KR-102964257-B1 - RGMc-selective inhibitors and their uses

Abstract

Selective inhibitors of the repulsion-inducing molecule C (RGMc) are described. Related methods, including methods for manufacturing these inhibitors, as well as their therapeutic use in the treatment of disorders, such as anemia, are also provided.

Inventors

• 니콜스, 사만다
• 슈츠, 케빈
• 부코스키, 존
• 도노반, 애드리아나
• 맥도널드, 메건
• 다타, 아브히세크
• 카필리, 앨런
• 닥베이, 케빈 비.
• 러너, 로레나
• 존, 레오나드, 이라
• 잭슨, 저스틴 더블유.

Assignees

• 스칼러 락, 인크.

Dates

Publication Date

20260513

Application Date

20191023

Priority Date

20181023

Claims (20)

1. It is an antibody that specifically binds to the human repulsion-inducing molecule C (RGMc), and a) The antibody is a full-length antibody or its antigen-binding fragment; b) The antibody does not bind to human repulsion-inducing molecule A (RGMa) and human repulsion-inducing molecule B (RGMb); c) The antibody inhibits or reduces the interaction of RGMc with BMP6; d) The antibody includes the following: i) H-CDR1, H-CDR2, and H-CDR3 sequences presented in sequence identification numbers: 30, 31, and 32, respectively, and L-CDR1, L-CDR2, and L-CDR3 sequences presented in sequence identification numbers: 33, 34, and 35, respectively; ii) H-CDR1, H-CDR2, and H-CDR3 sequences presented in sequence identification numbers: 38, 39, and 40, respectively, and L-CDR1, L-CDR2, and L-CDR3 sequences presented in sequence identification numbers: 41, 42, and 43, respectively; iii) Sequences H-CDR1, H-CDR2, and H-CDR3 presented in Sequence Identification Numbers 6, 7, and 8, respectively, and Sequence Identification Numbers 9, 10, and 11, respectively, L-CDR1, L-CDR2, and L-CDR3 sequences; iv) the H-CDR1, H-CDR2, and H-CDR3 sequences presented in Sequence Identification Numbers: 14, 15, and 16, respectively, and the L-CDR1, L-CDR2, and L-CDR3 sequences presented in Sequence Identification Numbers: 17, 18, and 19, respectively; or v) H-CDR1, H-CDR2, and H-CDR3 sequences presented in sequence identification numbers: 22, 23, and 24, respectively, and L-CDR1, L-CDR2, and L-CDR3 sequences presented in sequence identification numbers: 25, 26, and 27, respectively; and e) The antibody is a fully human or humanized antibody.
2. In paragraph 1, the antibody a) human IgG1, IgG2, or IgG4 antibody and/or; b) The antibody is a human IgG4 antibody and/or; c) An antibody that is a human IgG4 antibody comprising a backbone substitution from Ser to Pro that creates an IgG1 -like hinge.
3. The antibody of claim 1, wherein the antibody comprises the H-CDR1, H-CDR2, and H-CDR3 sequences presented in sequence identification numbers: 30, 31, and 32, respectively, and the L-CDR1, L-CDR2, and L-CDR3 sequences presented in sequence identification numbers: 33, 34, and 35, respectively.
4. In paragraph 3, the antibody a) a heavy chain variable region having an amino acid sequence at least 90% identical to Sequence Identification Number: 36; and/or b) Light chain variable region having an amino acid sequence at least 90% identical to Sequence Identification Number: 37 An antibody that includes
5. In paragraph 3, the antibody a) The heavy chain variable region sequence presented in sequence identification number: 36; and b) Sequence Identification Number: The light chain variable region sequence presented in 37 An antibody that includes
6. In paragraph 1, a) the antibody binds to RGMc with a K D value of less than 0.1 x 10⁻⁹ (0.1 nM); or b) An antibody that binds to RGMc with a K D value of less than 0.1 x 10⁻⁹ (0.1 nM) and induces the internalization of the antibody-antigen complex.
7. A pharmaceutical composition for treating an iron-deficiency disease in a human subject, comprising an antibody of any one of claims 1 to 6 and a pharmaceutically acceptable carrier.
8. In claim 7, the treatment comprises administering a composition to the subject in an amount effective for treating an iron-deficiency disease, and the iron-deficiency disease is a) iron-limiting anemia; or b) an iron-limiting anemia, wherein the iron-limiting anemia is iron-refractory iron deficiency anemia (IRIDA), anemia of chronic disease (ACD), cancer-related anemia, chemotherapy-induced anemia, anemia of serious disease, and/or microcytic anemia, pharmaceutical composition.
9. In Paragraph 7, a) Iron-deficiency disease is a condition involving functional iron deficiency and/or; b) A pharmaceutical composition in which the subject has received or is receiving chemotherapy and/or has or is at risk of having fatigue, joint pain, bone or joint disease, rheumatoid arthritis, inflammatory bowel disease, shortness of breath, irregular heartbeat, liver disease, diabetes, infertility, erectile dysfunction, depression, mood or mental disorder, cognitive decline or neurodegenerative disease, iron-refractory iron-deficiency anemia, anemia of chronic kidney disease, resistance to erythropoiesis-stimulating agents, aplastic anemia, hypoplastic anemia, paroxysmal nocturnal hemoglobinuria, von Willebrand disease, hemophilia hereditary hemorrhagic telangiectasia, cardiovascular disease, heart failure, restless legs syndrome, absolute iron deficiency, inflammatory disease, infectious disease and/or neurological disease.
10. In paragraph 8, a) ACD is anemia of chronic kidney disease (CKD) and/or; b) ACD is anemia of chronic kidney disease (CKD), and the subject is dialysis-dependent or non-dialysis-dependent and/or; c) ACD is anemia of rheumatoid arthritis and/or; d) ACD is anemia of inflammatory bowel disease and/or; e) ACD is associated with one or more conditions selected from the group consisting of chronic bacterial endocarditis, osteomyelitis, rheumatic fever, ulcerative colitis, and neoplastic disorders; f) Cancer-related anemia is myelofibrosis-induced anemia Pharmaceutical composition.
11. In Paragraph 7, a) the composition is administered in combination with an additional therapeutic agent; b) A pharmaceutical composition administered in combination with an erythropoietin stimulant (ESA), a hypoxia-inducible factor (HIF) stabilizer, an iron supplement, or a blood transfusion.
12. In Clause 11, the composition a) to reduce toxicity associated with ESA, HIF stabilizers, iron supplements, or blood transfusions; b) A pharmaceutical composition that reduces toxicity, including iron overload or cancer risk, associated with ESA, HIF stabilizers, iron supplements, or blood transfusions.
13. In paragraph 8, the subject a) While on iron therapy, but benefiting from a reduced dose of iron therapy; b) have received iron therapy but discontinued it due to toxicity; c) have received iron therapy and benefit from a reduced dose of iron therapy; d) having a risk of cancer and/or; e) have been diagnosed with cancer and/or; f) A pharmaceutical composition that has been diagnosed with cancer of myelofibrosis.
14. In Paragraph 13, the subject a) received or is receiving a Janus kinase (JAK) inhibitor; b) A pharmaceutical composition that has been provided with or is receiving a JAK1 inhibitor and/or a JAK2 inhibitor.
15. In paragraph 7, the treatment involves a composition to the subject: A pharmaceutical composition comprising: i) increasing serum iron levels in a subject; ii) downregulating hepcidin in a subject; iii) decreasing liver hepcidin mRNA levels; iv) decreasing liver hepcidin protein levels, serum (circulating) hepcidin protein levels, or both; v) increasing transferrin saturation in a subject; vi) increasing erythropoiesis in a subject; vii) decreasing unsaturated iron binding capacity in a subject; viii) decreasing total iron binding capacity in a subject; ix) increasing serum ferritin levels in a subject; and x) administering an amount effective to achieve serum ferritin levels of ≥20 nanograms per milliliter of blood.
16. In paragraph 8, the subject a) Have received erythropoietin (EPO/ESA) therapy, HIF stabilizer therapy, IV iron supplementation, or a combination thereof, or b) A pharmaceutical composition for which a person has been administered erythropoietin (EPO/ESA) therapy, HIF stabilizer therapy, IV iron supplementation, or a combination thereof, and has exhibited or is at risk of having an adverse event associated with EPO therapy, HIF stabilizer therapy, or IV iron supplementation.
17. A nucleic acid molecule encoding a polypeptide comprising a variable heavy chain region of an antibody according to claim 1.
18. A nucleic acid molecule encoding a polypeptide comprising a light chain variable region of an antibody according to claim 1.
19. An expression vector comprising the nucleic acid molecule of claim 17 and/or the nucleic acid molecule of claim 18.
20. A host cell transformed to express the nucleic acid molecule of paragraph 17 and the nucleic acid molecule of paragraph 18.

Description

RGMc-selective inhibitors and their uses Related applications This international patent application claims priority to U.S. provisional application serial number 62/749,469 filed on October 23, 2018, the contents of which are incorporated herein by reference in their entirety. Technology field The present invention relates to an RGMc-binding agent (e.g., an antibody and molecule containing an antigen-binding fragment) that specifically and selectively inhibits RGMc rather than RGMa or RGMb. Abnormalities in iron homeostasis are associated with numerous diseases that can be difficult to treat. These disorders can be broadly classified into two categories: i) iron-overload diseases, including cirrhosis, cardiomyopathy, and diabetes mellitus; and ii) iron-deficiency diseases, including iron-limiting anemia and anemia of chronic diseases ("ACD"). Hepcidin is a major regulator of systemic iron homeostasis, and its expression is primarily restricted to the liver. Hepcidin is produced as a propeptide and processed into a mature active peptide by purine or purine-like proteases. Hepcidin negatively regulates iron availability by binding to its receptor, ferroportin, the sole cellular iron exporter, thereby inducing both internalization and degradation. Consequently, hepcidin causes a decrease in systemic iron availability by blocking iron export from major cells (intestinal cells) for dietary iron absorption, the recycling of hemoglobin iron (macrophages), and the release of stored iron from hepatocytes. The central role of hepcidin in systemic iron homeostasis was soon clearly recognized by the discovery that the inactivation of its gene was associated with severe iron overload in the liver and pancreas. It has been confirmed that the expression of BMP6 and BMP2 is required to maintain iron homeostasis in mice. Bone morphogenetic proteins 6 and 2 (BMP6 and BMP2, respectively) are both members of the TGFβ superfamily of growth factors known to be involved in various biological processes, including iron metabolism and homeostasis. It has been confirmed that the expression of BMP6 and BMP2 is required to maintain iron homeostasis in mice. Consistent with the concept of involvement in iron regulation, genetic impairment of BMP6 leads to severe tissue iron overload. Similarly, BMP6 mutations have been found in patients with hereditary hemochromatosis, a heterogeneous group of genetic disorders characterized by parenchymal iron overload. BMP6 binds to type I and type II serine threonine kinase receptors (e.g., Alk2, Alk3, BMPR2, and ActRIIA). Furthermore, BMP6 has also been identified to directly bind to its co-receptors, the repulsion-inducing molecules C or RGMc, also known as hemojuvelin or HJV. When BMP6 binds to its receptors and to larger polymeric complexes including HJV, HFE, TFR2, and neogenin, it activates intracellular SMAD phosphorylation, which induces nuclear translocation and increased hepcidin transcription. Thus, the BMP6/HJV/SMAD axis is a regulator of hepcidin expression in response to iron status. Currently available therapies to treat clinical signs associated with anemia, such as chemotherapy-induced anemia and anemia in chronic kidney disease, include intravenous iron (e.g., iron supplements and blood transfusions) and erythropoietin-stimulating agents (ESAs). Examples of ESAs include erythropoietin (Epo); epoetin alpha (Procrit/Epogen); epoetin beta (NeoRecormon); darbepoetin alpha (Aranesp); and methoxypolyethylene glycol-epoetin beta (Mircera). These therapies are suboptimal and may also be associated with unwanted side effects or adverse events, such as iron overload, cardiovascular and tumorigenic risks. Iron overload is a dangerous adverse effect in anemic patients receiving frequent iron supplements, such as IV iron. Excessive iron in the body can be highly toxic and affect numerous organs, potentially leading to various severe conditions, such as liver disease, heart disease, diabetes mellitus, hormonal imbalances, and a dysfunctional immune system. Similarly, patients receiving blood transfusions are at risk of toxicity associated with iron overload. For example, a unit of transfused blood contains approximately 250 mg of iron. In patients receiving frequent transfusions, particularly those with conditions that can become transfusion-dependent—such as polysaccharidosis, sickle cell disease, myelodysplastic syndrome, aplastic anemia, hemolytic anemia, and refractory sideroblastic anemia—excessive iron from transfused red blood cells gradually accumulates in various tissues, leading to morbidity and mortality. Therefore, treatment-induced excess iron in the body can cause severe adverse effects, including toxicity to the cardiovascular, gastrointestinal, immune, bone/chondral, reproductive, and renal systems. As an add-on or alternative treatment option for IV iron, ESA therapy (e.g., EPO, epogen® by Amgen) has been widely administered to a broad patient population, including those sufferin