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  • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
  • C07K16/2866—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for cytokines, lymphokines, interferons
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
  • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
  • A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
  • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
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  • C07K—PEPTIDES
  • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • C07K14/52—Cytokines; Lymphokines; Interferons
  • C07K14/53—Colony-stimulating factor [CSF]
  • C07K14/535—Granulocyte CSF; Granulocyte-macrophage CSF
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  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
  • C07K14/715—Receptors; Cell surface antigens; Cell surface determinants for cytokines; for lymphokines; for interferons
  • C07K14/7153—Receptors; Cell surface antigens; Cell surface determinants for cytokines; for lymphokines; for interferons for colony-stimulating factors [CSF]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K2039/54—Medicinal preparations containing antigens or antibodies characterised by the route of administration
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
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  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K2317/00—Immunoglobulins specific features
  • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
  • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
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  • C07K2317/00—Immunoglobulins specific features
  • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
  • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
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  • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
  • C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value

Definitions

• the present invention relates to methods of treating sclerotic skin conditions and more specifically to method of treating chronic graft versus host disease with a preferred dose of an anti- CSF-1R antibody, Axatilimab.
• Colony stimulating factor 1 also known as macrophage colony stimulating factor (M-CSF) is a cytokine produced by a variety of cells, including endothelial cells and fibroblasts.
• CSF-1 is composed of two "monomer" polypeptides, which form a biologically active dimeric CSF-1 protein.
• CSF-1 exists in at least three mature forms due to alternative R A splicing, proteolytic processing of protein precursors and post-translational modifications including glycosylation and addition of proteoglycan (see, Cerretti DP et al.
• CSF-1 protein includes two secreted molecules, one that is glycosylated, the other comprised of a longer amino terminal sequence and proteoglycan modification.
• Another variant is a transmembrane (TM) molecule that is glycosylated but has no proteoglycan moieties. This membrane form can be shed via proteolytic cleavage to release an active, soluble molecule.
• TM transmembrane
• CSF-1 all forms are produced as precursor polypeptides having a 32 amino acid signal sequence at the amino terminus, a putative transmembrane region of approximately 23 amino acids near the carboxyl terminus and a short cytoplasmic COOH- terminal tail.
• the precursor peptides are subsequently processed by amino terminal and carboxyl terminal proteolytic cleavages to produce the mature forms of CSF-1 with residues 1-149 being identical and constituting the receptor binding domain.
• CSF-1 monomers are glycosylated, and dimerized via disulfide-linkage.
• CSF-1 belongs to a group of biological agonists that promote the production of blood cells.
• CSF-1 acts as a growth, differentiation and survival factor for bone marrow progenitor cells of the mononuclear phagocyte lineage. Further, CSF-1 stimulates the survival, proliferation and function of macrophages via a specific receptor on responding cells.
• CSF-1 R The CSF-1 receptor (CSF-1 R) is also referred to as the c-fms gene product or CD 115.
• CSF-1 R is a 165kDa type 1 TM glycoprotein belonging to the type III receptor tyrosine kinase family.
• the structurally similar but sequence unrelated molecule IL-34 has also been shown to be a ligand for CSF-1R (Lin, et al. 2008, Science 320:807-81 1). Expression of CSF-1 R is restricted mainly to cells of the monocyte-macrophage lineage, both circulating and resident tissue populations, including osteoclasts.
• Binding of the ligand CSF-1 to the CSF-1 receptor results in the phosphorylation of the receptor on one or more tyrosine residues through the action of its tyrosine kinase domain.
• This phosphorylation can be detected because antibodies are available that bind to the receptor only after phosphorylation (for example Phospho-M-CSF-Receptor (Tyr546) antibody #3083 from Cell Signaling Technology).
• Chronic graft versus host disease cGVHD
• an immune response of the donor-derived hematopoietic cells against recipient tissues is a serious, potentially life-threatening complication of allogeneic hematopoietic stem cell transplantation (HSCT).
• cGVHD is estimated to develop in approximately 40% of transplant recipients, is estimated to effect 14,000 patients in the US and can last for years.
• Chronic GVHD typically manifests across multiple organ systems, with the skin and mucosa being commonly involved and is characterized by the development of fibrotic tissue.
• Graft versus host disease (GVHD) is an immunologically mediated disease that contributes substantially to transplant-related morbidity and mortality. The overall incidence of GVHD remains between 30% and 60% and carries approximately a 50% mortality rate. Acute and chronic GVHD are complex clinical phenomena that require new and promising treatments.
• Chronic graft versus host disease (cGVHD) remains the major cause of morbidity and non-relapse mortality after allogeneic hematopoietic stem cell transplantation (HSCT).
• cGVHD typically manifests with multiorgan pathology which often occurs during the first-year post-HSCT but can also develop beyond the first year post-HSCT (Jagasia 2015).
• Treatment of cGVHD is currently based on steroid administration. While progress has been made with improvements in survival outcomes over time, current available therapies are associated with significant toxi cities, and many currently available salvage therapies are associated with increased immunosuppression, infectious complications, and potential loss of the graft versus leukemia (GVL) effect.
• GTL graft versus leukemia
• Axatilimab is a humanized IgG4 monoclonal antibody (mAh) with high affinity against CSF-1R.
• Axatilimab can affect the migration, proliferation, differentiation, and survival of TAMs by binding to CSF-1R and blocking activation by its two known ligands, Colony stimulating factor- 1 (CSF-1) and interleukin-34 (IL-34).
• CSF-1 Colony stimulating factor- 1
• IL-34 interleukin-34
• ibrutinib a BTK inhibitor
• Axatilimab has the potential, based on its high affinity to inhibit CSF-1R, to provide an immunotherapeutic approach to treat cGVHD and other scleroderma conditions.
• Scleroderma has a spectrum of manifestations and a variety of therapeutic implications. It comprises localized scleroderma, systemic sclerosis, scleroderma-like disorders, and Sine scleroderma (Smith, 2000). Whilst localized scleroderma is a rare dermatologic disease associated with fibrosis and manifestations limited to skin, systemic sclerosis is a multisystem disease with variable risk for internal organ involvement and variation in the extent of skin disease. Systemic sclerosis can be diffuse or limited.
• CREST calcinosis, Raynaud's esophageal dysfunction, sclerodaytyly, telangiectasiae.
• Scleroderma-like disorders are believed to be related to industrial environment exposure.
• Sine disease there is internal organ involvement without skin changes.
• the major manifestations of scleroderma and in particular of systemic sclerosis are inappropriate excessive collagen synthesis and deposition, endothelial dysfunction, spasm, collapse and obliteration by fibrosis.
• These patients with chronic GVHD including sclerosis and lung involvement are often difficult to treat and associated with poor outcomes therefore morbidity and mortality in these patients, especially those needing second or further lines of therapy remains high.
• Therfore the development of novel agents to treat chronic GVHD and these related conditions remains an unmet medical need
• Axatilimab is an anti-CSF-lR antibody or antigen binding fragment thereof, comprises a heavy chain, wherein the variable domain of the heavy chain comprises at least one of a CDR having the sequence given in SEQ ID NO:4 for CDR-H1, a CDR having the sequence given in SEQ ID NO: 5 for CDR-H2 and a CDR having the sequence given in SEQ ID NO:6 for CDR-H3; and/or a light chain, wherein the variable domain of the light chain comprises at least one of a CDR having the sequence given in SEQ ID NO: 1 for CDR-L1, a CDR having the sequence given in SEQ ID NO:2 for CDR-L2 and a CDR having the sequence given in SEQ ID NO: 3 for CDR-L3.
• the anti-CSF-lR antibody or antigen binding fragment thereof comprises a heavy chain and a light chain
• the variable domain of the heavy chain comprises three CDRs and the sequence of CDR-H1 has at least 60% identity or similarity to the sequence given in SEQ ID NO:4
• the sequence of CDR-H2 has at least 60% identity or similarity to the sequence given in SEQ ID NO: 5
• the sequence of CDR-H3 has at least 60% identity or similarity to the sequence given in SEQ ID NO: 6
• the variable domain of the light chain comprises three CDRs and the sequence of CDR-L1 has at least 60% identity or similarity to the sequence given in SEQ ID NO: 1
• the sequence of CDR-L2 has at least 60% identity or similarity to the sequence given in SEQ ID NO: 2
• the sequence of CDR-L3 has at least 60% identity or similarity to the sequence given in SEQ ID NO:3.
• the anti-CSF-lR antibody or antigen binding fragment thereof comprises a heavy chain, wherein the heavy chain comprises the sequence given in SEQ ID NO:23; and a light chain, wherein the light chain comprises the sequence given in SEQ ID NO: 15.
• the anti-CSF-lR antibody or anti-CSF-1 antibody or antigen binding fragment thereof is selected from the group consisting of a complete antibody molecule having full length heavy and light chains, a Fab, modified Fab’, Fab’, F(ab’)2, Fv, VH, VL and scFv fragment thereof.
• the anti-CSF-lR antibody or antigen binding fragment thereof comprises a heavy chain comprising the sequence given in SEQ ID NO: 27 and a light chain comprising the sequence given in SEQ ID NO: 19.
• the anti-CSF-lR antibody or antigen binding fragment thereof cross-blocks the binding of an antibody comprising the 6 CDRs given in sequence SEQ ID NO:l for CDR-L1, SEQ ID NO:2 for CDR-L2, SEQ ID NO:3 for CDR-L3, SEQ ID NO:4 for CDR-H1, SEQ ID NO: 5 for CDR-H2 and SEQ ID NO: 6 for CDR-H3.
• the anti-CSF-lR as defined herein is axatilimab.
• the dosing of axatilimab is 0.3 mg/kg Q2W, 1 mg/kg Q2W, or 3 mg/kg Q4W.
• the administration of axatilimab is for the prevention or treatment of a sclerotic skin condition. In some embodiments, the administration of axatilimab is for the prevention or treatment of chronic graft versus host disease.
• Fig. 1 shows the general schematic for treatment of cGVHD with the anti-CSF-lR antibody, or antigen binding fragment thereof, according to the current invention.
• Fig. 2 shows the pathway for CSF-1R signaling in cGVHD.
• Fig. 3 shows the general schematic for clinical trials according to the current invention.
• Fig. 4 shows the various cohorts treated according to various embodiments of the present invention.
• Fig. 5 shows the first evidence of CSF-1R inhibition inducing a response in cGVHD at a dosage of 1 mg/kg Q2W (every two weeks) of the anti-CSF-lR antibody or antigen binding fragment thereof.
• Fig. 6 shows evidence of CSF-1R inhibition inducing a response in cGVHD at a dosage of 3 mg/kg Q2W (every two weeks) of the anti-CSF-lR antibody or antigen binding fragment thereof.
• Fig. 7 shows antibody concentration and monocyte count including circulating CD14 + CD16 + nonclassical and CD14 ++ CD16 + intermediate monocyte kinetics, are consistent with those observed in healthy volunteers and patients. Shows that at doses of 3mg/kg q2wk the patient still has circulating antibodies at trough at doses ⁇ 3mg/kg not detectable, similarly on the right note a marked reduction in non-classical monocytes, significantly more profound when compared to Intermediate and Classical
• Fig. 8 shows responses observed across several organ systems following multiple treatments.
• Fig. 9 shows the Axatilimab dose escalation and expansion.
• Fig. 10 shows the characteristics of chronic GVHD.
• Fig. 11 shows patient demographics and characteristics.
• Fig. 12 shows the responses across cGVHD organ systems.
• Fig. 13 shows the symptom control from the administration of various dosages of Axatilimab at various intervals.
• Fig. 14 shows a waterfall plot and an improved Lee symptom scores in a majority of patients.
• Fig. 15 shows the summary and ongoing trials of Axatilimab.
• the present application is directed to the treatment of graft versus host disease using an anti-CSF-lR antibody or binding fragment thereof.
• the anti-CSF-lR antibody is Axatilimab.
• the anti-CSF-lR antibody or antigen binding fragment thereof comprises a heavy chain, wherein the variable domain of the heavy chain comprises at least one of a CDR having the sequence given in SEQ ID NO:4 for CDR- Hl, a CDR having the sequence given in SEQ ID NO:5 for CDR-H2 and a CDR having the sequence given in SEQ ID NO:6 for CDR-H3; and/or a light chain, wherein the variable domain of the light chain comprises at least one of a CDR having the sequence given in SEQ ID NO: 1 for CDR-L1, a CDR having the sequence given in SEQ ID NO:2 for CDR-L2 and a CDR having the sequence given in SEQ ID NO: 3 for CDR-L3.
• the anti-CSF-lR antibody or antigen binding fragment thereof comprises a heavy chain and a light chain
• the variable domain of the heavy chain comprises three CDRs and the sequence of CDR-H1 has at least 60% identity or similarity to the sequence given in SEQ ID NO:4
• the sequence of CDR-H2 has at least 60% identity or similarity to the sequence given in SEQ ID NO: 5
• the sequence of CDR-H3 has at least 60% identity or similarity to the sequence given in SEQ ID NO: 6
• the variable domain of the light chain comprises three CDRs and the sequence of CDR-L1 has at least 60% identity or similarity to the sequence given in SEQ ID NO: 1
• the sequence of CDR-L2 has at least 60% identity or similarity to the sequence given in SEQ ID NO: 2
• the sequence of CDR-L3 has at least 60% identity or similarity to the sequence given in SEQ ID NO:3.
• the anti-CSF-lR antibody or antigen binding fragment thereof comprises a heavy chain, wherein the heavy chain comprises the sequence given in SEQ ID NO:23; and a light chain, wherein the light chain comprises the sequence given in SEQ ID NO: 15.
• the antibody has a heavy chain comprising the sequence given in SEQ ID NO: 27 and a light chain comprising the sequence given in SEQ ID NO: 19. Also provided is an anti-CSF-lR antibody or binding fragment thereof, in which the heavy and light chains are at least 80% (preferably 85%, 90%, 95% or 98%) identical or similar to a heavy chain comprising the sequence given in SEQ ID NO: 27 and a light chain comprising the sequence given in SEQ ID NO: 19.
• the light chain has or consists of the sequence given in SEQ ID NO: 19 and the heavy chain has or consists of the sequence given in SEQ ID NO: 27.
• the light chain has or consists of the sequence of SEQ ID NO: 19 and the heavy chain has or consists of the sequence of SEQ ID NO: 27, wherein the amino acid lysine at position 453 of SEQ ID NO: 27 is missing or deleted.
• g2 comprising the heavy chain sequence gH2 (SEQ ID NO: 27) and/or the light chain sequence gL7 (SEQ ID NO: 19).
• the anti-CSF-lR antibody or anti-CSF-1 antibody or antigen binding fragment thereof is selected from the group consisting of a complete antibody molecule having full length heavy and light chains, a Fab, modified Fab’, Fab’, F(ab’)2, Fv, VH, VL and scFv fragment thereof.
• the anti-CSF-lR antibody or antigen binding fragment thereof comprises a heavy chain comprising the sequence given in SEQ ID NO: 27 and a light chain comprising the sequence given in SEQ ID NO: 19.
• the anti-CSF-lR antibody or antigen binding fragment thereof cross-blocks the binding of an antibody comprising the 6 CDRs given in sequence SEQ ID NO:l for CDR-L1, SEQ ID NO:2 for CDR-L2, SEQ ID NO:3 for CDR-L3, SEQ ID NO:4 for CDR-H1, SEQ ID NO: 5 for CDR-H2 and SEQ ID NO: 6 for CDR-H3.
• the anti-CSF-lR antibody or antigen binding fragment thereof cross-blocks the binding by binding the same epitope as the antibody which it blocks.
• the anti-CSF-1 antibody or antigen binding fragment thereof cross blocks the binding by binding the same epitope as the antibody which it blocks.
• the anti-CSF-lR antibody or anti-CSF-1 antibody or antigen binding fragment thereof or inhibitor of CSF-1R is administered once a week.
• the anti-CSF-lR antibody or anti-CSF-1 antibody or antigen binding fragment thereof or inhibitor of CSF-1R is administered once every two weeks. In some embodiments, the anti-CSF-lR antibody or anti-CSF-1 antibody or antigen binding fragment thereof or inhibitor of CSF-1R is administered twice every week.
• the anti-CSF-lR antibody or anti-CSF-1 antibody or antigen binding fragment thereof or inhibitor of CSF-1R is administered three times every week.
• the anti-CSF-lR antibody or anti-CSF-1 antibody antigen binding fragment thereof or inhibitor of CSF-1R is administered at a dose ranging between about 0.1 mg/kg and about 30 mg/kg. In some embodiments, the anti-CSF-lR antibody or anti-CSF-1 antibody antigen binding fragment thereof or inhibitor of CSF-1R activity is administered at a dose ranging between about 0.1 mg/kg and about 10 mg/kg. In some embodiments, the anti-CSF-lR antibody or anti-CSF-1 antibody antigen binding fragment thereof or inhibitor of CSF-1R activity is administered at a dose ranging between about 0.1 mg/kg and about 10 mg/kg for the treatment of chronic graft versus host disease.
• the anti-CSF-lR antibody or anti-CSF-1 antibody or antigen binding fragment thereof or inhibitor of CSF-1R activity is administered at a dose of about 0.1 mg/kg, 0.5 mg/kg, 1 mg/kg, 1.5 mg/kg, 3 mg/kg, 5 mg/kg, 6 mg/kg, 7.5 mg/kg, or about 10 mg/kg.
• the axatilimab is administered at a dose of 0.15 mg/kg every week. In some embodiments, the axatilimab is administered at a dose of 0.5 mg/kg every week. In some embodiments, the axatilimab is administered at a dose of 1.0 mg/kg every week. In some embodiment, the axatilimab is administered at a dose of 3.0 mg/kg every week. In some embodiments, the axatilimab is administered at a dose of 0.15 mg/kg every two weeks. In some embodiments, the axatilimab is administered at a dose of 0.5 mg/kg every two weeks.
• the axatilimab is administered at a dose of 1.0 mg/kg every two weeks. In some embodiment, the axatilimab is administered at a dose of 3.0 mg/kg every two weeks. In some embodiments, the axatilimab is administered at a dose of 0.15 mg/kg every three weeks. In some embodiments, the axatilimab is administered at a dose of 0.5 mg/kg every three weeks. In some embodiments, the axatilimab is administered at a dose of 1.0 mg/kg every three weeks. In some embodiment, the axatilimab is administered at a dose of 3.0 mg/kg every three weeks.
• the axatilimab is administered at a dose of 0.15 mg/kg every four weeks. In some embodiments, the axatilimab is administered at a dose of 0.5 mg/kg every four weeks. In some embodiments, the axatilimab is administered at a dose of 1.0 mg/kg every four weeks. In some embodiment, the axatilimab is administered at a dose of 3.0 mg/kg every four weeks. In some embodiments, from week to week the dosage is increased or decreased based on circulating classical monocyte levels.
• the anti-CSF-lR antibody or anti-CSF-1 antibody or antigen binding fragment thereof or inhibitor of CSF-1R is administered once every two weeks.
• the anti-CSF- 1R antibody or anti-CSF-1 antibody or antigen binding fragment thereof or inhibitor of CSF-1R is administered at a dose of 1 mg/kg.
• the anti-CSF-lR antibody or anti-CSF-1 antibody or antigen binding fragment thereof or inhibitor of CSF-1R is administered at a dose of 3 mg/kg.
• the anti-CSF-lR antibody or anti-CSF-1 antibody or antigen binding fragment thereof or inhibitor of CSF-1R is administered at a dose of 1 mg/kg every two weeks.
• the CSF-1R inhibitor is administered and decreases circulating classical monocytes. In some embodiments, the CSF-1R inhibitor is administered and depletes the circulating classical monocytes. In some embodiments, the CSF-1R inhibitor is administered and fully depletes the level of classical monocytes. In some embodiments, an initial administration of a CSF-1R inhibitor depletes the level of classical monocytes by a pre-determined percentage. In some embodiments, an initial administration of a CSF-1R inhibitor depletes the level of classical monocytes by a pre-determined percentage and a subsequent administration of the CSF-1R inhibitor occurs once the level of classical monocytes increases.
• an initial administration of a CSF-1R inhibitor depletes the level of classical monocytes by a pre-determined percentage and a subsequent administration of the CSF-1R inhibitor occurs once the level of classical monocytes increases to a pre-determined percentage.
• the method provides for the treatment of chronic graft versus host disease (cGVHD) in a human, the method comprising administering to the human in need thereof a pharmaceutically effective amount of axatilimab.
• the treatment methods herein are directed to scleroderma.
• the treatment methods are directed to preventing or alleviating the symptoms of chronic graft versus host disease (cGVHD).
• the cGVHD is liver cGVHD.
• the cGVHD is kidney cGVHD.
• the cGVHD is esophageal cGVHD.
• the cGVHD is stomach cGVHD.
• the treatment methods herein are directed to localized scleroderma, systemic sclerosis, scleroderma like disorders, and Sine scleroderma. In some embodiments, the treatment methods herein are directed to systemic sclerosis. In some embodiments, the treatment methods herein are directed to Systemic sclerosis, wherein the systemic sclerosis is diffuse or limited. In some embodiments, the treatment methods herein are directed to CREST (calcinosis, Raynaud's esophageal dysfunction, sclerodaytyly, telangiectasiae). Scleroderma-like disorders are believed to be related to industrial environment exposure. In Sine disease, there is internal organ involvement without skin changes.
• the cell transplantation is a hematopoietic cell transplantation.
• the GVHD is acute GVHD.
• the GVHD is chronic GVHD.
• the GVHD is sclerodermatous GVHD.
• the GVHD is steroid resistant GVHD.
• the GVHD is cyclosporin-resistant GVHD.
• the GVHD is refractory GVHD.
• the GHVD is oral GVHD.
• the oral GVHD is reticular oral GVHD.
• the oral GVHD is erosive oral GVHD.
• the oral GVHD is ulcerative oral GVHD.
• the oral GVHD is GVHD of the oral cavity.
• the oral GVHD is GVHD of the oropharyngeal region.
• the oral GVHD is GVHD of the pharyngeal region.
• the oral GVHD is GVHD of the esophageal region.
• the oral GVHD is acute oral GVHD.
• the oral GVHD is chronic oral GVHD.
• the patient exhibits one or more symptoms of GVHD.
• the patient has or will receive an allogeneic bone marrow or hematopoietic stem cell transplant.
• the presence of monocytes/marcophages provide both positive and negative effects.
• the monocytes/marcophages have been found to have positive and negative effects in the conditions discussed herein, and in some embodiments, the condition is a sclerotic skin condition as discussed herein and/or chronic graft versus host disease.
• the presence of circulating classical monocytes have beneficial effects if allowed to be present in reduced quantities. Allowing the monocyte/macrophage levels to increase between administrations of the CSF-1R inhibitor/antibody allows the treatment to harness the positive effects of the circulating monocyte/macrophages while avoiding the negative effects.
• an antibody inhibits monocyte proliferation.
• an antibody is considered to “inhibit monocyte proliferation” when it reduces the amount of monocyte proliferation by at least 50%, using the assay described, e.g., U.S. Pat. No. 8,206,715 B2. In some embodiments, an antibody reduces the amount of monocyte proliferation by at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or 100%. In some such embodiments, the antibody is said to inhibit monocyte proliferation by at least at least 50%, at least 60%, at least 70%, etc.
• Human monocytes exhibit pro-inflammatory features in a variety of disease contexts Human monocytes were identified by the expression of CD14. They can be further classified on the basis of CD 16 expression (the high affinity Fc receptor).
• CD 16- cells are referred to as classical monocytes since they are ordinarily about 90% of total monocytes in healthy individuals.
• CD 16+ cells appear to be expanded in many inflammatory diseases and exhibit a preferential migration across the endothelial layers in response to chemokines. They are thus usually referred to as non-classical or proinflammatory monocytes (non-classical (CD14+/CD16+) monocytes and classical (CD14+/CD16-) monocyte).
• administering the CSF-1R inhibitor of the present invention decreases circulating monocytes by at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or 100%.
• the antibody is said to inhibit monocyte proliferation by at least at least 50%, at least 60%, at least 70%, etc.
• the level of circulating monocytes is allowed to increase by at least 5%, at least 10%, at least 15%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50% before the administration of a subsequent dose of the CSF-1R inhibitor.
• the level of circulating monocytes is allowed to increase for 1 week before administration of a subsequent dose of the CSF-1R inhibitor.
• the level of circulating monocytes is allowed to increase for 2 weeks before administration of a subsequent dose of the CSF-1R inhibitor. In some embodiments, the level of circulating monocytes is allowed to increase for 3 weeks before administration of a subsequent dose of the CSF-1R inhibitor. In some embodiments, the level of circulating monocytes is allowed to increase for 4 weeks before administration of a subsequent dose of the CSF-1R inhibitor.
• the monocytes are non-classical. In some embodiments, the monocytes are classical. In some embodiments, the monocytes are a combination of classical and non-classical monocytes n some embodiments, the monocytes are a combination of classical and intermediate monocytes.
• the CSF-1R inhibitor is axatilimab. In some embodiments, the CSF-1R inhibitor is administered according to the following dosage scheme. In some embodiments, the dose schedule maximizes the benefits of circulating macrophages and minimizes negative effects. In some embodiments, the dose is increased inverse to the following dosage schedule.
• the method of the present invention is directed to the treatment of sclerotic skin conditions wherein the patient has progressed on one or more prior therapies.
• the sclerotic skin condition is active chronic graft versus host disease.
• the patient progressed on at least two prior therapies.
• the prior therapy was ibrutinib.
• at least one of the prior therapies was ibrutinib.
• the method of the present invention is directed to the treatment of cGVHD wherein the patient has progressed on one or more prior therapies. In one embodiment, the patient progressed on at least two prior therapies. In one embodiment, the prior therapy was ibrutinib. In one embodiment, at least one of the prior therapies was ibrutinib.
• the axatilimab is administered with one or more additional agents useful in the treatment of graft versus host disease is selected from the group of prednisone, methylprednisone, oral nonabsorbable corticosteroids, such as budesonide or beclomethasone diproprionate, immune modulators, such as cyclosporine, tacrolimus, mycophenolate mofetil, tilomisole, imuthiol, antithymocyte globulin, anti-TNF agents, azathioprine, inosine 5'- monophosphate dehydrogenase inhibitors, azodiacarbonide, bisindolyl maleimide VIII, brequinar, chlorambucil, CTLA-4Ig, corticosteroids, cyclophosphamide, deoxyspergualin, dexamethasone, glucocorticoids, leflunomide, mercaptopurine, 6-mercaptopurine, met
• CDR-L1 LASEDIYDNLA(SEQ ID NO: 1)
• CDRL2 YASSLQD (SEQ ID NO:2)
• CDR-L3 LQDSEYPWT (SEQ ID NO:3)
• CDR-H1 GFSLTTYGMGVG (SEQ ID NO:4)
• CDR-H2 NIWWDDDK YYNP SLKN (SEQ ID NO: 5)
• VY ACEVTHQG LSSPVTKSFN RGEC (SEQ ID NO:21)
• VLTMTNMDPV DTATYYCARI AFDIWGQGTM VTVS (SEQ ID NO: 33)
• colony stimulating factor- 1 receptor refers to a tyrosine-protein kinase that acts as cell-surface receptor for CSF1 and interleukin 34 (IL34) and plays an essential role in the regulation of survival, proliferation and differentiation of hematopoietic precursor cells, especially mononuclear phagocytes, such as macrophages and monocytes. It promotes the release of proinflammatory chemokines in response to IL34 and CSF1, and thereby plays an important role in innate immunity and in inflammatory processes.
• CSF1R also plays an important role in the regulation of osteoclast proliferation and differentiation, the regulation of bone resorption, and is required for normal bone and tooth development.
• CSF1R is required for normal male and female fertility, and for normal development of milk ducts and acinar structures in the mammary gland during pregnancy. It also promotes reorganization of the actin cytoskeleton, regulates formation of membrane ruffles, cell adhesion and cell migration, and promotes cell invasion.
• CSF1 is a cytokine that controls the production, differentiation, and function of macrophages, and CSF1R mediates most if not all of the biological effects of this cytokine.
• Ab969.g2 as used herein means an antibody specifically binding to CSF1-R and comprises (a) a light chain comprising CDR1, CDR2 and CDR3 as defined in SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3, respectively, and (b) a heavy chain comprising CDR1, CDR2, and CDR3 as defined in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6, respectively.
• This Ab969.g2 antibody has been previously described in PCT/EP2014/068050.
• the term “specifically binds to CSF1R”, “specifically binding to CSF1R”, and equivalents as used herein when referring to an antibody means the antibody will bind to CSF 1R with sufficient affinity and specificity to achieve a biologically meaningful effect.
• the antibody selected will normally have a binding affinity for CSF1R, for example, the antibody may bind CSF1R with a Kd value of between 100 nM and 1 pM.
• Antibody affinities may be determined by a surface plasmon resonance bases assay, such as the BIAcore assay; enzyme-linked immunoabsorbent assay (ELISA); and competition assays (e.g. RIA's), for example.
• an antibody specifically binding to CSF1R may also bind to another molecule; such as by way of a non-limiting example in the case of a bispecific antibody.
• Any antibody e.g., an anti-CSF-lR antibody or anti-CSF-1 antibody disclosed herein can be used for the methods, kits, or compositions of the disclosure.
• a pharmaceutical composition of the disclosure comprises an anti- CSF-1R antibody or anti-CSF-1 antibody or antigen binding fragment thereof or an inhibitor of CSF-1R activity and a pharmaceutically acceptable carrier.
• the combinations described herein are used for treating a skin condition.
• the method is directed to the use of an anti-CSF-lR antibody, or binding fragment thereof, for the treatment of systemic scleroderma, generalized scleroderma, localized scleroderma, morphea scleroderma, linear scleroderma, CREST syndrome, diffuse scleroderma, Circumscribed Morphea, Calcinosis, Raynaud’s phenomenon, Esophageal dysmotility, Sclerodactyly, Telangiectasias, Sine Sclerosis and/or diffuse scleroderma
• the method is directed to the use of an anti-CSF-lR antibody, or binding fragment thereof, for the treatment of acute graft versus host disease (aGvHD). In some embodiments, the method is directed to the use of an anti-CSF-lR antibody, or binding fragment thereof, for the treatment of chronic graft versus host disease (cGvHD).
• the method of treating a human patient identified as having cGVHD comprises determining the initial level of classical monocytes in the patient. In some embodiments, the method of treating a human patient identified as having cGVHD comprises determining the initial level of classical monocytes in the patient followed by administering an effective dose of axatilimab or an anti-CSF-lR antibody; and determining a second level of classical monocytes in a subsequent time period.
• the method of treating a human patient identified as having cGVHD comprises determining the initial level of classical monocytes in the patient followed by administering an effective dose of axatilimab or an anti-CSF-lR antibody; and determining a second level of classical monocytes in a subsequent time period, and continue treatment with the axatilimab or anti-CSF-lR antibody if the second classical monocyte level is greater than a pre-determined percentage.
• the method of treating a human patient identified as having cGVHD comprises determining the initial level of classical monocytes in the patient followed by administering an effective dose of axatilimab or an anti-CSF-lR antibody; and determining a second level of classical monocytes in a subsequent time period, and continue treatment with the axatilimab or anti-CSF-lR antibody if the ratio between the initial classical monocyte level and the second classical monocyte level is greater than a pre-determined percentage.
• the present application is directed to a method of treating cGVHD comprising treating a patient in need thereof with a therapeutically effective amount of axatilimab, wherein the axatilimab targets the pathogenic monocyte derived macrophages. In some embodiments, the present application is directed to a method of treating cGVHD comprising treating a patient in need thereof with a therapeutically effective amount of axatilimab, wherein the axatilimab targets the pathogenic monocyte derived macrophages and minimally impacts the non-classical monocytes.
• the present application is directed to a method of treating cGVHD comprising treating a patient in need thereof with a therapeutically effective amount of axatilimab, wherein the axatilimab targets the pathogenic monocyte derived macrophages and minimally impacts the intermediate monocytes.
• a method for treating graft versus host disease (GvHD) in a human comprising administering to a human in need thereof axatilimab or anti-CSF-lR antibody, wherein the antibody is administered at a dosage determined by the level of circulating classical monocytes.
• a method for treating graft versus host disease (GvHD) in a human comprising administering to a human in need thereof axatilimab or anti-CSF-lR antibody, wherein the antibody is administered at a dosage determined by the level of circulating intermediate monocytes.
• a method for treating graft versus host disease (GvHD) in a human comprising administering to a human in need thereof axatilimab or anti-CSF-lR antibody, wherein the antibody is administered at a dosage determined by the level of circulating non-classical monocytes.
• treat is meant to include alleviating or abrogating a disorder, disease, or condition; or one or more of the symptoms associated with the disorder, disease, or condition; or alleviating or eradicating the cause(s) of the disorder, disease, or condition itself.
• preventing or “prevent” describes reducing or eliminating the onset of the symptoms or complications of the disease, condition or disorder.
• the term “alleviate” is meant to describe a process by which the severity of a sign or symptom of a disorder is decreased.
• a sign or symptom can be alleviated without being eliminated.
• the administration of pharmaceutical compositions disclosed herein leads to the elimination of a sign or symptom, however, elimination is not required.
• Effective dosages are expected to decrease the severity of a sign or symptom.
• a sign or symptom of a disorder such as cGVHD, which can occur in multiple locations, is alleviated if the severity of the cGVHD is decreased within at least one of multiple locations.
• Treating the conditions listed herein can result in preventing the occurrence of the conditions described herein, including chronic graft versus host disease (cGVHD) or reducing the severity of cGVHD.
• a reduction in symptoms may also be referred to as “regression”.
• severity is reduced by 5% or greater relative to prior to treatment; more preferably, severity is reduced by 10% or greater; more preferably, reduced by 20% or greater; more preferably, reduced by 30% or greater; more preferably, reduced by 40% or greater; even more preferably, reduced by 50% or greater; and most preferably, reduced by greater than 75% or greater.
• Severity may be measured by any reproducible means of measurement. The severity may be measured as a diameter of the area of interest or according to various physician scales.
• a “pharmaceutical composition” or “therapeutic composition” is a formulation containing the active ingredient, such as an anti-CSF-lR antibody or anti-CSF-1 antibody or antigen binding fragment thereof or inhibitor of CSF-1R activity disclosed herein in a form suitable for administration to a subject.
• the pharmaceutical composition is in bulk or in unit dosage form.
• the unit dosage form is any of a variety of forms, including, for example, a capsule, an IV bag, a tablet, a single pump on an aerosol inhaler or a vial.
• the quantity of active ingredient e.g ., a formulation of the disclosed compound or salt, hydrate, solvate or isomer thereof) in a unit dose of composition is an effective amount and is varied according to the particular treatment involved.
• the dosage will also depend on the route of administration.
• routes of administration A variety of routes are contemplated, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalational, buccal, sublingual, intrapleural, intrathecal, intranasal, and the like.
• Dosage forms for the topical or transdermal administration of a compound of this disclosure include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
• the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that are required.
• Active ingredient refers to an ingredient with a pharmacological effect, such as a therapeutic effect, at a relevant dose.
• “Pharmaceutically acceptable carrier” means a carrier that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes excipient that is acceptable for veterinary use as well as human pharmaceutical use.
• the pharmaceutically acceptable carrier should not itself induce the production of antibodies harmful to the individual receiving the composition and should not be toxic.
• Suitable carriers may be large, slowly metabolised macromolecules such as proteins, polypeptides, liposomes, polysaccharides, polylactic acids, polyglycolic acids, polymeric amino acids, amino acid copolymers and inactive virus particles.
• salts can be used, for example mineral acid salts, such as hydrochlorides, hydrobromides, phosphates and sulphates, or salts of organic acids, such as acetates, propionates, malonates and benzoates.
• mineral acid salts such as hydrochlorides, hydrobromides, phosphates and sulphates
• organic acids such as acetates, propionates, malonates and benzoates.
• Pharmaceutically acceptable carriers in therapeutic compositions may additionally contain liquids such as water, saline, glycerol and ethanol. Additionally, auxiliary substances, such as wetting or emulsifying agents or pH buffering substances, may be present in such compositions. Such carriers enable the pharmaceutical compositions to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries and suspensions, for ingestion by the patient.
• Suitable forms for administration include forms suitable for parenteral administration, e.g. by injection or infusion, for example by bolus injection or continuous infusion.
• the product may take the form of a suspension, solution or emulsion in an oily or aqueous vehicle and it may contain formulatory agents, such as suspending, preservative, stabilizing and/or dispersing agents.
• the antibody molecule may be in dry form, for reconstitution before use with an appropriate sterile liquid.
• compositions of the disclosure can be administered directly to the subject.
• the pH of the final formulation is not similar to the value of the isoelectric point (pi) of the antibody or fragment, for example if the pH of the formulation is 7 then a pi of from 8-9 or above may be appropriate. Whilst not wishing to be bound by theory it is thought that this may ultimately provide a final formulation with improved stability, for example the antibody or fragment remains in solution.
• the pharmaceutical formulation at a pH in the range of 4.0 to 7.0 comprises: 1 to 200 mg/mL of an antibody according to the present disclosure, 1 to 100 mM of a buffer, 0.001 to 1% of a surfactant, a) 10 to 500mM of a stabilizer, b) 10 to 500 mM of a stabilizer and 5 to 500 mM of a tonicity agent, or c) 5 to 500 mM of a tonicity agent.
• compositions of this disclosure may be administered by any number of routes including, but not limited to, oral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, intraventricular, transdermal, transcutaneous (for example, see WO98/20734), subcutaneous, intraperitoneal, intranasal, enteral, topical, sublingual, intravaginal or rectal routes. Hyposprays may also be used to administer the pharmaceutical compositions of the disclosure.
• the therapeutic compositions may be prepared as injectables, either as liquid solutions or suspensions. Solid forms suitable for solution in, or suspension in, liquid vehicles prior to injection may also be prepared.
• Direct delivery of the compositions will generally be accomplished by injection, subcutaneously, intraperitoneally, intravenously or intramuscularly, or delivered to the interstitial space of a tissue.
• the compositions can also be administered into a lesion. Dosage treatment may be a single dose schedule or a multiple dose schedule.
• the active ingredient in the composition will be an antibody molecule. As such, it will be susceptible to degradation in the gastrointestinal tract. Thus, if the composition is to be administered by a route using the gastrointestinal tract, the composition will need to contain agents which protect the antibody from degradation but which release the antibody once it has been absorbed from the gastrointestinal tract.
• the formulation is provided as a formulation for topical administrations including inhalation.
• Suitable inhalable preparations include inhalable powders, metering aerosols containing propellant gases or inhalable solutions free from propellant gases.
• Inhalable powders according to the disclosure containing the active substance may consist solely of the abovementioned active substances or of a mixture of the abovementioned active substances with physiologically acceptable excipient.
• These inhalable powders may include monosaccharides (e.g. glucose or arabinose), disaccharides (e.g. lactose, saccharose, and maltose), oligo- and polysaccharides (e.g. dextrans), polyalcohols (e.g. sorbitol, mannitol, and xylitol), salts (e.g. sodium chloride, calcium carbonate) or mixtures of these with one another.
• monosaccharides e.g. glucose or arabinose
• disaccharides e.g. lactose, saccharose, and maltose
• oligo- and polysaccharides e.g. dextrans
• polyalcohols e.g. sorbitol, mannitol, and xylitol
• salts e.g. sodium chloride, calcium carbonate
• Particles for deposition in the lung require a particle size less than 10 microns, such as 1-9 microns for example from 0.1 to 5 pm, in particular from 1 to 5 pm.
• the particle size of the active ingredient (such as the antibody or fragment) is of primary importance.
• the propellent gases which can be used to prepare the inhalable aerosols are known in the art. Suitable propellent gases are selected from among hydrocarbons such as n-propane, n-butane or isobutane and halohydrocarbons such as chlorinated and/or fluorinated derivatives of methane, ethane, propane, butane, cyclopropane or cyclobutane. The abovementioned propellent gases may be used on their own or in mixtures thereof.
• Particularly suitable propellent gases are halogenated alkane derivatives selected from among TG 11, TG 12, TG 134a and TG227.
• halogenated alkane derivatives selected from among TG 11, TG 12, TG 134a and TG227.
• TG134a 1,1,1,2-tetrafluoroethane
• TG227 1,1,2,3,3,3-heptafluoropropane
• mixtures thereof are particularly suitable.
• the propellent-gas-containing inhalable aerosols may also contain other ingredients such as cosolvents, stabilizers, surface-active agents (surfactants), antioxidants, lubricants and means for adjusting the pH. All these ingredients are known in the art.
• the propellant-gas-containing inhalable aerosols according to the disclosure may contain up to 5 % by weight of active substance. Aerosols according to the disclosure contain, for example, 0.002 to 5 % by weight, 0.01 to 3 % by weight, 0.015 to 2 % by weight, 0.1 to 2 % by weight, 0.5 to 2 % by weight or 0.5 to 1 % by weight of active ingredient.
• topical administrations to the lung may also be by administration of a liquid solution or suspension formulation, for example employing a device such as a nebulizer, for example, a nebulizer connected to a compressor (e.g., the Pari LC-Jet Plus(R) nebulizer connected to a Pari Master(R) compressor manufactured by Pari Respiratory Equipment, Inc., Richmond, Va.).
• a nebulizer for example, a nebulizer connected to a compressor (e.g., the Pari LC-Jet Plus(R) nebulizer connected to a Pari Master(R) compressor manufactured by Pari Respiratory Equipment, Inc., Richmond, Va.).
• the antibody of the disclosure can be delivered dispersed in a solvent, e.g., in the form of a solution or a suspension. It can be suspended in an appropriate physiological solution, e.g., saline or other pharmacologically acceptable solvent or a buffered solution.
• Buffered solutions known in the art may contain 0.05 mg to 0.15 mg disodium edetate, 8.0 mg to 9.0 mg NaCl, 0.15 mg to 0.25 mg polysorbate, 0.25 mg to 0.30 mg anhydrous citric acid, and 0.45 mg to 0.55 mg sodium citrate per 1 ml of water so as to achieve a pH of about 4.0 to 5.0.
• a suspension can employ, for example, lyophilized antibody.
• the therapeutic suspensions or solution formulations can also contain one or more excipients.
• Excipients are well known in the art and include buffers (e.g., citrate buffer, phosphate buffer, acetate buffer and bicarbonate buffer), amino acids, urea, alcohols, ascorbic acid, phospholipids, proteins (e.g., serum albumin), EDTA, sodium chloride, liposomes, mannitol, sorbitol, and glycerol. Solutions or suspensions can be encapsulated in liposomes or biodegradable microspheres.
• the formulation will generally be provided in a substantially sterile form employing sterile manufacture processes.
• This may include production and sterilization by filtration of the buffered solvent/solution used for the formulation, aseptic suspension of the antibody in the sterile buffered solvent solution, and dispensing of the formulation into sterile receptacles by methods familiar to those of ordinary skill in the art.
• Nebulizable formulation according to the present disclosure may be provided, for example, as single dose units (e.g., sealed plastic containers or vials) packed in foil envelopes. Each vial contains a unit dose in a volume, e.g., 2 mL, of solvent/solution buffer.
• the antibodies disclosed herein may be suitable for delivery via nebulization.
• the antibody of the present disclosure may be administered by use of gene therapy.
• DNA sequences encoding the heavy and light chains of the antibody molecule under the control of appropriate DNA components are introduced into a patient such that the antibody chains are expressed from the DNA sequences and assembled in situ.
• compositions suitably comprise a therapeutically effective amount of the anti-CSF-lR antibody or anti-CSF-1 antibody or antigen binding fragment thereof or inhibitor of CSF-1R activity.
• therapeutically effective amount refers to an amount of a therapeutic agent needed to treat, ameliorate or prevent a targeted disease or condition, or to exhibit a detectable therapeutic, pharmacological or preventative effect.
• the therapeutically effective amount can be estimated initially either in cell culture assays, e.g., of neoplastic cells, or in animal models, usually rats, mice, rabbits, dogs, pigs or primates. The animal model may also be used to determine the appropriate concentration range and route of administration. Such information can then be used to determine useful doses and routes for administration in humans.
• Therapeutic/prophylactic efficacy and toxicity may be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g, EDso (the dose therapeutically effective in 50% of the population) and LDso (the dose lethal to 50% of the population).
• the dose ratio between toxic and therapeutic effects is the therapeutic index, and it can be expressed as the ratio, LD50/ED50.
• Pharmaceutical compositions that exhibit large therapeutic indices are preferred. The dosage may vary within this range depending upon the dosage form employed, sensitivity of the patient, and the route of administration.
• Dosage and administration are adjusted to provide sufficient levels of the active agent(s) or to maintain the desired effect. Factors which may be taken into account include the severity of the disease state, general health of the subject, age, weight, and gender of the subject, diet, time and frequency of administration, drug interaction(s), reaction sensitivities, and tolerance/response to therapy. Generally, the dose should be sufficient to result in slowing, and preferably regressing the severity of the condition. Dosages can range from about 0.01 mg/kg per day to about 10 mg/kg per day. In some embodiments, dosages can range from about 0.1 mg/kg, 0.5 mg/kg, 1 mg/kg, 1.5 mg/kg, or 3 mg/kg. In some embodiments, the dose will be in the range of about 0.1 mg/day to about 5 mg/kg. Pharmaceutical compositions may be conveniently presented in unit dose forms containing a predetermined amount of an active agent of the disclosure per dose.
• Therapeutic doses of the antibodies show no apparent or limited toxicology effects in vivo.
• the axatilimab or anti-CSF-lR antibody is administered every day, every other day, every week, every 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, or every 20 weeks, or every month.
• the term “antibody” is used according to its commonly known meaning in the art.
• the antibody molecules of the present disclosure may comprise a complete antibody molecule having full length heavy and light chains or a binding fragment thereof and may be, but are not limited to Fab, modified Fab, Fab’, modified Fab’, F(ab’)2, Fv, single domain antibodies (e.g. VH or VL or VHH), scFv, bi, tri or tetra-valent antibodies, Bis-scFv, diabodies, triabodies, tetrabodies and epitope-binding fragments of any of the above (see for example Holliger and Hudson, 2005, Nature Biotech.
• Multi-valent antibodies may comprise multiple specificities e.g. bispecific or may be monospecific (see for example W092/22853, WO05/113605, W02009/040562 and W02010/035012).
• Binding fragment of an antibody as employed herein refers to a fragment capable of binding an antigen with affinity to characterize the fragment as specific for the antigen.
• the antibody according to the present disclosure is provided as CSF- 1R binding antibody fusion protein which comprises an immunoglobulin moiety, for example a Fab or Fab’ fragment, and one or two single domain antibodies (dAb) linked directly or indirectly thereto, for example as described in W02009/040562, W02010/035012, WO2011/030107, WO201 1/061492 and WO2011/086091, all incorporated herein by reference.
• an immunoglobulin moiety for example a Fab or Fab’ fragment
• dAb single domain antibodies
• the fusion protein comprises two domain antibodies, for example as a variable heavy (VH) and variable light (VL) pairing, optionally linked by a disulfide bond.
• VH variable heavy
• VL variable light
• the Fab or Fab’ element of the fusion protein has the same or similar specificity to the single domain antibody or antibodies.
• the Fab or Fab’ has a different specificity to the single domain antibody or antibodies, that is to say the fusion protein is multivalent.
• a multivalent fusion protein according to the present disclosure has an albumin binding site, for example a VH/VL pair therein provides an albumin binding site.
• the constant region domains of the antibody molecule of the present disclosure may be selected having regard to the proposed function of the antibody molecule, and in particular the effector functions which may be required.
• the constant region domains may be human IgA, IgD, IgE, IgG or IgM domains.
• human IgG constant region domains may be used, especially of the IgGl and IgG3 isotypes when the antibody molecule is intended for therapeutic uses and antibody effector functions are required.
• IgG2 and IgG4 isotypes may be used when the antibody molecule is intended for therapeutic purposes and antibody effector functions are not required.
• antibodies may undergo a variety of posttranslational modifications.
• the type and extent of these modifications often depends on the host cell line used to express the antibody as well as the culture conditions.
• modifications may include variations in glycosylation, methionine oxidation, diketopiperazine formation, aspartate isomerization and asparagine deamidation.
• a frequent modification is the loss of a carboxy -terminal basic residue (such as lysine or arginine) due to the action of carboxypeptidases (as described in Harris, RJ. Journal of Chromatography 705: 129-134, 1995). Accordingly, the C- terminal lysine of the antibody heavy chain may be absent.
• humanized antibody refers to an antibody or antibody molecule wherein the heavy and/or light chain contains one or more CDRs (including, if desired, one or more modified CDRs) from a donor antibody (e.g. a murine monoclonal antibody) grafted into a heavy and/or light chain variable region framework of an acceptor antibody (e.g. a human antibody) (see, e.g. US 5,585,089; WO91/09967). For a review, see Vaughan et al , Nature Biotechnology, 16, 535-539, 1998.
• CDRs including, if desired, one or more modified CDRs
• only one or more of the specificity determining residues from any one of the CDRs described herein above are transferred to the human antibody framework (see for example, Kashmiri et al., 2005, Methods, 36:25-34).
• the specificity determining residues from one or more of the CDRs described herein above are transferred to the human antibody framework.
• only the specificity determining residues from each of the CDRs described herein above are transferred to the human antibody framework.
• any appropriate, acceptor variable region framework sequence may be used having regard to the class/type of the donor antibody from which the CDRs are derived, including mouse, primate and human framework regions.
• the term “approximately” or “about” refers to a range of values that fall within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less in either direction (greater than or less than) of the stated reference value unless otherwise stated or otherwise evident from the context (except where such number would exceed 100% of a possible value).
• “about” may mean +/- 10% of the recited value.
• Articles used in the claims and description, such as “a,” “an,” and “the,” may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include “or” between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context.
• the disclosure includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process.
• the disclosure includes embodiments in which more than one, or all, of the group members are present in, employed in, or otherwise relevant to a given product or process.
• Treatment is an approach for obtaining beneficial or desired results including clinical results.
• beneficial or desired clinical results may include one or more of the following: decreasing one more symptoms resulting from the disease; (ii) diminishing the extent of the disease and/or stabilizing the disease (e.g., delaying the worsening of the disease); (iii) delaying the spread of the disease; (iv) delaying or slowing the onset or recurrence of the disease and/or the progression of the disease; (v) ameliorating the disease state and/or providing a remission (whether partial or total) of the disease and/or decreasing the dose of one or more other medications required to treat the disease; (vi) increasing the quality of life, and/or (vii) prolonging survival.
• Delaying the development of a disease or condition means to defer, hinder, slow, retard, stabilize, and/or postpone development of the disease or condition. This delay can be of varying lengths of time, depending on the history of the disease or condition, and/or subject being treated.
• a method that "delays" development of a disease or condition is a method that reduces probability of disease or condition development in a given time frame and/or reduces the extent of the disease or condition in a given time frame, when compared to not using the method. Such comparisons are typically based on clinical studies, using a statistically significant number of subjects.
• Disease or condition development can be detectable using standard methods, such as routine physical exams, mammography, imaging, or biopsy. Development may also refer to disease or condition progression that may be initially undetectable and includes occurrence, recurrence, and onset.
• compositions or combinations are described as having, including, or comprising specific components or steps, it is contemplated that compositions or combinations also consist essentially of, or consist of, the recited components. Similarly, where methods or processes are described as having, including, or comprising specific process steps, the processes also consist essentially of, or consist of, the recited processing steps. Further, it should be understood that the order of steps or order for performing certain actions is immaterial so long as the invention remains operable. Moreover, two or more steps or actions can be conducted simultaneously.
• Clinical trial evaluated the safety and preliminary efficacy of the anti-CSF-lR (Ab535; axatilimab) in up to 30 patients with chronic graft versus host disease (cGVHD) who have received at least two prior lines of therapy. All patients tested received prior treatment with ibrutinib, steroids, and a calcineurin inhibitor, have been enrolled across three dose cohorts: one patient was treated at 0.15 mg/kg every two weeks (Q2W, Cohort 1), one is receiving a dose of 0.5 mg/kg Q2W (Cohort 2), and three patients are receiving 1.0 mg/kg Q2W (Cohort 3).
• the first patient (Cohort 1) achieved a short-lived partial response but subsequently discontinued due elevated liver function tests (LFTs) attributed to progression in their liver cGVHD.
• Cohort 4 which will explore a 3 mg/kg Q2W dose is now open for enrollment.
• CSF-1R blockade can prevent and treat disease in animal models of cGVHD.
• the initial data provides the first clinical evidence that targeting CSF-1R dependent macrophages may benefit patients with cGVHD.
• the anti-CSF-lR antibody or antigen binding fragment thereof has been safe and well-tolerated, with no dose-limiting toxicities observed. Dose escalation is ongoing in the Phase 1 portion of the trial.
• the preferable initial dosing schedule is 1 mg/kg of the axatilimab anti-CSF-lR antibody or antigen binding fragment thereof, administered every two weeks.
• Example 2 Study of Axatilimab (SNDX-6352), a CSF-1R Humanized Antibody, For Chronic Graft-Versus-Host Disease after 2 or More Lines of Systemic Treatment
• cGVHD Chronic graft versus host disease
• cGVHD Chronic graft versus host disease
• Patients (pts) with inadequate response to steroids have few effective therapeutic options and represent an unmet medical need.
• Available therapies are associated with significant toxicity, immunosuppression, and increased risk of infections.
• Preclinical studies demonstrate that CSF-1/CSF-1R is a key regulatory pathway involved in the expansion and infiltration of donor-derived macrophages that mediate cGVHD.
• Axatilimab (axa) is a humanized, full-length IgG4 antibody with high affinity to CSF-1R.
• axatilimab affects the migration, proliferation, differentiation, and survival of monocytes and macrophages by binding to CSF-1R and blocking its activation by its two known ligands, CSF-1 and IL-34. It offers a novel therapeutic option for treatment of these patients.
• Methods The Phase 1/2 dose-escalation and dose-expansion study evaluating safety, tolerability, pharmacokinetics (PK)/pharmacodynamics (PD), and efficacy of axatilimab in pts >6 years of age with active symptomatic cGVHD despite >2 prior lines of therapy.
• the Phase 1 endpoints were safety, tolerability, PK and PD with the primary objective of defining optimal biologic dose; the primary endpoint of the Phase 2 study is overall response rate (CR+PR) by 6 months. Patients were dosed in 28-day cycles.
• ibrutinib a BTK inhibitor
• cGVHD Chronic graft-versus-host disease
• HSCT allogeneic hematopoietic stem cell transplantation
• UVB ultraviolet B
• ECP extracorporeal photopheresis
• CSF-1R colony stimulating factor 1 receptor
• Axatilimab is a humanized IgG4 monoclonal antibody (mAb) directed against CSF-1R with the potential to treat cGVHD through blockade of macrophage activity.
• mAb monoclonal antibody
• Active cGVHD is defined as the presence of signs and symptoms of cGVHD per 2014 NIH Consensus Development Project on Criteria for Clinical trials in cGVHD (Jagasia 2015).
• Patients must have documented progressive disease as defined by the NIH 2014 consensus criteria, in terms of either organ specific algorithm or global assessment, or active, symptomatic cGVHD for which the physician believes that a new line of systemic therapy is required. Patients may have persistent active acute and cGVHD manifestations (overlap syndrome), as defined by 2014 NIH Consensus Development Project on Criteria for Clinical trials in cGVHD. Diagnostic Assessments
• Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
• Non-sterilized male patients who are not abstinent and intend to be sexually active with a female partner of childbearing potential must use a male condom plus spermicide from the time of screening throughout the total duration of the study intervention treatment period and 90 days after the last dose of study intervention. However, periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of contraception. Male patients should refrain from sperm donation throughout this period.
• Female patients Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal patients. Women will be considered post- menopausal if they have been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply:
• Women ⁇ 50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy).
• Women >50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses >1 year ago, had chemotherapy-induced menopause with last menses >1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy).
• Female patients of childbearing potential who are not abstinent and intend to be sexually active with a non-sterilized male partner must use at least 1 highly effective method of contraception from the time of screening throughout the total duration of the study intervention treatment period and 90 days after the last dose of study intervention.
• Non-sterilized male partners of a female patient of childbearing potential must use male condom plus spermicide throughout this period.
• Cessation of birth control after this point should be discussed with a responsible physician.
• Periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of birth control.
• Female patients should also refrain from breastfeeding throughout this period.
• ORR overall response rate
• DOR Duration of response
• DOR defined as the time from best response of PR or CR until documented progression of cGVHD, start of new therapy, or death for any reason (Definition 1).
• DOR defined as the time from initial response of PR or CR until documented progression of cGVHD, start of new therapy, or death for any reason (Definition 2).
• Sustained response rate Organ-specific response rate is based on 2014 NIH Consensus Development Project on Criteria for Clinical Trials in cGVHD. Joints and fascia response rate based on refined NIH response algorithm for cGVHD. Evaluation includes 1) Proportion of patients with a >5-point improvement in modified Lee Symptom Scale score; 2) Percent reduction in average daily dose (or equivalent) of corticosteroids; 3) Proportion of patients who discontinue corticosteroid use after study entry; 4) Percent reduction in average daily dose (or equivalent) of calcineurin inhibitors; 5) Proportion of patients who discontinue calcineurin inhibitors use after study entry.
• the baseline circulating monocyte number and phenotype was measured.
• FFS is defined as the time from randomization to death or unequivocal progression of cGVHD or relapse of underlying malignancy or addition of another systemic immune suppressive therapy or discontinuation of study treatment due to toxicity.
• OS Overall survival
• Time to response Time to next treatment
• physician-reported outcome Change in cGVHD severity as based on the Physician- reported global cGVHD Activity Assessment.
• Phase 2 open-label, randomized, multicenter study to evaluate the efficacy, safety and tolerability of axatilimab at 3 different dose levels, in patients with recurrent or refractory active cGVHD who have received at least 2 prior lines of systemic therapy due to progression of disease, intolerability or toxicity.
• Disease progression as defined by the NIH 2014 consensus criteria, either in terms of organ specific algorithm or global assessment or, active, symptomatic cGVHD or those requiring an additional or new line of systemic therapy.
• the study consists of 3 periods: Screening, Treatment, and Follow-up. Throughout the study, patients are evaluated. At enrollment, eligible patients are randomized to one of 3 dose cohorts (axatilimab 0.3 mg/kg every 2 weeks [Q2W], 1 mg/kg Q2W, and 3 mg/kg Q4W). Patients started treatment (Cycle 1 Day 1) within 3 days of randomization/enrollment and will receive axatilimab from Cycle 1 Day 1, in 4-week (28-day) treatment cycles, until disease progression (as defined by the NIH 2014 consensus criteria), withdrawal of consent, or unacceptable toxicity. Following treatment discontinuation, patients will receive an End of Treatment (EOT) visit 30 days after the last dose of study drug and 2 further safety and disease evaluation visits at 60 and 90 days post last dose of study drug.
• EOT End of Treatment
• Simon’s optimal 2-stage design is implemented within each dose cohort.
• patients are randomized to each of the 3 dose cohorts.
• the initial futility analysis is based on an early endpoint (ie, overall response in the first 3 cycles).
• Each dose is evaluated for futility and unacceptable toxicity, and the stopping boundaries for futility and unacceptable toxicity are as follows:
• Safety assessment safety assessment will occur whenever there is a futility analysis, and the boundary for unacceptable toxicity is >8 out of 27 patients having a toxic event defined as any serious or severe (>Grade 3) TEAE that is attributed to study drug. Grade 2 events that are considered treatment related and result in medical intervention or hospitalization are counted as a toxic event. Study randomization will not pause while data from the interim analyses are being evaluated. An Independent Data Monitoring Committee will evaluate all data that are available at the time of the data cut and determine, in light of the pre-determined futility and toxicity boundaries, which doses patients should no longer be enrolled to. Doses that don’t meet the futility or safety boundaries will go on to be evaluated in the second stage of the study in which an additional 43 patients are enrolled into that dose level.
• a final efficacy analysis is performed when all patients have had the opportunity to complete 6 cycles of treatment with axatilimab.
• a dose level is considered successful if >29 patients have had a response to axatilimab (PR or CR), as defined by NIH 2014 cGVHD criteria.
• Patients enrolled into a Q2W regimen may be eligible to change to a Q4W regimen during the study.
• Patients enrolled into the 0.3 mg/kg Q2W regimen may be eligible to have their dose escalated to 1 mg/kg Q2W.
• the on-treatment response criteria is assessed every 4 weeks and at the EOT visit or discontinuation of the study intervention using 2014 NIH Consensus Development Project on Criteria for Clinical Trials in cGVHD: CR, PR, lack of response (unchanged, mixed or progression). Number of Patients:
• Stage 1 27 patients are enrolled into each treatment arm (0.3 mg/kg Q2W,
• Stage 2 an additional 43 patients are enrolled into each of the treatment arms which have passed the futility and safety evaluations from Stage 1.
• NCMC time-averaged non-classical monocytes
• IMMC intermediate monocytes
• the modeling indicates that at 0.15 mg/kg Q2W both NCMC and IMMC are at or near baseline, while at 0.5 mg/kg q2w NCMC are ⁇ 25% decreased and IMMC are near baseline.
• a 1 mg/kg Q2W dose yields counts that are approximately 50% decreased for both NCMC and IMMC, while 3 mg/kg Q2W results in complete decrease of NCMC and IMMC over a 2-week dosing interval.
• modeling indicates a time-averaged decrease in NCMC and IMMC levels between 1 mg/kg Q2W and 2 mg/kg Q4W. While the clinical relevance of monocyte counts as pharmacodynamic markers of probability of response remains to be determined, circulating monocyte levels are a direct biological readout of CSF-1R inhibition and may be used to guide optimization of dose and schedule.
• a dose of 0.3 mg/kg Q2W is expected to result in some, but relatively minimal, decrease in time-averaged NCMC and IMMC, generating a sufficient dose range to provide more certainty around the optimal dosing regimen for any subsequent studies.
• Patients enrolled into Q2W regimens may have their dosing regimens changed to Q4W if they meet the criteria provided.
• a patient may return to a Q2W schedule.
• the dose intensity must remain the same ie, the dose intensity immediately before the change must equate to the dose intensity immediately after the change.
• a patient has experienced a PR/CR or has not progressed following dose escalation to 1 mg/kg Q2W and their best response is maintained for 20 weeks, they may change their dose schedule from Q2W to Q4W. They will maintain their dose intensity by going from 1 mg/kg to 2 mg/kg. Their new dose is 2 mg/kg Q4W.
• a patient experiences an axatilimab infusion-related reaction they may continue on study intervention treatment per guidance presented. Patients who previously experienced an infusion- related reaction will receive a premedication regimen of 25 to 50 mg IV or oral equivalent diphenhydramine and 650 mg IV or oral equivalent acetaminophen/paracetamol approximately 30 to 60 minutes prior to each subsequent dose of axatilimab.
• a Grade 2 infusion-related reaction does not improve or worsens after implementation of the modifications indicated (including reducing the infusion rate by 50%)
• the Investigator may consider treatment with corticosteroids, and the infusion should be stopped for that day.
• administration of oral premedication with antihistamine and anti-pyretic is required. Prophylactic steroids are NOT permitted.
• the patient has a second infusion-related reaction of Grade 2 or higher on the slower 50% infusion rate, with or without the addition of further medication to the mandatory premedication, the infusion should be stopped, and the patient removed from axatilimab treatment.
• All patients are centrally assigned to axatilimab dose in a 1:1:1 randomization ratio using an Interactive Response Technology (IRT).
• IRT Interactive Response Technology
• Patient assignments are stratified for severity of cGVHD (mild/moderate vs. severe) and prior use of at least one of the following therapies: ibrutinib, ruxolitinib and KD025 (prior therapy vs. no prior therapy).
• IRT Interactive Response Technology
• axatilimab drug product must be diluted to 50 mL with 0.9% saline solution (sodium chloride injection) supplied in an infusion bag. No other drugs should be added to the solution for infusion containing axatilimab.
• the dose amount required to prepare the axatilimab infusion solution is based on the patient’s weight in kilograms (kg). All patients should be weighed within 3 days prior to dosing. If the patient experiences either a weight loss or gain >10% compared to the weight used for the last dose calculation, the amount of study intervention must be recalculated. For weight change ⁇ 10%, the decision to recalculate the axatilimab dose can be in accordance with institutional practice.
• cGVHD assessments be done by the same health care provider who completed the C1D1 assessment.
• the C7D1 assessment should be performed by the same health care provider who performed the C1D1 assessment.
• any assessments leading to changes in cGVHD therapy must be confirmed by the PI or primary treating physician.
• CR is defined as resolution of all manifestations in each organ or site
• PR is defined as improvement in at least 1 organ or site without progression in any other organ or site.
• Table 9 contains the Working Group proposed consensus definitions of CR, PR and progression for assessment of organ- specific responses as well as a global response determination.
• PFT assessments will include pulse oximetry and as clinically indicated, CT scan with inspiratory and expiratory phases to assess air trapping.
• Axatilimab levels in plasma samples are determined using a validated enzyme-linked immunosorbent assay (ELISA).
• ELISA enzyme-linked immunosorbent assay
• Levels of blood immune parameters that may include IFNgamma, IL-lbeta, IL-4, IL-5, IL- 6, IL-8, IL-10, IL-12p70, TNF alpha, CSF1 and IL-34. and change from baseline compared to PK, safety endpoints.
• samples are stored, and analysis may be performed on biomarker variants thought to play a role in immune-modulation including, but not limited to, emergent candidate genes/genome-wide analysis for RNA, serum analytes, or tissue biomarkers to evaluate their association with observed clinical responses to axatilimab.
• Antibodies to axatilimab are evaluated in plasma samples collected from all patients. Plasma samples are screened for antibodies binding to axatilimab, and the titer of confirmed positive samples is reported. Other analyses are performed to verify the stability of antibodies to axatilimab and/or further characterize the immunogenicity of axatilimab.
• the detection and characterization of antibodies to axatilimab is performed using a validated assay. All samples collected for detection of antibodies to axatilimab also have matching samples evaluated for axatilimab plasma concentration to enable interpretation of the antibody data. Antibodies may be characterized further and/or evaluated for their ability to neutralize the activity of the study intervention(s).
• the Karnofsky/Lansky Performance Status allows patients to be classified as to their functional impairment on a scale from 0 to 100. The lower the score, the worse the survival for most serious illnesses. The score can be used to compare effectiveness of different therapies and to assess the prognosis in individual patients.
• the Karnofsky Scale is designed for patients aged 16 years and older, and the Lansky scale is designed for patients less than 16 years old (Lansky 1987).
• the Karnofsky scale is widely used validated tool in oncology settings, especially HSCT (Schag 1984, Crooks 1991, O'Toole and Golden 1991). The Karnofsky and Lansky performance status are presented in the table.

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