Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
  • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
  • 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
  • C07K16/2803—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
  • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
  • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/02—Antineoplastic agents specific for leukemia
• • 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
  • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
  • 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
• • C—CHEMISTRY; METALLURGY
  • 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K2317/00—Immunoglobulins specific features
  • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
  • C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K2317/00—Immunoglobulins specific features
  • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
  • C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
  • C07K2317/732—Antibody-dependent cellular cytotoxicity [ADCC]

Definitions

• the present disclosure provides a treatment comprising an anti-CD19 antibody for use in the treatment of various cancers.
• B cells are lymphocytes that play a large role in the humoral immune response. They are produced in the bone marrow of most mammals, and represent 5-15% of the circulating lymphoid pool.
• the principal function of B cells is to make antibodies against various antigens, and are an essential component of the adaptive immune system. Because of their critical role in regulating the immune system, dysregulation of B cells is associated with a variety of disorders, such as cancer. These include lymphomas and leukemia such as non-Hodgkin's lymphoma (NHL), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL) and acute lymphoblastic leukemia (ALL).
• NHL non-Hodgkin's lymphoma
• CLL chronic lymphocytic leukemia
• SLL small lymphocytic lymphoma
• ALL acute lymphoblastic leukemia
• NHL is a heterogeneous malignancy originating from lymphocytes. While the disease can occur in all ages, the usual onset begins in adults over 40 years, with the incidence increasing with age. NHL is characterized by a clonal proliferation of lymphocytes that accumulate in the lymph nodes, blood, bone marrow and spleen, although any major organ may be involved.
• the current classification system used by pathologists and clinicians is the World Health Organization (WHO) Classification of Tumors, which organizes NHL into precursor and mature B-cell or T-cell neoplasms.
• WHO World Health Organization
• the Physician’s Data Query is currently dividing NHL as indolent or aggressive for entry into clinical trials.
• the indolent NHL group is comprised primarily of follicular subtypes, small lymphocytic lymphoma, MALT (mucosa- associated lymphoid tissue), and marginal zone; indolent encompasses approximately 50% of newly diagnosed B-cell NHL patients.
• Aggressive NHL includes patients with histologic diagnoses of primarily diffuse large B cell cancers (DLBL, DLBCL, or DLCL; where 40% of all newly diagnosed patients have diffuse large cell), Burkitt lymphoma, and mantle cell lymphoma.
• NHL In addition to NHL there are several types of leukemia that result from dysregulation of B cells.
• Chronic lymphocytic leukemia also known as “chronic lymphoid leukemia” or "CLL"
• CLL chronic lymphocytic leukemia
• the malignant lymphocytes may look normal and mature, but they are not able to cope effectively with infection.
• CLL is the most common form of leukemia in adults. Men are twice as likely to develop CLL as women.
• the key risk factor is age.
• CLL is an incurable disease but progresses slowly in most cases. Many people with CLL lead normal and active lives for many years. Because of its slow onset, early-stage CLL is generally not treated since it is believed that early CLL intervention does not improve survival time or quality of life. Instead, the condition is monitored over time.
• SLL small lymphocytic lymphoma
• CLL small lymphocytic lymphoma
• the definition of SLL requires the presence of lymphadenopathy and/or splenomegaly.
• the number of B lymphocytes in the peripheral blood should not exceed 5 x 10 9 /L.
• the diagnosis should be confirmed by histopathologic evaluation of a lymph node biopsy whenever possible (Hallek et al., 2008).
• Acute lymphoblastic leukemia is characterized by the overproduction and continuous multiplication of malignant and immature white blood cells (also known as lymphoblasts) in the bone marrow.
• Acute lymphoblastic leukemia is most common in childhood with a peak incidence of 4-5 years of age.
• the human CD19 molecule is a structurally distinct cell surface receptor expressed on the surface of human B cells, including, but not limited to, pre-B cells, B cells in early development (i.e., immature B cells), mature B cells through terminal differentiation into plasma cells, and malignant B cells.
• CD 19 is expressed by most pre-B acute lymphoblastic leukemias (ALL), non-Hodgkin's lymphomas, B cell chronic lymphocytic leukemias (CLL), small lymphocytic lymphomas (SLL), pro-lymphocytic leukemias, hairy cell leukemias, common acute lymphocytic leukemias, and some Null-acute lymphoblastic leukemias (Nadler et al, J.
• ALL acute lymphoblastic leukemias
• CLL B cell chronic lymphocytic leukemias
• SLL small lymphocytic lymphomas
• pro-lymphocytic leukemias hairy cell leukemias, common
• CD19 on plasma cells further suggests it may be expressed on differentiated B cell tumors such as multiple myeloma, plasmacytomas, Waldenstrom's tumors (Grossbard et al., Br. J. Haematol, 102:509- 15(1998); Treon et al, Semin. Oncol, 30:248-52(2003)).
• the CD19 antigen is a target for immunotherapy in the treatment of various cancers, such as non-Hodgkin’s lymphoma (NHL), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL) and/or acute lymphoblastic leukemia, including each of the subtypes described herein.
• NHL non-Hodgkin’s lymphoma
• CLL chronic lymphocytic leukemia
• SLL small lymphocytic lymphoma
• acute lymphoblastic leukemia including each of the subtypes described herein.
• the anti-CD19 antibody is administered at a dose of at least 24 mg/kg wherein the anti-CD19 antibody is administered as an intravenous infusion.
• said intravenous infusion is administered within at least 1.5 hours, at least 2 hours, at least 2.5 hours, at least 3 hours, at least 3.5 hours, at least 4 hours or at least 4.5 hours.
• the anti-CD19 antibody is administered at a dose of at least 24 mg/kg wherein the anti-CD19 antibody is administered as an intravenous infusion and wherein said intravenous infusion is administered within 1.5 to 2.5 hours. In some other embodiments, the anti-CD19 antibody is administered at a dose of at least 24 mg/kg wherein the anti-CD19 antibody is administered as an intravenous infusion and wherein said intravenous infusion is administered within 1.5 to 2 hours. In some other embodiments, the anti-CD19 antibody is administered at a dose of at least 24 mg/kg wherein the anti-CD19 antibody is administered as an intravenous infusion and wherein said intravenous infusion is administered within 2 hours.
• the anti-CD19 antibody is administered at a dose of at least 24 mg/kg wherein the anti-CD19 antibody is administered as an intravenous infusion and wherein said intravenous infusion is administered within 3 to 4.5 hours. In some other embodiments, the anti-CD19 antibody is administered at a dose of at least 24 mg/kg wherein the anti-CD19 antibody is administered as an intravenous infusion and wherein said intravenous infusion is administered within 3 to 4 hours. In some other embodiments, the anti-CD19 antibody is administered at a dose of at least 24 mg/kg wherein the anti-CD19 antibody is administered as an intravenous infusion and wherein said intravenous infusion is administered within 3.5 to 4 hours.
• the present disclosure relates to a method of treating a cancer in a human subject in need thereof, the method comprising administering to the human subject an anti-CD19 antibody, wherein said anti-CD19 antibody is administered as an intravenous infusion at a dose of 12mg/kg within 1.5 to 2.5 hours prior to an increase to the dose of at least 24 mg/kg (for example 24 mg/kg or 30 mg/kg) and wherein said increased dose of at least 24 mg/kg (for example 24 mg/kg or 30 mg/kg) is administered as an intravenous infusion within 3 to 4.5 hours.
• said increased dose of at least 24 mg/kg is administered as an intravenous infusion within 3 to 4 hours.
• said increased dose of at least 24 mg/kg is administered as an intravenous infusion within 3.5 to 4 hours. In some other embodiments, said increased dose of at least 24 mg/kg (for example 24 mg/kg or 30 mg/kg) is administered as an intravenous infusion within 3.5 to 4.5 hours. In some other embodiments, said increased dose of at least 24 mg/kg (for example 24 mg/kg or 30 mg/kg) is administered as an intravenous infusion within 4 hours.
• said increased dose of at least 24 mg/kg is administered as an intravenous infusion within 3.5 to 4 hours. In some other embodiments, said increased dose of at least 24 mg/kg (for example 24 mg/kg or 30 mg/kg) is administered as an intravenous infusion within 3.5 to 4.5 hours. In some other embodiments, said increased dose of at least 24 mg/kg (for example 24 mg/kg or 30 mg/kg) is administered as an intravenous infusion within 4 hours. In some embodiments, the anti-CD19 antibody is administered at a dose of at least 24mg/kg (for example 24 mg/kg or 30 mg/kg) once a week, once every two weeks or once every four weeks.
• the present disclosure relates to a method of treating a cancer in a human subject in need thereof, the method comprising administering to the human subject an anti-CD19 antibody, wherein said anti-CD19 antibody is administered as an intravenous infusion at a dose of 12mg/kg within 1.5 to 2.5 hours prior to an increase to the dose of at least 24 mg/kg (for example 24 mg/kg or 30 mg/kg) and wherein said increased dose of at least 24 mg/kg (for example 24 mg/kg or 30 mg/kg) is administered as an intravenous infusion within 1.5 to 2.5 hours.
• said increased dose of at least 24 mg/kg is administered as an intravenous infusion within 1.5 to 2 hours.
• said anti-CD19 antibody On days 1 , 4 and 8 of a first 28 day treatment cycle said anti-CD19 antibody is administered at a dose of 12mg/kg and within 1 .5 to 2.5 hours; on day 15 of the first 28 days treatment cycle and on days 1 and 15 of the second and any subsequent 28 days treatment cycle said anti-CD19 antibody is administered at a dose of at least 24 mg/kg (for example 24 mg/kg or 30 mg/kg) and within 3 to 4.5 hours.
• the present disclosure relates to a method of treating a cancer in a human subject in need thereof, the method comprising administering to the human subject an anti-CD19 antibody, wherein said anti-CD19 antibody is administered as an intravenous infusion according to the following schedule:,
• the present disclosure relates to a method of treating a cancer in a human subject in need thereof, the method comprising administering to the human subject an anti-CD19 antibody, wherein said anti-CD19 antibody is administered as an intravenous infusion according to the following schedule:,
• the present disclosure relates to a method of treating a cancer in a human subject in need thereof, the method comprising administering to the human subject an anti-CD19 antibody, wherein said anti-CD19 antibody is administered as an intravenous infusion according to the following schedule:,
• said anti-CD19 antibody On days 1 , 4 and 8 of a first 28 day treatment cycle said anti-CD19 antibody is administered at a dose of 12mg/kg and within 1.5 to 2.5 hours; on day 15 of the first 28 days treatment cycle and on days 1 and 15 of the second and any subsequent 28 days treatment cycle said anti-CD19 antibody is administered at a dose of at least 24 mg/kg (for example 24 mg/kg or 30 mg/kg) and within 2 to 2.5 or within 3 hours.
• said anti-CD19 antibody On days 1 , 4 and 8 of a first 28 day treatment cycle said anti-CD19 antibody is administered at a dose of 12mg/kg and within 1 .5 to 2.5 hours; on day 15 of the first 28 days treatment cycle and on days 1 and 15 of the second and any subsequent 28 days treatment cycle said anti-CD19 antibody is administered at a dose of at least 24 mg/kg (for example 24 mg/kg or 30 mg/kg) and within 2 hours.
• the present disclosure relates to a method of treating a cancer in a human subject in need thereof, the method comprising administering to the human subject an anti-CD19 antibody, wherein said anti-CD19 antibody is administered as an intravenous infusion according to the following schedule:,
• said anti-CD19 antibody is administered at a dose of 12mg/kg and within 2 hours; on day 15 of the first 28 days treatment cycle and on days 1 and 15 of the second and the third 28 days treatment cycles said anti-CD19 antibody is administered at a dose of at least 24 mg/kg (for example 24 mg/kg or 30 mg/kg) and within 4 hours and on day 1 of the fourth 28 days treatment cycle and on day 1 of any subsequent 28 days treatment cycle said anti-CD19 antibody is administered at a dose of at least 24 mg/kg (for example 24 mg/kg or 30 mg/kg) and within 2 hours.
• said anti-CD19 antibody is administered at a dose of 12mg/kg and within 1.5 to 2.5 hours; on day 15 of the first 28 days treatment cycle and on days 1 and 15 of the second and the third 28 days treatment cycles said anti-CD19 antibody is administered at a dose of at least 24 mg/kg (for example 24 mg/kg or 30 mg/kg) and within 3 to 4.5 hours and on day 1 of the fourth 28 days treatment cycle and on day 1 of any subsequent 28 days treatment cycle said anti-CD19 antibody is administered at a dose of at least 24 mg/kg (for example 24 mg/kg or 30 mg/kg) and within 1.5 to 2 hours.
• said anti-CD19 antibody is administered at a dose of 12mg/kg and within 2 hours; on day 15 of the first 28 days treatment cycle and on days 1 and 15 of the second and the third 28 days treatment cycles said anti-CD19 antibody is administered at a dose of at least 24 mg/kg (for example 24 mg/kg or 30 mg/kg) and within 4 hours and on day 1 of the fourth 28 days treatment cycle and on day 1 of any subsequent 28 days treatment cycle said anti-CD19 antibody is administered at a dose of at least 24 mg/kg (for example 24 mg/kg or 30 mg/kg) and within 2 hours.
• the anti-CD19 antibody is administered at a dose of 12 mg/kg on day 1 , day 4 and day 8 from the start of treatment and from day 15 the anti-CD19 antibody is administered as an intravenous infusion at a dose of at least 24 mg/kg (for example 24 mg/kg or 30 mg/kg) and within 4 hours. In some embodiments, the anti-CD19 antibody is administered at a dose in the range of between 24 mg/kg to 30mg/kg once a week, once every two weeks or once every four weeks.
• the anti-CD19 antibody is administered at a dose of 12 mg/kg on day 1 , day 4 and day 8 from the start of treatment and from day 15 the anti-CD19 antibody is administered as an intravenous infusion at a dose of at least 24 mg/kg (for example 24 mg/kg or 30 mg/kg) and within 1.5 to 2.5 hours, within 1.5 to 2 hours, within 2 hours, within 2 to 2.5 hours, within 2 to 3 hours or within 3 hours.
• the anti-CD19 antibody is administered at a dose in the range of between 24 mg/kg to 30mg/kg once a week, once every two weeks or once every four weeks.
• the anti-CD19 antibody is administered at a dose of at least 24 mg/kg wherein the anti-CD19 antibody is administered as an intravenous infusion and wherein said intravenous infusion is administered within 1.5 to 2.5 hours and wherein the intravenous infusion is administered with an infusion rate of 70 mL/h for the first 30 minutes.
• the anti-CD19 antibody is administered at a dose of at least 24 mg/kg wherein the anti-CD19 antibody is administered as an intravenous infusion and wherein said intravenous infusion is administered within 1.5 to 2 hours and wherein the intravenous infusion is administered with an infusion rate of 70 mL/h for the first 30 minutes.
• the anti-CD19 antibody is administered at a dose of at least 24 mg/kg wherein the anti-CD19 antibody is administered as an intravenous infusion and wherein said intravenous infusion is administered within 2 hours and wherein the intravenous infusion is administered with an infusion rate of 70 mL/h for the first 30 minutes.
• the anti-CD19 antibody is administered at a dose of at least 24 mg/kg wherein the anti-CD19 antibody is administered as an intravenous infusion and wherein said intravenous infusion is administered within 3 to 4.5 hours and wherein the intravenous infusion is administered with an infusion rate of at least 30 mL/h for the first 30 minutes.
• the anti-CD19 antibody is administered at a dose of at least 24 mg/kg wherein the anti-CD19 antibody is administered as an intravenous infusion and wherein said intravenous infusion is administered within 3 to 4 hours and wherein the intravenous infusion is administered with an infusion rate of at least 30 mL/h for the first 30 minutes.
• the anti-CD19 antibody is administered at a dose of at least 24 mg/kg wherein the anti-CD19 antibody is administered as an intravenous infusion and wherein said intravenous infusion is administered within 4 hours and wherein the intravenous infusion is administered with an infusion rate of at least 30 mL/h for the first 30 minutes.
• the one or more subsequent intravenous infusions are administered within 1.5 to 2.5 hours, within 1.5 to 2 hours, or within 2 hours.
• the anti-CD19 antibody is administered in multiple administrations comprising a first administration and one or more subsequent administrations at a dose of at least 24 mg/kg, wherein each of the first administration and one or more subsequent administrations of the anti-CD19 antibody is administered as an intravenous infusion and wherein said first intravenous infusion is administered within 1.5 to 2.5 hours with an infusion rate of 70 mL/h for the first 30 minutes and the one or more subsequent intravenous infusions are administered within 1.5 to 2 hours or within 2 hours.
• the anti-CD19 antibody is administered at a dose of at least 24 mg/kg (for example 24 mg/kg or 30 mg/kg) wherein the anti-CD19 antibody is administered as an intravenous infusion and wherein said intravenous infusion is administered within 2 hours.
• the anti-CD19 antibody is administered at a dose of at least 24 mg/kg (for example 24 mg/kg or 30 mg/kg) wherein the anti-CD19 antibody is administered as an intravenous infusion and wherein said intravenous infusion is administered within 4 hours.
• the anti-CD19 antibody is administered at a dose of 24 mg/kg or 30mg/kg wherein the anti-CD19 antibody is administered as an intravenous infusion and wherein said intravenous infusion is administered within 1.5 to 2.5 hours and wherein the intravenous infusion is administered with an infusion rate of 70 mL/h for the first 30 minutes.
• the anti-CD19 antibody is administered at a dose of at least 24 mg/kg (for example 24 mg/kg or 30 mg/kg) wherein the anti-CD19 antibody is administered as an intravenous infusion and wherein said intravenous infusion is administered within 1.5 to 2 hours and wherein the intravenous infusion is administered with an infusion rate of 70 mL/h for the first 30 minutes.
• the anti-CD19 antibody is administered at a dose of at least 24 mg/kg (for example 24 mg/kg or 30 mg/kg) wherein the anti-CD19 antibody is administered as an intravenous infusion and wherein said intravenous infusion is administered within 2 hours and wherein the intravenous infusion is administered with an infusion rate of 70 mL/h for the first 30 minutes.
• the anti-CD19 antibody is administered at a dose of 24 mg/kg or 30mg/kg wherein the anti-CD19 antibody is administered as an intravenous infusion and wherein said intravenous infusion is administered within 3 to 4.5 hours and wherein the intravenous infusion is administered with an infusion rate of at least 30 mL/h for the first 30 minutes.
• the anti-CD19 antibody is administered at a dose of at least 24 mg/kg (for example 24 mg/kg or 30 mg/kg) wherein the anti-CD19 antibody is administered as an intravenous infusion and wherein said intravenous infusion is administered within 3 to 4 hours and wherein the intravenous infusion is administered with an infusion rate of at least 30 mL/h for the first 30 minutes.
• the anti-CD19 antibody is administered at a dose of at least 24 mg/kg (for example 24 mg/kg or 30 mg/kg) wherein the anti-CD19 antibody is administered as an intravenous infusion and wherein said intravenous infusion is administered within 3.5 to 4 hours and wherein the intravenous infusion is administered with an infusion rate of at least 30 mL/h for the first 30 minutes.
• the anti-CD19 antibody is administered at a dose of at least 24 mg/kg (for example 24 mg/kg or 30 mg/kg) wherein the anti-CD19 antibody is administered as an intravenous infusion and wherein said intravenous infusion is administered within 3.5 to 4.5 hours and wherein the intravenous infusion is administered with an infusion rate of at least 30 mL/h for the first 30 minutes.
• the anti-CD19 antibody is administered in multiple administrations comprising a first administration and one or more subsequent administrations at a dose of at least 24 mg/kg, for example 24 mg/kg or 30mg/kg, wherein each of the first administration and one or more subsequent administrations of the anti-CD19 antibody is administered as an intravenous infusion and wherein said first intravenous infusion is administered within 1.5 to 2.5 hours with an infusion rate of 70 mL/h for the first 30 minutes. In some other embodiments, the first intravenous infusion is administered within 1.5 to 2 hours with an infusion rate of 70 mL/h for the first 30 minutes.
• the first intravenous infusion is administered within 2 hours with an infusion rate of 70 mL/h for the first 30 minutes.
• the one or more subsequent intravenous infusions are administered within 1.5 to 2.5 hours, within 1.5 to 2 hours, or within 2 hours.
• the anti-CD19 antibody is administered in multiple administrations comprising a first administration and one or more subsequent administrations at a dose of at least 24 mg/kg, for example 24 mg/kg or 30 mg/kg, wherein each of the first administration and one or more subsequent administrations of the anti-CD19 antibody is administered as an intravenous infusion and wherein said first intravenous infusion is administered within 1.5 to 2.5 hours with an infusion rate of 70 mL/h for the first 30 minutes and the one or more subsequent intravenous infusions are administered within 1.5 to 2 hours or within 2 hours.
• the first intravenous infusion is administered within 3.5 to 4 hours with an infusion rate of at least 30 mL/h for the first 30 minutes. In some other embodiments, the first intravenous infusion is administered within 3.5 to 4.5 hours with an infusion rate of at least 30 mL/h for the first 30 minutes. In some other embodiments, the first intravenous infusion is administered within 4 hours with an infusion rate of at least 30 mL/h for the first 30 minutes. In some embodiments, the one or more subsequent intravenous infusions are administered within 3 to 4.5 hours, within 3 to 4 hours, within 3.5 to 4 hours, within 3.5 to 4. 5 hours, or within 4 hours.
• the anti-CD19 antibody is administered on Day 1 of a treatment cycle. In some embodiments, the treatment cycle is 28 days.
• the anti-CD19 antibody is administered at a dose of at least 24mg/kg. In some embodiments, the anti-CD19 antibody is administered at a dose of at least 24mg/kg once a week, once every two weeks or once every four weeks.
• the anti-CD19 antibody is administered at a dose of 12 mg/kg on day 1, day 4 and day 8 from the start of treatment and from day 15 the anti-CD19 antibody is administered at a dose of at least 24mg/kg. In some embodiments, the anti-CD19 antibody is administered at a dose of at least 24mg/kg once a week, once every two weeks or once every four weeks.
• the anti-CD19 antibody is administered in 28-day cycles, wherein on: a) Days 1, 4 and 9 of the first cycle, a dose of 12 mg/kg is administered and on day 15 of the first cycle a dose of at least 24mg/kg is administered; b) Days 1 and 15 of cycles 2-3, a dose of at least 24mg/kg is administered; and c) Day 1 of further subsequent cycles, a dose of at least 24mg/kg is administered.
• the anti-CD19 antibody is administered at a dose in the range of between 24 mg/kg to 30mg/kg. In some embodiments, the anti-CD19 antibody is administered at a dose in the range of between 24 mg/kg to 30mg/kg. In some embodiments, the anti-CD19 antibody is administered at a dose in the range of between 24 mg/kg to 30mg/kg once a week, once every two weeks or once every four weeks.
• the anti-CD19 antibody is administered at a dose in the range of between 24 mg/kg to 30mg/kg, wherein the anti-CD19 antibody is administered at a dose of 12mg/kg prior to an increase to the dose in the range of between 24 mg/kg to 30mg/kg.
• the anti-CD19 antibody is administered at a dose of 12 mg/kg for the first one, two or three administration and wherein after such first one, two or three administrations the anti-CD19 antibody is administered at a dose in the range of between 24 mg/kg to 30mg/kg.
• the anti-CD19 antibody is administered at a dose in the range of between 24 mg/kg to 30mg/kg once a week, once every two weeks or once every four weeks.
• the anti-CD19 antibody is administered at a dose of 12 mg/kg on day 1, day 4 and day 8 from the start of treatment and from day 15 the anti-CD19 antibody is administered at a dose in the range of between 24 mg/kg to 30mg/kg. In some embodiments, the anti-CD19 antibody is administered at a dose in the range of between 24 mg/kg to 30mg/kg once a week, once every two weeks or once every four weeks.
• the anti-CD19 antibody is administered in 28-day cycles, wherein on: a) Days 1, 4 and 9 of the first cycle, a dose of 12 mg/kg is administered and on day 15 of the first cycle a dose in the range of between 24 mg/kg to 30mg/kg is administered; b) Days 1 and 15 of cycles 2-3, a dose in the range of between 24 mg/kg to 30mg/kg is administered; and c) Days 1 of further subsequent cycles, a dose in the range of between 24 mg/kg to 30mg/kg is administered.
• the anti-CD19 antibody is administered at a dose of 24mg/kg. In some embodiments, the anti-CD19 antibody is administered at a dose of at 24mg/kg once every two weeks.
• the anti-CD19 antibody is administered at a dose of 24mg/kg, wherein the anti-CD19 antibody is administered at a dose of 12mg/kg prior to an increase to the dose of 24 mg/kg. In some embodiments, the anti-CD19 antibody is administered at a dose of 12 mg/kg for the first one, two or three administrations and wherein after such first one, two or three administrations the anti-CD19 antibody is administered at a dose of 24mg/kg. In some embodiments, the anti-CD19 antibody is administered at a dose of 24mg/kg once a week, once every two weeks or once every four weeks.
• the anti-CD19 antibody is administered at a dose of 12 mg/kg on day 1, day 4 and day 8 from the start of treatment and from day 15 the anti-CD19 antibody is administered at a dose of 24mg/kg. In some embodiments, the anti-CD19 antibody is administered at a dose of 24mg/kg once a week, once every two weeks or once every four weeks.
• the anti-CD19 antibody is administered at a dose of 30mg/kg, wherein the anti-CD19 antibody is administered at a dose of 12mg/kg prior to an increase to the dose of 30mg/kg. In some embodiments, the anti-CD19 antibody is administered at a dose of 12 mg/kg for the first one, two or three administrations and wherein after such first one, two or three administrations the anti-CD19 antibody is administered at a dose of 30mg/kg. In some embodiments, the anti-CD19 antibody is administered at a dose of 30mg/kg once a week, once every two weeks or once every four weeks.
• the anti-CD19 antibody is administered in 28-day cycles, wherein on: a) Days 1, 4 and 9 of the first cycle, a dose of 12 mg/kg is administered and on day 15 of the first cycle a dose of 30mg/kg is administered; b) Days 1 and 15 of cycles 2-3, a dose of 30mg/kg is administered; and c) Day 1 of further subsequent cycles, a dose of 30mg/kg is administered.
• the anti-CD19 antibody is administered in combination with lenalidomide.
• lenalidomide is administered orally.
• lenalidomide is administered daily on days 1-21 of repeated 28-day cycles.
• lenalidomide is administered daily on days 1-21 of up to 12 repeated 28-day cycles.
• the dose of lenalidomide is at least 20 mg daily. In certain aspects, the dose of lenalidomide is 25 mg daily.
• the anti-CD19 antibody is administered in combination with lenalidomide wherein lenalidomide is administered orally at a dose of 25 mg on days 1-21 of repeated 28-day cycles. In some embodiments, the anti-CD19 antibody is administered in combination with lenalidomide wherein lenalidomide is administered orally at a dose of 25 mg and daily on days 1-21 of 12 repeated 28-day cycles.
• Figure 1 & Figure 2 Boxplots of Model-predicted PK Parameters Based on 2000 Randomly Generated Patients Dosed According to the L-MIND, the 12/24 mg/kg (Cohort 1) and the 12/30mg/kg (Cohort 2) Dosing Regimen.
• Figure 3 Overlay of the Model-predicted Median of the Concentration-time Profiles of Tafasitamab Dosed According to the L MIND and the 12/30 mg/kg Dosing Regimen.
• CD19 refers to the protein known as CD19, having the following synonyms: B4, B-lymphocyte antigen CD19, B-lymphocyte surface antigen B4, CVID3, Differentiation antigen CD19, MGC12802, and T-cell surface antigen Leu-12.
• B4 B-lymphocyte antigen CD19
• B-lymphocyte surface antigen B4 B4, CVID3, Differentiation antigen CD19
• MGC12802 MGC12802
• T-cell surface antigen Leu-12 T-cell surface antigen Leu-12.
• the term also encompasses naturally occurring variants of CD19, e.g., splice variants, allelic variants, and isoforms.
• human CD19 has the amino acid sequence of:
• MOR208 and XmAb 5574” and “tafasitamab” are used as synonyms for the anti- CD19 antibody according to Table A.
• Table A provides the amino acid sequences of MOR208/ tafasitamab.
• the MOR208 antibody is described in US Patent No. 8,524,867, which is incorporated by reference in its entirety (in U.S. Patent No. 8,524,867, the full heavy chain of MOR208 is SEQ ID NO:87 and the full light chain of MOR208 is SEQ ID NQ:106).
• Fc region means the constant region of an antibody, which in humans may be of the lgG1 , 2, 3, 4 subclass or others. The sequences of human Fc regions are available at the IMGT website.
• antibody means an immunoglobulin molecule that recognizes and specifically binds to a target, such as a protein, polypeptide, peptide, carbohydrate, polynucleotide, lipid, or combinations of the foregoing through at least one antigen recognition site within the variable region of the immunoglobulin molecule.
• antibody encompasses polyclonal antibodies, monoclonal antibodies, antibody fragments (such as Fab, Fab', F(ab')2, and Fv fragments), single chain Fv (scFv) mutants, multispecific antibodies such as bispecific antibodies for example generated from at least two intact antibodies, chimeric antibodies, humanized antibodies, human antibodies, fusion proteins comprising an antigen determination portion of an antibody, and any other modified immunoglobulin molecule comprising an antigen recognition site.
• antibody fragments such as Fab, Fab', F(ab')2, and Fv fragments
• scFv single chain Fv mutants
• multispecific antibodies such as bispecific antibodies for example generated from at least two intact antibodies, chimeric antibodies, humanized antibodies, human antibodies, fusion proteins comprising an antigen determination portion of an antibody, and any other modified immunoglobulin molecule comprising an antigen recognition site.
• the antibodies can be of any isotype (e.g., IgG, IgE, IgM, IgD, IgA and IgY), class (e.g., lgG1 , lgG2, lgG3, lgG4, lgA1 and lgA2) or subclass. Both the light and heavy chains are divided into regions of structural and functional homology.
• the different classes of immunoglobulins have different and well- known subunit structures and three-dimensional configurations.
• Antibodies can be naked or conjugated to other molecules such as toxins, radioisotopes, etc., either directly or through one or more linkers.
• anti-CD19 antibody or "an antibody that binds to CD19” refers to an antibody that is capable of binding CD19 with sufficient affinity such that the antibody is useful as a diagnostic and/or therapeutic agent in targeting CD19.
• a “monoclonal antibody” refers to a homogeneous or substantially homogeneous antibody population involved in the highly specific recognition and binding of a single antigenic determinant, or epitope. This is in contrast to polyclonal antibodies that typically include different antibodies directed against different antigenic determinants.
• the term “monoclonal antibody” encompasses both intact and full-length monoclonal antibodies as well as antibody fragments (such as Fab, Fab', F(ab')2, Fv), single chain (scFv) mutants, fusion proteins comprising an antibody portion, and any other modified immunoglobulin molecule comprising an antigen recognition site.
• “monoclonal antibody” refers to such antibodies made in any number of manners including but not limited to by hybridoma, phage selection, recombinant expression, and transgenic animals.
• chimeric antibodies refers to antibodies wherein the amino acid sequence of the immunoglobulin molecule is derived from two or more species.
• the variable region of both light and heavy chains corresponds to the variable region of antibodies derived from one species of mammals (e.g., mouse, rat, rabbit, etc.) with the desired specificity, affinity, and capability while the constant regions are homologous to the sequences in antibodies derived from another (usually human) to avoid eliciting an immune response in that species.
• administering includes but is not limited to delivery by an injectable form, such as, for example, an intravenous, intramuscular, intradermal or subcutaneous route, or by a mucosal route, for example, as a nasal spray or aerosol for inhalation or as an ingestable solution, capsule or tablet.
• an injectable form such as, for example, an intravenous, intramuscular, intradermal or subcutaneous route, or by a mucosal route, for example, as a nasal spray or aerosol for inhalation or as an ingestable solution, capsule or tablet.
• CD19 is broadly and homogeneously expressed across different B-cell derived blood cancers. CD19 is able to enhance B-cell receptor signaling, which is important for B-cell survival, and is therefore a therapeutic target for drugs aimed at treating B cell-related lymphomas and leukemias.
• Antibodies such as tafasitamab, can be made, for example, by preparing and expressing synthetic genes that encode the recited amino acid sequences or by mutating human germline genes to provide a gene that encodes the recited amino acid sequences. Moreover, this antibody and other anti-CD19 antibodies can be obtained, e.g., using one or more of the following methods.
• Humanized antibodies can be generated by replacing sequences of the Fv variable region that are not directly involved in antigen binding with equivalent sequences from human Fv variable regions.
• General methods for generating humanized antibodies are provided by Morrison, S. L., Science, 229:1202-1207 (1985), by Oi et al., BioTechniques, 4:214 (1986), and by US 5,585,089; US 5,693,761 ; US 5,693,762; US 5,859,205; and US 6,407,213. Those methods include isolating, manipulating, and expressing the nucleic acid sequences that encode all or part of immunoglobulin Fv variable regions from at least one of a heavy or light chain.
• Sources of such nucleic acid are well known to those skilled in the art and, for example, may be obtained from a hybridoma producing an antibody against a predetermined target, as described above, from germline immunoglobulin genes, or from synthetic constructs.
• the recombinant DNA encoding the humanized antibody can then be cloned into an appropriate expression vector.
• sequences can be used as a source of human sequence, e.g., for framework regions and CDRs. Consensus human framework regions can also be used, e.g., as described in U.S. Pat. No. 6,300,064. Other methods for humanizing antibodies can also be used. For example, other methods can account for the three dimensional structure of the antibody, framework positions that are in three dimensional proximity to binding determinants, and immunogenic peptide sequences. See, e.g., WO 90/07861 ; U.S. Pat. Nos. 5,693,762; 5,693,761 ; 5,585,089; 5,530,101 ; and 6,407,213; Tempest et al. (1991) 1 Biotechnology 9:266-271. Still another method is termed “humaneering” and is described, for example, in U.S. 2005-008625.
• the antibody can include a human Fc region, e.g., a wild-type Fc region or an Fc region that includes one or more alterations.
• the constant region is altered, e.g., a human lgG1 constant region is mutated to include the S239D and/or I332E substitutions.
• Antibodies may also have mutations that stabilize the disulfide bond between the two heavy chains of an immunoglobulin, such as mutations in the hinge region of I gG4, as disclosed in the art (e.g., Angal et al. (1993) Mol. Immunol. 30:105-08). See also, e.g., U.S. 2005-0037000.
• the anti-CD19 antibodies can be in the form of full length antibodies, or in the form of low molecular weight forms (e.g., biologically active antibody fragments or minibodies) of the anti- CD19 antibodies, e.g., Fab, Fab’, F(ab’)2, Fv, Fd, dAb, scFv, and sc(Fv)2.
• Other anti-CD19 antibodies encompassed by this disclosure include single domain antibody (sdAb) containing a single variable chain such as, VH or VL, or a biologically active fragment thereof. See, e.g., Moller et al., J. Biol.
• sdAb is able to bind selectively to a specific antigen.
• sdAbs are much smaller than common antibodies and even smaller than Fab fragments and single-chain variable fragments.
• compositions comprising a mixture of an anti-CD19 antibody or antigen-binding fragment thereof and one or more acidic variants thereof, e.g., wherein the amount of acidic variant(s) is less than about 80%, 70%, 60%, 60%, 50%, 40%, 30%, 30%, 20%, 30 10%, 5% or 1 %.
• compositions comprising an anti-CD19 antibody or antigen binding fragment thereof comprising at least one deamidation site, wherein the pH of the composition is from about 5.0 to about 6.5, such that, e.g., at least about 90% of the anti-CD19 antibodies are not deamidated (i.e., less than about 10% of the antibodies are deamidated).
• the pH may be from 5.0 to 6.0, such as 5.5 or 6.0. In certain embodiments, the pH of the composition is 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1 , 6.2, 6.3, 6.4 or 6.5.
• an “acidic variant” is a variant of a polypeptide of interest which is more acidic (e.g., as determined by cation exchange chromatography) than the polypeptide of interest.
• An example of an acidic variant is a deamidated variant.
• a "deamidated” variant of a polypeptide molecule is a polypeptide wherein one or more asparagine residue(s) of the original polypeptide have been converted to aspartate, i.e., the neutral amide side chain has been converted to a residue with an overall acidic character.
• composition as used herein in reference to a composition comprising an antiCD19 antibody or antigen-binding fragment thereof, means the presence of both the desired antiCDI 9 antibody or antigen-binding fragment thereof and one or more acidic variants thereof.
• the acidic variants may comprise predominantly deamidated anti-CD19 antibody, with minor amounts of other acidic variant(s).
• the binding affinity (KD), on-rate (KD on) and/or off-rate (KD off) of the antibody that was mutated to eliminate deamidation is similar to that of the wild-type antibody, e.g., having a difference of less than about 5 fold, 2 fold, 1 fold (100%), 50%, 30%, 20%, 10%, 5%, 3%, 2% or 1%.
• an anti-CD19 antibody or antigen-binding fragment thereof described herein is present in a bispecific antibody.
• Exemplary bispecific antibodies may bind to two different epitopes of the CD19 protein. Other such antibodies may combine a CD19 binding site with a binding site for another protein.
• Bispecific antibodies can be prepared as full length antibodies or low molecular weight forms thereof (e.g., F(ab') 2 bispecific antibodies, sc(Fv)2 bispecific antibodies, diabody bispecific antibodies).
• the interface between a pair of antibody molecules can be engineered to maximize the percentage of heterodimers that are recovered from recombinant cell culture.
• the preferred interface comprises at least a part of the CH3 domain.
• one or more small amino acid side chains from the interface of the first antibody molecule are replaced with larger side chains (e.g., tyrosine or tryptophan).
• human embryonic kidney 293 cells e.g., 293, 293E, 293T
• COS cells e.g., NIH3T3 cells
• lymphocytic cell lines e.g., NS0 myeloma cells and SP2 cells
• a cell from a transgenic animal e.g., a transgenic mammal.
• the cell is a mammary epithelial cell.
• the study will enroll approximately 51 patients with histologically confirmed diagnosis of R/R DLBCL (as specified in inclusion criterion 3) based on the local pathology report.
• lymphoma Any other histological type of lymphoma including primary mediastinal (thymic) large B-cell (PMBL) or Burkitt lymphoma
• PMBL primary mediastinal
• Burkitt lymphoma b.
• Primary refractory DLBCL see Appendix 3: Study Specific Definitions for definition
• Known "double/triple hit" genetics high grade B-cell lymphoma characterized by simultaneous detection of MYC with BCL2 and/or BCL6 translocation(s) defined by fluorescence in situ hybridization. MYC, BCL2, BCL6 testing prior to study enrollment is not required
• a Primary analysis will be performed when all enrolled patients have either completed C3D28 or discontinued the study prior to C3D28 for any reason. Final analysis will be performed at the end of the study.
• End of Study The end of the study is defined as the date when the last patient has completed last visit (approximately 3 years after the last patient received the first study treatment).
• Start of a clinical study means the first act of recruitment of a potential subject for a specific clinical study, unless defined differently in the protocol.
• Live vaccines must not be administered to patients in this study. Killed, inactivated vaccines, such as an injectable annual influenza vaccine, are permitted. Investigators should follow institutional guidelines concerning infection chemoprophylaxis for patients regarded to be at high risk for infection.
• Appendix 8 Hepatitis Virus Serology
• HBV surface antigen negative, HBV surface antibody positive and/or HBV core antibody positive and detectable viral DNA are eligible.
• HBV-DNA becomes detectable during treatment, patients should be prophylactically treated and followed-up for potential hepatitis B reactivation as per local medical practice or institutional guidelines for CD20 antibodies such as RTX. If the HBV-DNA assay is positive, then patients can only stay in the study if they are assessed by a physician experienced in the treatment of hepatitis B and pre-emptive treatment is initiated, if deemed appropriate, and/or according to local practice/guidelines.
• Hepatitis C serology is to be done at screening only.
• Hepatitis C biomarkers include anti- HCV antibody.
• HCV-RNA For patients who are positive for anti-HCV antibody, HCV-RNA should be measured.

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