variations (e.g., a maximum of 3, 2 or 1 amino acid variation) compared to HC CDR2 having the amino acid sequence of SEQ ID NO: 43; and / or an HC CDR3 with a maximum of 3 amino acid variations (e.g., a maximum of 3, 2 or 1 amino acid variation) compared to HC CDR3 having the amino acid sequence of SEQ ID NO: 15.Alternatively or additionally, the anti-TMPRSS6 antibody of the present disclosure comprises: a CDR1 LC with a maximum of 3 amino acid variations (e.g., a maximum of 3, 2, or 1 amino acid variation) compared to a CDR1 LC having the amino acid sequence of SEQ ID NO: 16; a CDR2 LC with a maximum of 3 amino acid variations (e.g., a maximum of 3, 2, or 1 amino acid variation) compared to a CDR2 LC having the amino acid sequence of WAF; and / or a CDR3 LC with a maximum of 3 amino acid variations (e.g., a maximum of 3, 2, or 1 amino acid variation) compared to a CDR3 LC having the amino acid sequence of SEQ ID NO: 18. Petition 870250088518, dated 09 / 30 / 2025, p. 93 / 245 80 / 213

[00131] In some embodiments, an anti-TMPRSS6 antibody of the present disclosure comprises: an HC CDR1 that is at least 80% (for example, 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 that has the amino acid sequence of SEQ ID NO: 13; a HC CDR2 that is at least 80% (for example, 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 CDR2 having the amino acid sequence of SEQ ID NO: 43;and / or an HC CDR3 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 HC CDR3 having the amino acid sequence of SEQ ID NO: 15. Alternatively or additionally, the anti-TMPRSS6 antibody of the present disclosure comprises: an LC CDR1 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 LC CDR1 which has the amino acid sequence of SEQ ID; NO: 16; an LC CDR2 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 LC CDR2 that has the amino acid sequence of WAF; and / or an LC CDR3 that is at least 80% (for example, 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 CDR3 that has the amino acid sequence SEQ ID NO: 18. Petition 870250088518, dated 09 / 30 / 2025, p. 94 / 245 81 / 213

[00132] In some embodiments, an anti-TMPRSS6 antibody of the present disclosure comprises a VH comprising the amino acid sequence of SEQ ID NO: 44. Alternatively or additionally, the anti-TMPRSS6 antibody of the present disclosure comprises a VL comprising the amino acid sequence of SEQ ID NO: 45.

[00133] In some embodiments, an anti-TMPRSS6 antibody of the present disclosure comprises a VH containing no more than 20 amino acid variations (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 variation) compared to VH as set forth in SEQ ID NO: 44. Alternatively or additionally, the anti-TMPRSS6 antibody of the present disclosure comprises a VL containing no more than 20 amino acid variations (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 variation) compared to VL as established in SEQ ID NO: 45. In some embodiments, the number of amino acid variations (e.g., not 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 variation) may occur within a VH of SEQ ID NO: 44 and / or a VL of SEQ ID NO: 45, excluding any of the CDR sequences contained therein. In some embodiments, the anti-TMPRSS6 antibodies provided herein comprise a variable heavy chain sequence comprising a structure sequence containing 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 variation for the structural sequence of a VH with SEQ ID NO: 44, and / or a variable light chain sequence comprising a structural sequence containing 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 variation for the structural sequence of a VL with SEQ ID NO: 45. Petition 870250088518, dated 09 / 30 / 2025, p. 95 / 245 82 / 213

[00134] In some embodiments, an anti-TMPRSS6 antibody of the present disclosure comprises a VH comprising an amino acid sequence that is at least 80% (for example, 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%) of the VH as set forth in SEQ ID NO: 44. Alternatively or additionally, the anti-TMPRSS6 antibody of the present disclosure comprises a VL comprising an amino acid sequence that is at least 80% (for example, 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%, by less than 97%, at least 98%, or at least 99% identical to the VL as established in SEQ ID NO: 45.In some forms, the 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 a VH of SEQ ID NO: 44 and / or a VL of SEQ ID NO: 45 excluding any of the CDR sequences contained therein.In some embodiments, an anti-TMPRSS6 antibody provided herein comprises a variable heavy chain 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 structural sequence of a VH with SEQ ID NO: 44, and / or a variable light chain sequence comprising a structural 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 structural sequence of a VL of SEQ ID NO: 45. Petition 870250088518, dated 09 / 30 / 2025, page 96 / 245 83 / 213

[00135] In some embodiments, an anti-TMPRSS6 antibody of the present disclosure comprises an HC CDR1, HC CDR2 and HC CDR3 of a variable heavy chain domain having the amino acid sequence of SEQ ID NO: 49. Alternatively or additionally, the anti-TMPRSS6 antibody of the present disclosure comprises an LC CDR1, LC CDR2 and LC CDR3 of a variable light chain domain having the amino acid sequence of SEQ ID NO: 50.

[00136] In some embodiments, according to Kabat's system of definition, an anti-TMPRSS6 antibody of the present disclosure comprises an HC CDR1 having the amino acid sequence of SEQ ID NO: 24, an HC CDR2 having the amino acid sequence of SEQ ID NO: 48, an HC CDR3 having the amino acid sequence of SEQ ID NO: 26, an LC CDR1 having the amino acid sequence of SEQ ID NO: 27, an LC CDR2 having the amino acid sequence of WAT and an LC CDR3 having the amino acid sequence of SEQ ID NO: 29.

[00137] In some embodiments, an anti-TMPRSS6 antibody of the present disclosure comprises an HC CDR1, an HC CDR2, and an HC CDR3, which collectively contain no more than 5 amino acid variations (e.g., no more than 5, 4, 3, 2, or 1 amino acid variation) compared to HC CDR1 having the amino acid sequence of SEQ ID NO: 24, HC CDR2 having the amino acid sequence of SEQ ID NO: 48, and HC CDR3 having the amino acid sequence of SEQ ID NO: 26. Alternatively or additionally, the anti-TMPRSS6 antibody of the present disclosure comprises an LC CDR1, an LC CDR2, and an LC CDR3, which collectively contain no more than 5 amino acid variations (e.g., no more than 5, 4, 3, 2, or 1 amino acid variation) compared to LC CDR1 having the amino acid sequence of SEQ ID NO: 27, LC CDR2 having the amino acid sequence of WAT and LC CDR3 having the amino acid sequence of SEQ ID NO: 29.

[00138] In some embodiments, an anti-TMPRSS6 antibody of the present disclosure comprises an HC CDR1, an HC CDR2 and an HC Petition 870250088518, dated 09 / 30 / 2025, p. 97 / 245 84 / 213 CDR3s that collectively represent at least 80% (for example, 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%) of HC CDR1 having the amino acid sequence SEQ ID NO: 24, HC CDR2 having the amino acid sequence SEQ ID NO: 48, and HC CDR3 having the amino acid sequence SEQ ID NO: 26. Alternatively or additionally, the anti-TMPRSS6 antibody of the present disclosure comprises an LC CDR1, an LC CDR2, and an LC CDR3 that collectively are at least 80% (for example, 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 having the amino acid sequence of SEQ ID NO: 27, to LC CDR2 having the amino acid sequence of WAT, and to LC CDR3 having the amino acid sequence SEQ ID NO: 29.

[00139] In some embodiments, an anti-TMPRSS6 antibody of the present disclosure comprises: an HC CDR1 with a maximum of 3 amino acid variations (e.g., a maximum of 3, 2 or 1 amino acid variation) compared to HC CDR1 having the amino acid sequence of SEQ ID NO: 24; an HC CDR2 with a maximum of 3 amino acid variations (e.g., a maximum of 3, 2 or 1 amino acid variation) compared to HC CDR2 having the amino acid sequence of SEQ ID NO: 48; and / or an HC CDR3 with a maximum of 3 amino acid variations (e.g., a maximum of 3, 2 or 1 amino acid variation) compared to HC CDR3 having the amino acid sequence of SEQ ID NO: 26.Alternatively or additionally, the anti-TMPRSS6 antibody of the present disclosure comprises: a CDR1 LC with a maximum of 3 amino acid variations (e.g., a maximum of 3, 2, or 1 amino acid variation) compared to a CDR1 LC having the amino acid sequence of SEQ ID NO: 27; a CDR2 LC with a maximum of 3 amino acid variations (e.g., a maximum of 3, 2, or 1 amino acid variation) compared to a CDR1 LC having the amino acid sequence of SEQ ID NO: 27. Petition 870250088518, dated 09 / 30 / 2025, p. 98 / 245 85 / 213 or 1 amino acid variation) compared to a CDR2 LC having the amino acid sequence WAT; and / or a CDR3 LC with a maximum of 3 amino acid variations (e.g., a maximum of 3, 2, or 1 amino acid variation) compared to a CDR3 LC having the amino acid sequence SEQ ID NO: 29.

[00140] In some embodiments, an anti-TMPRSS6 antibody of the present disclosure comprises: an HC CDR1 that is at least 80% (for example, 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 that has the amino acid sequence of SEQ ID NO: 24; a HC CDR2 that is at least 80% (for example, 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 CDR2 having the amino acid sequence of SEQ ID NO: 48;and / or an HC CDR3 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 HC CDR3 having the amino acid sequence of SEQ ID NO: 26. Alternatively or additionally, the anti-TMPRSS6 antibody of the present disclosure comprises: an LC CDR1 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 LC CDR1 which has the amino acid sequence of SEQ ID; NO: 27; an LC CDR2 that is at least 80% (for example, at least 80%, at least 85%, at least 90%, at least 91% 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 CDR2 LC that has the amino acid sequence of WAT; and / or an LC Petition 870250088518, dated 09 / 30 / 2025, p. 99 / 245 86 / 213 CDR3 that is at least 80% (for example, 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 CDR3 having the amino acid sequence of SEQ ID NO: 29.

[00141] In some embodiments, an anti-TMPRSS6 antibody of the present disclosure comprises a VH comprising the amino acid sequence of SEQ ID NO: 49. Alternatively or additionally, the anti-TMPRSS6 antibody of the present disclosure comprises a VL comprising the amino acid sequence of SEQ ID NO: 50.

[00142] In some embodiments, an anti-TMPRSS6 antibody of the present disclosure comprises a VH containing no more than 20 amino acid variations (for example, 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 variation) compared to VH as set forth in SEQ ID NO: 49. Alternatively, or additionally, the anti-TMPRSS6 antibody of the present disclosure comprises a VL containing no more than 20 amino acid variations (for example, no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 9, 8, 7, 6, 5, 4, 3, 2 or 1 variation of amino acid) compared to VL as set out in SEQ ID NO: 50. In some embodiments, the number of amino acid variations (e.g., not 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 variation) may occur within a VH of SEQ ID NO: 49 and / or a VL of SEQ ID NO: 50, excluding any of the CDR sequences contained therein.In some embodiments, the anti-TMPRSS6 antibodies provided herein comprise a variable heavy chain sequence comprising a structure sequence containing 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 variation for the structure sequence of a VH of SEQ ID NO: 49, and / or a... Petition 870250088518, dated 09 / 30 / 2025, pp. 100 / 245 87 / 213 variable light chain sequence comprising a structure sequence containing 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 variation for the structure sequence of a VL of SEQ ID NO: 50.

[00143] In some embodiments, an anti-TMPRSS6 antibody of the present disclosure comprises a VH comprising an amino acid sequence that is at least 80% (for example, 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 as set forth in SEQ ID NO: 49. Alternatively or additionally, the anti-TMPRSS6 antibody of the present disclosure comprises a VL comprising an amino acid sequence that is at least 80% (for example, 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 as established in SEQ ID NO: 50.In some forms, the 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 a VH of SEQ ID NO: 49 and / or a VL of SEQ ID NO: 50 excluding any of the CDR sequences contained therein. In some embodiments, an anti-TMPRSS6 antibody provided herein comprises a variable heavy chain 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 structural sequence of a VH with SEQ ID NO: 49, and / or a variable light chain sequence comprising a structural sequence that is at least 75% identical. Petition 870250088518, dated 09 / 30 / 2025, page 101 / 245 88 / 213 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 structural sequence of a VL with SEQ ID NO: 50.

[00144] In some embodiments, an anti-TMPRSS6 antibody described herein is a chimeric antibody, which may include a heavy constant region and a light constant region of a human antibody. Chimeric antibodies refer to antibodies that possess a variable region or part of a variable region from a first species and a constant region from a second species. Typically, in these chimeric antibodies, the variable region of the light and heavy chains mimics the variable regions of antibodies derived from one mammalian species (e.g., a non-human mammal such as a mouse, rabbit, and rat), while the constant portions are homologous to sequences in antibodies derived from another mammal, such as humans. In some embodiments, amino acid modifications may be made to the variable region and / or the constant region.

[00145] In some embodiments, an anti-TMPRSS6 antibody of the present disclosure comprises a VH domain and / or VL domain of any of the anti-TMPRSS6 antibodies selected from Table 2 and comprises a constant region comprising the amino acid sequences of the constant regions of an IgG, IgE, IgM, IgD, IgA or IgY immunoglobulin molecule, any class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2) or any subclass (e.g., IgG2a and IgG2b) of the immunoglobulin molecule. Non-limiting examples of human constant regions are described in the art, for example, see Kabat E A et al., (1991) above.

[00146] In some embodiments, the light chain of any of the anti-TMPRSS6 antibodies described herein may further comprise a constant light chain (LC) region, which may be any LC known in the art. In some examples, the LC is a Petition 870250088518, dated 09 / 30 / 2025, p. 102 / 245 89 / 213 kappa light chain. In other examples, CL is a lambda light chain. In some embodiments, CL is a kappa light chain.

[00147] Other constant regions of antibody heavy and light chains are well known in the art, for example, those provided in the IMGT database (www.imgt.org) or at www.vbase2.org / vbstat.php, both incorporated herein by reference.

[00148] In some embodiments, an anti-TMPRSS6 antibody described herein comprises a heavy chain comprising any of the VHs listed in Table 2 or any variants thereof, and a constant region of the heavy chain that is 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% of SEQ ID NO: 9. In some embodiments, an anti-TMPRSS6 antibody described herein comprises a heavy chain comprising any of the VHs listed in Table 2 or any variants thereof and a constant region of the heavy chain containing no more than 20 amino acid variations (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 variation) compared to SEQ ID NO: 9.In some embodiments, an anti-TMPRSS6 antibody described herein comprises a heavy chain comprising any of the VHs listed in Table 2 or any variants thereof and a constant heavy chain region set at SEQ ID NO: 9.

[00149] In some embodiments, an anti-TMPRSS6 antibody described herein comprises a heavy chain comprising any of the VHs listed in Table 2 or any variants thereof, and a constant region of the heavy chain that is 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% Petition 870250088518, dated 09 / 30 / 2025, page 103 / 245 90 / 213 identical to SEQ ID NO: 21. In some embodiments, an anti-TMPRSS6 antibody described herein comprises a heavy chain comprising any of the VHs listed in Table 2 or any variants thereof and a constant region of the heavy chain containing no more than 20 amino acid variations (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 variation) compared to SEQ ID NO: 21. In some embodiments, an anti-TMPRSS6 antibody described herein comprises a heavy chain comprising any of the VHs listed in Table 2 or any variants thereof and a constant heavy chain region set at SEQ ID NO: 21.

[00150] In some embodiments, an anti-TMPRSS6 antibody described herein comprises a heavy chain comprising any of the VHs listed in Table 2 or any variants thereof, and a constant region of the heavy chain that is 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 SEQ ID NO: 39. In some embodiments, an anti-TMPRSS6 antibody described herein comprises a heavy chain comprising any of the VHs listed in Table 2 or any variants thereof and a constant region of the heavy chain containing no more than 20 amino acid variations (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 variation) compared to SEQ ID NO: 39. In some embodiments, an anti-TMPRSS6 antibody described herein comprises a heavy chain comprising any of the VHs listed in Table 2 or any variants thereof and a constant heavy chain region set at SEQ ID NO: 39.

[00151] In some embodiments, an anti-TMPRSS6 antibody described herein comprises a heavy chain comprising Petition 870250088518, dated 09 / 30 / 2025, page 104 / 245 91 / 213 any of the VHs listed in Table 2 or any variants thereof, and a constant region of the heavy chain that is 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 SEQ ID NO: 51. In some embodiments, an anti-TMPRSS6 antibody described herein comprises a heavy chain comprising any of the VHs listed in Table 2 or any variants thereof and a constant region of the heavy chain containing no more than 20 amino acid variations (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 variation) compared to SEQ ID NO: 51. In some embodiments, an anti-TMPRSS6 antibody described herein comprises a heavy chain comprising any of the VHs listed in Table 2 or any variants thereof and a constant heavy chain region set at SEQ ID NO: 51.

[00152] In some embodiments, an anti-TMPRSS6 antibody described herein comprises a light chain comprising any of the VLs listed in Table 2 or any variants thereof, and a constant region of the light chain that is 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% of the SEQ ID NO: 10. In some embodiments, an anti-TMPRSS6 antibody described herein comprises a light chain comprising any of the VLs listed in Table 2 or any variants thereof and a constant region of the light chain containing a maximum of 20 amino acid variations (e.g., not 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 variation) compared with SEQ ID NO: 10. In some embodiments, an anti-TMPRSS6 antibody described herein comprises a light chain comprising any of the VL Petition 870250088518, dated 09 / 30 / 2025, p. 105 / 245 92 / 213 listed in Table 2 or any variants thereof and a constant region of the light chain established in SEQ ID NO: 10.

[00153] In some embodiments, an anti-TMPRSS6 antibody described herein comprises a light chain comprising any of the VLs listed in Table 2 or any variants thereof, and a constant region of the light chain that is 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% of the SEQ ID NO: 40. In some embodiments, an anti-TMPRSS6 antibody described herein comprises a light chain comprising any of the VLs listed in Table 2 or any variants thereof and a constant region of the light chain containing a maximum of 20 amino acid variations (e.g., not 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 variation) compared to SEQ ID NO: 40. In some embodiments, an anti-TMPRSS6 antibody described herein comprises a light chain comprising any of the VLs listed in Table 2 or any variants thereof and a constant region of the light chain set at SEQ ID NO: 40. Examples of heavy and light chain amino acid sequences of the IgG anti-TMPRSS6 antibodies described are provided in Table 2 above.

[00154] In some embodiments, an anti-TMPRSS6 antibody of the present disclosure comprises a heavy chain containing no more than 20 amino acid variations (for example, 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 variation) compared to the heavy chain as set forth in SEQ ID NO: 11. Alternatively or additionally, the anti-TMPRSS6 antibody of the present disclosure comprises a light chain containing no more than 20 amino acid variations (e.g., no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 9, 8, 7, 6, 5, 4, 3, 2 Petition 870250088518, dated 09 / 30 / 2025, p. 106 / 245 93 / 213 or 1 amino acid variation) compared to the light chain as established in SEQ ID NO: 12. In some embodiments, an anti-TMPRSS6 antibody described herein comprises a heavy chain comprising an amino acid sequence that is at least 80%, 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% of SEQ ID NO: 11. Alternatively or additionally, the anti-TMPRSS6 antibody described herein comprises a light chain comprising an amino acid sequence that is at least 80%, 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 SEQ ID NO: 12.In some embodiments, an anti-TMPRSS6 antibody described herein comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 11. Alternatively or additionally, the anti-TMPRSS6 antibody described herein comprises a light chain comprising the amino acid sequence of SEQ ID NO: 12.

[00155] In some embodiments, an anti-TMPRSS6 antibody of the present disclosure comprises a heavy chain containing no more than 20 amino acid variations (for example, 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 variation) compared to the heavy chain as set forth in SEQ ID NO: 17 or 22. Alternatively or additionally, the anti-TMPRSS6 antibody of the present disclosure comprises a light chain containing no more than 20 amino acid variations (for example, no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 9, 8, 7, 6, 5, 4, 3, 2 or 1 variation of amino acid) compared to the light chain as established in SEQ ID NO: 23. In some embodiments, an anti-TMPRSS6 antibody described herein comprises a heavy chain comprising an amino acid sequence that is at least Petition 870250088518, dated 09 / 30 / 2025, p. 107 / 245 94 / 213 minus 80% (e.g., 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) identical to SEQ ID NO: 17 or 22. Alternatively or additionally, the anti-TMPRSS6 antibody described herein comprises a light chain comprising an amino acid sequence that is at least 80% (e.g., 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) identical to SEQ ID NO: 23. In some embodiments, an anti-TMPRSS6 antibody described herein comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 17 or 22. Alternatively or additionally, the antibody The anti-TMPRSS6 described herein comprises a light chain comprising the amino acid sequence SEQ ID NO: 23.

[00156] In some embodiments, an anti-TMPRSS6 antibody of the present disclosure comprises a heavy chain containing no more than 20 amino acid variations (for example, 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 variation) compared to the heavy chain as set forth in SEQ ID NO: 33. Alternatively or additionally, the anti-TMPRSS6 antibody of the present disclosure comprises a light chain containing no more than 20 amino acid variations (for example, 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 variation). compared to the light chain as set forth in SEQ ID NO: 34. In some embodiments, an anti-TMPRSS6 antibody described herein comprises a heavy chain comprising an amino acid sequence that is at least 80% (e.g., 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) identical to SEQ ID NO: 33.Alternatively or additionally, the anti-TMPRSS6 antibody described herein comprises a light chain comprising an amino acid sequence that is at least 80% (e.g., 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) identical to SEQ ID NO: 34. In some embodiments, an anti-TMPRSS6 antibody described herein... Petition 870250088518, dated 09 / 30 / 2025, p. 108 / 245 The 95 / 213 described comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 33. Alternatively or additionally, the anti-TMPRSS6 antibody described herein comprises a light chain comprising the amino acid sequence of SEQ ID NO: 34.

[00157] In some embodiments, an anti-TMPRSS6 antibody of the present disclosure comprises a heavy chain containing no more than 20 amino acid variations (for example, 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 variation) compared to the heavy chain as set forth in SEQ ID NO: 41. Alternatively or additionally, the anti-TMPRSS6 antibody of the present disclosure comprises a light chain containing no more than 20 amino acid variations (for example, 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 variation). compared to the light chain as set forth in SEQ ID NO: 42. In some embodiments, an anti-TMPRSS6 antibody described herein comprises a heavy chain comprising an amino acid sequence that is at least 80% (e.g., 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) identical to SEQ ID NO: 41.Alternatively or additionally, the anti-TMPRSS6 antibody described herein comprises a light chain comprising an amino acid sequence that is at least 80% (e.g., 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) identical to SEQ ID NO: 42. In some embodiments, an anti-TMPRSS6 antibody described herein comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 41. Alternatively or additionally, the anti-TMPRSS6 antibody described herein comprises a light chain comprising the amino acid sequence of SEQ ID NO: 42.

[00158] In some embodiments, an anti-TMPRSS6 antibody of the present disclosure comprises a heavy chain containing no Petition 870250088518, dated 09 / 30 / 2025, p. 109 / 245 96 / 213 more than 20 amino acid variations (e.g., not 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 variation) compared to the heavy chain as set forth in SEQ ID NO: 46. Alternatively or additionally, the anti-TMPRSS6 antibody of the present disclosure comprises a light chain containing not more than 20 amino acid variations (e.g., not more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) compared to the light chain as set forth in SEQ ID NO: 47. In In some embodiments, an anti-TMPRSS6 antibody described herein comprises a heavy chain comprising an amino acid sequence that is at least 80% (e.g., 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) identical to SEQ ID NO: 46.Alternatively or additionally, an anti-TMPRSS6 antibody described herein comprises a light chain comprising an amino acid sequence that is at least 80% (e.g., 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) identical to SEQ ID NO: 47. In some embodiments, an anti-TMPRSS6 antibody described herein comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 46. Alternatively or additionally, the anti-TMPRSS6 antibody described herein comprises a light chain comprising the amino acid sequence of SEQ ID NO: 47.

[00159] In some embodiments, an anti-TMPRSS6 antibody of the present disclosure comprises a heavy chain containing no more than 20 amino acid variations (for example, 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 variation) compared to the heavy chain as set forth in SEQ ID NO: 52. Alternatively or additionally, the anti-TMPRSS6 antibody of the present disclosure comprises a light chain containing no more than 20 amino acid variations (for example, no more than Petition 870250088518, dated 09 / 30 / 2025, p. 110 / 245 97 / 213 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 9, 8, 7, 6, 5, 4, 3, 2 or 1 amino acid variation) compared to the light chain as established in SEQ ID NO: 53. In some embodiments, an anti-TMPRSS6 antibody described herein comprises a heavy chain comprising an amino acid sequence that is at least 80% (e.g., 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) identical to SEQ ID NO: 52. Alternatively or additionally, the anti-TMPRSS6 antibody described herein comprises a light chain comprising an amino acid sequence that is at least 80% (e.g., 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) identical to the SEQ ID NO: 53. In some embodiments, an anti-TMPRSS6 antibody described herein comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 52. Alternatively or additionally, the anti-TMPRSS6 antibody described herein comprises a light chain comprising the amino acid sequence of SEQ ID NO: 53.

[00160] The anti-TMPRSS6 antibodies described herein may be in any antibody form, including, but not limited to, intact (i.e., full-length) antibodies, antigen-binding fragments (such as Fab, F(ab'), F(ab')2, Fv), single-chain antibodies, bispecific antibodies, or nanobodies. In some embodiments, an anti-TMPRSS6 antibody described herein is an scFv. In some embodiments, an anti-TMPRSS6 antibody described herein is an scFvFab (e.g., scFv fused to a portion of a constant region).

[00161] In some embodiments, conservative mutations can be introduced into antibody sequences (e.g., CDRs or framework sequences) at positions where the residues are unlikely to be involved in interaction with a target antigen (e.g., TMPRSS6), for example, as determined based on a crystal structure. In some embodiments, Petition 870250088518, dated 09 / 30 / 2025, page 111 / 245 98 / 213 One, two, or more mutations (e.g., amino acid substitutions) are introduced into the Fc region of an antiTMPRSS6 antibody described herein (e.g., in a CH2 domain (residues 231 to 340 of human IgG1) and / or CH3 domain (residues 341 to 447 of human IgG1) and / or in the hinge region, numbered according to the Kabat numbering system (e.g., the EU index in Kabat)) to alter one or more functional properties of the antibody, such as serum half-life, complement fixation, Fc receptor binding, and / or antigen-dependent cellular cytotoxicity.

[00162] 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) so that the number of cysteine ​​residues in the hinge region is altered (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 may be altered to, for example, facilitate the assembly of the light and heavy chains, or to alter (e.g., increase or decrease) the stability of the antibody, or to facilitate connector conjugation.

[00163] In some embodiments, one, two, or more mutations (e.g., amino acid substitutions) are introduced into the Fc region of an antibody described herein (e.g., in a CH2 domain (residues 231 to 340 of human IgG1) and / or CH3 domain (residues 341 to 447 of human IgG1) and / or in the hinge region, numbered according to the Kabat numbering system (e.g., the EU index in Kabat) to increase or decrease the antibody's affinity for an Fc receptor (e.g., an activated Fc receptor) on the surface of an effector cell. Mutations in the Fc region of an antibody that decrease or increase the antibody's affinity for an Fc receptor and techniques for introducing such mutations into the Fc receptor or a fragment thereof. Petition 870250088518, dated 09 / 30 / 2025, page 112 / 245 99 / 213 are known to a person skilled in the art. Examples of mutations in the Fc receptor of an antibody that can be made to alter the antibody's affinity for an Fc receptor are described in, for example, Smith P et al., (2012) PNAS 109: 6181-6186, Pat. US No. 6,737,056 and International Publication No. WO 97 / 34631, which are incorporated herein by reference.

[00164] In some embodiments, one, two, or more amino acid mutations (i.e., substitutions, insertions, or deletions) are introduced into an IgG constant domain, or FcRn binding fragment thereof (preferably an Fc domain fragment or Fc hinge fragment) to alter (e.g., decrease or increase) the antibody half-life in vivo. See, for example, International Publication No. WO 97 / 34631; and U.S. Patents Nos. 5,869,046, 6,121,022, 6,277,375, and 6,165,745 for examples of mutations that will alter (e.g., decrease or increase) the half-life of an antibody in vivo.

[00165] In some embodiments, one, two, or more amino acid mutations (i.e., substitutions, insertions, or deletions) are introduced into an IgG constant domain, or an FcRn-binding fragment thereof (preferably an Fc domain fragment or Fc hinge fragment) to decrease the half-life of the anti-TMPRSS6 antibody in vivo. In some embodiments, one, two, or more amino acid mutations (i.e., substitutions, insertions, or deletions) are introduced into an IgG constant domain, or an FcRn-binding fragment thereof (preferably an Fc domain fragment or Fc hinge fragment) to increase the half-life of the antibody in vivo. In some embodiments, antibodies may have one or more amino acid mutations (e.g., substitutions) in the second constant domain (CH2) (residues 231 to 340 of human IgG1) and / or in the third constant domain (CH3) (residues 341 to 447 of human IgG1), numbered according to the EU index in Kabat (Kabat EA et al., (1991) supra).In some forms, the constant region of IgG1 of an antibody. Petition 870250088518, dated 09 / 30 / 2025, page 113 / 245 The 100 / 213 described herein comprises a methionine (M) to tyrosine (Y) substitution at position 252, a serine (S) to threonine (T) substitution at position 254, and a threonine (T) to glutamic acid (E) substitution at position 256, numbered according to the EU index as in Kabat, see US Patent No. 7,658,921, which is incorporated herein by reference. This type of mutant IgG, termed the YTE mutant, has been shown to have a half-life four times longer compared to wild-type versions of the same antibody (see Dall'Acqua WF et al., (2006) J Biol Chem 281: 23514-24).

[00166] In some embodiments, one, two, or more amino acid substitutions are introduced into an Fc region of the IgG constant domain to alter the effector function(s) of the anti-TMPRSS6 antibody. The effector ligand whose affinity is altered may be, for example, an Fc receptor or the C1 component of complement. This approach is described in more detail in U.S. Patent Nos. 5,624,821 and 5,648,260. In some embodiments, one or more amino acid substitutions may be introduced into the Fc region of an antibody described herein to remove potential glycosylation sites in the Fc region, which may reduce Fc receptor binding (see, for example, Shields RL et al., (2001) J Biol Chem 276: 6591-604).

[00167] In some embodiments, one or more amino acids in the constant region of an anti-TMPRSS6 antibody described herein may be replaced by a different amino acid residue, so that the antibody has altered Clq binding and / or reduced or abolished complement-dependent cytotoxicity (CDC). This approach is described in more detail in US Patent 6,194,551 (Idusogie et al.). In some embodiments, one or more amino acid residues in the N-terminal region of the CH2 domain of an antibody described herein are altered to thereby alter the antibody's ability to fix complement. This approach is described in more detail in International Publication No. WO 94 / 29351. In some embodiments, the Fc region of an antibody Petition 870250088518, dated 09 / 30 / 2025, pp. 114 / 245 The 101 / 213 described here is modified to increase the antibody's ability to mediate antibody-dependent cellular cytotoxicity (ADCC) and / or increase the antibody's affinity for an Fcy receptor. This approach is described in more detail in International Publication No. WO 00 / 42072.

[00168] In some embodiments, the variable domain sequence(s) of the heavy and / or light chain of the antibodies provided herein may be used to generate, for example, human CDR-grafted, chimeric, humanized, or compound antibodies or antigen-binding fragments, as described elsewhere herein. To the extent understood by a person skilled in the art, any variant, CDR-grafted, chimeric, humanized, or compound antibody derived from any of the antibodies provided herein may be useful in the compositions and methods described herein and will retain the ability to bind specifically to TMPRSS6, such that the variant, CDR-grafted, chimeric, humanized, or compound antibody has at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95% or more binding to TMPRSS6 relative to the original antibody from which it is derived.

[00169] In some embodiments, the antibodies provided here comprise mutations that confer desirable properties to the antibodies. For example, to avoid potential complications due to Fab arm switching, which occurs with native IgG4 mAbs, the antibodies provided here may comprise a stabilizing 'Adair' mutation (Angal S., et al., A single amino acid substitution abolished the heterogeneity of the chimeric mouse / human antibody (IgG4), Mol Immunol 30, 105-108; 1993), where serine 228 (EU numbering; residue 241 Kabat numbering) is converted to proline, resulting in a hinge sequence similar to IgG1. Consequently, any of the antibodies may include a stabilizing 'Adair' mutation. Petition 870250088518, dated 09 / 30 / 2025, pp. 115 / 245 102 / 213

[00170] In some embodiments, an antibody is modified, for example, modified by glycosylation, phosphorylation, sumoylation, and / or methylation. In some embodiments, an antibody is a glycosylated antibody, which is conjugated to one or more sugar or carbohydrate molecules. In some embodiments, one or more sugar or carbohydrate molecules are conjugated to the antibody by N-glycosylation, O-glycosylation, C-glycosylation, glypiation (GPI anchor attachment), and / or phosphoglycosylation. In some embodiments, one or more sugar or carbohydrate molecules are monosaccharides, disaccharides, oligosaccharides, or glycans. In some embodiments, one or more sugar or carbohydrate molecules are a branched oligosaccharide or a branched glycan.In some embodiments, one or more sugar or carbohydrate molecules include a mannose unit, a glucose unit, an N-acetylglucosamine unit, an N-acetylgalactosamine unit, a galactose unit, a fucose unit, or a phospholipid unit. In some embodiments, there are approximately 1 to 10, approximately 1 to 5, approximately 5 to 10, approximately 1 to 4, approximately 1 to 3, or approximately 2 sugar molecules. In some embodiments, a glycosylated antibody is totally or partially glycosylated. In some embodiments, an antibody is glycosylated by chemical reactions or by enzymatic means. In some embodiments, an antibody is glycosylated in vitro or within a cell, which may optionally be deficient in an enzyme in the N- or O-glycosylation pathway, for example, a glycosyltransferase.In some embodiments, an antibody is functionalized with sugar or carbohydrate molecules, as described in International Patent Application Publication WO 2014 / 065661, published on May 1, 2014, entitled “Modified antibody, antibody conjugate and process for the preparation thereof”.

[00171] In some embodiments, any of the anti-TMPRSS6 antibodies described herein may comprise a signal peptide. Petition 870250088518, dated 09 / 30 / 2025, page 116 / 245 103 / 213 in the heavy and / or light chain sequence (e.g., an N-terminal signal peptide). In some embodiments, the antiTMPRSS6 antibody described herein comprises any of the VH and VL sequences, any of the IgG heavy and light chain sequences, or any of the F(ab') heavy and light chain sequences described herein, and further comprises a signal peptide (e.g., an N-terminal signal peptide). III. Preparation of anti-TMPRSS6 antibodies

[00172] Antibodies capable of binding to TMPRSS6, as described herein, can be produced by any method known in the art. See, for example, Harlow and Lane, (1998) Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory, New York.

[00173] In some embodiments, antibodies specific to a target antigen (e.g., TMPRSS6) can be produced by conventional hybridoma technology. The full-length target antigen or a fragment thereof, optionally coupled to a carrier protein such as KLH, can be used to immunize a host animal to generate antibodies that bind to that antigen. The route and timing of host animal immunization generally conform to established and conventional techniques for antibody stimulation and production, as described in more detail herein. General techniques for producing mouse, humanized, and human antibodies are known in the art and are described herein. It is considered that any mammalian individual, including humans, or antibody-producing cells, can be manipulated to serve as a basis for the production of mammalian, including human, hybrid cell lines.Typically, the host animal is inoculated intraperitoneally, intramuscularly, orally, subcutaneously, intraplantarly, and / or intradermally with a quantity of immunogen, including as described here. Petition 870250088518, dated 09 / 30 / 2025, p. 117 / 245 104 / 213

[00174] If desired, an antibody (monoclonal or polyclonal) of interest (e.g., produced by a hybridoma) can be sequenced, and the polynucleotide sequence can then be cloned into a vector for expression or propagation. The sequence encoding the antibody of interest can be maintained in the vector in a host cell, and the host cell can then be expanded and frozen for future use. Alternatively, the polynucleotide sequence can be used for genetic manipulation to humanize the antibody or to improve the affinity (affinity maturation) or other characteristics of the antibody. For example, the constant region can be modified to more closely resemble human constant regions to avoid an immune response if the antibody is used in clinical trials and treatments in humans. It may be desirable to genetically manipulate the antibody sequence to achieve higher affinity for the target antigen and greater efficacy.It will be evident to a person skilled in the art that one or more polynucleotide changes can be made to the antibody and still maintain its specificity for binding to the target antigen.

[00175] In other embodiments, fully human antibodies can be obtained using commercially available mice that have been modified to express specific human immunoglobulin proteins. Transgenic animals engineered to produce a more desirable (e.g., fully human antibodies) or more robust immune response can also be used for the generation of humanized or human antibodies. Examples of this technology are the XenomouseRTM from Amgen, Inc. (Fremont, CA) and the HuMAb-MouseRTM and TC MouseTM from Medarex, Inc. (Princeton, NJ) or H2L2 mice from Harbour Antibodies BV (Netherlands). Alternatively, antibodies can be produced recombinantly by phage display or yeast technology. See, for example, US Patent Nos. 5,565,332; 5,580,717; 5,733,743; and 6,265,150; and Winter et al., (1994) Annu. Petition 870250088518, dated 09 / 30 / 2025, page 118 / 245 105 / 213 Rev. Imunol. 12:433-455. Alternatively, phage display technology (McCafferty et al., (1990) Nature 348:552-553) can be used to produce human antibodies and antibody fragments in vitro from immunoglobulin variable domain (V) gene repertoires from non-immunized donors.

[00176] Antigen-binding fragments of an intact antibody (full-length antibody) can be prepared using routine methods. For example, F(ab')2 fragments can be produced by pepsin digestion of an antibody molecule, and Fab fragments can be generated by reducing the disulfide bridges of F(ab')2 fragments. Genetically modified antibodies, such as humanized antibodies, chimeric antibodies, single-chain antibodies, and bispecific antibodies, can be produced using, for example, conventional recombinant technology. In one example, the DNA encoding a monoclonal antibody specific for a target antigen can be easily isolated and sequenced using conventional procedures (e.g., using oligonucleotide probes that are capable of specifically binding to genes encoding the heavy and light chains of monoclonal antibodies). Hybridoma cells serve as a preferred source of this DNA.Once isolated, the DNA can be placed into one or more expression vectors, which are then transfected into host cells, such as E. coli cells, simian COS cells, Chinese hamster ovary (CHO) cells, human HEK293 cells, or myeloma cells that do not produce immunoglobulin protein, to obtain the synthesis of recombinant host monoclonal antibodies. See, for example, PCT Publication No. WO 87 / 04462. The DNA can then be modified, for example, by replacing the coding sequence of the constant domains of the human heavy and light chains in place of homologous murine sequences, Morrison et al., (1984) Proc. Nat. Acad. Sci. 81:6851, or by covalent joining to the sequence. Petition 870250088518, dated 09 / 30 / 2025, p. 119 / 245 106 / 213 coding sequence of the immunoglobulin from all or part of the coding sequence of a non-immunoglobulin polypeptide. In this way, genetically modified antibodies, such as chimeric or “hybrid” antibodies, can be prepared with the specificity to bind to a target antigen.

[00177] A single-chain antibody can be prepared using recombinant technology by linking a nucleotide sequence encoding a variable region of the heavy chain and a nucleotide sequence encoding a variable region of the light chain. Preferably, a flexible connector is incorporated between the two variable regions.

[00178] Alternatively, techniques described for the production of single-chain antibodies (US Patents Nos. 4,946,778 and 4,704,692) can be adapted to produce a phage or yeast scFv library, and TMPRSS6-specific scFv clones can be identified from the library following routine procedures. Positive clones can be subjected to further screening to identify those with high binding affinity to TMPRSS6.

[00179] Antibodies obtained following a method known in the art and described herein can be characterized using methods well known in the art. For example, one method is to identify the epitope to which the antigen binds, or epitope mapping. There are many known methods in the field for mapping and characterizing the location of epitopes on proteins, including crystal structure resolution of an antibody-antigen complex, competition assays, gene fragment expression assays, and synthetic peptide-based assays, as described, for example, in Chapter 11 of Harlow and Lane, Using Antibodies, a Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, 1999. In one example, epitope mapping can be performed using H / D-Ex (hydrogen-deuterium exchange) coupled with proteolysis and Petition 870250088518, dated 09 / 30 / 2025, pp. 120 / 245 107 / 213 mass spectrometry. In a further example, epitope mapping can be used to determine the sequence to which an antibody binds. The epitope can be a linear epitope, i.e., contained in a single amino acid stretch, or a conformational epitope formed by a three-dimensional interaction of amino acids that may not necessarily be contained in a single stretch (linear sequence of the primary structure). Peptides of varying lengths (e.g., at least 4 to 6 amino acids in length) can be isolated or synthesized (e.g., recombinantly) and used for antibody binding assays. In another example, the epitope to which the antibody binds can be determined in a systematic screening using overlapping peptides derived from the target antigen sequence and determining antibody binding.According to gene fragment expression assays, the open reading frame encoding the target antigen is fragmented randomly or by specific genetic constructs, and the reactivity of the expressed antigen fragments with the antibody to be tested is determined. Gene fragments can, for example, be produced by PCR and then transcribed and translated into proteins in vitro, in the presence of radioactive amino acids. The binding of the antibody to the radioactively labeled antigen fragments is then determined by immunoprecipitation and gel electrophoresis. Certain epitopes can also be identified using large libraries of random peptide sequences displayed on the surface of phage particles (phage libraries). Alternatively, a defined library of overlapping peptide fragments can be tested for binding to the test antibody in single binding assays. In a further example, antigen-binding domain mutagenesis, domain exchange experiments, and alanine screening mutagenesis can be performed to identify required, sufficient, and / or necessary residues for epitope binding. Alternatively, Petition 870250088518, dated 09 / 30 / 2025, pp. 121 / 245 108 / 213 Competition assays can be performed using other antibodies known to bind to the same antigen to determine if an antibody binds to the same epitope as the other antibodies. Competition assays are well known to those skilled in the art.

[00180] In some examples, an anti-TMPRSS6 antibody is prepared by recombinant technology, as exemplified below. The nucleic acids encoding the heavy and light chains of an anti-TMPRSS6 antibody, as described herein, can be cloned into an expression vector, with each nucleotide sequence operably bound to a suitable promoter. In one example, each of the nucleotide sequences encoding the heavy and light chains is operably bound to a distinct promoter. Alternatively, the nucleotide sequences encoding the heavy and light chains can be operably bound to a single promoter, so that both the heavy and light chains are expressed from the same promoter. When necessary, an internal ribosomal entry site (IRES) can be inserted between the heavy and light chain coding sequences.

[00181] In some examples, the nucleotide sequences that encode the two antibody chains are cloned into two vectors, which can be introduced into the same cell or into different cells. When the two chains are expressed in different cells, each can be isolated from the host cells that express them, and the isolated heavy and light chains can be mixed and incubated under suitable conditions, allowing antibody formation.

[00182] Generally, a nucleic acid sequence encoding one or all of the strands of an antibody can be cloned into a suitable expression vector and operable with a suitable promoter using methods known in the art. For example, the nucleotide sequence and the vector may be Petition 870250088518, dated 09 / 30 / 2025, pp. 122 / 245 109 / 213 contacted, under suitable conditions, with a restriction enzyme to create complementary ends on each molecule that can pair with each other and be joined with a ligase. Alternatively, synthetic nucleic acid ligands can be ligated to the ends of a gene. These synthetic ligands contain nucleic acid sequences that correspond to a specific restriction site on the vector. The selection of vectors / expression promoters would depend on the type of host cells to be used in antibody production.

[00183] A variety of promoters can be used for expression of the antibodies described herein, including, but not limited to, cytomegalovirus (CMV) intermediate early promoter, a viral LTR such as the Rous sarcoma virus LTR, HIV-LTR, HTLV-1 LTR, simian virus 40 (SV40) early promoter, E. coli lac UV promoter and herpes simplex virus tk promoter.

[00184] Regulated promoters can also be used. Such regulated promoters include those that use the E. coli lac repressor as a transcription modulator to regulate the transcription of mammalian cell promoters carrying the lac operator (Brown, M. et al., Cell, 49:603-612 (1987)), those that use the tetracycline repressor (tetR) (Gossen, M., and Bujard, H., Proc. Natl. Acad. Sci. US 89:5547-555115 (1992); Yao, F. et al., Human Gene Therapy, 9:1939-1950 (1998); Shockelt, P., et al., Proc. Natl. Acad. Sci. US, 92:6522-6526 (1995)). Other systems include FK506, VP16, or p65 dimers using astradiol, RU486, the diphenol murislerone, or rapamycin. Inducible systems are available from Invitrogen, Clontech, and Ariad, among others.

[00185] Regulated promoters that include a repressor with the operon can be used. In one embodiment, the lac repressor of E. coli can function as a transcriptional modulator to regulate the transcription of mammalian cell promoters. Petition 870250088518, dated 09 / 30 / 2025, pp. 123 / 245 110 / 213 carriers of the lac operator (M. Brown et al., Cell, 49:603-612 (1987)); Gossen and Bujard (1992); (M. Gossen et al., Natl. Acad. Sci. US, 89:5547-5551(1992)) combined the tetracycline repressor (tetR) with the transcription activator (VP 16) to create a tetR-mammalian cell transcription activator fusion protein, tTa (tetR-VP16), with the tetO-bearing minimal promoter derived from the human cytomegalovirus (hCMV) promoter, to create a tetR-tet operator system to control gene expression in mammalian cells. In one embodiment, a tetracycline-inducible activator is used. The tetracycline repressor (tetR) alone, instead of the mammalian cell transcription factor tetR fusion derivatives, can function as a potent transmodulator to regulate gene expression in mammalian cells when the tetracycline operator is correctly positioned downstream of the TATA element of the CMVIE promoter (Yao et al., Human Gene Therapy).A particular advantage of this tetracycline-inducible activator is that it does not require the use of a transactivating or repressor fusion protein from mammalian cells with tetracycline repressor, which in some cases can be toxic to cells (Gossen 5 et al., Natl. Academic. Sci. US, 89:5547-5551 (1992); Shockett et al., Proc. Natl. Acad. Sci. US, 92:6522-6526 (1995)), to achieve its regulable effects.

[00186] In addition, the vector may contain, for example, some or all of the following: a selectable marker gene, such as the neomycin gene for selection of stable or transient transfectants in mammalian cells; enhancer / promoter sequences of the human CMV immediate early gene for high transcription levels; transcription termination signals and RNA processing of SV40 for mRNA stability; SV40 and ColE1 polyome replication origins for proper episomal replication; internal ribosome binding sites (IRESes), versatile multiple cloning sites; and Petition 870250088518, dated 09 / 30 / 2025, pages 124 / 245 111 / 213 T7 and SP6 RNA promoters for in vitro transcription of sense and antisense RNA. Suitable vectors and methods for producing vectors containing transgenes are well known and available in the art. Examples of polyadenylation signals useful for practicing the methods described herein include, but are not limited to, human collagen I polyadenylation signal, human collagen II polyadenylation signal, and SV40 polyadenylation signal.

[00187] One or more vectors (e.g., expression vectors) comprising nucleic acids encoding any of the antibodies (e.g., the nucleic acid coding sequence listed in Table 3) may be introduced into suitable host cells to produce the antibodies. Non-limiting examples of host cells include Chinese hamster ovary (CHO) cells, dhfr-CHO cells, human embryonic kidney (HEK)-293 cells, verda reno (VERO) cells, non-secretory null cells (NS0), human embryonic retinal (PER.C6) cells, Sp2 / 0 cells, baby hamster kidney (BHK) cells, Madin-Darby canine kidney (MDCK) cells, Madin-Darby bovine kidney (MDBK) cells, and SV40 cell-transformed monkey kidney CV1 cell line (COS). In some embodiments, the host cell expressing the anti-TMPRSS6 antibodies are CHO cells.Host cells can be cultured under suitable conditions for expression of the antibody or any polypeptide chain thereof. Such antibodies or polypeptide chains thereof can be recovered by the cultured cells (e.g., from the cells or the culture supernatant) by means of a conventional method, for example, affinity purification. If necessary, the antibody polypeptide chains can be incubated under suitable conditions for an appropriate period of time, allowing antibody production. In some embodiments, the host cell comprises the nucleic acid encoding the heavy chain of the antibody. Petition 870250088518, dated 09 / 30 / 2025, pages 125 / 245 112 / 213 anti-TMPRSS6 antibody. In some embodiments, the host cell comprises the nucleic acid encoding the light chain of the anti-TMPRSS6 antibody. In some embodiments, the host cell comprises the nucleic acid encoding the heavy chain and the nucleic acid encoding the light chain.

[00188] In some embodiments, the methods for preparing an antibody described herein involve a recombinant expression vector encoding both the heavy and light chains of an anti-TMPRSS6 antibody, as also described herein. The recombinant expression vector can be introduced into a suitable host cell (e.g., a CHO dhfr- cell) by a conventional method, e.g., calcium phosphate-mediated transfection. Positive transforming host cells can be selected and cultured under suitable conditions, allowing the expression of the two polypeptide chains that form the antibody, which can be recovered from the cells or the culture medium. When necessary, the two chains recovered from the host cells can be incubated under suitable conditions, allowing antibody formation.

[00189] In one example, two recombinant expression vectors are provided, one encoding the heavy chain of the anti-TMPRSS6 antibody and the other encoding the light chain of the anti-TMPRSS6 antibody. Both recombinant expression vectors can be introduced into a suitable host cell (e.g., CHO dhfr- cell) by a conventional method, e.g., calcium phosphate-mediated transfection.

[00190] Alternatively, each of the expression vectors can be introduced into a suitable host cell. Positive transformants can be selected and cultured under suitable conditions, allowing the expression of the antibody polypeptide chains. When the two expression vectors are introduced into the same host cells, the antibody Petition 870250088518, dated 09 / 30 / 2025, pp. 126 / 245 The 113 / 213 produced can be recovered from the host cells or culture medium. If necessary, the polypeptide chains can be recovered from the host cells or culture medium and then incubated under suitable conditions, allowing antibody formation. When the two expression vectors are introduced into different host cells, each can be recovered from the corresponding host cells or culture medium. The two polypeptide chains can then be incubated under suitable conditions for antibody formation.

[00191] Standard molecular biology techniques are used to prepare the recombinant expression vector, transfect the host cells, select the transformants, culture the host cells, and recover the antibodies from the culture medium. For example, some antibodies can be isolated by affinity chromatography with a Protein A or Protein G coupled matrix.

[00192] Any of the nucleic acids encoding the heavy chain, the light chain, or both of an antiTMPRSS6 antibody as described herein (e.g., as provided in Table 3), vectors (e.g., expression vectors) containing such; and host cells comprising the vectors are within the scope of the present disclosure. Table 3: Nucleic acid sequences encoding VH / VL of the anti-TMPRSS6 antibodies listed in Table 2 Antibody Nucleic Acid Sequence SEQ ID NO A1 VH caggtccaactgcagcagcctggggctgag cttgcgaagcctggggcttcagtgaagatg tcctgcaaggcttctggctacaccttcacc agctactggataacctgggtgaagcagagg cctggacaagaccttgagtggattggaaat atttatcctggtagtggtagtacttactac aatgagaagttcaagagcaaggccacactg actgtagacacatcctccagaacagcctac atgcagctcagcagtctgacatctgcggac tctgcggtctattactgtgccccctatgat 54 Petition 870250088518, dated 09 / 30 / 2025, pp. 127 / 245 114 / 213 Anticorpo Sequência de Ácido Nucleico SEQ ID NO tccgactatgctatggactactggggtcaa ggaacctcagtcaccgtctcctca VL gacatcaagatgacccagtctccatcttcc atgtatgcatctctaggagagagagtcact atcacttgcaaggcgagtcaggacattaat aactatttaagctggttccagcagaaacca gggaaatctcctaagaccctgatctatcgt gcaaacagattggtagatggggtcccatca agggtcagtggcagtggatctgggcaagat tattctctcaccatcagcagcctggagtat gaagatgtgggaatttatttttgtctacag tatgatgagtttcctctcacgttcggtgct gggaccaagctggagctgaaa 55 Cadeia Pesada caggtccaactgcagcagcctggggctgag cttgcgaagcctggggcttcagtgaagatg tcctgcaaggcttctggctacaccttcacc agctactggataacctgggtgaagcagagg cctggacaagaccttgagtggattggaaat atttatcctggtagtggtagtacttactac aatgagaagttcaagagcaaggccacactg actgtagacacatcctccagaacagcctac atgcagctcagcagtctgacatctgcggac tctgcggtctattactgtgccccctatgat tccgactatgctatggactactggggtcaa ggaacctcagtcaccgtctcctcagctaaa acaacagccccatcggtctatccactggcc cctgtgtgtggagatacaactggctcctcg gtgactctaggatgcctggtcaagggttat ttccctgagccagtgaccttgacctggaac tctggttccctgtccagtggtgtgcacaccttcccagctgtcctgcagtctgacctctac accctcagctcaagcgtgactgtaaccagc tcgacctggcccagccagtccatcacctgc aatgtggcccacccggcaagcagcaccaag gtggacaagaaaattgagcccagagggccc acaatcaagccctgtcctccatgcaaatgc ccagcacctaacctcttgggtggaccatcc gtcttcatcttccctccaaagatcaaggat gtactcatgatctccctgagccccatagtc acatgtgtagtcgttgatgtgagcgaggat gacccagatgtccagatcagctggtttgtg aacaacgtggaagtgcacactgctcagaca 56 Petição 870250088518, de 30 / 09 / 2025, pág. 128 / 245 115 / 213 Anticorpo Sequência de Ácido Nucleico SEQ ID NO cagacgcatagagaggattacaacagtact ctccgggttgtcagtgccctccccatccag caccaggactggatgagtggcaaggagttc aaatgcaaggtcaacaacaaagacctccca gcgcccatcgagagaaccatctcaaaaccc aaagggtcagtaagagctccacaggtatat gtcttgcctccaccagaagaggagatgact aagaaacaggtcactctgacctgcatggtc acagacttcatgcctgaagacatttacgtg gagtggaccaacaacgggaaaacagagcta aactacaagaacactgaaccagtcctggac tctgatggttcttacttcatgtacagcaag ctgagagtggagaagaagaactgggtggag agaaatagctactcctgttcagtggtccac gagggtctgcacaatcaccacacgactaag agcttctcccggactccgggttagtaa Cadeia Leve gacatcaagatgacccagtctccatcttcc atgtatgcatctctaggagagagagtcact atcacttgcaaggcgagtcaggacattaat aactatttaagctggttccagcagaaacca gggaaatctcctaagaccctgatctatcgt gcaaacagattggtagatggggtcccatca agggtcagtggcagtggatctgggcaagat tattctctcaccatcagcagcctggagtat gaagatgtgggaatttatttttgtctacag tatgatgagtttcctctcacgttcggtgct gggaccaagctggagctgaaaagagctgac gccgctcctaccgtgtccatctttccacct agcagcgagcagctgacaagcggcggagcc agcgtcgtgtgcttcctgaacaacttctaccccaaggacacacaacgtgaagtgagatc gacggcagcgagagacagaacggcgtgctg atagctggaccgaccgacagcaggac tccacctacagcagtgtccagcagcac agctacacacgcagcgacccagccagcaccac cggaacgagtgc 57 B1 VH gaggttcagctgcagcagtctggggcagaa cttgtgaagccaggggcctcagtcaagttg tcctgcacagcctctggcttcacattaaa gactactatacactggtgaagagagg 58 Petition 870250088518, dated 09 / 30 / 2025, p. 129 / 245 116 / 213 Anticorpo Sequência de Ácido Nucleico SEQ ID NO actgaacagggcctggagtggtttggaagg attgatcctgaggatggtgaaagtgaatat gccccgaaattccagggcaaggccacttta acagcagacacatcctccaatacagcctac ctgcagctcagcagcctgacatctgaggac actgccgtctattactgtactagaggagac tctatgatggttacctactttgactactgg ggccaaggcaccactctcacggtctcctca VL gacattgtgatgacccagtctcacaaattc atgtccacatcagtaggagacagggtcagc atcacctgcaaggccagtcaggatgtgagt actgctgtagcctggtatcaacaaaaacca gggcaatctcctaaactactgatttactgg gctttcacccgtcacactggagtccctgat cgcttcacaagcactggatctgggacagat tatgctctcaccatcagcagtgtgcaggct gaagacctggcactttattactgtcagcaa cattatcgcagtccgtggacgttcggtgga ggcaccaaactggaaatcaaa 59 Cadeia Pesada gaggttcagctgcagcagtctggggcagaa cttgtgaagccaggggcctcagtcaagttg tcctgcacagcctctggcttcaacattaaa gactactatatacactgggtgaaagagagg actgaacagggcctggagtggtttggaagg attgatcctgaggatggtgaaagtgaatat gccccgaaattccagggcaaggccacttta acagcagacacatcctccaatacagcctac ctgcagctcagcagcctgacatctgaggac actgccgtctattactgtactagaggagac tctatgatggttacctactttgactactggggccaaggcaccactctcacggtctctca aagaccacaccctctagcgtgtaccctg gctcctggctgtggcgatacaacaggcagc tctgtgacactgggctgcctggtcaagggc tactttcctgagagcgtgacagtgacctg aacagcggcgcgtcgtgcgcgc acctttccagctctgctccagagcggcctg tacaccatgtcctctagtgtgaccgtgcct agcagcacctggcctagccagacagtgaca tgtagcgtggcccatcctgcagcagcaca accgtggacaagaagctggaactagcgc cccatcagcaccatcaatccctcctcc 60 Petition 870250088518, of 30 / 09 / 2025, p. 130 / 245 117 / 213 Anticorpo Sequência de Ácido Nucleico SEQ ID NO tgcaaagaatgccacaagtgccccgctcct aacctggaaggtggcccaagcgtgttcatc ttcccacctaacatcaaggacgtgctgatg atcagcctgacacctaaagtgacctgcgtg gtggtggacgtgtccgaggatgatcccgat gtgcagatcagttggttcgtgaacaacgtg gaagtgcacacagcccagacacagacccac agagaggactacaatagcaccattcgcgtg gtgtccacactgcctatccagcaccaggat tggatgagcggcaaagagttcaagtgcaaa gtgaacaacaaggacctgccttctccaatc gagcggaccatcagcaagatcaagggactc gtcagagcccctcaggtgtacatcttgcct ccaccagccgagcagctgagcagaaaggat gtgtccctgacctgtctggtcgtgggcttc aaccctggcgacatcagcgtggaatggacc agcaatggccacaccgaggaaaactacaag gacacagcccctgtgctggacagcgacggc agctacttcatctacagcaagctgaacatg aagaccagcaagtgggagaaaaccgacagc ttctcctgcaacgtgcggcacgagggcctg aagaactactacctgaagaaaaccatctct cggagccccggcaag Cadeia Leve gacattgtgatgacccagtctcacaaattc atgtccacatcagtaggagacagggtcagc atcacctgcaaggccagtcaggatgtgagt actgctgtagcctggtatcaacaaaaacca gggcaatctcctaaactactgatttactgg gctttcacccgtcacactggagtccctgat cgcttcacaagcactggatctgggacagattatgctctcaccatcagcagtgtgcaggct gaagacctggcactttattactgtcagcaa cattatcgcagtccgtggacgttcggtgga ggcaccaaactggaaatcaaaagagctgac gccgctcctaccgtgtccatctttccacct agcagcgagcagctgacaagcggcggagcc agcgtcgtgtgcttcctgaacaacttctac cccaaggacatcaacgtgaagtggaagatc gacggcagcgagagacagaacggcgtgctg aatagctggaccgaccaggacagcaaggac tccacctacagcatgtccagcacactgacc ctgaccaaggacgagtacgagcggcacaac 61 Petição 870250088518, de 30 / 09 / 2025, pág. 131 / 245 118 / 213 Antibody Nucleic Acid Sequence SEQ ID NO agctacacatgcgaggccacacaagacc agcacaagccccatcgtgaagtccttcaac cggaacgagtgc C1 VH gaagttcagctgcagcagtctggggcagaa cttgtcaagccaggggcctcaagttg tctgcctccatccatcgtc gactactatatacactgggtgaaggagagg actgaacagggcctggagtggattggaagg attgatcctgaggatggtgaaactacatat gccccgcagttccagggcaaggccactata ataccagacacatcctccaacagcctac atgcagctcagcagcctgacatctgagc gctgccctcgtcgtc taccttgatcctatggactactggggtcaa ggaacctcagtcaccgtctcctca 62 VL gacattgtgatgatgacccagtctcacaaattc atgtccacatcagtaggagacagggtcagc atcacctgcaaggcagtcaggatgtgact actgctgtcgcctggtatcaaaaaactccactcacgattactacttactta gcaaccacccggcacactggagtccctgat cgcttcacaggcagtatatctgggacaact tatattctcaccatcagtagtgtgcaggct gaagacctggcactttattactgtcagcaa cattatagcactccgtacacgttcggaggg gggaccaagctggaaataaaaaa 63 Cadeia Pects cttgtgaagccaggggcctcagtcaagttg tcctgcacagcttctggcttcacattgaa gactactatatacactgggtgaaggagaggactgaacagggcctggagtggattggaagg attgatcctgaggatggtgaaactacatat gccccgcagttccagggcaaggccactata ataccagacacatcctccaacacagcctac atgcagctcagcagcctgacatctgaggac gctgccgtctattactgtgctagatcgatc taccttgatcctatggactactggggtcaa ggaacctcagtcaccgtctcctcaaagacc acacctcctagcgtgtaccctctggctcct ggctgtggcgatacaacaggcagctctgtg acactgggctgcctggtcaagggctacttt cctgagagcgtgacagtgacctggaacagc 5 Petição 870250088518, de 30 / 09 / 2025, pág. 132 / 245 119 / 213 Antibody Nucleic Acid Sequence SEQ ID NO ggcagcctgtctagcagcgtgcacaccttt ccagctctgctccagagcggcgcgtacacc atgtcctctagtgtgaccgtgcctagcagc acctggcctagccagacagtgacatgtagc gtggcccatcctgccagcagcagcgc gacaagaagctggaacctagcggccccatc agcaccatcaatccctgtcctccatgcaaa gaatgccacaagtgccccgctcctaacctg gaaggtggcccaagcgtgttcatcttccca cctaacatcaaggacgtgctgatgatcgc ctgacacctaaagtgacctgcggcgcgtcggcgcgcgcgcg atcagttggttgtcgaacacgtggaagtg cacacagcccagacacagacccacagagag gactacaatagcaccattcggtggtc acactgcctatccagcaccaggattggatg agcggcaaagagttcaagtgcaaagtgaac aacaaggacctgccttctccatcgagcagcagcagcagcagcacgactc gccctcaggtgtacatcttgcctccacca gccgagcagctgagcagaaaggatgtgtcc ctgacctgtctggtcgtgggcttcaaccct ggcgacatcagcgtggaatggaccagcaat ggccacaccgaggaaaactacaaggacaca gccctgtgctggacgacgcgcgcatcactacgacc agcaagtgggagaaaccgacagcttctc tgcaacgtgcggcacgagggcctgaagaac tactacctgaagaaaaccatctctcggagc cccggcaag Cadeia Leve gacattgtgatgacccagtctcaaattcatgtccacatcagtaggagacagggtcagc atcacctgcaaggccagtcaggatgtgact actgctgtcgcctggtatcaacaaaaacca ggacagtctcctaaaatactgatttactgg gcaaccacccggcacactggagtccctgat cgcttcacaggcagtatatctgggacaact tatattctcaccatcagtagtgtgcaggct gaagacctggcactttattactgtcagcaa cattatagcactccgtacacgttcggaggg gggaccaagctggaaataaaaagagctgac gccgctcctaccgtgtccatctttccacct 32 Petição 870250088518, de 30 / 09 / 2025, pág. 133 / 245 120 / 213 Anticorpo Sequência de Ácido Nucleico SEQ ID NO agcagcgagcagctgacaagcggcggagcc agcgtcgtgtgcttcctgaacaacttctac cccaaggacatcaacgtgaagtggaagatc gacggcagcgagagacagaacggcgtgctg aatagctggaccgaccaggacagcaaggac tccacctacagcatgtccagcacactgacc ctgaccaaggacgagtacgagcggcacaac agctacacatgcgaggccacacacaagacc agcacaagccccatcgtgaagtccttcaac cggaacgagtgc VH ctactacatccactgggtcaaagagcggac cgagcagggactcgagtggatcggaagaat cgaccccgaggacggcgagacaacatacgc ccctcagtttcagggcaaagccacaatcat ccccgacaccagcagcaacaccgcctacat gcaactgagcagcctgacctctgaagatgc cgccgtgtactactgcgcccggtccatcta tctggaccccatggattattggggccaggg cacaagcgtgaccgtgtcctct 79 VL gacatcgtgatgacccagagccacaagttc atgagcaccagcgtgggcgacagagtgtcc atcacctgtaaagccagccaggacgtgaca acagccgtggcctggtatcagcagaagcct ggccagtctcctaagatcctgatctactgg gccaccaccagacacaccggcgtgccagat agattcaccggcagcatcagcggcaccacc tacatcctgacaatcagctctgtgcaggcc gaggatctggccctgtactactgtcagcag cactacagcaccccttacacctttggcgga ggcaccaagctggaaatcaag 28 Cadeia Pesada gaggttcagctgcagcagtctggcgccgagcttgtgaaacctggcgcctctgtgaagctg agctgtaccgccagcggcttcaacatcgag gactactacatccactgggtcaaagagcgg accgagcagggactcgagtggatcggaaga atcgaccccgaggacggcgagacaacatac gcccctcagtttcagggcaaagccacaatc atccccgacaccagcagcaacaccgcctac atgcaactgagcagcctgacctctgaagat gccgccgtgtactactgcgcccggtccatc tatctggaccccatggattattggggccag ggcacaagcgtgaccgtgtcctctaagacc 64 Petition 870250088518, dated 09 / 30 / 2025, pp. 134 / 245 121 / 213 Anticorpo Sequência de Ácido Nucleico SEQ ID NO acacctcctagcgtgtaccctctggctcct ggctgtggcgatacaacaggcagctctgtg acactgggctgcctggtcaagggctacttt cctgagagcgtgacagtgacctggaacagc ggcagcctgtctagcagcgtgcacaccttt ccagctctgctccagagcggcctgtacacc atgtcctctagtgtgaccgtgcctagcagc acctggcctagccagacagtgacatgtagc gtggcccatcctgccagcagcacaaccgtg gacaagaagctggaacctagcggccccatc agcaccatcaatccctgtcctccatgcaaa gaatgccacaagtgccccgctcctaacctg gaaggtggcccaagcgtgttcatcttccca cctaacatcaaggacgtgctgatgatcagc ctgacacctaaagtgacctgcgtggtggtg gacgtgtccgaggatgatcccgatgtgcag atcagttggttcgtgaacaacgtggaagtg cacacagcccagacacagacccacagagag gactacaatagcaccattcgcgtggtgtcc acactgcctatccagcaccaggattggatg agcggcaaagagttcaagtgcaaagtgaac aacaaggacctgccttctccaatcgagcgg accatcagcaagatcaagggactcgtcaga gcccctcaggtgtacatcttgcctccacca gccgagcagctgagcagaaaggatgtgtcc ctgacctgtctggtcgtgggcttcaaccct ggcgacatcagcgtggaatggaccagcaat ggccacaccgaggaaaactacaaggacaca gcccctgtgctggacagcgacggcagctac ttcatctacagcaagctgaacatgaagaccagcaagtgggagaaaccgacagcttctc tgcaacgtgcggcacgagggcctgagaac tactacctgaagaaaaccatctccggagc cccggcaag Cadeia Leve gacatcgtgatgacccagagccacaagttc atgagcaccagcgtcggcgacaggtc atcacctagccagcgcgc acagccgtggcctggtatcagcagaagcct ggccagtctcctaagatcctgatctactgg gccaccagacaccggcgtgccagat agattcaccggcagcatcagcggcaccacc tacatcctgacaatcagctctgtgcaggcc 65 Petition 870250088518, of 30 / 09 / 2025, p. 135 / 245 122 / 213 Antibody Nucleic Acid Sequence SEQ ID NO gaggatctggccctgtactactgtcagcag cactacagcacccttacacctttggcgga ggcaccaagctggaaatcaagagagctgac gccgctcctaccgtgtccatctttccacct agcagcgagcagctgacagcggc agcgtcgtgtgcttcctgaaacttctac cccaaggacatcaacgtgaagtggaagatc gacggcagcgagagacagaacggcgtgctg aatagctgaccgaccagacagcaaggac tccacctacagcatgtccagcacactgacc ctgaccaaggacgagtac agcacaagccccatcgtgaagtccttcaac cggaacgagtgc A2 VH gaagtgcagctggtgcaatctggcgccgaa gtgaagaaacctggcgccctgtgaaggtg tcctgcaagcttccggctacacctttacc agctactggatcacctcggcgacggctc atctaccctggctccggctccacctactac aacgagaagttcaagtccaaggccacaatc acccgggacacccttccagaaccgcctac atggaactgtccagcctgagatctgaggac accgccgtgtactactgcgccccttacgac gccgactacgccatggattattggccctcgcgcgcgt6 gacatccagatgacccagtctccatcctct ctgtccgcctctgtgggcgacagagtgacc atcacatgcaaggccagccaggacatctcc aactacctgtcctggttccagcagaagcct ggcaaggctcccaagctgctgatctacagagccaacagactggtggaaggcgtgccctcc agattctccggatctggctctggcaccgac tttaccctgacaatctccagcctgcagcct gaggacttcgctacctacttctgcctgcaa tacgacgagttccctctgacctttggcgga ggcaccaaggtggaaatcaag 67 Heavy Chain gaagtgcagctggtgcaatctggcgccgaa gtgaagaaacctggcgcctctgtgaaggtg tcctgcaaggcttccggctacacctttacc agctactggatcacctgggtccgacaggct cctggccagagactggaatggatcggcaac 68 Petition 870250088518, dated 09 / 30 / 2025, pp. 136 / 245 123 / 213 Anticorpo Sequência de Ácido Nucleico SEQ ID NO atctaccctggctccggctccacctactac aacgagaagttcaagtccaaggccacaatc acccgggacacctcttccagaaccgcctac atggaactgtccagcctgagatctgaggac accgccgtgtactactgcgccccttacgac gccgactacgccatggattattggggccag ggcaccctggtcaccgtgtcctctgcttct accaagggacccagcgtgttccctctggct ccttccagcaagtctacctctggcggaaca gctgctctgggctgcctggtcaaggactac tttcctgagcctgtgaccgtgtcttggaac tctggcgctctgacatccggcgtgcacaca tttccagctgtgctgcagtcctccggcctg tactctctgtcctctgtcgtgaccgtgcct tcctctagcctgggcacccagacctacatc tgcaatgtgaaccacaagccttccaacacc aaggtggacaagaaggtggaacccaagtcc tgcgacaagacccacacctgtcctccatgt cctgctccagaactgctcggcggaccttcc gtgttcctgtttcctccaaagcctaaggac accctgatgatctctcggacccctgaagtg acctgcgtggtggtggatgtgtctcacgag gacccagaagtgaagttcaattggtacgtg gacggcgtggaagtgcacaacgccaagacc aagcctagagaggaacagtacgccagcacc tacagagtggtgtccgtgctgacagtgctg caccaggattggctgaacggcaaagagtac aagtgcaaggtgtccaacaaggccctgcct gctcctatcgaaaagaccatcagcaaggcc aagggccagcctagagaaccccaggtttacaccttgcctccatctcgggacgagctgacc aagaaccaggtgtccctgacctgtctcgtg aagggcttctacccctccgacatcgccgtg gaatgggagtctaatggccagccagagaac aactacaagacaacccctcctgtgctggac tccgacggctcattcttcctgtactccaag ctgaccgtggacaagtccagatggcagcag ggcaacgtgttctcctgctccgtgatgcac gaggccctgcacaatcactacacacagaag tccctgtctctgtcccctggc Light Chain gacatccagatgacccagtctccatcctct ctgtccgcctctgtgggcgacagagtgacc 69 Petition 870250088518, dated 09 / 30 / 2025, pp. 137 / 245 124 / 213 Antibody Nucleic Acid Sequence SEQ ID NO atcacatgcaaggccagccaggacatctcc aactacctgtcctggttccagcagaagcct ggcaaggctcccaagctgctgatctacaga gccaacagactggtggaaggcgtgccctc gaggacttcgctacctactctgcctgcaa tacgacgagttcctctgacctttggcgga ggcaccaaggtggaaatcaagggacagtg gccgctccttccgtgttcatcttcccacct tccgacgagcagctgaagtccggcagct tctgtctgctgctgctc cctcgggaagccaaggtgcagtggaaggtg gacaatgccctgcagtccggcaactcccaa gagtctgtgaccgagcaggactccaaggac agcacctacagcctgtcctccacactgacc ctgtccaaggccgactacgagaagcacaag gtgtacgcctgcgaagctc cggggcgagtgt B2 VH gaagtgcagctggtgcaatctggcgccgaa gtgaagaaacctggcgcctgtgaaggtg tcctgcaaggcctggcttcaacatcaag gactactacatccactgggtccgacaggct accggacagggacttgagtggatgggcga atcggacgcgc gccctaagtttcagggcagagtgaccatc accgccgacacctctaccgacaccgcctac atggaactgtccagcctgagatctgaggac accgccgtgtactactgcaccagaggcgac tccatgatgttacctactcgactactggggccagggcaccctggtcacagtttcttcc 70 VL gacatccagatgacccagtctccatcctct ctgtccgcctctgtgggcgacagagtgacc atcacatgcaaggcctctcaggacgtgtcc accgccgttgcttggtatcagcagaagcct ggcaaggcccctaagctgctgatctactgg gccttcaccagacacaccggcgtgccctct aggttctccggctctggctctggcaccgat tacgctctgacaatctccagcctgcagcct gaggacttcgccacctactactgccagcag 71 Petição 870250088518, de 30 / 09 / 2025, pág. 138 / 245 125 / 213 Anticorpo Sequência de Ácido Nucleico SEQ ID NO cactacagaagcccctggacatttggcgga ggcaccaaggtggaaatcaag Cadeia Pesada gaagtgcagctggtgcaatctggcgccgaa gtgaagaaacctggcgcctctgtgaaggtg tcctgcaaggcctctggcttcaacatcaag gactactacatccactgggtccgacaggct accggacagggacttgagtggatgggcaga atcgaccctgaggacgccgagtctgagtac gcccctaagtttcagggcagagtgaccatc accgccgacacctctaccgacaccgcctac atggaactgtccagcctgagatctgaggac accgccgtgtactactgcaccagaggcgac tccatgatggttacctacttcgactactgg ggccagggcaccctggtcacagtttcttcc gcttccaccaagggacccagcgtgttccct ctggctccttccagcaagtctacctctggc ggaacagctgctctgggctgcctggtcaag gattacttccctgagcctgtgaccgtgtcc tggaactctggcgctctgacatccggcgtg cacacctttccagctgtgctgcaatcctcc ggcctgtactctctgtcctccgtcgtgacc gtgccttctagctctctgggcacccagacc tacatctgcaatgtgaaccacaagccttcc aacaccaaggtggacaagaaggtggaaccc aagtcctgcgacaagacccacacctgtcct ccatgtcctgctccagaactgctcggcgga ccttccgtgttcctgtttcctccaaagcct aaggacaccctgatgatctctcggacccct gaagtgacctgcgtggtggtggatgtgtct cacgaggacccagaagtgaagttcaattggtacgtggacggcgtggaagtgcacaacgcc aagaccaagcctagagaggaacagtacgcc tccacctacagagtggtgtccgtgctgaca gtgctgcaccaggattggctgaacggcaaa gagtacaagtgcaaggtgtccaacaaggca ctgcccgctcctatcgaaaagaccatctcc aaggccaagggccagcctagagaaccccag gtttacaccttgcctccatctcgggacgag ctgaccaagaaccaggtgtccctgacctgt ctcgtgaagggcttctacccctccgacatc gccgtggaatgggagtctaatggccagcca gagaacaactacaagacaacccctcctgtg 72 Petição 870250088518, de 30 / 09 / 2025, pág. 139 / 245 126 / 213 Anticorpo Sequência de Ácido Nucleico SEQ ID NO ctggactccgacggctcattcttcctgtac tccaagctgaccgtggacaagtccagatgg cagcagggcaacgtgttctcctgctccgtg atgcacgaggccctgcacaatcactacaca cagaagtctctgtccctgtctcctggc Cadeia Leve gacatccagatgacccagtctccatcctct ctgtccgcctctgtgggcgacagagtgacc atcacatgcaaggcctctcaggacgtgtcc accgccgttgcttggtatcagcagaagcct ggcaaggcccctaagctgctgatctactgg gccttcaccagacacaccggcgtgccctct aggttctccggctctggctctggcaccgat tacgctctgacaatctccagcctgcagcct gaggacttcgccacctactactgccagcag cactacagaagcccctggacatttggcgga ggcaccaaggtggaaatcaagcggacagtg gccgctccttccgtgttcatcttcccacct tccgacgagcagctgaagtccggcacagct tctgtcgtgtgcctgctgaacaacttctac cctcgggaagccaaggtgcagtggaaggtg gacaatgccctgcagtccggcaactcccaa gagtctgtgaccgagcaggactccaaggac agcacctacagcctgtcctccacactgacc ctgtccaaggccgactacgagaagcacaag gtgtacgcctgcgaagtgacccatcagggc ctgtctagccctgtgaccaagtctttcaac cggggcgagtgt 73 C2 VH caggtgcagctggtgcagtctggcgccgaa gtgaaaaagcctggcgcctctgtgaaggtg tcctgcaaggcctctggcttcaacatcgaggactactacatgcactgggtccgacaggcc cctggccagagattggaatggatgggcaga atcgaccccgaggacgccgagacaacctac tctctaagttccagggcgcgtgacaatc atccctgacacctgccaacaccgcctac atggaactgtccagcctgagatcgacgcgctc tacctggaccctatgactattggggccag ggcaccctggtcacagtgtctctct 74 VL gacatccagatgacccagtctccaaagtct ctgtccgcctccgtgggcgacagagtgacc atcacctgtagacctctcaggacgtgacc 75 Petition 870250088518, of 30 / 09 / 2025, p. 140 / 245 127 / 213 Anticorpo Sequência de Ácido Nucleico SEQ ID NO accgctctggcttggtatcagcagaagcct ggccagtctcctaagctgctgatctactgg gccaccaccagacactctggcgtgccctct agattctccggctctggctctggcaccgac tttaccctgacaatctccagcctgcagcct gaggacttcgccacctactactgccagcag cactacagcaccccttacacctttggccag ggcaccaagctggaaatcaag Cadeia Pesada caggtgcagctggtgcagtctggcgccgaa gtgaaaaagcctggcgcctctgtgaaggtg tcctgcaaggcctctggcttcaacatcgag gactactacatgcactgggtccgacaggcc cctggccagagattggaatggatgggcaga atcgaccccgaggacgccgagacaacctac tctcctaagttccagggccgcgtgacaatc atccctgacacctctgccaacaccgcctac atggaactgtccagcctgagatctgaggac accgccgtgtactactgcgcccggtctatc tacctggaccctatggactattggggccag ggcaccctggtcacagtgtcctctgcttct accaagggacccagcgtgttccctctggct ccttccagcaagtctacctctggcggaaca gctgctctgggctgcctggtcaaggactac tttccagagcctgtgaccgtgtcctggaac tctggcgctctgacatctggcgtgcacacc tttccagctgtgctgcagtcctccggcctg tactctctgtcctctgtcgtgaccgtgcct tccagctctctgggaacccagacctacatc tgcaatgtgaaccacaagccttccaacacc aaggtggacaagaaggtggaacccaagtcctgcgacaagacccacacctgtcctccatgt cctgctccagaagctgctggcggcccttcc gtgtttctgttccctccaaagcctaaggac accctgatgatctctcggacccctgaagtg acctgcgtggtggtggatgtgtctcacgag gacccagaagtgaagttcaattggtacgtg gacggcgtggaagtgcacaacgccaagacc aagcctagagaggaacagtacaactccacc tacagagtggtgtccgtgctgaccgtgctg caccaggattggctgaacggcaaagagtac aagtgcaaggtgtccaacaaggcactgccc gctcctatcgaaaagaccatctccaaggcc 76 Petição 870250088518, de 30 / 09 / 2025, pág. 141 / 245 128 / 213 Anticorpo Sequência de Ácido Nucleico SEQ ID NO aagggccagcctagggaaccccaggtttac accctgcctccaagccgggaagagatgacc aagaaccaggtgtccctgacctgcctcgtg aagggcttctacccttccgacatcgccgtg gaatgggagagcaatggccagccagagaac aactacaagacaacccctcctgtgctggac tccgacggctcattcttcctgtactccaag ctgacagtggacaagtccagatggcagcag ggcaacgtgttctcctgctccgtgatgcac gaggccctgcacaatcactacacacagaag tccctgtctctgtcccctggc Cadeia Leve gacatccagatgacccagtctccaaagtct ctgtccgcctccgtgggcgacagagtgacc atcacctgtagagcctctcaggacgtgacc accgctctggcttggtatcagcagaagcct ggccagtctcctaagctgctgatctactgg gccaccaccagacactctggcgtgccctct agattctccggctctggctctggcaccgac tttaccctgacaatctccagcctgcagcct gaggacttcgccacctactactgccagcag cactacagcaccccttacacctttggccag ggcaccaagctggaaatcaagcggacagtg gccgctccttccgtgttcatcttcccacct tccgacgagcagctgaagtccggcacagct tctgtcgtgtgcctgctgaacaacttctac cctcgggaagccaaggtgcagtggaaggtg gacaatgccctgcagtccggcaactcccaa gagtctgtgaccgagcaggactccaaggac agcacctacagcctgtcctccacactgacc ctgtccaaggccgactacgagaagcacaaggtgtacgcctgcgaagtgacccatcagggc ctgtctagccctgtgaccaagtctttcaac cggggcgagtgt 77

[00193] In some embodiments, the present disclosure provides an isolated nucleic acid comprising a sequence at least 60% (for example, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to SEQ ID NO: 54, and / or an isolated nucleic acid comprising a sequence at least 60% (for example, 60%, 65%, 70%, 75%, 80%, 85%, 90%, Petition 870250088518, dated 09 / 30 / 2025, pp. 142 / 245 129 / 213 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 55. In some embodiments, the present disclosure provides an expression vector comprising: an isolated nucleic acid comprising a sequence at least 60% (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to SEQ ID NO: 54, and / or an isolated nucleic acid comprising a sequence at least 60% (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to SEQ ID NO: 55.

[00194] In some embodiments, the present disclosure provides an isolated nucleic acid comprising a sequence at least 60% (for example, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to SEQ ID NO: 56, and / or an isolated nucleic acid comprising a sequence at least 60% (for example, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to SEQ ID NO: 57. In some embodiments, the present disclosure provides an expression vector comprising: an isolated nucleic acid comprising a sequence at least 60% (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to SEQ ID NO: 56, and / or an isolated nucleic acid comprising a sequence at least 60% (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to SEQ ID NO: 57.

[00195] In some embodiments, the present disclosure provides an isolated nucleic acid comprising a sequence at least 60% (for example, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to SEQ ID NO: 58, and / or an isolated nucleic acid comprising a sequence at least 60% (for example, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to SEQ ID NO: 59. In some embodiments, the present disclosure provides an expression vector comprising: a nucleic acid Petition 870250088518, dated 09 / 30 / 2025, pp. 143 / 245 130 / 213 isolate comprising a sequence at least 60% (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to SEQ ID NO: 58, and / or an isolated nucleic acid comprising a sequence at least 60% (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to SEQ ID NO: 59.

[00196] In some embodiments, the present disclosure provides an isolated nucleic acid comprising a sequence at least 60% (for example, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to SEQ ID NO: 60, and / or an isolated nucleic acid comprising a sequence at least 60% (for example, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to SEQ ID NO: 61. In some embodiments, the present disclosure provides an expression vector comprising: an isolated nucleic acid comprising a sequence at least 60% (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to SEQ ID NO: 60, and / or an isolated nucleic acid comprising a sequence at least 60% (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to SEQ ID NO: 61.

[00197] In some embodiments, the present disclosure provides an isolated nucleic acid comprising a sequence at least 60% (for example, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to SEQ ID NO: 62, and / or an isolated nucleic acid comprising a sequence at least 60% (for example, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to SEQ ID NO: 63. In some embodiments, the present disclosure provides an expression vector comprising: an isolated nucleic acid comprising a sequence at least 60% (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to SEQ ID NO: 62, and / or an acid Petition 870250088518, dated 09 / 30 / 2025, pp. 144 / 245 131 / 213 isolated nucleic acid comprising a sequence at least 60% (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to SEQ ID NO: 63.

[00198] In some embodiments, the present disclosure provides an isolated nucleic acid comprising a sequence at least 60% (for example, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to SEQ ID NO: 5, and / or an isolated nucleic acid comprising a sequence at least 60% (for example, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to SEQ ID NO: 32. In some embodiments, the present disclosure provides an expression vector comprising: an isolated nucleic acid comprising a sequence at least 60% (for example, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to SEQ ID NO: 5, and / or an isolated nucleic acid comprising a sequence at least 60% (for example, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to SEQ ID NO: 32.

[00199] In some embodiments, the present disclosure provides an isolated nucleic acid comprising a sequence at least 60% (for example, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to SEQ ID NO: 79, and / or an isolated nucleic acid comprising a sequence at least 60% (for example, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to SEQ ID NO: 28. In some embodiments, the present disclosure provides an expression vector comprising: an isolated nucleic acid comprising a sequence at least 60% (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to SEQ ID NO: 79, and / or an isolated nucleic acid comprising a sequence at least 60% (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to SEQ ID NO: 28. Petition 870250088518, dated 09 / 30 / 2025, pp. 145 / 245 132 / 213

[00200] In some embodiments, the present disclosure provides an isolated nucleic acid comprising a sequence at least 60% (for example, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to SEQ ID NO: 64, and / or an isolated nucleic acid comprising a sequence at least 60% (for example, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to SEQ ID NO: 65. In some embodiments, the present disclosure provides an expression vector comprising: an isolated nucleic acid comprising a sequence at least 60% (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to SEQ ID NO: 64, and / or an isolated nucleic acid comprising a sequence at least 60% (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to SEQ ID NO: 65.

[00201] In some embodiments, the present disclosure provides an isolated nucleic acid comprising a sequence at least 60% (for example, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to SEQ ID NO: 66, and / or an isolated nucleic acid comprising a sequence at least 60% (for example, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to SEQ ID NO: 67. In some embodiments, the present disclosure provides an expression vector comprising: an isolated nucleic acid comprising a sequence at least 60% (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to SEQ ID NO: 66, and / or an isolated nucleic acid comprising a sequence at least 60% (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to SEQ ID NO: 67.

[00202] In some embodiments, the present disclosure provides an isolated nucleic acid comprising a sequence of at least 60% (for example, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, Petition 870250088518, dated 09 / 30 / 2025, pp. 146 / 245 133 / 213 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to SEQ ID NO: 68, and / or an isolated nucleic acid comprising a sequence at least 60% (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to SEQ ID NO: 69. In some embodiments, the present disclosure provides an expression vector comprising: an isolated nucleic acid comprising a sequence at least 60% (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to SEQ ID NO: 68, and / or an isolated nucleic acid comprising a sequence at least 60% (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to SEQ ID NO: 69.

[00203] In some embodiments, the present disclosure provides an isolated nucleic acid comprising a sequence at least 60% (for example, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to SEQ ID NO: 70, and / or an isolated nucleic acid comprising a sequence at least 60% (for example, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to SEQ ID NO: 71. In some embodiments, the present disclosure provides an expression vector comprising: an isolated nucleic acid comprising a sequence at least 60% (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to SEQ ID NO: 70, and / or an isolated nucleic acid comprising a sequence at least 60% (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to SEQ ID NO: 71.

[00204] In some embodiments, the present disclosure provides an isolated nucleic acid comprising a sequence at least 60% (for example, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to SEQ ID NO: 72, and / or an isolated nucleic acid comprising a sequence at least 60% (for example, 60%, 65%, 70%, 75%, 80%, 85%, 90%, Petition 870250088518, dated 09 / 30 / 2025, pp. 147 / 245 134 / 213 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 73. In some embodiments, the present disclosure provides an expression vector comprising: an isolated nucleic acid comprising a sequence at least 60% (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to SEQ ID NO: 72, and / or an isolated nucleic acid comprising a sequence at least 60% (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to SEQ ID NO: 73.

[00205] In some embodiments, the present disclosure provides an isolated nucleic acid comprising a sequence at least 60% (for example, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to SEQ ID NO: 74, and / or an isolated nucleic acid comprising a sequence at least 60% (for example, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to SEQ ID NO: 75. In some embodiments, the present disclosure provides an expression vector comprising: an isolated nucleic acid comprising a sequence at least 60% (for example, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to SEQ ID NO: 74, and / or an isolated nucleic acid comprising a sequence at least 60% (for example, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to SEQ ID NO: 75.

[00206] In some embodiments, the present disclosure provides an isolated nucleic acid comprising a sequence at least 60% (for example, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to SEQ ID NO: 76, and / or an isolated nucleic acid comprising a sequence at least 60% (for example, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to SEQ ID NO: 77. In some embodiments, the present disclosure provides an expression vector comprising: a nucleic acid Petition 870250088518, dated 09 / 30 / 2025, pp. 148 / 245 135 / 213 isolate comprising a sequence at least 60% (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to SEQ ID NO: 76, and / or an isolated nucleic acid comprising a sequence at least 60% (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to SEQ ID NO: 77.

[00207] In some embodiments, the anti-TMPRSS6 described herein is produced by the expression of (i) a nucleic acid at least 60% (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to SEQ ID NO: 54, and / or (ii) a nucleic acid at least 60% (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to SEQ ID NO: 55.

[00208] In some embodiments, the anti-TMPRSS6 described herein is produced by the expression of (i) a nucleic acid at least 60% (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to SEQ ID NO: 56, and / or (ii) a nucleic acid at least 60% (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to SEQ ID NO: 57.

[00209] In some embodiments, the anti-TMPRSS6 described herein is produced by the expression of (i) a nucleic acid at least 60% (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to SEQ ID NO: 58, and / or (ii) a nucleic acid at least 60% (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to SEQ ID NO: 59.

[00210] In some embodiments, the anti-TMPRSS6 described herein is produced by the expression of (i) a nucleic acid at least 60% (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to SEQ ID NO: 60, and / or (ii) a nucleic acid at least 60% (e.g., Petition 870250088518, dated 09 / 30 / 2025, pp. 149 / 245 136 / 213 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to SEQ ID NO: 61.

[00211] In some embodiments, the anti-TMPRSS6 described herein is produced by the expression of (i) a nucleic acid at least 60% (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to SEQ ID NO: 62, and / or (ii) a nucleic acid at least 60% (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to SEQ ID NO: 63.

[00212] In some embodiments, the anti-TMPRSS6 described herein is produced by the expression of (i) a nucleic acid at least 60% (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to SEQ ID NO: 5, and / or (ii) a nucleic acid at least 60% (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to SEQ ID NO: 32.

[00213] In some embodiments, the anti-TMPRSS6 described herein is produced by the expression of (i) a nucleic acid at least 60% (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to SEQ ID NO: 79, and / or (ii) a nucleic acid at least 60% (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to SEQ ID NO: 80.

[00214] In some embodiments, the anti-TMPRSS6 described herein is produced by the expression of (i) a nucleic acid at least 60% (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to SEQ ID NO: 64, and / or (ii) a nucleic acid at least 60% (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to SEQ ID NO: 65.

[00215] In some embodiments, the anti-TMPRSS6 described herein is produced by the expression of (i) a nucleic acid at least 60% (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, Petition 870250088518, dated 09 / 30 / 2025, pp. 150 / 245 137 / 213 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to SEQ ID NO: 66, and / or (ii) a nucleic acid at least 60% (for example, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to SEQ ID NO: 67.

[00216] In some embodiments, the anti-TMPRSS6 described herein is produced by the expression of (i) a nucleic acid at least 60% (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to SEQ ID NO: 68, and / or (ii) a nucleic acid at least 60% (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to SEQ ID NO: 69.

[00217] In some embodiments, the anti-TMPRSS6 described herein is produced by the expression of (i) a nucleic acid at least 60% (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to SEQ ID NO: 70, and / or (ii) a nucleic acid at least 60% (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to SEQ ID NO: 71.

[00218] In some embodiments, the anti-TMPRSS6 described herein is produced by the expression of (i) a nucleic acid at least 60% (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to SEQ ID NO: 72, and / or (ii) a nucleic acid at least 60% (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to SEQ ID NO: 73.

[00219] In some embodiments, the anti-TMPRSS6 described herein is produced by the expression of (i) a nucleic acid at least 60% (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to SEQ ID NO: 74, and / or (ii) a nucleic acid at least 60% (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to SEQ ID NO: 75. Petition 870250088518, dated 09 / 30 / 2025, pp. 151 / 245 138 / 213

[00220] In some embodiments, the anti-TMPRSS6 described herein is produced by the expression of (i) a nucleic acid at least 60% (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to SEQ ID NO: 76, and / or (ii) a nucleic acid at least 60% (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to SEQ ID NO: 77.

[00221] In some embodiments, the present disclosure provides a recombinant cell (e.g., a recombinant cell to produce the antibody) that expresses the anti-TMPRSS6 antibody described herein.

[00222] Consequently, the present disclosure provides methods for producing the antibody, the methods comprising cultivating recombinant cells under conditions suitable for expression of the antibody from the recombinant cell expression vector. Recombinant cells expressing the antibody can be cultured under any suitable condition known in the art. In some embodiments, the method further comprises isolating the antibody from the culture medium in which the cell or cells were cultured using any suitable methods known in the art. IV. Pharmaceutical Composition

[00223] Antibodies, as well as coding nucleic acids or sets of nucleic acids, vectors comprising them, or host cells comprising the vectors, as described herein, may be mixed with a pharmaceutically acceptable vehicle (excipient) to form a pharmaceutical composition for use in the treatment of a target disease. “Acceptable” means that the vehicle must be compatible with the active ingredient of the composition (and preferably capable of stabilizing the active ingredient) and not harmful to the individual being treated. Pharmaceutically acceptable excipients (vehicles), including buffers, which are well Petition 870250088518, dated 09 / 30 / 2025, pp. 152 / 245 139 / 213 known in the art. See, for example, Remington: The Science and Practice of Pharmacy 20th Ed. (2000) Lippincott Williams and Wilkins, Ed. KE Hoover.

[00224] The pharmaceutical composition containing anti-TMPRSS6 antibody disclosed herein may further comprise a suitable buffering agent. A buffering agent is a weak acid or base used to maintain the pH of a solution close to a chosen value after the addition of another acid or base. In some examples, the buffering agent disclosed herein may be a buffering agent capable of maintaining physiological pH despite changes in carbon dioxide concentration (produced by cellular respiration). Exemplary buffering agents include, but are not limited to, HEPES buffer (4-(2-hydroxyethyl)-1-piperazinoethanesulfonic acid), Dulbecco's phosphate-buffered saline (DPBS) buffer, or phosphate-buffered saline (PBS) buffer. These buffers may comprise disodium hydrogen phosphate and sodium chloride, or dipotassium potassium phosphate and potassium chloride.

[00225] In some embodiments, the buffering agent in the pharmaceutical composition described herein may maintain a pH value of about 5 to 8. For example, the pH of the pharmaceutical composition may be about 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9 or 8.0. In other examples, the pharmaceutical composition may have a pH value less than 7, for example, about 7, 6.8, 6.5, 6.3, 6, 5.8, 5.5, 5.3 or 5.

[00226] The pharmaceutical composition described herein comprises one or more suitable salts. A salt is an ionic compound that can be formed by the neutralization reaction of an acid and a base. (Skoog, DA; West, DM; Holler, JF; Crouch, SR (2004). “Chapters 14 to 16”. Fundamentals of Analytical Chemistry (8th ed.)). Salts are composed of related numbers of cations (positively charged ions) and anions (negative ions), so that the product is electrically neutral (no net charge). Petition 870250088518, dated 09 / 30 / 2025, pp. 153 / 245 140 / 213

[00227] In some embodiments, pharmaceutical compositions may comprise pharmaceutically acceptable vehicles, excipients, or stabilizers in the form of lyophilized formulations or aqueous solutions. (Remington: The Science and Practice of Pharmacy 20th Ed. (2000) Lippincott Williams and Wilkins, Ed. KE Hoover). In some embodiments, the pharmaceutical composition may be formulated for intravenous injection. In some embodiments, the pharmaceutical composition may be formulated for subcutaneous injection.

[00228] Pharmaceutical compositions to be used for in vivo administration must be sterile. This is easily achieved, for example, by filtration through sterile filtration membranes. Therapeutic antibody compositions are usually placed in a container with a sterile access port, for example, an intravenous or subcutaneous solution bag or bottle with a stopper that can be pierced by a hypodermic injection needle. V. Methods of use

[00229] In certain respects, the disclosure provides related methods and compositions (e.g., anti-TMPRSS6 antibodies) for treating iron overload and conditions associated with iron overload, including, for example, sickle cell disease (SCD), thalassemia (e.g., α-thalassemia, β-thalassemia major, β-thalassemia minor), hemochromatosis (e.g., hemochromatosis type 1, hemochromatosis type 2, hemochromatosis type 3, hemochromatosis type 4), transfusion-related iron overload (e.g., repeated blood transfusion for anemia; large-volume transfusion for blood loss due to trauma), hemolytic anemia (e.g., transfusion-dependent hemolytic anemia, pyruvate kinase deficiency hemolytic anemia), African iron overload, Blackfan-Diamond anemia, refractory anemia with ring sideroblasts (ARSA), myelodysplastic syndrome (MDS) (e.g., MDS) Petition 870250088518, dated 09 / 30 / 2025, pages 154 / 245 141 / 213 associated with SF3B1). In some modalities, the discovery provides methods to treat sickle cell disease (SCD). In some modalities, the discovery provides methods to treat sickle cell disease in an individual with iron overload.

[00230] Aspects of the disclosure relate to methods and compositions (e.g., anti-TMPRSS6 antibodies) useful for treating iron overload. Iron overload occurs when there is excess iron in the body. In some modalities, iron overload is a primary iron overload caused by a hereditary disorder (e.g., hemochromatosis). In some modalities, iron overload is a secondary iron overload caused by a condition that increases iron stores in the body (e.g., transfusion or hemolysis) or a disorder that impairs red blood cell production (e.g., ineffective erythropoiesis) (e.g., sickle cell disease, thalassemia, refractory anemia with ring sideroblasts (RARS), MDS). Excess iron is deposited in organs throughout the body, which can cause organ damage. Organs that are commonly damaged due to iron deposition are the liver, heart, and endocrine glands.

[00231] In some respects, matriptase-2 regulates iron homeostasis by regulating the level of hepcidin in an individual. Iron is an essential component for almost all living cells and organisms. Excess iron is dangerous (e.g., due to its redox reactivity which promotes oxidative stress). Thus, dysregulation of iron metabolism leads to disease. In mammals, most of the body's iron (e.g., >70%) is distributed in red blood cells and mediates oxygen transport within hemoglobin. Senescent red blood cells are eliminated by tissue macrophages, and the iron from senescent red blood cells is recycled to erythroblasts for reuse. Iron release into the plasma involves ferroportin, a ferrous iron exporter (Fe). Petition 870250088518, dated 09 / 30 / 2025, pages 155 / 245 142 / 2132+). After its export, ferrous iron undergoes oxidation to ferric iron (Fe3+) by ceruloplasmin, a circulating ferroxidase, and is captured by the iron-transporting transferrin. The main function of transferrin is to supply iron to tissues via transferrin receptor 1 (TfR1). Duodenal enterocytes internalize iron from the intestinal lumen via divalent metal transporter 1 (DMT1) and export it to the plasma via ferroportin.

[00232] Iron uptake into the bloodstream is critical for systemic iron homeostasis and is negatively regulated by hepcidin, an iron-regulating hormone (see, for example, Ganz T. Systemic iron homeostasis. Physiol Rev. (2013) 93:1721-41). Hepcidin is expressed in hepatocytes as a prepropeptide and undergoes proteolytic processing. Mature hepcidin is a 25-amino acid cysteine-rich peptide. In some situations, hepcidin binding to ferroportin in tissue macrophages, duodenal enterocytes, and other target cells triggers the ubiquitination, internalization, and degradation of ferroportin in lysosomes, leading to iron sequestration within macrophages, inhibition of dietary iron absorption, and, in turn, decreased plasma iron levels. Therefore, iron levels can be regulated by manipulating hepcidin levels in an individual.Hepcidin expression is regulated by the BMP signaling pathway and the IL-6-JAK-STAT signaling pathway. Through the BMP pathway, the binding of BMPs (e.g., BMP6 or BMP2) to BMP receptors (e.g., type I (ALK2 and ALK3) and type II (ActRIIA and BMPR2) BMP receptors) on the hepatocyte plasma membrane promotes hepcidin expression. The BMP coreceptors, human homeostatic iron regulatory protein (HFE), hemojuvelin (HJV), and transferrin receptor 2 (TFR2), are required for hepcidin expression via the BMP signaling pathway. Petition 870250088518, dated 09 / 30 / 2025, pp. 156 / 245 143 / 213 by the serine protease matriptase-2 (TMPRSS6), which cleaves and therefore inactivates BMP type I and II receptors, and HJV (Wahedi et al. Matriptase-2 suppresses hepcidin expression by cleaving multiple components of the hepcidin induction pathway. J Biol Chem. (2017) 292:18354–71). In some modalities, HJV cleavage by matriptase-2 reduces the amount of cell surface HJV available to participate in BMP signaling and, in turn, decreases hepcidin expression. In some modalities, loss of hemojuvelin function may be associated with iron overload (e.g., hemochromatosis type 2). In some modalities, HJV inhibition reduces hepcidin expression induced by the IL-6-JAK-STAT signaling pathway. For example, in some modalities, homozygous animals with HJV knockdown are unable to amplify hepcidin synthesis in response to IL-6 and are unable to mount an effective hypoferremic response to acute inflammation.Therefore, in some modalities, inhibition of matriptase-2 (e.g., by an anti-TMPRSS6 antibody) positively regulates hepcidin expression, maintaining / increasing HJV activity. In some modalities, increasing hepcidin levels by inhibiting matriptase-2 (e.g., by an anti-TMPRSS6 antibody) decreases iron levels in an individual, thus treating iron overload.

[00233] In some embodiments, the methods provided herein comprise administering an effective amount of an anti-TMPRSS6 antibody to an individual with the intention of increasing hepcidin expression. The increased hepcidin level in the individual reduced iron levels. In some embodiments, the methods provided herein treat iron overload in an individual by increasing the individual's hepcidin level. In some embodiments, the methods provided herein reduce systemic iron. In some embodiments, the reduction in systemic iron leads to a decrease in corpuscular hemoglobin concentration. Petition 870250088518, dated 09 / 30 / 2025, pp. 157 / 245 144 / 213 mean (CHCM). In some embodiments, the methods provided herein comprise administering an effective amount of an anti-TMPRSS6 antibody to an individual with the intention of treating and / or improving symptoms and conditions associated with iron overload. For example, administration of the anti-TMPRSS6 antibody treats and / or improves one or more of the following symptoms: joint pain, fatigue, weight loss, skin discoloration, abdominal pain, hair loss, loss of libido, impaired memory, or arrhythmia. In some embodiments, the methods provided herein comprise administering an effective amount of an anti-TMPRSS6 antibody to an individual with the intention of improving symptoms and conditions associated with secondary iron overload (e.g., sickle cell disease, thalassemia, refractory anemia with ring sideroblasts (RARS), MDS), as described elsewhere herein.In some embodiments, the methods provided herein comprise administering an effective amount of an anti-TMPRSS6 antibody to an individual to treat sickle cell disease (SCD), thalassemia (e.g., α-thalassemia, β-thalassemia major, β-thalassemia minor), hemochromatosis (e.g., hemochromatosis type 1, hemochromatosis type 2, hemochromatosis type 3, hemochromatosis type 4), transfusion-related iron overload (e.g., repeated blood transfusion for anemia; large-volume transfusion for blood loss due to trauma), hemolytic anemia (e.g., transfusion-dependent hemolytic anemia, pyruvate kinase deficiency hemolytic anemia), African iron overload, Blackfan Diamond anemia, refractory anemia with ring sideroblasts (ARSA), myelodysplastic syndrome (MDS) (e.g., SF3B1-associated MDS).

[00234] Other aspects of the disclosure relate to methods and compositions (e.g., anti-TMPRSS6 antibody) useful for the treatment of sickle cell disease (SCD). In some embodiments, the methods provided herein comprise administering an effective amount of an anti-TMPRSS6 antibody to an individual. Petition 870250088518, dated 09 / 30 / 2025, pages 158 / 245 145 / 213 to treat SCD in an individual. In some embodiments, the methods provided herein comprise administering an effective amount of an anti-TMPRSS6 antibody to an individual with the intent of treating SCD in an individual with iron overload. In some embodiments, the methods provided herein reduce iron overload in an individual with SCD. In some embodiments, the methods described herein reduce the systemic iron level in an individual with SCD. In some embodiments, the methods provided herein reduce the mean corpuscular hemoglobin concentration (MCHC) in an individual with SCD. In some embodiments, the methods provided herein comprise administering an effective amount of an anti-TMPRSS6 antibody to an individual with the intent of treating and / or improving symptoms and conditions associated with SCD (e.g., vaso-occlusive crisis). Sickle cell disease (SCD) is a generic term for a group of genetic diseases that affect the hemoglobin gene.Sickle cell disease (SCD) is generally caused by an autosomal recessive mutation (e.g., a single nucleotide substitution) in the β-globin gene, which results in the synthesis of sickle hemoglobin (HbS) and sickle-shaped red blood cells (SBCs) (Sundd et al., Pathophysiology of sickle cell disease. Annu Rev Pathol. 2019;14(1):263-292; Kato GJ, et al. Sickle cell disease. Nat Rev Dis Primers. 2018;4(1):18010). There are several types of sickle cell disease: hemoglobin SS disease, hemoglobin SC disease, hemoglobin SB+ (Beta) thalassemia, hemoglobin SB 0 (Beta Zero) thalassemia, hemoglobin SD, hemoglobin SE, and hemoglobin SO. In hemoglobin SS disease (i.e., sickle cell disease), an individual is homozygous for the hemoglobin S (HbS) gene mutation and produces only hemoglobin S. In hemoglobin SS disease, the typical shape of the red blood cell disc is altered to a sickle shape; this deformation of the red blood cells disrupts their primary functions. Other symptoms of Hemoglobin SS disease include fatigue, repeated infections, periodic pain, and damage to internal organs. Petition 870250088518, dated 09 / 30 / 2025, pp. 159 / 245 146 / 213 Iron supplements are not considered effective in increasing hemoglobin levels in the blood. In hemoglobin SC disease, an individual has one allele of the HbS gene and one allele of the hemoglobin C (HbC) gene. Generally, in hemoglobin SC disease, anemia is less severe than in hemoglobin SS disease. This is likely because the hemoglobin C gene does not polymerize as rapidly as hemoglobin S. Therefore, this results in the formation of fewer sickle cells. The symptoms of hemoglobin SS disease and hemoglobin SC disease are similar, but differ slightly in severity.

[00235] In sickle cell disease (e.g., hemoglobin SS disease and / or hemoglobin SC disease), after deoxygenation in the capillaries, HbS polymerizes into rigid fibers, causing distortion of the erythrocyte membrane that can lead to intravascular hemolysis and inflammation. In some modalities, the extent of HbS polymerization is related to the concentration of hemoglobin in red blood cells. The concentration of hemoglobin in red blood cells can be measured by the mean corpuscular hemoglobin concentration (MCHC). MCHC is a measure of the average amount of hemoglobin in a single red blood cell. In some modalities, HbS polymerization in patients with sickle cell disease can be decreased by reducing the concentration of hemoglobin in red blood cells (see, for example, Sunshine et al., Requirements for therapeutic inhibition of sickle haemoglobin gelation, Nature volume 275, pages 238-240 (1978)).In some modalities, decreased systemic iron results in decreased HbS polymerization. In some modalities, decreased systemic iron leads to decreased MCHC, which results in decreased HbS polymerization (see, for example, Castro et al., Iron restriction in sickle cell anemia: Time for controlled clinical studies, American Journal of Hematology, Vol. 90, No. 12, December 2015; Brugnara, Less (Fe) is more (Hb)). Petition 870250088518, dated 09 / 30 / 2025, pp. 160 / 245 147 / 213 in SCA, Blood (2021) 137 (11): 1446-1447; Embury et al. Concurrent sickle cell anemia and alpha-thalassemia. Effect on pathological properties of sickle erythrocytes, J Clin Invest. 1984 Jan; 73(1): 116-123; Brewin et al., The pleiotropic effects of α-thalassemia on HbSS and HbSC sickle cell disease: Reduced erythrocyte cation co-transport activity, serum erythropoietin, and transfusion burden, do not translate into increased survival, Am J Hematol. 2022 Oct;97(10):1275-1285). Intravascular hemolysis in sickle cell disease results in the release of cell-free hemoglobin into the circulation, which oxidizes and releases reactive heme into the vasculature. In some modalities, the release of cell-free hemoglobin into the circulation causes iron overload in patients with sickle cell disease. In some modalities, cell-free heme activates endothelial cell adhesion molecules and induces leukocyte activation and migration, as well as the release of reactive oxygen species, cytokines, and chemokines.In some forms, HbS polymerization, hemolysis, and the release of cell-free hemoglobin and / or heme lead to vaso-occlusive crisis (VOC). As used herein, the terms vaso-occlusive crisis (VOC), vaso-occlusion, painful crisis(es), and vaso-occlusive painful crisis(es) are interchangeable. Blood vessel occlusion is a fundamental pathological process in SCD (Frenette P. Sickle cell vaso-occlusion: multistep and multicellular paradigm. Curr Opin Hematol. (2002). 9:101-6; Pathare et al., Cytokines in sickle cell disease. Hematology. (2003) 8:329-37). During CVO, in some forms, the vessel lumen is blocked by cells that interrupt capillary blood flow to various organs and other parts of the body. This precipitates an inflammatory process that leads to painful crises and damage to various tissues (e.g., brain, liver, kidneys, lungs, spleen, etc.). Painful crises affect virtually all patients with SCD, usually beginning in late childhood and recurring throughout life. Petition 870250088518, dated 09 / 30 / 2025, pp. 161 / 245 148 / 213 In some modalities, patients with sickle cell disease are treated with blood transfusions (e.g., periodic on-demand or chronic blood transfusions). In some modalities, blood transfusion accelerates hemolysis and / or iron overload (e.g., Raghunath et al., Iron Overload in Sickle Cell Disease, Advances in Hematology, Volume 2010 | Article ID 272940).

[00236] In some forms, an individual with SCD has splenic sequestration. The main function of the spleen is the removal of defective RBCs, including sickle-shaped RBCs. In patients with SCD, blood flow through the spleen is slow, leading to reduced oxygen tension and therefore increased HbS polymerization. Due to the narrow capillaries in the splenic vascular bed, the spleen becomes congested with blood cells. Splenic sequestration (also known as splenic enlargement) is characterized by an acute enlargement of the spleen (splenomegaly), with hemoglobin more than 2 g / dL below the baseline value of the affected individual (Bender and Carlberg, 2003 Sep 15 [updated 2023 Dec 28]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024.) In some forms, an individual with splenic sequestration requires hospitalization, splenectomy, and / or blood transfusion.In some embodiments, administration of an anti-TMPRSS6 antibody reduces splenic sequestration (e.g., frequency and / or severity) in an individual with SCD compared to the individual before administration, or compared to an untreated individual with SCD. In some embodiments, administration of an anti-TMPRSS6 antibody reduces hospitalization (e.g., hospitalization associated with splenectomy) associated with splenic sequestration in an individual with SCD compared to the individual before administration or compared to an untreated individual with SCD. In some embodiments, administration of an anti-TMPRSSS6 antibody... [Petition 870250088518, 09 / 30 / 2025, p. 162 / 245.] 149 / 213 TMPRSS6 reduces the frequency of blood transfusions needed in an individual with SCD compared to the individual before administration or compared to an untreated individual with SCD. In some embodiments, administration of an anti-TMPRSS6 antibody reduces the size of an enlarged spleen (e.g., an individual with splenomegaly) in an individual with SCD compared to the individual before administration, or compared to an untreated individual with SCD.

[00237] In some modalities, an individual with SCD has extramedullary hematopoiesis (EMH) (see, for example, Gupta, et al., Clinicopathological characteristics and management of extramedullary hematopoiesis: A review. Pediatric Hematology Oncology Journal 7.4 (2022): 182-186). EMH refers to the production of blood cells outside the bone marrow, normally occurring in organs such as the liver, spleen, and lymph nodes. In an individual with SCD, EMH may occur due to chronic anemia and the body's compensatory response to maintain adequate blood cell production. In some modalities, EMH in an individual with SCD occurs due to chronic hemolytic anemia, splenomegaly, ineffective erythropoiesis, CVO, and / or organ damage and dysfunction, all of which contribute to an increased need for blood cell production.In some modalities, administration of an anti-TMPRSS6 antibody reduces HEM in an individual with DF compared to the individual before administration or compared to an untreated individual with DF.

[00238] In some forms, an individual with SCD has hepatomegaly (see, for example, Burley et al., Acute Liver Failure in Sickle Cell Disease: A Perfect Storm. Cureus. 2021 Jun 16;13(6):e15680). In some forms, hepatomegaly in an individual with SCD is caused by congestion in the blood vessels caused by sickle-shaped red blood cells, which, in some forms, leads to liver infarction. In some forms, Petition 870250088518, dated 09 / 30 / 2025, pp. 163 / 245 150 / 213 The liver increases in size due to congestion caused by blocked blood flow. In some modalities, hepatomegaly in an individual with SCD is caused by sickle cell disease crises (e.g., hepatic sequestration). In some modalities, during a splenic sequestration crisis, blood also becomes trapped in the liver, leading to its enlargement. In some modalities, hepatomegaly in an individual with SCD is caused by liver dysfunction. In some modalities, liver dysfunction in an individual with SCD is caused by chronic hemolysis, iron overload (e.g., from repeated blood transfusions), and / or liver congestion. In some modalities, hepatomegaly in an individual with SCD is caused by gallbladder complications (e.g., gallstones and cholecystitis), which can lead to biliary obstruction and liver enlargement.In some modalities, hepatomegaly in an individual with SCD is caused by hepatic iron overload (e.g., from chronic transfusion therapy) (e.g., secondary hemochromatosis). Excess iron deposition in the liver can lead to hepatomegaly and liver dysfunction. In some modalities, hepatomegaly in an individual with SCD is caused, at least in part, by hepatotoxicity related to medications taken for the treatment of SCD (e.g., hydroxyurea), leading to drug-induced liver injury. In some modalities, administration of an anti-TMPRSS6 antibody reduces hepatomegaly in an individual with SCD compared to the individual before administration or compared to an untreated individual with SCD. In some modalities, administration of an anti-TMPRSS6 antibody reduces hepatic sequestration in an individual with SCD compared to the individual before administration, or compared to an untreated individual with SCD.In some modalities, administration of an anti-TMPRSS6 antibody reduces hepatic congestion in an individual with DF compared to the individual before administration or in the same condition. Petition 870250088518, dated 09 / 30 / 2025, pages 164 / 245 151 / 213 compared to an untreated individual with DF. In some embodiments, administration of an anti-TMPRSS6 antibody reduces gallbladder complications (e.g., gallstones and / or cholecystitis) in an individual with DF compared to the individual before administration, or compared to an untreated individual with DF. In some embodiments, administration of an anti-TMPRSS6 antibody reduces hepatic iron overload in an individual with DF compared to the individual before administration or compared to an untreated individual with DF. In some embodiments, administration of an anti-TMPRSS6 antibody reduces hepatic dysfunction in an individual with DF compared to the individual before administration or compared to an untreated individual with DF.In some embodiments, administration of an anti-TMPRSS6 antibody reduces hepatic infarction in an individual with DF compared to the individual before administration or compared to an untreated individual with DF. In some embodiments, administration of an anti-TMPRSS6 antibody reduces hepatic congestion (e.g., biliary obstruction) in an individual with DF compared to the individual before administration or compared to an untreated individual with DF.

[00239] In some embodiments, the present disclosure provides methods and compositions (e.g., anti-TMPRSS6 antibodies) useful for reducing CVO in individuals with DF (e.g., individuals with DF with or without blood transfusion) through iron restriction. In some embodiments, administration of anti-TMPRSS6 antibodies reduces the frequency of CVO in individuals with DF (e.g., individuals with DF with or without blood transfusion). In some embodiments, administration of anti-TMPRSS6 antibodies reduces the severity of CVO in individuals with DF (e.g., individuals with DF with or without blood transfusion). In some embodiments, administration of anti-TMPRSS6 antibody results in increased hepcidin levels, thereby decreasing the Petition 870250088518, dated 09 / 30 / 2025, pages 165 / 245 152 / 213 circulating iron (e.g., circulating iron available for HbS synthesis) in an individual with SCD (e.g., individual with SCD with or without blood transfusion) compared to the individual before receiving the anti-TMPRSS6 antibody or an individual with SCD (e.g., individual with SCD with or without blood transfusion) but who did not receive the anti-TMPRSS6 antibody.

[00240] In some embodiments, administration of an anti-TMPRSS6 antibody results in a decrease in circulating iron (e.g., a decrease in circulating iron of at least 5%, 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%, at least 95%) in an individual with DF (e.g., an individual with DF with or without blood transfusion) compared to the individual before receiving the anti-TMPRSS6 antibody or an individual with DF (e.g., an individual with DF with or without blood transfusion) but who did not receive the anti-TMPRSS6 antibody.In some embodiments, administration of an anti-TMPRSS6 antibody results in a decrease in circulating iron (e.g., a decrease in circulating iron of at least 5%, 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%, at least 95%) in an individual with DF (e.g., hemoglobin SC disease) compared to the individual before receiving the anti-TMPRSS6 antibody or an individual with DF (e.g., hemoglobin SC disease) but who did not receive the anti-TMPRSS6 antibody. The level of circulating iron can be assessed by conventional laboratory tests, for example. Petition 870250088518, dated 09 / 30 / 2025, pp. 166 / 245 153 / 213 measurement of iron in serum, transferrin saturation (TSAT) or total iron-binding capacity (TIBC).

[00241] In some embodiments, administration of an anti-TMPRSS6 antibody results in an increase in the circulating level of hepcidin-25 (e.g., an increase in the circulating level of hepcidin-25 by at least 5%, 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%, at least 95%, at least 100%, at least 1.5 times, at least 2 times, at least 3 times, at least 4 times, at least 5 times, at least 10 times, at least 20 times, at least 50 times or at least 100 times) in an individual with DF (e.g., an individual with DF with or without blood transfusion) compared to the individual before receiving the anti-TMPRSS6 antibody or an individual with DF (e.g., an individual with DF with or without blood transfusion) but who did not receive the anti-TMPRSS6 antibody.In some embodiments, administration of an anti-TMPRSS6 antibody results in an increase in the circulating level of hepcidin-25 (e.g., an increase in the circulating level of hepcidin-25 by at least 5%, 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%, at least 95%, at least 100%, at least 1.5 times, at least 2 times, at least 3 times, at least 4 times, at least 5 times, at least 10 times, at least 20 times, at least 50 times, or at least 100 times). times) in an individual with DF (e.g., hemoglobin SC disease) compared to the individual before receiving the anti-TMPRSS6 antibody or an individual with DF (e.g., hemoglobin SC disease) but who did not receive the anti-TMPRSS6 antibody. Petition 870250088518, dated 09 / 30 / 2025, pp. 167 / 245 154 / 213

[00242] In some modalities, administration of an anti-TMPRSS6 antibody results in increased Hamp expression. In some embodiments, administration of an anti-TMPRSS6 antibody results in increased Hamp expression (e.g., increased Hamp expression by at least 5%, 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%, at least 95%, or 100%) in an individual with SCD (e.g., an individual with SCD with or without blood transfusion) compared to the individual before receiving the anti-TMPRSS6 antibody or an individual with SCD (e.g., an individual with SCD with or without blood transfusion) but who did not receive the anti-TMPRSS6 antibody.In some embodiments, administration of an anti-TMPRSS6 antibody results in increased Hamp expression (e.g., decreased bilirubin by at least 5%, 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%, at least 95%, or 100%) in an individual with FD (e.g., hemoglobin SC disease) compared to the individual before receiving the anti-TMPRSS6 antibody or an individual with FD (e.g., hemoglobin SC disease) but who did not receive the anti-TMPRSS6 antibody.

[00243] In some embodiments, administration of an anti-TMPRSS6 antibody results in decreased transferrin saturation (TSAT). In some embodiments, administration of an anti-TMPRSS6 antibody results in decreased TSAT (e.g., decreased TSAT by at least 5%, 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%, by Petition 870250088518, dated 09 / 30 / 2025, pp. 168 / 245 155 / 213 less 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or 100%) in an individual with DF (e.g., an individual with DF with or without blood transfusion) compared to the individual before receiving the anti-TMPRSS6 antibody or an individual with DF (e.g., an individual with DF with or without blood transfusion) but who did not receive the anti-TMPRSS6 antibody.In some embodiments, administration of an anti-TMPRSS6 antibody results in decreased TSAT (e.g., decreased TSAT by at least 5%, 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%, at least 95%, or 100%) in an individual with DF (e.g., hemoglobin SC disease) compared to the individual before receiving the anti-TMPRSS6 antibody or an individual with DF (e.g., hemoglobin SC disease) but who did not receive the anti-TMPRSS6 antibody.

[00244] In some modalities, administration of an anti-TMPRSS6 antibody results in decreased extramedullary hematopoiesis. In some modalities, administration of an anti-TMPRSS6 antibody results in decreased extramedullary hematopoiesis (e.g., decreased extramedullary hematopoiesis by at least 5%, 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%, at least 95%, or 100%) in an individual with SCD (e.g., an individual with SCD with or without blood transfusion) compared to the individual before receiving the anti-TMPRSS6 antibody or an individual with SCD (e.g., an individual with SCD with or without blood transfusion) but who did not receive the antibody. anti-TMPRSS6 antibody. In some Petition 870250088518, dated 09 / 30 / 2025, pp. 169 / 245 156 / 213 modalities, administration of an anti-TMPRSS6 antibody results in decreased extramedullary hematopoiesis (e.g., decreased extramedullary hematopoiesis by at least 5%, 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%, at least 95%, or 100%) in an individual with FD (e.g., hemoglobin SC disease) compared to the individual before receiving the anti-TMPRSS6 antibody or an individual with FD (e.g., hemoglobin SC disease) but who did not receive the anti-TMPRSS6 antibody.Extramedullary hematopoiesis can be assessed by known and appropriate methods, for example, the ratio between spleen weight and body weight, imaging studies (e.g., X-rays, computed tomography, magnetic resonance imaging, ultrasound), biopsy, blood tests (e.g., blood cell morphology or blast cell levels), bone marrow examination (e.g., changes in cellularity, composition, and bone marrow architecture), or erythropoietin levels and reticulocyte count.

[00245] In some modalities, administration of an anti-TMPRSS6 antibody results in a decrease in hepatomegaly. In some embodiments, administration of an anti-TMPRSS6 antibody results in decreased hepatomegaly (e.g., decreased hepatomegaly by at least 5%, 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%, at least 95%, or 100%) in an individual with SCD (e.g., an individual with SCD with or without blood transfusion) compared to the individual before receiving the anti-TMPRSS6 antibody or an individual with SCD (e.g., an individual with SCD with or without blood transfusion). Petition 870250088518, dated 09 / 30 / 2025, pp. 170 / 245 157 / 213 but did not receive the anti-TMPRSS6 antibody. In some embodiments, administration of the anti-TMPRSS6 antibody results in a decrease in hepatomegaly (e.g., a decrease in hepatomegaly of at least 5%, 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%, at least 95%, or 100%) in an individual with FD (e.g., hemoglobin SC disease) compared to the individual before receiving the anti-TMPRSS6 antibody or an individual with FD (e.g., hemoglobin SC disease) but who did not receive the anti-TMPRSS6 antibody.Hepatomegaly can be assessed by appropriate known methods, for example, the ratio between liver weight and body weight, imaging studies (e.g., computed tomography, magnetic resonance imaging, ultrasound, liver elastography), blood tests (e.g., liver function tests, markers of liver injury [alanine transaminase and aspartate transaminase]), and biopsy.

[00246] In some embodiments, administration of the anti-TMPRSS6 antibody results in a decrease in the frequency of vaso-occlusive crisis (VOC) (e.g., a decrease in the frequency of VOC by at least 5%, 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%, at least 95%, or 100%) in an individual with SCD (e.g., an individual with SCD with or without blood transfusion) compared to the individual before receiving the anti-TMPRSS6 antibody or an individual with SCD (e.g., an individual with SCD with or without blood transfusion) but who does not received the anti-TMPRSS6 antibody. In some modalities, administration of the anti-TMPRSS6 antibody results in a frequency Petition 870250088518, dated 09 / 30 / 2025, pp. 171 / 245 158 / 213 reduced CVO (e.g., reduced CVO frequency by at least 5%, at least 10%, at least 15%, at least 20%, by 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%, by less than 85%, at least 90%, at least 95%, or 100%) in an individual with FD (e.g., hemoglobin SC disease) compared to the individual before receiving the anti-TMPRSS6 antibody, or an individual with FD (e.g., hemoglobin SC disease) but who did not receive the anti-TMPRSS6 antibody.

[00247] In some embodiments, administration of the anti-TMPRSS6 antibody results in a decrease in the severity (e.g., hospitalization and / or duration) of vaso-occlusive crisis (VOC) (e.g., a decrease in the severity of VOC (e.g., hospitalization and / or duration) by at least 5%, 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%, at least 95% or 100%) in an individual with SCD (e.g., an individual with SCD with or without blood transfusion) compared to the individual before receiving the anti-TMPRSS6 antibody or a An individual with sickle cell disease (e.g., an individual with sickle cell disease with or without a blood transfusion) but who has not received the anti-TMPRSS6 antibody.In some modalities, administration of the anti-TMPRSS6 antibody results in a decrease in the frequency of vaso-occlusive crises (VOCs) (e.g., a decrease in VOCs of at least 5%, 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%, at least 95%, or 100%) in an individual with FD (e.g., hemoglobin SC disease) compared to the individual. Petition 870250088518, dated 09 / 30 / 2025, pp. 172 / 245 159 / 213 before receiving the anti-TMPRSS6 antibody or an individual with DF (e.g., hemoglobin SC disease) but who has not received the anti-TMPRSS6 antibody. In some modalities, administration of the anti-TMPRSS6 antibody results in a decrease in the severity (e.g., hospitalization and / or duration) of vaso-occlusive crisis (VOC) (e.g., a decrease in VOC by at least 5%, 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%, at least 95%, or 100%) in an individual with DF (e.g., hemoglobin SC disease) compared to the individual before receiving the anti-TMPRSS6 antibody or an individual with DF (e.g., hemoglobin SC disease) but who did not receive the antibody. anti-TMPRSS6.Void-related cardiovascular disease (VOC) (e.g., frequency and / or severity) can be assessed by appropriate known methods, such as complete blood count with leukocyte differential, platelet count, reticulocyte count, and a comprehensive metabolic panel with liver and kidney function tests. Typical laboratory findings include an acute drop in hemoglobin concentration, an increase in platelet count, an increase in reticulocyte count, and an elevation in serum urea.

[00248] In some embodiments, decreased administration of an anti-TMPRSS6 antibody results in decreased systemic iron. In some embodiments, administration of an anti-TMPRSS6 antibody results in decreased MCHC. In some embodiments, decreased MCHC results in decreased HbS polymerization. In some embodiments, administration of the anti-TMPRSS6 antibody results in decreased MCHC (e.g., decreased MCHC by at least 5%, 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%, Petition 870250088518, dated 09 / 30 / 2025, pp. 173 / 245 160 / 213 at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or 100%) in an individual with DF (e.g., an individual with DF with or without blood transfusion) compared to the individual before receiving the anti-TMPRSS6 antibody or an individual with DF (e.g., an individual with DF with or without blood transfusion) but who did not receive the anti-TMPRSS6 antibody.In some embodiments, administration of the anti-TMPRSS6 antibody results in a decrease in MCHC (e.g., a decrease in MCHC of at least 5%, 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%, at least 95%, or 100%) in an individual with FD (e.g., hemoglobin SC disease) compared to the individual before receiving the anti-TMPRSS6 antibody or an individual with FD (e.g., hemoglobin SC disease) but who did not receive the anti-TMPRSS6 antibody.In some embodiments, administration of the anti-TMPRSS6 antibody results in reduced HbS polymerization (e.g., reduced HbS polymerization by at least 5%, 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%, at least 95%, or 100%) in an individual with SCD (e.g., an individual with SCD with or without blood transfusion) compared to the individual before receiving the anti-TMPRSS6 antibody or an individual with SCD (e.g., an individual with SCD with or without blood transfusion) but who did not receive the anti-TMPRSS6 antibody. In some modalities, administration of an anti-TMPRSS6 antibody results in reduced HbS polymerization (e.g., reduced HbS polymerization by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, etc.). Petition 870250088518, dated 09 / 30 / 2025, pp. 174 / 245 161 / 213 less 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%, at least 95% or 100%) of an individual with DF (e.g., hemoglobin SC disease) compared to the individual before receiving the anti-TMPRSS6 antibody or an individual with DF (e.g., hemoglobin SC disease) but who did not receive the anti-TMPRSS6 antibody. HbS polymerization can be assessed by known suitable methods, for example, solubility sickling test, hemoglobin electrophoresis, isoelectric focusing or high-performance liquid chromatography (see, for example, Arishi et al., Techniques for the Detection of Sickle Cell Disease: A Review, Micromachines 2021, 12(5), 519).

[00249] In some embodiments, administration of an anti-TMPRSS6 antibody results in a decrease in red blood cell sickling (e.g., a decrease in red blood cell sickling by at least 5%, 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%, at least 95%, or 100%) in an individual with SCD (e.g., an individual with SCD with or without blood transfusion) compared to the individual before receiving the anti-TMPRSS6 antibody or an individual with SCD (e.g., an individual with SCD with or without blood transfusion). but who did not receive the anti-TMPRSS6 antibody.In some modalities, administration of an anti-TMPRSS6 antibody results in a decrease in red blood cell sickling (e.g., a decrease in red blood cell sickling by at least 5%, 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%, etc.). Petition 870250088518, dated 09 / 30 / 2025, pages 175 / 245 162 / 213 less than 75%, at least 80%, at least 85%, at least 90%, at least 95% or 100%) in an individual with SCI (e.g., hemoglobin SC disease) compared to the individual before receiving the anti-TMPRSS6 antibody or an individual with SCI (e.g., hemoglobin SC disease) but who did not receive the anti-TMPRSS6 antibody. Erythrocyte sickling can be assessed by known suitable methods, e.g., blood smear.

[00250] In some embodiments, administration of an anti-TMPRSS6 antibody results in reduced levels of hypochromic red blood cells (e.g., reduced levels of hypochromic red blood cells by at least 5%, 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%, at least 95%, or 100%) in an individual with SCD (e.g., an individual with SCD with or without blood transfusion) compared to the individual before receiving the anti-TMPRSS6 antibody or an individual with SCD (e.g., an individual with SCD with or without blood transfusion), but who did not receive the anti-TMPRSS6 antibody.In some embodiments, administration of an anti-TMPRSS6 antibody results in reduced levels of hypochromic red blood cells (e.g., hypochromic red blood cell levels by at least 5%, 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%, at least 95%, or 100%) in an individual with FD (e.g., hemoglobin SC disease) compared to the individual before receiving the anti-TMPRSS6 antibody or an individual with FD (e.g., hemoglobin SC disease) but who did not receive the anti-TMPRSS6 antibody. Petition 870250088518, dated 09 / 30 / 2025, pp. 176 / 245 163 / 213

[00251] In some embodiments, administration of an anti-TMPRSS6 antibody results in reduced levels of microcytic red blood cells (e.g., reduced levels of microcytic red blood cells by at least 5%, 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%, at least 95%, or 100%) in an individual with SCD (e.g., an individual with SCD with or without blood transfusion) compared to the individual before receiving the anti-TMPRSS6 antibody or an individual with SCD (e.g., an individual with SCD with or without blood transfusion), but who did not receive the anti-TMPRSS6 antibody.In some embodiments, administration of an anti-TMPRSS6 antibody results in reduced levels of microcytic red blood cells (e.g., microcytic red blood cell levels by at least 5%, 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%, at least 95%, or 100%) in an individual with FD (e.g., hemoglobin SC disease) compared to the individual before receiving the anti-TMPRSS6 antibody or an individual with FD (e.g., hemoglobin SC disease) but who did not receive the anti-TMPRSS6 antibody.

[00252] In some embodiments, administration of an anti-TMPRSS6 antibody results in decreased hemolysis (e.g., decreased hemolysis by at least 5%, 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%, at least 95%, or 100%) in an individual with DF (e.g., Petition 870250088518, dated 09 / 30 / 2025, pp. 177 / 245 164 / 213 individual with DF with or without blood transfusion) in relation to the individual before receiving the anti-TMPRSS6 antibody or an individual with DF (e.g., individual with DF with or without blood transfusion) but who did not receive the anti-TMPRSS6 antibody. In some embodiments, administration of an anti-TMPRSS6 antibody results in decreased hemolysis (e.g., decreased hemolysis by at least 5%, 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%, at least 95%, or 100%) in an individual with FD (e.g., hemoglobin SC disease) compared to the individual before receiving the anti-TMPRSS6 antibody or an individual with FD (e.g., hemoglobin SC disease) but who did not receive the anti-TMPRSS6 antibody.Hemolysis can be assessed by known suitable methods, for example, lactate dehydrogenase (LDH), unconjugated bilirubin, total bilirubin, direct bilirubin and haptoglobin tests, reticulocyte count or total heme and hemopexin (see, for example, Hemolytic Anemias. ARUP Consult®. Retrieved March 15, 2023, arupconsult.com / content / hemolyticanemias).

[00253] In some embodiments, administration of an anti-TMPRSS6 antibody results in a decrease in lactate dehydrogenase (LDH). In some embodiments, administration of the anti-TMPRSS6 antibody results in a decrease in LDH (e.g., a decrease in LDH of at least 5%, 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%, at least 95%, or 100%) in an individual with AF (e.g., an individual with AF with or without blood transfusion) relative to Petition 870250088518, dated 09 / 30 / 2025, pp. 178 / 245 165 / 213 individual before receiving the anti-TMPRSS6 antibody or an individual with AF (e.g., individual with AF with or without blood transfusion) but who has not received the anti-TMPRSS6 antibody. In some embodiments, administration of the anti-TMPRSS6 antibody results in a decrease in LDH (e.g., a decrease in LDH of at least 5%, 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%, at least 95% or 100%) in an individual with AF (e.g., hemoglobin SC disease) compared to the individual before receiving the anti-TMPRSS6 antibody or an individual with AF (e.g., hemoglobin SC disease) but who did not receive the anti-TMPRSS6 antibody.

[00254] In some embodiments, administration of an anti-TMPRSS6 antibody results in a decrease in bilirubin (e.g., direct bilirubin and / or total bilirubin). In some embodiments, administration of the anti-TMPRSS6 antibody results in a decrease in bilirubin (e.g., direct bilirubin and / or total bilirubin) (e.g., a decrease in bilirubin by at least 5%, 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% 60%, at least 65%, at least 70%, at least 75% 80%, at least 85%, at least 90%, at least 95%, or 100% in an individual with AF (e.g., an individual with AF with or without blood transfusion) compared to the individual before receiving the anti-TMPRSS6 antibody, or an individual with AF (e.g., an individual with AF with or without blood transfusion) but who did not receive the anti-TMPRSS6 antibody. In some embodiments, administration of the anti-TMPRSS6 an...

Claims

1. Method for treating sickle cell disease (SCD), characterized in that it comprises administering to an individual an effective amount of an anti-serine transmembrane protease 6 antibody (TMPRSS6) comprising: (a) a HC CDR1, HC CDR2 and HC CDR3 of a variable heavy chain domain having the amino acid sequence of SEQ ID NO: 49 and a LC CDR1, LC CDR2 and LC CDR3 of a variable light chain domain having the amino acid sequence of SEQ ID NO: 50; (b) a HC CDR1, HC CDR2 and HC CDR3 of a variable heavy chain domain having the amino acid sequence of SEQ ID NO: 7 and a LC CDR1, LC CDR2 and LC CDR3 of a variable light chain domain having the amino acid sequence of SEQ ID NO: 8; (c) an HC CDR1, HC CDR2 and HC CDR3 of a variable heavy chain domain having the amino acid sequence of SEQ ID NO: 19 or 78 and an LC CDR1, LC CDR2 and LC CDR3 of a variable light chain domain having the amino acid sequence of SEQ ID NO: 20;(d) an HC CDR1, HC CDR2 and HC CDR3 of a variable heavy chain domain having the amino acid sequence of SEQ ID NO: 30 and an LC CDR1, LC CDR2 and LC CDR3 of a variable light chain domain having the amino acid sequence of SEQ ID NO: 31; (e) an HC CDR1, HC CDR2 and HC CDR3 of a variable heavy chain domain having the amino acid sequence of SEQ ID NO: 37 and an LC CDR1, LC CDR2 and LC CDR3 of a variable light chain domain having the amino acid sequence of SEQ ID NO: 38; or (f) an HC CDR1, HC CDR2 and HC CDR3 of a variable heavy chain domain having the amino acid sequence of SEQ ID NO: 44 and an LC CDR1, LC CDR2 and LC CDR3 of a variable light chain domain having the amino acid sequence of SEQ ID NO: 45.; 2. Method according to claim 1, characterized in that the anti-TMPRSS6 antibody comprises an HC CDR1, HC CDR2 and HC CDR3 of a variable heavy chain domain having the amino acid sequence of SEQ ID NO: 49 and an LC CDR1, LC Petition 870250088518, dated 09 / 30 / 2025, page 228 / 245 2 / 6 CDR2 and LC CDR3 of a variable light chain domain having the amino acid sequence of SEQ ID NO:

50.

3. Method according to claim 1 or 2, characterized in that the anti-TMPRSS6 antibody comprises: (a) an HC CDR1 having the amino acid sequence of SEQ ID NO: 24, an HC CDR2 having the amino acid sequence of SEQ ID NO: 48, an HC CDR3 having the amino acid sequence of SEQ ID NO: 26, an LC CDR1 having the amino acid sequence of SEQ ID NO: 27, an LC CDR2 having the amino acid sequence of WAT and an LC CDR3 having the amino acid sequence of SEQ ID NO: 29; (b) 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 RAN and an LC CDR3 having the amino acid sequence of SEQ ID NO: 6;(c) an HC CDR1 having the amino acid sequence of SEQ ID NO: 13, an HC CDR2 having the amino acid sequence of SEQ ID NO: 14, an HC CDR3 having the amino acid sequence of SEQ ID NO: 15, an LC CDR1 having the amino acid sequence of SEQ ID NO: 16, an LC CDR2 having the amino acid sequence of WAF and an LC CDR3 having the amino acid sequence of SEQ ID NO: 18; (d) an HC CDR1 having the amino acid sequence SEQ ID NO: 24, an HC CDR2 having the amino acid sequence SEQ ID NO: 25, an HC CDR3 having the amino acid sequence SEQ ID NO: 26, an LC CDR1 having the amino acid sequence SEQ ID NO: 27, an LC CDR2 having the amino acid sequence WAT and an LC CDR3 having the amino acid sequence SEQ ID NO: 29;(e) 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: 35, an LC CDR1 having the amino acid sequence of SEQ ID Petition 870250088518, dated 09 / 30 / 2025, p. 229 / 245 3 / 6 NO: 36, an LC CDR2 having the amino acid sequence of RAN and an LC CDR3 having the amino acid sequence of SEQ ID NO: 6; or (f) an HC CDR1 having the amino acid sequence of SEQ ID NO: 13, an HC CDR2 having the amino acid sequence of SEQ ID NO: 43, an HC CDR3 having the amino acid sequence of SEQ ID NO: 15, an LC CDR1 having the amino acid sequence of SEQ ID NO: 16, an LC CDR2 having the amino acid sequence of WAF and an LC CDR3 having the amino acid sequence of SEQ ID NO: 18.; 4. Method according to any one of claims 1 to 3, characterized in that the anti-TMPRSS6 antibody comprises an HC CDR1 having the amino acid sequence of SEQ ID NO: 24, an HC CDR2 having the amino acid sequence of SEQ ID NO: 48, an HC CDR3 having the amino acid sequence of SEQ ID NO: 26, an LC CDR1 having the amino acid sequence of SEQ ID NO: 27, an LC CDR2 having the amino acid sequence of WAT and an LC CDR3 having the amino acid sequence of SEQ ID NO:

29.

5. Method according to any one of claims 1 to 4, characterized in that the anti-TMPRSS6 antibody comprises: (a) a variable heavy chain domain having the amino acid sequence of SEQ ID NO: 49 and a variable light chain domain having the amino acid sequence of SEQ ID NO: 50; (b) a variable heavy chain domain having the amino acid sequence of SEQ ID NO: 7 and a variable light chain domain having the amino acid sequence of SEQ ID NO: 8; (c) a variable heavy chain domain having the amino acid sequence of SEQ ID NO: 19 or 78 and a variable light chain domain having the amino acid sequence of SEQ ID NO: 20; (d) a variable heavy chain domain having the amino acid sequence of SEQ ID NO: 30 and a variable light chain domain having the amino acid sequence of SEQ ID NO: 31; Petition 870250088518, dated 09 / 30 / 2025, page.230 / 245 4 / 6 (e) a variable heavy chain domain having the amino acid sequence SEQ ID NO: 37 and a variable light chain domain having the amino acid sequence SEQ ID NO: 38; or (f) a variable heavy chain domain having the amino acid sequence SEQ ID NO: 44 and a variable light chain domain having the amino acid sequence SEQ ID NO:

45.

6. Method according to any one of claims 1 to 5, characterized in that the anti-TMPRSS6 antibody comprises a variable heavy chain domain having the amino acid sequence of SEQ ID NO: 49 and a variable light chain domain having the amino acid sequence of SEQ ID NO:

50.

7. Method according to any one of claims 1 to 6, characterized in that the anti-TMPRSS6 antibody comprises: (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 52 and a light chain comprising the amino acid sequence of SEQ ID NO: 53; (b) a heavy chain comprising the amino acid sequence of SEQ ID NO: 11 and a light chain comprising the amino acid sequence of SEQ ID NO: 12; (c) a heavy chain comprising the amino acid sequence of SEQ ID NO: 17 or 22 and a light chain comprising the amino acid sequence of SEQ ID NO: 23; (d) a heavy chain comprising the amino acid sequence of SEQ ID NO: 33 and a light chain comprising the amino acid sequence of SEQ ID NO: 34; (e) a heavy chain comprising the amino acid sequence of SEQ ID NO: 41 and a light chain comprising the amino acid sequence of SEQ ID NO: 42;or (f) a heavy chain comprising the amino acid sequence of SEQ ID NO: 46 and a light chain comprising the amino acid sequence of SEQ ID NO:

47. Petition 870250088518, dated 09 / 30 / 2025, p. 231 / 245 5 / 6; 8. Method according to any one of claims 1 to 7, characterized in that the anti-TMPRSS6 antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 52 and a light chain comprising the amino acid sequence of SEQ ID NO:

53.

9. A method according to any one of claims 1 to 8, characterized in that administration of the antibody reduces iron overload in the individual.

10. A method according to any one of claims 1 to 9, characterized in that administration of the antibody reduces hemolysis in the individual compared to the individual before administration.

11. A method according to any one of claims 1 to 10, characterized in that the individual has recurrent moderate to severe vaso-occlusive crisis (VOC).

12. Method according to any one of claims 1 to 11, characterized in that administration of the antibody reduces the frequency of CVO in the individual compared to the individual before administration.

13. A method according to any one of claims 1 to 12, characterized in that administration reduces the severity of CVO compared to the individual before administration.

14. Method according to claim 13, characterized in that the severity of CVO is measured by the frequency of hospitalization and / or duration of hospitalization.

15. A method according to any one of claims 1 to 14, characterized in that administration of the antibody reduces systemic iron in the individual prior to administration.

16. Method according to any one of claims 1 to 15, characterized in that administration of the antibody reduces the mean corpuscular hemoglobin concentration (MCHC) relative to the period prior to administration. Petition 870250088518, dated 09 / 30 / 2025, pp. 232 / 245 6 / 6 17. A method according to any one of claims 1 to 16, characterized in that administration reduces the polymerization of hemoglobin S (HbS) compared to the individual before administration.

18. A method according to any one of claims 1 to 17, characterized in that administration reduces the frequency with which the individual needs blood transfusions compared to the individual before administration.

19. Method according to any one of claims 1 to 18, characterized in that sickle cell disease is the disease of hemoglobin SS.

20. Method according to any one of claims 1 to 18, characterized in that sickle cell disease is the disease of hemoglobin SC.

21. A method according to any one of claims 1 to 20, characterized in that the anti-TMPRSS6 antibody is administered as co-therapy in combination with a hemoglobin S polymerization inhibitor (e.g., voxelotor), therapeutic agents to reduce CVO (e.g., hydroxyurea, L-glutamine powder for oral administration, crizanlizumab, selective pyruvate kinase-R (PKR) activator), pain-relieving medications (e.g., narcotics, opioids, gabapentin, cannabis), a blood transfusion, a stem cell transplant, Exagamglogene autotemcel (exa-cel), LentiGlobin, GMI-1070, VIT-2763 (vamifeport), Ticagrelor, vitamin D, simvastatin, AG-348 (mitapivat sulfate), propranolol, epinephrine, regadenoson, atorvastatin, prasugrel, L-arginine, OTQ923, oxygen therapy or gene therapy.

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