Treatment paradigms for anti-CD19 antibody therapy

Abstract

The present disclosure provides anti-CD19 antibodies for use in treating various cancers. The anti-CD19 antibodies are administered to cancer patients at specific doses or dosing regimens.

Description

[Technical field]

[0001] The present disclosure provides therapies comprising anti-CD19 antibodies for use in the treatment of various cancers. [Background technology]

[0002] B cells are lymphocytes that play a major role in the humoral immune response. They are produced in the bone marrow of most mammals and represent 5-15% of the circulating lymphocyte pool. The primary function of B cells is to make antibodies against various antigens and are an essential component of the adaptive immune system. Due to their important role in regulating the immune system, dysregulation of B cells has been linked to various disorders, including cancer. These include lymphomas and leukemias, such as non-Hodgkin's lymphoma (NHL), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), and acute lymphoblastic leukemia (ALL).

[0003] NHL is a heterogeneous malignancy arising from lymphocytes. While the disease can occur at any age, onset usually begins in adults over 40 years of age, with incidence rates increasing with age. NHL is characterized by clonal proliferation of lymphocytes that accumulate in 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 divides NHL into precursor and mature B-cell or T-cell neoplasms. Physician's Data Query currently classifies NHL as indolent or aggressive for purposes of clinical trial participation. The indolent NHL group is primarily composed of follicular subtype, small lymphocytic lymphoma, MALT (mucosa-associated lymphoid tissue), and marginal zone; indolent comprises approximately 50% of newly diagnosed B-cell NHL patients. Aggressive NHL primarily includes patients with a histologic diagnosis of diffuse large B-cell carcinoma (DLBL, DLBCL, or DLCL; 40% of all newly diagnosed patients have the diffuse large cell subtype), Burkitt lymphoma, and mantle cell lymphoma.

[0004] In addition to NHL, there are several types of leukemia that result from dysregulation of B cells.

[0005] Chronic lymphocytic leukemia (also known as "chronic lymphocytic leukemia" or "CLL") is a type of adult leukemia caused by an abnormal accumulation of B lymphocytes. In CLL, the malignant lymphocytes may appear normal and mature, but they are unable to respond efficiently to infections. CLL is the most common form of leukemia in adults. Men are twice as likely as women to develop CLL; however, the major risk factor is age. Although CLL is an incurable disease, it progresses slowly in most cases. Many people with CLL lead normal, active lives for many years. Because of its slow onset, early CLL intervention is not thought to improve survival or quality of life, so early CLL is generally not treated. Instead, the condition is monitored over time. Treatment of early CLL depends on the exact diagnosis and how advanced the disease is. Dozens of drugs are used in CLL therapy. Combination chemotherapy regimens such as FCR (Fludarabine, cyclophosphamide, and rituximab) and BR (Ibrutinib and rituximab) are effective for both newly diagnosed and relapsed CLL. Allogeneic bone marrow (stem cell) transplantation is rarely used as a first-line treatment for CLL due to its risks.

[0006] Another type of leukemia is small lymphocytic lymphoma (SLL), which does not have the clonal lymphocytosis required for the diagnosis of CLL but is otherwise considered a CLL variant that shares pathological and immunophenotypic features (Campo et al., 2011). The definition of SLL requires the presence of lymphadenopathy and / or splenomegaly. In addition, the number of peripheral blood B lymphocytes must be greater than or equal to 5x10 9 / L. In SLL, the diagnosis should be confirmed by histopathological evaluation of lymph node biopsy whenever possible (Hallek et al., 2008).

[0007] Another type of leukemia, acute lymphoblastic leukemia, is characterized by the overproduction and continuous proliferation 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 between 4 and 5 years of age.

[0008] 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, early developing B cells (i.e., immature B cells), mature B cells upon terminal differentiation into plasma cells, and malignant B cells. CD19 is expressed in 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 leukemia, common acute lymphocytic leukemias, and some null-acute lymphoblastic leukemias (Nadler et al, J. Immunol., 131:244-250 (1983), Loken et al, Blood, 70:1316-1324 (1987), Uckun et al, Blood, 71:13- 29 (1988), Anderson et al. al, 1984. Blood, 63:1424-1433 (1984); Scheuermann, Leuk. Lymphoma, 18:385-397 (1995)). Expression of CD19 on plasma cells further suggests that CD19 may be expressed on differentiated B-cell tumors such as multiple myeloma, plasma cell neoplasms, and Waldenstrom's tumors (Grossbard et al., Br. J. Haematol, 102:509-15 (1998); Treon et al, Semin. Oncol, 30:248-52 (2003)). Thus, the CD19 antigen is an immunotherapeutic target in the treatment of a variety of cancers, including each of the subtypes described herein, such as non-Hodgkin's lymphoma (NHL), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), and / or acute lymphoblastic leukemia.

[0009] Tafasitamab (formerly MOR208 and XmAb® 5574) is a humanized monoclonal antibody that targets the antigen CD19. Tafasitamab has been engineered in the IgG Fc region to enhance antibody-dependent cell-mediated cytotoxicity (ADCC), thereby improving a key mechanism for tumor cell killing and potentially enhancing efficacy compared to conventional, i.e., non-enhanced, antibodies. Tafasitamab has been or is currently being studied in several clinical trials, including CLL, ALL, and NHL. Based on the L-MIND trial, tafasitamab was approved in July 2020 by the U.S. Food and Drug Administration (FDA) for accelerated use in combination with lenalidomide to treat adults with R / R DLBCL. The recommended dose of tafasitamab is 12 mg / kg, administered as an intravenous (iv) infusion.

[0010] Despite the recent discovery and development of several anti-cancer drugs, due to the poor prognosis of many types of cancer, including CD19-expressing tumors, there remains a need for improved methods or therapeutic approaches to treat such types of cancer. Summary of the Invention

[0011] The need to optimize the dosing regimen of tafasitamab was identified to reduce the frequency of hospital / clinic visits for patients treated with tafasitamab. Reducing the overall frequency of clinic visits by half is expected to reduce patient burden and aid long-term treatment compliance. Furthermore, given the severity of the disease, reducing hospital visits may result in less exposure to hospital-acquired infections in an already susceptible population.

[0012] The present disclosure provides a treatment paradigm for a therapy involving an anti-CD19 antibody, where the anti-CD19 antibody is administered at a dose of at least 24 mg / kg.

[0013] In one aspect, the disclosure relates to an anti-CD19 antibody for use in the treatment of cancer, wherein the anti-CD19 antibody is administered at a dose of at least 24 mg / kg.

[0014] In one aspect, the disclosure relates to a method of treating cancer comprising administering an anti-CD19 antibody to a human subject in need of cancer treatment, wherein the anti-CD19 antibody is administered at a dose of at least 24 mg / kg.

[0015] In one aspect, the disclosure relates to an anti-CD19 antibody for use in the treatment of cancer, wherein the anti-CD19 antibody is administered at a dose of at least 24 mg / kg, and such dosing reduces the dosing frequency from once per week to at least once every two weeks. In one embodiment, the dosing frequency is reduced to once per two weeks. In one embodiment, the dosing frequency is reduced to once per four weeks. In one embodiment, the dosing frequency is reduced to once per five weeks. In one embodiment, the dosing frequency is reduced to once per six weeks. In one embodiment, the dosing frequency is reduced to once per seven weeks. In one embodiment, the dosing frequency is reduced to once per eight weeks.

[0016] In one aspect, the disclosure relates to an anti-CD19 antibody for use in the treatment of cancer, wherein the anti-CD19 antibody is administered at a dose of at least 24 mg / kg, with such dosing reducing the dosing frequency from once per week to once every four weeks.

[0017] In one aspect, the disclosure relates to an anti-CD19 antibody for use in the treatment of cancer, wherein the anti-CD19 antibody is administered at a dose of at least 24 mg / kg, and such dosing reduces the dosing frequency from once every two weeks to once every four weeks.

[0018] In one aspect, the disclosure relates to an anti-CD19 antibody for use in the treatment of cancer, wherein the anti-CD19 antibody is administered at a dose of at least 24 mg / kg, with such dosing decreasing the dosing frequency from once a week (QW) to once every two weeks (Q2W) starting on day 15 of cycle 1 (C1D15), and from Q2W to once every four weeks (Q4W) starting on day 1 of cycle 4.

[0019] In one aspect, the disclosure relates to an anti-CD19 antibody for use in the treatment of cancer, wherein the anti-CD19 antibody is administered at a dose of at least 24 mg / kg, where such dosing reduces the infusion dosing regimen by 20%, 30%, 40%, 50%, 60%, 70% or more compared to administering such anti-CD19 antibody at a dose of 12 mg / kg.

[0020] In one aspect, the disclosure relates to a method of reducing the dosing frequency of an anti-CD19 antibody in the treatment of cancer, wherein the anti-CD19 antibody is administered at a dose of at least 24 mg / kg.

[0021] In one aspect, the disclosure relates to a method of reducing the dosing frequency of an anti-CD19 antibody in the treatment of cancer, wherein the anti-CD19 antibody is administered at a dose of at least 24 mg / kg, and such dosing reduces the dosing frequency from once per week to at least once every two weeks. In one embodiment, the dosing frequency is reduced to once per two weeks. In one embodiment, the dosing frequency is reduced to once per four weeks. In one embodiment, the dosing frequency is reduced to once per five weeks. In one embodiment, the dosing frequency is reduced to once per six weeks. In one embodiment, the dosing frequency is reduced to once per seven weeks. In one embodiment, the dosing frequency is reduced to once per eight weeks.

[0022] In one aspect, the disclosure relates to a method of reducing the dosing frequency of an anti-CD19 antibody in the treatment of cancer, wherein the anti-CD19 antibody is administered at a dose of at least 24 mg / kg, and such dosing reduces the dosing frequency from once per week to once every four weeks.

[0023] In one aspect, the disclosure relates to a method of reducing the dosing frequency of an anti-CD19 antibody in the treatment of cancer, wherein the anti-CD19 antibody is administered at a dose of at least 24 mg / kg, and such dosing reduces the dosing frequency from once per week to once every two weeks to once every four weeks.

[0024] In one aspect, the disclosure relates to a method of reducing the dosing frequency of an anti-CD19 antibody in the treatment of cancer, wherein the anti-CD19 antibody is administered at a dose of at least 24 mg / kg, and such dosing reduces the dosing frequency from once a week (QW) to once every two weeks (Q2W) starting on day 15 of cycle 1 (C1D15), and from Q2W to once every four weeks (Q4W) starting on day 1 of cycle 4.

[0025] In one aspect, the disclosure relates to a method of reducing the dosing frequency of an anti-CD19 antibody in the treatment of cancer, wherein the anti-CD19 antibody is administered at a dose of at least 24 mg / kg, such dosing reducing the infusion dosing regimen by 20%, 30%, 40%, 50%, 60%, 70% or more compared to administering such anti-CD19 antibody at a dose of 12 mg / kg.

[0026] In one aspect, the disclosure relates to a method of reducing adverse effects of an anti-CD19 antibody for use in treating cancer at a dose of at least 24 mg / kg, where the anti-CD19 antibody is at a dose of 12 mg / kg before being increased to a dose of at least 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 doses, and after such first one, two, or three doses, the anti-CD19 antibody is administered at a dose of at least 24 mg / kg. In some embodiments, the anti-CD19 antibody is administered at a dose of at least 24 mg / kg once a week, once every two weeks, or once every four weeks.

[0027] In one aspect, the disclosure relates to a method of reducing adverse effects of an anti-CD19 antibody for use in treating cancer at a dose of at least 24 mg / kg, where the anti-CD19 antibody is administered at a dose of 12 mg / kg on days 1, 4, and 8 from the start of treatment, and from day 15 onwards, the anti-CD19 antibody is administered at a dose of at least 24 mg / kg. In some embodiments, the anti-CD19 antibody is administered at a dose of at least 24 mg / kg once a week, once every two weeks, or once every four weeks.

[0028] In some embodiments, the anti-CD19 antibody comprises a heavy chain variable region comprising an HCDR1 region comprising the sequence SYVMH (SEQ ID NO: 1), an HCDR2 region comprising the sequence NPYNDG (SEQ ID NO: 2), and an HCDR3 region comprising the sequence GTYYYGTRVFDY (SEQ ID NO: 3), and a light chain variable region comprising an LCDR1 region comprising the sequence RSSKSLQNVNGNTYLY (SEQ ID NO: 4), an LCDR2 region comprising the sequence RMSNLNS (SEQ ID NO: 5), and an LCDR3 region comprising the sequence MQHLEYPIT (SEQ ID NO: 6).

[0029] In some embodiments, the anti-CD19 antibody comprises a heavy chain variable region comprising an HCDR1 region of SYVMH (SEQ ID NO: 1), an HCDR2 region of NPYNDG (SEQ ID NO: 2), and an HCDR3 region of GTYYYGTRVFDY (SEQ ID NO: 3), and a light chain variable region comprising an LCDR1 region of RSSKSLQNVNGNTYLY (SEQ ID NO: 4), an LCDR2 region of RMSNLNS (SEQ ID NO: 5), and an LCDR3 region of MQHLEYPIT (SEQ ID NO: 6).

[0030] In some embodiments, the anti-CD19 antibody comprises a heavy chain variable region of EVQLVESGGGLVKPGGSLKLSCAASGYTFTSYVMHWVRQAPGKGLEWIGYINPYNDGTKYNEKFQGRVTISSDKSISTAYMELSSLRSEDTAMYYCARGTYYYGTRVFDYWGQGTLVTVSS (SEQ ID NO: 7) and a light chain variable region of DIVMTQSPATLSLSPGERATLSCRSSKSLQNVNGNTYLYWFQQKPGQSPQLLIYRMSNLNSGVPDRFSGSGSGTEFTLTISSLEPEDFAVYYCMQHLEYPITFGAGTKLEIK (SEQ ID NO: 8).

[0031] In some embodiments, the anti-CD19 antibody has an effector function. In another aspect, the CD19-specific antibody or antibody fragment has an enhanced effector function. In one embodiment, the effector function is ADCC. In one embodiment, the CD19-specific antibody or antibody fragment has enhanced ADCC activity. In a further embodiment, the CD19-specific antibody or antibody fragment comprises an Fc domain comprising an amino acid substitution at positions S239 and / or I332, where the numbering is according to the EU index as in Kabat. In a further embodiment, the CD19-specific antibody or antibody fragment comprises an Fc domain comprising an S239D amino acid substitution and an I332E amino acid substitution, where the numbering is according to the EU index as in Kabat.

[0032] In some embodiments, an anti-CD19 antibody comprises a heavy chain constant region of ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPDVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKALPAPEEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 9).

[0033] In some embodiments, the anti-CD19 antibody comprises a light chain constant region of RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 10).

[0034] In some embodiments, the anti-CD19 antibody is ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPDVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKALPAPEEKTISKTKGQP and a light chain constant region of RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 10).

[0035] In some embodiments, the anti-CD19 antibody is EVQLVESGGGLVKPGGSLKLSCAASGYTFTSYVMHWVRQAPGKGLEWIGYINPYNDGTKYNEKFQGRVTISSDKSISTAYMELSSLRSEDTAMYYCARGTYYYGTRVFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPDVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKALPAPEEKTIS and a light chain region of DIVMTQSPATLSLSPGERATLSCRSSKSLQNVNGNTYLYWFQQKPGQSPQLLIYRMSNLNSGVPDRFSGSGSGTEFTLTISSLEPEDFAVYYCMQHLEYPITFGAGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 12).

[0036] In some embodiments, the anti-CD19 antibody is tafasitamab.

[0037] In some embodiments, the anti-CD19 antibody is administered intravenously.

[0038] In some embodiments, the anti-CD19 antibody is administered by intravenous infusion.

[0039] In some embodiments, the anti-CD19 antibody is administered by subcutaneous injection.

[0040] In some embodiments, the anti-CD19 antibody is administered subcutaneously.

[0041] In some embodiments, the cancer is a CD19-positive cancer.

[0042] In some embodiments, the cancer is a hematological malignancy.

[0043] In some embodiments, the cancer is lymphoma or leukemia.

[0044] In some embodiments, the cancer is chronic lymphocytic leukemia or non-Hodgkin's lymphoma.

[0045] In some embodiments, the cancer is CD19-positive chronic lymphocytic leukemia or CD19-positive non-Hodgkin's lymphoma.

[0046] In some embodiments, the cancer is non-Hodgkin's lymphoma. In some embodiments, the human subject is afflicted with relapsed or refractory non-Hodgkin's lymphoma. In some embodiments, the human subject is afflicted with relapsed or refractory CD19-positive aggressive non-Hodgkin's lymphoma. In some embodiments, the human subject is afflicted with relapsed or refractory CD19-positive aggressive non-Hodgkin's lymphoma and has progressed on at least one previous treatment regimen. In some embodiments, the cancer is follicular lymphoma (FL), marginal zone lymphoma (MZL), mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), or Burkitt's lymphoma. In some embodiments, the human subject is afflicted with relapsed or refractory diffuse large B-cell lymphoma (r / r DLBCL).

[0047] In some embodiments, the anti-CD19 antibody is administered at a dose of at least 24 mg / kg, where the anti-CD19 antibody is administered as an intravenous infusion, hi some embodiments, the 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.

[0048] In some other embodiments, the intravenous infusion is administered within at least 1.5-2.5 hours, at least 2.5-3 hours, at least 2.5-3.5 hours, at least 3-4 hours, or at least 3.5-4.5 hours. In some other embodiments, the intravenous infusion is administered within 1.5-2.5 hours, 2 hours, 2.5-3 hours, 3 hours, 2.5-3.5 hours, 3-4 hours, or 3.5-4.5 hours. In some other embodiments, the intravenous infusion is administered at an infusion rate of at least 30 mL / h, at least 40 mL / h, at least 50 mL / h, at least 60 mL / h, or at least 70 mL / h. In some other embodiments, the intravenous infusion is administered initially at an infusion rate of 30 mL / h, 40 mL / h, 50 mL / h, 60 mL / h, or 70 mL / h for the first 30 minutes, and then increased thereafter.

[0049] In some embodiments, the anti-CD19 antibody is administered at a dose of at least 24 mg / kg, where the anti-CD19 antibody is administered as an intravenous infusion, and the 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, where the anti-CD19 antibody is administered as an intravenous infusion, and the 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, where the anti-CD19 antibody is administered as an intravenous infusion, and the intravenous infusion is administered within 2 hours.

[0050] In some embodiments, the anti-CD19 antibody is administered at a dose of at least 24 mg / kg, where the anti-CD19 antibody is administered as an intravenous infusion, and the 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, where the anti-CD19 antibody is administered as an intravenous infusion, and the 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, where the anti-CD19 antibody is administered as an intravenous infusion, and the intravenous infusion is administered within 3.5 to 4 hours. In some other embodiments, the anti-CD19 antibody is administered at a dose of at least 24 mg / kg, where the anti-CD19 antibody is administered as an intravenous infusion, and the intravenous infusion is administered within 3.5 to 4.5 hours. In some other embodiments, the anti-CD19 antibody is administered at a dose of at least 24 mg / kg, where the anti-CD19 antibody is administered as an intravenous infusion, and where the intravenous infusion is administered within 4 hours.

[0051] In some embodiments, the disclosure relates to a method of treating cancer in a human subject in need thereof, the method comprising administering to the human subject an anti-CD19 antibody, wherein the anti-CD19 antibody is administered at a dose of 12 mg before escalating to a dose of at least 24 mg / kg (e.g., 24 mg / kg or 30 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 after such first one, two, or three administrations, the anti-CD19 antibody is administered at a dose of at least 24 mg / kg (e.g., 24 mg / kg or 30 mg / kg). In some embodiments, the anti-CD19 antibody is administered at a dose of at least 24 mg / kg weekly, biweekly, or biweekly, or biweekly.

[0052] In some embodiments, the disclosure relates to a method of treating cancer in a human subject in need of such treatment, the method comprising administering to the human subject an anti-CD19 antibody, wherein the anti-CD19 antibody is administered at a dose of 12 mg / kg on days 1, 4, and 8 from the start of treatment, and from day 15 onwards, the anti-CD19 antibody is administered at a dose of at least 24 mg / kg. In some embodiments, the anti-CD19 antibody is administered at a dose of at least 24 mg / kg once a week, once every two weeks, or once every four weeks.

[0053] In some embodiments, the disclosure relates to a method of treating cancer in a human subject in need thereof, the method comprising administering to the human subject an anti-CD19 antibody, wherein the anti-CD19 antibody is administered as an intravenous infusion within 1.5 to 2.5 hours at a dose of 12 mg / kg before being increased to a dose of at least 24 mg / kg (e.g., 24 mg / kg or 30 mg / kg), and the increased dose of at least 24 mg / kg (e.g., 24 mg / kg or 30 mg / kg) is administered as an intravenous infusion within 3 to 4.5 hours. In some other embodiments, the increased dose of at least 24 mg / kg (e.g., 24 mg / kg or 30 mg / kg) is administered as an intravenous infusion within 3 to 4 hours. In some other embodiments, the increased dose of at least 24 mg / kg (e.g., 24 mg / kg or 30 mg / kg) is administered as an intravenous infusion within 3.5 to 4 hours. In some other embodiments, the increased dose of at least 24 mg / kg (e.g., 24 mg / kg or 30 mg / kg) is administered as an intravenous infusion within 3.5 to 4.5 hours. In some other embodiments, the increased dose of at least 24 mg / kg (e.g., 24 mg / kg or 30 mg / kg) is administered as an intravenous infusion within 4 hours.

[0054] In some embodiments, the anti-CD19 antibody is administered as an intravenous infusion at a dose of 12 mg / kg within 1.5 to 2.5 hours for the first one, two, or three doses, and after such first one, two, or three doses, the anti-CD19 antibody is administered at a dose of at least 24 mg / kg (e.g., 24 mg / kg or 30 mg / kg), with an increased dose of at least 24 mg / kg (e.g., 24 mg / kg or 30 mg / kg) administered as an intravenous infusion within 3 to 4.5 hours. In some other embodiments, an increased dose of at least 24 mg / kg (e.g., 24 mg / kg or 30 mg / kg) is administered as an intravenous infusion within 3 to 4 hours. In some other embodiments, an increased dose of at least 24 mg / kg (e.g., 24 mg / kg or 30 mg / kg) is administered as an intravenous infusion within 3.5 to 4 hours. In some other embodiments, an increased dose of at least 24 mg / kg (e.g., 24 mg / kg or 30 mg / kg) is administered as an intravenous infusion within 3.5 to 4.5 hours. In some other embodiments, an increased dose of at least 24 mg / kg (e.g., 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 24 mg / kg (e.g., 24 mg / kg or 30 mg / kg) once a week, once every two weeks, or once every four weeks.

[0055] In some embodiments, the disclosure relates to a method of treating cancer in a human subject in need thereof, the method comprising administering to the human subject an anti-CD19 antibody, wherein the anti-CD19 antibody is administered as an intravenous infusion within 1.5-2.5 hours at a dose of 12 mg / kg before being increased to a dose of at least 24 mg / kg (e.g., 24 mg / kg or 30 mg / kg), wherein the increased dose of at least 24 mg / kg (e.g., 24 mg / kg or 30 mg / kg) is administered as an intravenous infusion within 1.5-2.5 hours. In some other embodiments, the increased dose of at least 24 mg / kg (e.g., 24 mg / kg or 30 mg / kg) is administered as an intravenous infusion within 1.5-2 hours. In some other embodiments, the increased dose of at least 24 mg / kg (e.g., 24 mg / kg or 30 mg / kg) is administered as an intravenous infusion within 2 hours. In some other embodiments, the increased dose of at least 24 mg / kg (eg, 24 mg / kg or 30 mg / kg) is administered as an intravenous infusion within 2 hours.

[0056] In some embodiments, the anti-CD19 antibody is administered as an intravenous infusion at a dose of 12 mg / kg within 1.5 to 2.5 hours for the first one, two, or three doses, and after such first one, two, or three doses, the anti-CD19 antibody is administered at a dose of at least 24 mg / kg (e.g., 24 mg / kg or 30 mg / kg), with an increased dose of at least 24 mg / kg (e.g., 24 mg / kg or 30 mg / kg) administered as an intravenous infusion within 1.5 to 2.5 hours. In some other embodiments, the increased dose of at least 24 mg / kg (e.g., 24 mg / kg or 30 mg / kg) is administered as an intravenous infusion within 1.5 to 2 hours. In some other embodiments, the increased dose of at least 24 mg / kg (e.g., 24 mg / kg or 30 mg / kg) is administered as an intravenous infusion within 2 hours.

[0057] In some embodiments, the anti-CD19 antibody is administered as an intravenous infusion at a dose of 12 mg / kg within 1.5 to 2.5 hours for the first 1, 2, and 3 doses, and after such first 1, 2, and 3 doses, the anti-CD19 antibody is administered at a dose of at least 24 mg / kg (e.g., 24 mg / kg or 30 mg / kg), where for the first 1, 2, and 3 doses, an increased dose of at least 24 mg / kg (e.g., 24 mg / kg or 30 mg / kg) is administered as an intravenous infusion within 3 to 4.5 hours, and where for all subsequent doses, an increased dose of at least 24 mg / kg (e.g., 24 mg / kg or 30 mg / kg) is administered as an intravenous infusion within 1.5 to 2 hours.

[0058] In some embodiments, the anti-CD19 antibody is administered as an intravenous infusion at a dose of 12 mg / kg within 2 hours for the first 1, 2, and 3 doses, and after such first 1, 2, and 3 doses, the anti-CD19 antibody is administered at a dose of at least 24 mg / kg (e.g., 24 mg / kg or 30 mg / kg), where for the first 1, 2, and 3 doses, an increased dose of at least 24 mg / kg (e.g., 24 mg / kg or 30 mg / kg) is administered as an intravenous infusion within 4 hours, and where for all subsequent doses, an increased dose of at least 24 mg / kg (e.g., 24 mg / kg or 30 mg / kg) is administered as an intravenous infusion within 2 hours.

[0059] In some embodiments, the disclosure relates to a method of treating cancer in a human subject in need of such treatment, the method comprising administering to the human subject an anti-CD19 antibody, wherein the anti-CD19 antibody is administered as an intravenous infusion according to the following schedule: On days 1, 4, and 8 of the first 28-day treatment cycle, anti-CD19 antibody is administered at a dose of 12 mg / kg within 1.5 to 2.5 hours; On day 15 of the first 28-day treatment cycle, and days 1 and 15 of the second and any subsequent 28-day treatment cycles, the anti-CD19 antibody is administered within 3 to 4.5 hours at a dose of at least 24 mg / kg (e.g., 24 mg / kg or 30 mg / kg).

[0060] In some embodiments, the disclosure relates to a method of treating cancer in a human subject in need of such treatment, the method comprising administering to the human subject an anti-CD19 antibody, wherein the anti-CD19 antibody is administered as an intravenous infusion according to the following schedule: On days 1, 4, and 8 of the first 28-day treatment cycle, anti-CD19 antibody is administered at a dose of 12 mg / kg within 1.5 to 2.5 hours; On day 15 of the first 28-day treatment cycle, and days 1 and 15 of the second and any subsequent 28-day treatment cycle, the anti-CD19 antibody is administered within 4 hours at a dose of at least 24 mg / kg (e.g., 24 mg / kg or 30 mg / kg).

[0061] In some embodiments, the disclosure relates to a method of treating cancer in a human subject in need of such treatment, the method comprising administering to the human subject an anti-CD19 antibody, wherein the anti-CD19 antibody is administered as an intravenous infusion according to the following schedule: On days 1, 4, and 8 of the first 28-day treatment cycle, anti-CD19 antibody is administered at a dose of 12 mg / kg within 1.5 to 2.5 hours; On day 15 of the first 28 day treatment cycle, and days 1 and 15 of the second and any subsequent 28 day treatment cycles, the anti-CD19 antibody is administered within 1.5 to 2.5 hours at a dose of at least 24 mg / kg (e.g., 24 mg / kg or 30 mg / kg).

[0062] In some embodiments, the disclosure relates to a method of treating cancer in a human subject in need of such treatment, the method comprising administering to the human subject an anti-CD19 antibody, wherein the anti-CD19 antibody is administered as an intravenous infusion according to the following schedule: On days 1, 4, and 8 of the first 28-day treatment cycle, anti-CD19 antibody is administered at a dose of 12 mg / kg within 1.5 to 2.5 hours; On day 15 of the first 28 day treatment cycle, and days 1 and 15 of the second and any subsequent 28 day treatment cycles, the anti-CD19 antibody is administered at a dose of at least 24 mg / kg (e.g., 24 mg / kg or 30 mg / kg) within 2 to 2.5 hours or within 3 hours.

[0063] In some embodiments, the disclosure relates to a method of treating cancer in a human subject in need of such treatment, the method comprising administering to the human subject an anti-CD19 antibody, wherein the anti-CD19 antibody is administered as an intravenous infusion according to the following schedule: On days 1, 4, and 8 of the first 28-day treatment cycle, anti-CD19 antibody is administered at a dose of 12 mg / kg within 1.5 to 2.5 hours; On day 15 of the first 28-day treatment cycle, and days 1 and 15 of the second and any subsequent 28-day treatment cycle, the anti-CD19 antibody is administered within 2 hours at a dose of at least 24 mg / kg (e.g., 24 mg / kg or 30 mg / kg).

[0064] In some embodiments, the disclosure relates to a method of treating cancer in a human subject in need of such treatment, the method comprising administering to the human subject an anti-CD19 antibody, wherein the anti-CD19 antibody is administered as an intravenous infusion according to the following schedule: On days 1, 4, and 8 of the first 28-day treatment cycle, the anti-CD19 antibody is administered within 2 hours at a dose of 12 mg / kg; on day 15 of the first 28-day treatment cycle and days 1 and 15 of the second and third 28-day treatment cycles, the anti-CD19 antibody is administered within 4 hours at a dose of at least 24 mg / kg (e.g., 24 mg / kg or 30 mg / kg); and On day 1 of the fourth 28-day treatment cycle, and day 1 of any 28-day treatment cycle thereafter, the anti-CD19 antibody is administered within 2 hours at a dose of at least 24 mg / kg (e.g., 24 mg / kg or 30 mg / kg).

[0065] In some embodiments, the disclosure relates to a method of treating cancer in a human subject in need of such treatment, the method comprising administering to the human subject an anti-CD19 antibody, wherein the anti-CD19 antibody is administered as an intravenous infusion according to the following schedule: On days 1, 4, and 8 of the first 28-day treatment cycle, anti-CD19 antibody is administered at a dose of 12 mg / kg within 1.5 to 2.5 hours; On day 15 of the first 28-day treatment cycle and days 1 and 15 of the second and third 28-day treatment cycles, the anti-CD19 antibody is administered at a dose of at least 24 mg / kg (e.g., 24 mg / kg or 30 mg / kg) within 3 to 4.5 hours; and On day 1 of the fourth 28-day treatment cycle, and day 1 of any 28-day treatment cycle thereafter, the anti-CD19 antibody is administered within 1.5 to 2 hours at a dose of at least 24 mg / kg (e.g., 24 mg / kg or 30 mg / kg).

[0066] In some embodiments, the disclosure relates to a method of treating cancer in a human subject in need of such treatment, the method comprising administering to the human subject an anti-CD19 antibody, wherein the anti-CD19 antibody is administered as an intravenous infusion according to the following schedule: On days 1, 4, and 8 of the first 28-day treatment cycle, the anti-CD19 antibody is administered within 2 hours at a dose of 12 mg / kg; on day 15 of the first 28-day treatment cycle and days 1 and 15 of the second and third 28-day treatment cycles, the anti-CD19 antibody is administered within 4 hours at a dose of at least 24 mg / kg (e.g., 24 mg / kg or 30 mg / kg); and On day 1 of the fourth 28-day treatment cycle, and day 1 of any 28-day treatment cycle thereafter, the anti-CD19 antibody is administered within 2 hours at a dose of at least 24 mg / kg (e.g., 24 mg / kg or 30 mg / kg).

[0067] In some embodiments, the anti-CD19 antibody is administered at a dose of 12 mg / kg on days 1, 4, and 8 after initiation of treatment, and from day 15 onwards, the anti-CD19 antibody is administered as an intravenous infusion within 4 hours at a dose of at least 24 mg / kg (e.g., 24 mg / kg or 30 mg / kg). In some embodiments, the anti-CD19 antibody is administered weekly, every two weeks, or every four weeks at a dose ranging from 24 mg / kg to 30 mg / kg.

[0068] In some embodiments, the anti-CD19 antibody is administered at a dose of 12 mg / kg on days 1, 4, and 8 of treatment initiation, and from day 15 onwards, the anti-CD19 antibody is administered at a dose of at least 24 mg / kg (e.g., 24 mg / kg or 30 mg / kg) as an intravenous infusion within 1.5-2.5 hours, 1.5-2 hours, 2 hours, 2-2.5 hours, 2-3 hours, or 3 hours. In some embodiments, the anti-CD19 antibody is administered weekly, every two weeks, or every four weeks at a dose ranging from 24 mg / kg to 30 mg / kg.

[0069] In some embodiments, the anti-CD19 antibody is administered at a dose of at least 24 mg / kg, where the anti-CD19 antibody is administered as an intravenous infusion, where the intravenous infusion is administered within 1.5 to 2.5 hours, where the intravenous infusion is administered at an infusion rate of 70 mL / h for the first 30 minutes. In some other embodiments, the anti-CD19 antibody is administered at a dose of at least 24 mg / kg, where the anti-CD19 antibody is administered as an intravenous infusion, where the intravenous infusion is administered within 1.5 to 2 hours, where the intravenous infusion is administered at an infusion rate of 70 mL / h for the first 30 minutes. In some other embodiments, the anti-CD19 antibody is administered at a dose of at least 24 mg / kg, where the anti-CD19 antibody is administered as an intravenous infusion, where the intravenous infusion is administered within 2 hours, where the intravenous infusion is administered at an infusion rate of 70 mL / h for the first 30 minutes.

[0070] In some embodiments, the anti-CD19 antibody is administered at a dose of at least 24 mg / kg, where the anti-CD19 antibody is administered as an intravenous infusion, where the intravenous infusion is administered within 3-4.5 hours, where the intravenous infusion is administered at an infusion rate of at least 30 mL / h for the first 30 minutes. In some other embodiments, the anti-CD19 antibody is administered at a dose of at least 24 mg / kg, where the anti-CD19 antibody is administered as an intravenous infusion, where the intravenous infusion is administered within 3-4 hours, where the intravenous infusion is administered at an infusion rate of at least 30 mL / h for the first 30 minutes. In some other embodiments, the anti-CD19 antibody is administered at a dose of at least 24 mg / kg, where the anti-CD19 antibody is administered as an intravenous infusion, where the intravenous infusion is administered within 3.5-4 hours, where the intravenous infusion is administered at an infusion rate of at least 30 mL / h for the first 30 minutes. In some other embodiments, the anti-CD19 antibody is administered at a dose of at least 24 mg / kg, where the anti-CD19 antibody is administered as an intravenous infusion, and where the intravenous infusion is administered within 3.5 to 4.5 hours, and where the intravenous infusion is administered at an infusion rate of at least 30 mL / h for the first 30 minutes. In some other embodiments, the anti-CD19 antibody is administered at a dose of at least 24 mg / kg, where the anti-CD19 antibody is administered as an intravenous infusion, and where the intravenous infusion is administered within 4 hours, and where the intravenous infusion is administered at an infusion rate of at least 30 mL / h for the first 30 minutes.

[0071] In some embodiments, the anti-CD19 antibody is administered in multiple doses, including a first dose at a dose of at least 24 mg / kg and one or more subsequent doses, and each of the first dose and one or more subsequent doses of the anti-CD19 antibody is administered as an intravenous infusion, and the first intravenous infusion is administered within 1.5 to 2.5 hours at an infusion rate of 70 mL / hour for the first 30 minutes. In some other embodiments, the first intravenous infusion is administered within 1.5 to 2 hours at an infusion rate of 70 mL / hour for the first 30 minutes. In some other embodiments, the first intravenous infusion is administered within 2 hours at an infusion rate of 70 mL / hour for the first 30 minutes. In some embodiments, 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. In other embodiments, the anti-CD19 antibody is administered in multiple doses, including a first dose at a dose of at least 24 mg / kg and one or more subsequent doses, wherein each of the first dose and one or more subsequent doses of the anti-CD19 antibody are administered as an intravenous infusion, wherein the first intravenous infusion is administered within 1.5 to 2.5 hours, at an infusion rate of 70 mL / hour 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.

[0072] In some embodiments, the anti-CD19 antibody is administered in multiple doses, including a first dose at a dose of at least 24 mg / kg and one or more subsequent doses, each of the first dose and one or more subsequent doses of the anti-CD19 antibody being administered as an intravenous infusion, the first intravenous infusion being administered within 3-4.5 hours at an infusion rate of at least 30 mL / hour for the first 30 minutes. In some other embodiments, the first intravenous infusion is administered within 3-4 hours at an infusion rate of at least 30 mL / hour for the first 30 minutes. In some other embodiments, the first intravenous infusion is administered within 3.5-4 hours at an infusion rate of at least 30 mL / hour for the first 30 minutes. In some other embodiments, the first intravenous infusion is administered within 3.5-4.5 hours at an infusion rate of at least 30 mL / hour for the first 30 minutes. In some other embodiments, the first intravenous infusion is administered within 4 hours at an infusion rate of at least 30 mL / hour for the first 30 minutes. In some embodiments, 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.

[0073] In some embodiments, the anti-CD19 antibody is administered at a dose of at least 24 mg / kg or 30 mg / kg, where the anti-CD19 antibody is administered as an intravenous infusion, and the 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 (e.g., 24 mg / kg or 30 mg / kg), where the anti-CD19 antibody is administered as an intravenous infusion, and the 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 (e.g., 24 mg / kg or 30 mg / kg), where the anti-CD19 antibody is administered as an intravenous infusion, and the intravenous infusion is administered within 2 hours.

[0074] In some embodiments, the anti-CD19 antibody is administered at a dose of at least 24 mg / kg or 30 mg / kg, where the anti-CD19 antibody is administered as an intravenous infusion, and the 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 (e.g., 24 mg / kg or 30 mg / kg), where the anti-CD19 antibody is administered as an intravenous infusion, and the 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 (e.g., 24 mg / kg or 30 mg / kg), where the anti-CD19 antibody is administered as an intravenous infusion, and the intravenous infusion is administered within 3.5 to 4 hours. In some other embodiments, the anti-CD19 antibody is administered at a dose of at least 24 mg / kg (e.g., 24 mg / kg or 30 mg / kg), where the anti-CD19 antibody is administered as an intravenous infusion, and the intravenous infusion is administered within 3.5 to 4.5 hours. In some other embodiments, the anti-CD19 antibody is administered at a dose of at least 24 mg / kg (e.g., 24 mg / kg or 30 mg / kg), where the anti-CD19 antibody is administered as an intravenous infusion, and the intravenous infusion is administered within 4 hours.

[0075] In some embodiments, the anti-CD19 antibody is administered at a dose of 24 mg / kg or 30 mg / kg, where the anti-CD19 antibody is administered as an intravenous infusion, and the intravenous infusion is administered within 1.5 to 2.5 hours, and where the intravenous infusion is administered at an infusion rate of 70 mL / h for the first 30 minutes. In some other embodiments, the anti-CD19 antibody is administered at a dose of at least 24 mg / kg (e.g., 24 mg / kg or 30 mg / kg), where the anti-CD19 antibody is administered as an intravenous infusion, and the intravenous infusion is administered within 1.5 to 2 hours, and where the intravenous infusion is administered at an infusion rate of 70 mL / h for the first 30 minutes. In some other embodiments, the anti-CD19 antibody is administered at a dose of at least 24 mg / kg (e.g., 24 mg / kg or 30 mg / kg), where the anti-CD19 antibody is administered as an intravenous infusion, where the intravenous infusion is administered within 2 hours, where the intravenous infusion is administered at an infusion rate of 70 mL / h for the first 30 minutes.

[0076] In some embodiments, the anti-CD19 antibody is administered at a dose of 24 mg / kg or 30 mg / kg, where the anti-CD19 antibody is administered as an intravenous infusion, and the intravenous infusion is administered within 3 to 4.5 hours, and where the intravenous infusion is administered at an infusion rate of at least 30 mL / h for the first 30 minutes. In some other embodiments, the anti-CD19 antibody is administered at a dose of at least 24 mg / kg (e.g., 24 mg / kg or 30 mg / kg), where the anti-CD19 antibody is administered as an intravenous infusion, and the intravenous infusion is administered within 3 to 4 hours, and where the intravenous infusion is administered at an infusion rate of at least 30 mL / h for the first 30 minutes. In some other embodiments, the anti-CD19 antibody is administered at a dose of at least 24 mg / kg (e.g., 24 mg / kg or 30 mg / kg), where the anti-CD19 antibody is administered as an intravenous infusion, and the intravenous infusion is administered within 3.5 to 4 hours, and where the intravenous infusion is administered at an infusion rate of at least 30 mL / h for the first 30 minutes. In some other embodiments, the anti-CD19 antibody is administered at a dose of at least 24 mg / kg (e.g., 24 mg / kg or 30 mg / kg), where the anti-CD19 antibody is administered as an intravenous infusion, and the intravenous infusion is administered within 3.5 to 4.5 hours, and where the intravenous infusion is administered at an infusion rate of at least 30 mL / h for the first 30 minutes. In some other embodiments, the anti-CD19 antibody is administered at a dose of at least 24 mg / kg (e.g., 24 mg / kg or 30 mg / kg), where the anti-CD19 antibody is administered as an intravenous infusion, where the intravenous infusion is administered within 4 hours, where the intravenous infusion is administered at an infusion rate of at least 30 mL / h for the first 30 minutes.

[0077] In some embodiments, the anti-CD19 antibody is administered in multiple doses, including a first dose and one or more subsequent doses at a dose of at least 24 mg / kg, e.g., 24 mg / kg or 30 mg / kg, and each of the first dose and one or more subsequent doses of the anti-CD19 antibody are administered as an intravenous infusion, the first intravenous infusion being administered within 1.5 to 2.5 hours at an infusion rate of 70 mL / hour for the first 30 minutes. In some other embodiments, the first intravenous infusion is administered within 1.5 to 2 hours at an infusion rate of 70 mL / hour for the first 30 minutes. In some other embodiments, the first intravenous infusion is administered within 2 hours at an infusion rate of 70 mL / hour for the first 30 minutes. In some embodiments, 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. In other embodiments, the anti-CD19 antibody is administered in multiple doses, including a first dose and one or more subsequent doses at a dose of at least 24 mg / kg, e.g., 24 mg / kg or 30 mg / kg, wherein each of the first dose and one or more subsequent doses of the anti-CD19 antibody are administered as an intravenous infusion, the first intravenous infusion being administered within 1.5 to 2.5 hours, at an infusion rate of 70 mL / hour for the first 30 minutes, and the one or more subsequent intravenous infusions being administered within 1.5 to 2 hours or within 2 hours.

[0078] In some embodiments, the anti-CD19 antibody is administered in multiple doses, including a first dose and one or more subsequent doses at a dose of at least 24 mg / kg, e.g., 24 mg / kg or 30 mg / kg, and each of the first dose and one or more subsequent doses of the anti-CD19 antibody is administered as an intravenous infusion, the first intravenous infusion being administered within 3-4.5 hours at an infusion rate of at least 30 mL / hour for the first 30 minutes. In some other embodiments, the first intravenous infusion is administered within 3-4 hours at an infusion rate of at least 30 mL / hour for the first 30 minutes. In some other embodiments, the first intravenous infusion is administered within 3.5-4 hours at an infusion rate of at least 30 mL / hour for the first 30 minutes. In some other embodiments, the first intravenous infusion is administered within 3.5-4.5 hours at an infusion rate of at least 30 mL / hour for the first 30 minutes. In some other embodiments, the first intravenous infusion is administered within 4 hours, at an infusion rate of at least 30 mL / hour for the first 30 minutes, in some embodiments, one or more subsequent intravenous infusions are administered within 3-4.5 hours, 3-4 hours, 3.5-4 hours, 3.5-4.5 hours, or within 4 hours.

[0079] In some embodiments, the anti-CD19 antibody is administered on day 1 of the treatment cycle. In some embodiments, the treatment cycle is 28 days.

[0080] In some embodiments, the anti-CD19 antibody is administered at a dose of at least 24 mg / kg. In some embodiments, the anti-CD19 antibody is administered at a dose of at least 24 mg / kg once a week, once every two weeks, or once every four weeks.

[0081] In some embodiments, the anti-CD19 antibody is administered at a dose of at least 24 mg / kg, and the anti-CD19 antibody is administered at a dose of 12 mg / kg before escalating to a dose of at least 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 after such first one, two, or three administrations, the anti-CD19 antibody is administered at a dose of at least 24 mg / kg. In some embodiments, the anti-CD19 antibody is administered at a dose of at least 24 mg / kg once a week, once every two weeks, or once every four weeks.

[0082] In some embodiments, the anti-CD19 antibody is administered at a dose of 12 mg / kg on days 1, 4, and 8 after initiation of treatment, and from day 15 onwards, the anti-CD19 antibody is administered at a dose of at least 24 mg / kg. In some embodiments, the anti-CD19 antibody is administered at a dose of at least 24 mg / kg once a week, once every two weeks, or once every four weeks.

[0083] In some embodiments, the anti-CD19 antibody is administered in 28 day cycles, where a) a dose of 12 mg / kg is administered on days 1, 4, and 9 of the first cycle and a dose of at least 24 mg / kg is administered on day 15 of the first cycle; b) a dose of at least 24 mg / kg is administered on days 1 and 15 of cycles 2-3; and c) a dose of at least 24 mg / kg is administered on day 1 of each further subsequent cycle.

[0084] In some embodiments, the anti-CD19 antibody is administered at a dose ranging from 24 mg / kg to 30 mg / kg. In some embodiments, the anti-CD19 antibody is administered at a dose ranging from 24 mg / kg to 30 mg / kg. In some embodiments, the anti-CD19 antibody is administered at a dose ranging from 24 mg / kg to 30 mg / kg once a week, once every two weeks, or once every four weeks.

[0085] In some embodiments, the anti-CD19 antibody is administered at a dose ranging from 24 mg / kg to 30 mg / kg, where the anti-CD19 antibody is administered at a dose of 12 mg / kg before increasing the dose to the range of 24 mg / kg to 30 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 doses, where after such first one, two, or three doses, the anti-CD19 antibody is administered at a dose ranging from at least 24 mg / kg to 30 mg / kg. In some embodiments, the anti-CD19 antibody is administered at a dose ranging from 24 mg / kg to 30 mg / kg once a week, once every two weeks, or once every four weeks.

[0086] In some embodiments, the anti-CD19 antibody is administered at a dose of 12 mg / kg on days 1, 4, and 8 after the start of treatment, and from day 15 onwards, the anti-CD19 antibody is administered at a dose ranging from 24 mg / kg to 30 mg / kg. In some embodiments, the anti-CD19 antibody is administered at a dose ranging from 24 mg / kg to 30 mg / kg once a week, once every two weeks, or once every four weeks.

[0087] In some embodiments, the anti-CD19 antibody is administered in 28 day cycles, where a) a dose of 12 mg / kg is administered on days 1, 4, and 9 of the first cycle and a dose in the range of 24 mg / kg to 30 mg / kg is administered on day 15 of the first cycle; b) a dose in the range of 24 mg / kg to 30 mg / kg is administered on days 1 and 15 of cycles 2 to 3; and c) a dose in the range of 24 mg / kg to 30 mg / kg is administered on day 1 of further subsequent cycles.

[0088] In some embodiments, the anti-CD19 antibody is administered at a dose of 24 mg / kg. In some embodiments, the anti-CD19 antibody is administered at a dose of 24 mg / kg once every two weeks.

[0089] In some embodiments, the anti-CD19 antibody is administered at a dose of 24 mg / kg, and prior to escalation to the dose of 24 mg / kg, the anti-CD19 antibody is administered at a dose of 12 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 doses, and after such first one, two, or three doses, the anti-CD19 antibody is administered at a dose of 24 mg / kg. In some embodiments, the anti-CD19 antibody is administered at a dose of 24 mg / kg once a week, once every two weeks, or once every four weeks.

[0090] In some embodiments, the anti-CD19 antibody is administered at a dose of 12 mg / kg on days 1, 4, and 8 after the start of treatment, and from day 15 onwards, the anti-CD19 antibody is administered at a dose of 24 mg / kg. In some embodiments, the anti-CD19 antibody is administered at a dose of 24 mg / kg once a week, once every two weeks, or once every four weeks.

[0091] In some embodiments, the anti-CD19 antibody is administered in 28 day cycles, where a) a 12 mg / kg dose is administered on days 1, 4, and 9 of the first cycle and a 24 mg / kg dose is administered on day 15 of the first cycle; b) a 24 mg / kg dose is administered on days 1 and 15 of cycles 2-3; and c) a 24 mg / kg dose is administered on day 1 of each further subsequent cycle.

[0092] In some embodiments, the anti-CD19 antibody is administered at a dose of 30 mg / kg. In some embodiments, the anti-CD19 antibody is administered at a dose of 30 mg / kg once every two weeks.

[0093] In some embodiments, the anti-CD19 antibody is administered at a dose of 30 mg / kg, and prior to escalation to the dose of 30 mg / kg, the anti-CD19 antibody is administered at a dose of 12 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 doses, and after such first one, two, or three doses, the anti-CD19 antibody is administered at a dose of 30 mg / kg. In some embodiments, the anti-CD19 antibody is administered at a dose of 30 mg / kg once a week, once every two weeks, or once every four weeks.

[0094] In some embodiments, the anti-CD19 antibody is administered at a dose of 30 mg / kg, and the anti-CD19 antibody is administered at a dose of 12 mg / kg before increasing to a dose of 24 mg / kg and before increasing to a dose of 30 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 doses, and after such first one, two, or three doses, the anti-CD19 antibody is administered at a dose of 24 mg / kg, and after the dose of 24 mg / kg, the anti-CD19 antibody is administered at a dose of 30 mg / kg. In some embodiments, the anti-CD19 antibody is administered at a dose of 30 mg / kg once a week, once every two weeks, or once every four weeks.

[0095] In some embodiments, the anti-CD19 antibody is administered at a dose of 12 mg / kg on days 1, 4, and 8 after the start of treatment, and from day 15 onwards, the anti-CD19 antibody is administered at a dose of 30 mg / kg. In some embodiments, the anti-CD19 antibody is administered at a dose of 30 mg / kg once a week, once every two weeks, or once every four weeks.

[0096] In some embodiments, the anti-CD19 antibody is administered in 28 day cycles, where a) a 12 mg / kg dose is administered on days 1, 4, and 9 of the first cycle and a 30 mg / kg dose is administered on day 15 of the first cycle; b) a 30 mg / kg dose is administered on days 1 and 15 of cycles 2-3; and c) a 30 mg / kg dose is administered on day 1 of each further subsequent cycle.

[0097] In some embodiments, the anti-CD19 antibody is administered in combination with lenalidomide. In certain embodiments, lenalidomide is administered orally. In certain embodiments, lenalidomide is administered daily on days 1-21 of a repeated 28-day cycle. In certain embodiments, lenalidomide is administered daily on days 1-21 of up to 12 repeated 28-day cycles. In certain embodiments, the dose of lenalidomide is at least 20 mg per day. In certain embodiments, the dose of lenalidomide is 25 mg per day.

[0098] In some embodiments, the anti-CD19 antibody is administered in combination with lenalidomide, which is administered orally at a dose of 25 mg on days 1-21 of a repeated 28 day cycle. In some embodiments, the anti-CD19 antibody is administered in combination with lenalidomide, which is administered orally at a dose of 25 mg daily on days 1-21 of 12 repeated 28 day cycles. [Brief description of the drawings]

[0099] [Figure 1] Box plots of model-predicted PK parameters based on 2000 randomly generated patients dosed according to the L-MIND, 12 / 24 mg / kg (cohort 1) and 12 / 30 mg / kg (cohort 2) dosing regimens are shown. [Diagram 2] Box plots of model-predicted PK parameters based on 2000 randomly generated patients dosed according to the L-MIND, 12 / 24 mg / kg (cohort 1) and 12 / 30 mg / kg (cohort 2) dosing regimens are shown. [Diagram 3] 13. Overlay of model-predicted median concentration-time profiles for tafasitamab administered according to the LMIND and 12 / 30 mg / kg dosing regimens. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0100] The term "CD19" refers to the protein known as CD19, which has 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. The term also encompasses naturally occurring variants of CD19, such as splice variants, allelic variants, and isoforms.

[0101] In one embodiment, the human CD19 has the following amino acid sequence: .(SEQ ID NO:13)

[0102] "MOR208" and "XmAb5574" and "tafasitamab" are used as synonyms for anti-CD19 antibodies according to Table 1. Table 1 shows the amino acid sequence of MOR208 / tafasitamab. The MOR208 antibody is described in U.S. Pat. No. 8,524,867, which is incorporated by reference in its entirety (in U.S. Pat. No. 8,524,867, the complete heavy chain of MOR208 is SEQ ID NO: 87 and the complete light chain of MOR208 is SEQ ID NO: 106).

[0103] "Fc region" means the constant region of an antibody, which in humans can be of IgG1, 2, 3, 4 subclass or other. Human Fc region sequences are available on the IMGT website.

[0104] The term "antibody" refers to an immunoglobulin molecule that recognizes and binds to a target, such as a protein, polypeptide, peptide, carbohydrate, polynucleotide, lipid, or a combination thereof, through at least one antigen recognition site in the variable region of the immunoglobulin molecule. As used herein, the term "antibody" includes polyclonal antibodies, monoclonal antibodies, antibody fragments (e.g., Fab, Fab, F(ab')2, and Fv fragments), single-chain Fv (scFv) variants, multispecific antibodies, such as bispecific antibodies generated from at least two intact antibodies, chimeric antibodies, humanized antibodies, human antibodies, fusion proteins containing an antigenic determinant of an antibody, and any other modified immunoglobulin molecule containing an antigen recognition site. Antibodies can be of any isotype (e.g., IgG, IgE, IgM, IgD, IgA, and IgY), class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2), and subclasses thereof. Both the light and heavy chains are divided into regions of structural and functional homology. Different classes of immunoglobulins have different and well-known subunit structures and three-dimensional configurations. Antibodies can be naked or conjugated, either directly or through one or more linkers, to other molecules such as toxins, radioisotopes, etc.

[0105] The term "anti-CD19 antibody" or "antibody that binds to CD19" refers to an antibody that is capable of binding to CD19 with sufficient affinity such that the antibody is useful as a diagnostic and / or therapeutic agent in targeting CD19.

[0106] A "monoclonal antibody" refers to a homogeneous or substantially homogeneous antibody population involved in highly specific recognition and binding of a single antigenic determinant or epitope. This is in contrast to polyclonal antibodies, which usually contain different antibodies against different antigenic determinants. The term "monoclonal" antibody encompasses intact and full-length monoclonal antibodies, as well as antibody fragments (e.g., Fab, Fab', F(ab')2, Fv), single-chain (scFv) variants, fusion proteins containing an antibody portion, and any other immunoglobulin molecule that contains an antigen recognition site. Furthermore, "monoclonal antibody" refers to antibodies produced in any number of ways, including, but not limited to, by hybridoma, phage selection, recombinant expression, and transgenic animals.

[0107] The term "chimeric" antibody refers to an antibody in which the amino acid sequences of the immunoglobulin molecule are derived from more than one species. Usually, the variable regions of both the light and heavy chains correspond to the variable regions of antibodies from one species of mammal (e.g., mouse, rat, rabbit, etc.) having the desired specificity, affinity, and function, and the constant regions are homologous to the sequences of antibodies from another species (usually human) to avoid eliciting an immune response in that species.

[0108] As used herein, the term "effective amount" or "therapeutically effective amount" refers to an amount of a compound or a combination of one or more compounds that, when administered (sequentially or simultaneously), induces a desired biological or pharmaceutical response, e.g., destroys, delays, or stops the growth of a target cancer cell, delays or stops the progression of cancer in a patient, and / or delays, eliminates, reduces, or otherwise improves one or more symptoms of cancer in a patient. The therapeutically effective amount may vary depending on the intended application or the patient and disease state to be treated, and may depend on factors such as, for example, the patient's weight and age, the severity of the disease state, the method of administration, and the like, which can be readily determined by one of ordinary skill in the art. The term "effective amount" or "therapeutically effective amount" also applies to an amount, such as one or more doses, that induces a particular response in a target cell, e.g., reduced platelet adhesion and / or cell migration.

[0109] "Administered" or "administration" includes, but is not limited to, delivery in injectable form, e.g., intravenous, intramuscular, intradermal or subcutaneous routes, or by mucosal routes, e.g., as a nasal spray, or an aerosol for inhalation, or as an ingestible solution, capsule or tablet.

[0110] Anti-CD19 antibody CD19 is widely and uniformly expressed on various B cell-derived hematological cancers. CD19 is a therapeutic target for drugs aimed at treating B cell-associated lymphomas and leukemias because it can enhance B cell receptor signaling, which is important for B cell survival.

[0111] Antibodies such as tafasitamab can be made, for example, by preparing and expressing a synthetic gene encoding the recited amino acid sequence, or by mutating a human germline gene to provide a gene encoding the recited amino acid sequence. Additionally, this and other anti-CD19 antibodies can be obtained, for example, using one or more of the following methods:

[0112] Humanized antibodies can be generated by replacing sequences of Fv variable regions 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, SL, Science, 229:1202-1207 (1985), Oi et al., BioTechniques, 4:214 (1986), as well as US5,585,089, US5,693,761, US5,693,762, US5,859,205, and US6,407,213. These methods include isolating, manipulating, and expressing nucleic acid sequences that encode all or part of an immunoglobulin Fv variable region from at least one of the heavy or light chains. Sources of such nucleic acids are well known to those skilled in the art and can be obtained, for example, from hybridomas producing antibodies against a given target, from germline immunoglobulin genes, or from synthetic constructs, as described above. The recombinant DNA encoding the humanized antibody can then be cloned into an appropriate expression vector.

[0113] Human germline sequences are disclosed, for example, in Tomlinson, IA et al., J. Mol. Biol., 227:776-798 (1992); Cook, GP et al., Immunol. Today, 16:237-242 (1995); Chothia, D. et al., J. Mol. Bio. 227:799-817 (1992); and Tomlinson et al., EMBO J., 14:4628-4638 (1995). The V BASE directory provides a comprehensive directory of human immunoglobulin variable region sequences (compiled by Tomlinson, IA et al., MRC Centre for Protein Engineering, Cambridge, UK). These sequences can be used, for example, as a source of human sequences for framework regions and CDRs. Consensus human framework regions can also be used, for example, as described in U.S. Patent 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, the framework positions three-dimensionally adjacent to the binding determinants, and the immunogenic peptide sequence. See, for example, WO90 / 07861, U.S. Patent Nos. 5,693,762, 5,693,761, 5,585,089, 5,530,101, and 6,407,213, Tempest et al. (1991) Biotechnology 9:266-271. Yet another method is called "humaneering" and is described, for example, in US 2005-008625.

[0114] The antibody can include a human Fc region, e.g., a wild-type Fc region or an Fc region that includes one or more modifications. In one embodiment, the constant region is modified, e.g., a human IgG1 constant region is mutated to include substitutions of S239D and / or I332E. The antibody can also have a mutation that stabilizes the disulfide bond between the two heavy chains of the immunoglobulin, such as a mutation in the hinge region of IgG4 (e.g., Angal et al. (1993) Mol. Immunol. 30:105-08), as disclosed in the art. See also, e.g., US2005 / 0037000. The anti-CD19 antibody can be in the form of a full-length antibody or in the form of a low molecular weight form (e.g., biologically active antibody fragment or minibody) of the anti-CD19 antibody, e.g., Fab, Fab', F(ab')2, Fv, Fd, dAb, scFv, and sc(Fv)2. Other anti-CD19 antibodies encompassed by the present disclosure include single domain antibodies (sdAbs) that contain a single variable chain, such as VH or VL, or a biologically active fragment thereof. See, e.g., Moller et al., J. Biol. Chem., 285(49):38348-38361(2010); Harmsen et al., Appl. Microbiol. Biotechnol., 77(1):13-22(2007); US2005 / 0079574 and Davieset al.(1996) Protein Eng., 9(6):531-7. Like whole antibodies, sdAbs can selectively bind to specific antigens. With a molecular weight of only 12-15 kDa, sdAbs are much smaller than typical antibodies, even smaller than Fab fragments and single chain variable fragments.

[0115] Provided herein are compositions comprising an anti-CD19 antibody, or antigen-binding fragment thereof, and a mixture of one or more acidic variants, e.g., the amount of acidic variant(s) is less than about 80%, 70%, 60%, 60%, 50%, 40%, 30%, 30%, 20%, 30 10%, 5%, or 1%. Also provided are compositions comprising an anti-CD19 antibody, or antigen-binding fragment thereof, comprising at least one deamidation site, the pH of the composition being, e.g., about 5.0 to about 6.5, such that at least about 90% of the anti-CD19 antibody is not deamidated (i.e., less than about 10% of the antibody is deamidated). In certain embodiments, less than about 5%, 3%, 2%, or 1% of the antibody is deamidated. The pH may be 5.0 to 6.0, e.g., 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.

[0116] An "acidic variant" is a variant of a polypeptide of interest that 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.

[0117] "Deamidated" variants of a polypeptide molecule are those in which one or more asparagine residue(s) of the original polypeptide have been converted to aspartic acid, i.e., the neutral amide side chain has been converted to a residue having overall acidic properties.

[0118] The term "mixture" as used herein, in reference to a composition comprising an anti-CD19 antibody or antigen-binding fragment thereof, means that both the desired anti-CD19 antibody or antigen-binding fragment thereof and one or more acidic variants thereof are present. The acidic variants may comprise primarily deamidated anti-CD19 antibody along with minor amounts of other acidic variant(s).

[0119] In certain embodiments, the binding affinity (KD), on-rate (KDon) and / or off-rate (KDoff) of an antibody mutated to eliminate deamidation is similar to that of a wild-type antibody, e.g., with less than about 5-fold, 2-fold, 1-fold (100%), 50%, 30%, 20%, 10%, 5%, 3%, 2% or 1% difference.

[0120] bispecific antibody In certain embodiments, the anti-CD19 antibodies or antigen-binding fragments thereof described herein are present in bispecific antibodies. 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 of 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).

[0121] Traditional production of full-length bispecific antibodies is based on the co-expression of two immunoglobulin heavy-light chain pairs, where these two chains have different specificities (Millstein et al., Nature, 305:537-539 (1983)). According to a different approach, antibody variable domains with the desired binding specificities are fused to immunoglobulin constant domain sequences. DNAs encoding the immunoglobulin heavy chain fusions and, if desired, the immunoglobulin light chain are inserted into separate expression vectors and co-transfected into a suitable host cell. This provides greater flexibility in adjusting the ratio of the three polypeptide fragments. However, it is possible to insert the coding sequences for two or all three polypeptide chains into one expression vector, provided that expression of at least two polypeptide chains in equal ratios results in high yields.

[0122] According to another approach described in US Pat. No. 5,731,168, the interface between a pair of antibody molecules may be engineered to maximize the percentage of heterodimers recovered from recombinant cell culture. A preferred interface comprises at least a portion of the CH3 domain. In this method, one or more small amino acid side chains from the interface of a first antibody molecule are replaced with larger side chains (e.g., tyrosine or tryptophan). By replacing the large amino acid side chains with smaller amino acid side chains (e.g., alanine or threonine), a compensatory "cavity" of identical or similar size to the large side chain(s) is created on the interface of the second antibody molecule. This provides a mechanism for increasing the yield of heterodimers over other undesired end products such as homodimers.

[0123] Bispecific antibodies include cross-linked or "heteroconjugate" antibodies. For example, one of the antibodies in the heteroconjugate can be coupled to avidin, the other to biotin. Heteroconjugate antibodies can be made using any convenient cross-linking method.

[0124] "Diabody" technology provides an alternative mechanism for the production of bispecific antibody fragments. These fragments contain a VH connected to a VL by a linker that is too short to allow pairing between the two domains on the same chain. Thus, the VH and VL domains of one fragment are forced to pair with the complementary VL and VH domains of another fragment, thereby forming two antigen-binding sites.

[0125] Multivalent antibodies In certain embodiments, the anti-CD19 antibodies or antigen-binding fragments thereof described herein are present in multivalent antibodies. Multivalent antibodies may be internalized (and / or catabolized) faster than bivalent antibodies by cells expressing the antigen to which the antibody binds. The antibodies provided herein may be multivalent antibodies (e.g., tetravalent antibodies) having three or more antigen-binding sites, which may be readily produced by recombinant expression of nucleic acids encoding the polypeptide chains of the antibody. The multivalent antibody may comprise a dimerization domain and three or more antigen-binding sites. Exemplary dimerization domains include (or consist of) an Fc region or a hinge region. The multivalent antibody may comprise (or consist of) from three to about eight (e.g., four) antigen-binding sites. The multivalent antibody optionally comprises at least one polypeptide chain (e.g., at least two polypeptide chains), where the polypeptide chain(s) comprises two or more variable domains. For example, the polypeptide chain(s) may comprise VD1-(X1)n-VD2-(X2)n-Fc, where VD1 is a first variable domain, VD2 is a second variable domain, Fc is one polypeptide chain of an Fc region, X1 and X2 represent amino acids or peptide spacers, and n is 0 or 1.

[0126] Conjugated antibodies The antibodies disclosed herein may be conjugated antibodies that are attached to a variety of molecules, including macromolecular substances such as polymers (e.g., polyethylene glycol (PEG), polyethyleneimine (PEI) modified with PEG (PEI-PEG), polyglutamic acid (PGA) (N-(2-hydroxypropyl) methacrylamide (HPMA) copolymers), hyaluronic acid, radioactive substances (e.g., 90Y, 131I), fluorescent substances, luminescent substances, haptens, enzymes, metal chelates, drugs, and toxins (e.g., calcheamicin, Pseudomonas exotoxin A, ricin (e.g., deglycosylated ricin A chain)), and auristatins such as auristatin E and auristatin F).

[0127] In one embodiment, to improve the cytotoxicity of anti-CD19 antibodies and thus their therapeutic efficacy, the antibodies are conjugated with highly toxic substances, including radioisotopes and cytotoxic agents. These conjugates can selectively deliver a toxic load to the target site (i.e., cells expressing the antigen recognized by the antibody), while cells not recognized by the antibody are spared. To minimize toxicity, the conjugates are generally engineered based on molecules with short serum half-lives (hence the use of mouse sequences and IgG3 or IgG4 isotypes).

[0128] In certain embodiments, the anti-CD19 antibody or antigen-binding fragment thereof is modified with a moiety that improves its stabilization and / or retention in the circulation, e.g., at least 1.5, 2, 5, 10, or 50-fold, e.g., in blood, serum, or other tissues. For example, the anti-CD19 antibody or antigen-binding fragment thereof can be associated (e.g., conjugated) with a polymer, e.g., a substantially non-antigenic polymer, such as a polyalkylene oxide or polyethylene oxide. Suitable polymers vary substantially by weight. Polymers having molecular number average weights ranging from about 200 to about 35,000 daltons (or about 1,000 to about 15,000, and 2,000 to about 12,500) can be used. For example, the anti-CD19 antibody or antigen-binding fragment thereof can be conjugated to a water-soluble polymer, e.g., a hydrophilic polyvinyl polymer, e.g., polyvinyl alcohol or polyvinylpyrrolidone. Examples of such polymers include polyalkylene oxide homopolymers such as polyethylene glycol (PEG) or polypropylene glycol, polyoxyethylenated polyols, copolymers thereof and block copolymers thereof, provided that the water solubility of the block copolymers is maintained. Further useful polymers include polyoxyalkylenes such as polyoxyethylene, polyoxypropylene, and block copolymers of polyoxyethylene and polyoxypropylene, polymethacrylates, carbomers, and branched or unbranched polysaccharides. The above-mentioned conjugated antibodies can be prepared by chemically modifying the antibodies described herein or their low molecular weight forms. Methods for modifying antibodies are well known in the art (e.g., US5,057,313 and US15 5,156,840).

[0129] Methods for producing antibodies Antibodies can be produced in bacteria or eukaryotic cells. Some antibodies, e.g., Fab', can be produced in bacterial cells, e.g., E. coli cells. Antibodies can also be produced in eukaryotic cells, such as transformed cell lines (e.g., CHO, 293E, COS). In addition, antibodies (e.g., scFv') can be expressed in yeast cells, such as Pichia (e.g., Powers et al., J Immunol Methods. 251:123-35 (2001)), Hanseula, or Saccharomyces. To produce the antibody of interest, a polynucleotide encoding the antibody is constructed, introduced into an expression vector, and then expressed in a suitable host cell. Standard molecular biology techniques are used to prepare the recombinant expression vector, transfect the host cell, select for transformants, culture the host cell, and recover the antibody.

[0130] If the antibody is expressed in bacterial cells (eg, E. coli), the expression vector will possess features that allow for amplification of the vector within the bacterial cell. Furthermore, when E. coli such as JM109, DH5I, HB101, or XL1-Blue is used as a host, the vector must have a promoter, such as the lacZ promoter (Ward et al., 341:544-546 (1989)), the araB promoter (Better et al., Science, 240:1041-1043 (1988)), or the T7 promoter, which can allow efficient expression in E. coli. Examples of such vectors include, for example, M13 series vectors, pUC series vectors, pBR322, pBluescript, pCR-Script, pGEX-5X-1 (Pharmacia), "QIAexpress system" (QIAGEN), pEGFP, and pET (when this expression vector is used, the host is preferably BL21, which expresses T7 RNA polymerase). The expression vector may contain a signal sequence for antibody secretion. For production into the periplasm of E. coli, the pelB signal sequence (Lei et al., 2002). al., J. Bacteriol., 169:4379 (1987)) can be used as a signal sequence for antibody secretion. For bacterial expression, the expression vector can be introduced into bacterial cells using the calcium chloride method or electroporation. When antibodies are expressed in animal cells such as CHO, COS, and NIH3T3 cells, the expression vector contains a promoter necessary for expression in these cells, for example, the SV40 promoter (Mulligan et al. Nature, 277:108 (1979)), the MMLV-LTR promoter, the EF1I promoter (Mizushima et al., Nucleic Acids Res., 18:5322 (1990)), or the CMV promoter. In addition to the nucleic acid sequence encoding an immunoglobulin or a domain thereof, the recombinant expression vector can carry additional sequences, for example, sequences that regulate replication of the vector in host cells (e.g., origins of replication) and selectable marker genes.The selectable marker gene can facilitate the selection of host cells into which the vector has been introduced (see, for example, U.S. Patent Nos. 4,399,216, 4,634,665, and 5,179,017). For example, the selectable marker gene usually confers resistance to drugs such as G418, hygromycin, and methotrexate to the host cells into which the vector has been introduced. Examples of vectors having a selectable marker include pMAM, pDR2, pBK-RSV, pBK-CMV, pOPRSV, and pOP13.

[0131] In one embodiment, the antibody is produced in a mammalian cell. Exemplary mammalian host cells for expressing the antibody include Chinese hamster ovary (CHO cells) (including dhfr-CHO cells described in Urlaub and Chasin (1980) Proc. Natl. Acad. Sci. USA 77:4216-4220, e.g., used with a DHFR selection marker as described in Kaufman and Sharp (1982) Mol. Biol. 159:601-621), human embryonic kidney 293 cells (e.g., 293, 293E, 293T), COS cells, NIH3T3 cells, lymphocytic cell lines, e.g., NS0 myeloma cells and SP2 cells, and cells derived from transgenic animals, e.g., transgenic mammals.

[0132] In an exemplary system for antibody expression, a recombinant expression vector encoding both the antibody heavy and light chains of an anti-CD19 antibody (e.g., tafasitamab) is introduced into dhfr-CHO cells by calcium phosphate-mediated transfection. Within the recombinant expression vector, the antibody heavy and light chain genes are each operably linked to enhancer / promoter regulatory elements (e.g., derived from SV40, CMV, adenovirus, etc., such as the CMV enhancer / AdMLP promoter regulatory element or the SV40 enhancer / AdMLP promoter regulatory element) to drive high level transcription of the genes. The recombinant expression vector also carries a DHFR gene, which allows for the selection of CHO cells transfected with the vector using methotrexate selection / amplification. The selected transformed host cells are cultured to allow expression of the antibody heavy and light chains, and the antibody is recovered from the culture medium. Antibodies can also be produced by transgenic animals. For example, U.S. Patent No. 5,849,992 describes a method for expressing antibodies in the mammary gland of a transgenic mammal. A transgene is constructed that contains a milk-specific promoter and a nucleic acid encoding the antibody of interest and a signal sequence for secretion. The milk produced by females of such transgenic mammals contains, secreted therein, the antibody of interest. The antibody can be purified from the milk or used directly for several applications. Animals that contain one or more of the nucleic acids described herein are also provided.

[0133] The antibody of the present disclosure may be isolated from the inside or outside (such as the medium) of a host cell and purified as a substantially pure and homogeneous antibody. Isolation and purification methods commonly used for antibody purification may be used for antibody isolation and purification, and are not limited to any particular method. The antibody may be isolated and purified by appropriately selecting and combining, for example, column chromatography, filtration, ultrafiltration, salting out, solvent precipitation, solvent extraction, distillation, immunoprecipitation, SDS-polyacrylamide gel electrophoresis, isoelectric focusing, dialysis, and recrystallization. Examples of chromatography include affinity chromatography, ion exchange chromatography, hydrophobic chromatography, gel filtration, reversed phase chromatography, and adsorption chromatography (Strategies for Protein Purification and Characterization: A Laboratory Course Manual. Ed Daniel R. Marshak et al., Cold Spring Harbor Laboratory Press, 1996). Chromatography may be performed using liquid phase chromatography such as HPLC and FPLC. Columns used for affinity chromatography include protein A columns and protein G columns. Examples of columns that use Protein A columns include Hyper D, POROS, and Sepharose FF (GE Healthcare Biosciences). The present disclosure also includes antibodies that are highly purified using these purification methods.

[0134] Antibody Pharmaceutical Compositions and Administration The anti-CD19 antibodies or antigen-binding fragments thereof described herein can be formulated as pharmaceutical compositions for administration to a subject, for example, to treat a disorder described herein. Typically, a pharmaceutical composition includes a pharma- ceutically acceptable carrier. As used herein, "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, that are physiologically compatible. The composition can include pharma- ceutically acceptable salts, such as acid addition salts or base addition salts (see, e.g., Berge, SM, et al. (1977) J. Pharm. Sci. 66:1-19).

[0135] Pharmaceutical formulation is a well-established art and is further described, for example, in Gennaro (ed.), Remington: The Science and Practice of Pharmacy, 20th ed., Lippincott, Williams & Wilkins (2000) (ISBN: 0683306472), Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th Ed., Lippincott Williams & Wilkins Publishers (1999) (ISBN: 0683305727); and Kibbe (ed.), Handbook of Pharmaceutical Excipients American Pharmaceutical Association, 3rd ed. (2000) (ISBN: 091733096X).

[0136] The anti-CD19 antibody or antigen-binding fragment thereof can be administered to a subject, eg, a subject in need thereof, eg, a human subject, by a variety of methods.

[0137] In many applications, the route of administration is one of intravenous injection or infusion (IV), subcutaneous injection (SC), intraperitoneal (IP), or intramuscular injection. It may also be possible to use intraarticular delivery. Other methods of parenteral administration may also be used. In some cases, oral administration is also possible. The route and / or mode of administration of the antibody or antigen-binding fragment thereof may also be tailored to individual cases, for example, by monitoring the subject, for example, using tomography imaging to visualize the tumor.

[0138] A pharmaceutical composition may comprise a "therapeutically effective amount" of an anti-CD19 antibody or antigen-binding fragment thereof as described herein. Such an effective amount may be determined based on the effect of the administered agent, or the combined effect of the agents when two or more agents are used, within the doses and dosing regimens disclosed herein. A "therapeutically effective amount" of an agent may also vary depending on factors such as the disease state, age, sex, and weight of the individual, as well as the ability of the compound to elicit a desired response in the individual, e.g., improvement of at least one disorder parameter, or improvement of at least one disorder symptom. A therapeutically effective amount is also one in which any toxic or deleterious effects of the composition are outweighed by the therapeutically beneficial effects.

[0139] In certain embodiments, the anti-CD19 antibody substituted for tafasitamab is a human antibody, a humanized antibody, or a chimeric antibody. In another embodiment of the present disclosure, the anti-CD19 antibody substituted for tafasitamab is an antibody of IgG isotype. In another embodiment, the antibody is an IgG1, IgG2, or an IgG1 / IgG2 chimera substituted for tafasitamab. In another embodiment of the present disclosure, the isotype of the anti-CD19 antibody substituted for tafasitamab is engineered to enhance antibody-dependent cell-mediated cytotoxicity. In another embodiment, the heavy chain constant region of the anti-CD19 antibody substituted for tafasitamab comprises amino acids 239D and 332E, where Fc numbering is according to the EU index as in Kabat. In another embodiment, the anti-CD19 antibody substituted for tafasitamab is an IgG1, IgG2, or IgG1 / IgG2, and the chimeric heavy chain constant region of the anti-CD19 antibody comprises amino acids 239D and 332E, where Fc numbering is according to the EU index as in Kabat. [Table 1-1] [Table 1-2]

[0140] Working Example Study: A phase 1b / 2, open-label, multicenter study (MINDway) to evaluate the safety and pharmacokinetics of a modified tafasitamab IV dosing regimen in combination with lenalidomide (LEN) in patients with relapsed or refractory diffuse large B-cell lymphoma (R / R DLBCL). To evaluate a tafasitamab dosing regimen that requires approximately 50% less intravenous infusion than the currently approved drug regimen, the following modifications to the currently approved dosing regimen were defined: Dosing frequency is scheduled to decrease from once a week (QW) to once every two weeks (Q2W) from day 15 of cycle 1 (C1D15) and from Q2W to once every four weeks (Q4W) from C4D1. · We plan to maintain tafasitamab at the previous dose level of 12 mg / kg for the first three infusions (i.e., days 1, 4, and 8); we will increase the tafasitamab dose level from C1D15 onwards.

[0141] Dose escalation will be implemented as a risk minimization measure to limit potential AEs (e.g., IRR or tumor lysis syndrome [TLS]) occurring soon after treatment initiation. Taking this new dosing schedule into account (see Table 2), a POP-PK model for tafasitamab was used to identify new dose levels that would result in similar tafasitamab trough levels as observed in the pivotal clinical trial L-MIND in order to maintain the previously established exposure / efficacy relationship. 24 mg / kg and 30 mg / kg, administered according to the dosing schedule outlined in Table 2, were identified as potential new dose levels tested in this study.

[0142] Predicted minimum concentrations (C) at the end of cycle 3 for the L-MIND, 12 / 24 mg / kg, and 12 / 30 mg / kg dosing schedules trough ) and maximum concentration (C max Box plots comparing the values ​​of α, β, and predicted area under the curve (AUC) levels (AUC28 and AUC56) after one and two treatment cycles are shown in Figures 1 and 2. The model predictions were consistent with the previously observed C trough In contrast, a dose of 30 mg / kg of tafasitamab was required to achieve C levels with the 12 / 24 mg / kg dosing regimen. trough Levels are predicted to be lower than trough levels for L-MIND (reduction in geometric mean concentrations compared to L-MIND: 2.9% for 12 / 30 mg / kg and 21.8% for 12 / 24 mg / kg).

[0143] Figure 3 shows a comparison of model-predicted median tafasitamab concentrations over time between L-MIND and the target 12 / 30 mg / kg dosing regimen, demonstrating similar tafasitamab C concentrations with the two different dosing schedules. troughIt is verified that the levels are achieved. Additional details regarding the simulation can be found in MorphoSys report MOR208L050.

[0144] In addition, simulations were used to compare expected exposures in the planned studies. Previous non-clinical safety studies and clinical trials of MOR208C115: In cynomolgus monkeys receiving a QW dose of 100 mg / kg (i.e., the NOAEL), the steady-state AUC0-144h and C max is expected to be approximately 6-7 times higher compared to R / R DLBCL patients dosed according to the 12 / 24 mg / kg regimen and approximately 5 times higher compared to patients dosed according to the 12 / 30 mg / kg regimen. Compared with the clinical trial L-MIND, C max Concentrations are expected to be 1.4-fold and 1.7-fold higher for the 12 / 24 mg / kg and 12 / 30 mg / kg doses, respectively. Compared to B-MIND, C max Concentrations are expected to be 1.2- and 1.4-fold higher at the 12 / 24 mg / kg and 12 / 30 mg / kg doses, respectively.

[0145] In conclusion, the 12 / 30 mg / kg dosing regimen produced C-regression results similar to those expected in L-MIND. trough However, tafasitamab C max To allow for a gradual assessment of the safety of escalating levels, patient enrollment will begin in Cohort 1 according to a 12 / 24 mg / kg dosing scheme. If safety data support further dose escalation, a target 12 / 30 mg / kg dosing scheme will be explored in Cohort 2.

[0146] Benefit / Risk Assessment The risk assessment of tafasitamab and LEN is based on data from nonclinical trials, as well as clinical experience from completed and ongoing trials. Tafasitamab monotherapy was well tolerated in R / RB cell lymphoma (BCL) (Jurczak et al., 2018). Similarly, tafasitamab plus LEN showed a manageable safety profile in the L-MIND trial in R / R DLBCL (Salles et al., 2020) and was FDA approved in the United States on July 31, 2020.

[0147] In June 2021, the European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) issued a positive opinion recommending the conditional marketing authorisation of tafasitamab in combination with lenalidomide followed by tafasitamab monotherapy for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who are not eligible for autologous stem cell transplantation (ASCT).

[0148] Further information regarding the known and expected benefits and risks of tafasitamab, as well as reasonably expected AEs, is available in the current version of the IB.

[0149] Risk assessment Tafasitamab is approved for use at a dose of 12 mg / kg. The study dosing regimens shown in Table 2 (12 / 24 mg / kg or 12 / 30 mg / kg combinations) demonstrated higher tafasitamab C than previously observed in L-MIND. max Based on current nonclinical and clinical safety data, the incidence and exposure of AEs (C max No correlation was observed between the C maxThe expected range of values ​​is higher than and not included in previous clinical data. To reduce the risk of potential AEs occurring soon after starting treatment, such as IRR and TLS, all patients will maintain a dose of 12 mg / kg for the first three tafasitamab doses on C1D1, C1D4, and C1D8 before increasing the dose to 24 mg / kg or 30 mg / kg. In addition, the infusion duration for the higher tafasitamab doses will be doubled and the tafasitamab infusion rate (mg / h) will be maintained similar to L-MIND. An internal DSMC will monitor safety events during the study and make dose modifications decisions based on new safety, pharmacokinetic, and pharmacodynamic data. Based on the clinical experience of tafasitamab in combination with LEN in L-MIND, the most common adverse events (≥20%) with tafasitamab plus LEN were neutropenia, fatigue, anemia, diarrhea, thrombocytopenia, cough, pyrexia, peripheral edema, respiratory tract infection, and decreased appetite. Serious adverse events (SAEs) were reported in ≥6% of patients and included infections, including pneumonia and febrile neutropenia.

[0150] At the initial data cutoff of October 10, 2022, two patients who received a 24 mg / kg dose with a double infusion duration (4 hours) tolerated the infusion well and had no overt IRRs. One patient received a 24 mg / kg dose with a 2 hour infusion duration and tolerated the infusion without any overt IRRs.

[0151] The modified dosing regimen (i.e., reducing the overall frequency of clinic visits by half) reduces patient burden and supports long-term treatment compliance. Furthermore, given the severity of the disease, reducing hospital visits may result in less exposure to hospital-acquired infections in an already susceptible patient population.

[0152] The combination of tafasitamab plus LEN provides clinical benefit to patients with R / R DLBCL, as demonstrated in the L-MIND trial. Based on clinical efficacy data as of the data cutoff of October 30, 2020, in patients with a diagnosis of DLBCL confirmed by central pathology, the combination of tafasitamab plus LEN demonstrated an ORR of 53.5% (95% CI: 41.3; 65.5), a CR rate of 35.2% (95% CI: 24.2; 47.5), and a median DoR of 43.9 months (95% CI: 15.0; no response [NR]). Compared with tafasitamab and LEN monotherapy, an ORR of >50% is considered clinically highly meaningful in the relapsed / refractory setting of DLBCL ineligible for high-dose chemotherapy and ASCT. Furthermore, safety data from the L-MIND trial indicate that the addition of tafasitamab to LEN adds little additional toxicity based on the characterized safety profile of LEN administered as monotherapy.

[0153] The new dosing regimen is expected to reduce patient burden while achieving the same trough levels as L-MIND. Furthermore, the same clinical benefit rate is expected. max Because of the large overlap in values ​​predicted (L-MIND vs. 12 / 24 mg / kg and 12 / 30 mg / kg predictions), no new types of safety events are predicted.

[0154] Objectives, Evaluation Items, and Estimands The following objectives and endpoints will be assessed in this study. See Table 1: [Table 2] Abbreviation:C max = maximum concentration, C trough = minimum dose; DLBCL = diffuse large B-cell lymphoma; NK = natural killer; Q2W = once every 2 weeks; Q4W = once every 4 weeks; R / R = relapsed / refractory, TEAE = treatment-emergent adverse event. Each treatment cycle is 28 days.

[0155] Estimand Primary clinical question of interest: Given the proposed alternative treatment dosing regimen using tafasitamab at a higher dose than previously investigated, what is the observed incidence and severity of treatment-emergent adverse events (TEAEs) in patients with R / R DLBCL who received at least one dose at either 24 or 30 mg / kg? This will allow for an evaluation of the safety and tolerability of the alternative treatment-dosing regimens. The main estimands and their attributes are described in Section 4. Possible intercurrent events and strategies to capture them are described in Section 4.

[0156] Test Design MOR208C115 (MINDway) is an open-label, multicenter, phase 1b / 2 study of tafasitamab in combination with lenalidomide (LEN) to evaluate modified tafasitamab dosing regimens in adult patients with R / R DLBCL. Overall, approximately 51 patients will be enrolled in the study. Patients will receive LEN in combination with tafasitamab in 28-day cycles. The modified tafasitamab dosing regimen will be investigated in a stepwise design with two consecutive cohorts followed by an expansion cohort at the recommended dose level. Tafasitamab will be administered as an intravenous infusion according to the following dosing schedule (Table 2): [Table 3] 1 Each treatment cycle is 28 days.

[0157] LEN (25 mg) will be administered for up to 12 cycles or until disease progression, unacceptable toxicity, withdrawal, death, or loss to follow-up. After cycle 12 or discontinuation of LEN, patients will continue tafasitamab monotherapy at the assigned dosing regimen until disease progression, unacceptable toxicity, withdrawal, death, or loss to follow-up. This study will not include follow-up for overall survival after end of treatment (EOT).

[0158] A Data and Safety Monitoring Committee (DSMC), consisting of representatives from the sponsor and the investigators, will continue to monitor the study and may recommend stopping enrollment at any time based on new safety data. In addition, a predefined DSMC meeting will be held when at least six patients in Cohort 1 and at least six patients in Cohort 2 have completed the 5-week (35-day) safety observation period.

[0159] Details of the DSMC's specific responsibilities, composition, meeting format and frequency are outlined in the DSMC Charter.

[0160] Study population The study will enroll approximately 51 patients with histologically confirmed R / R DLBCL (specified in inclusion criterion 3) based on pathology reports from each country.

[0161] All patients must meet the eligibility criteria listed below to be enrolled in the study. Prospective approval of deviations from the eligibility criteria, also known as protocol waivers or exclusions, will not be permitted.

[0162] Selection Criteria Patients are eligible for inclusion in the study only if all of the following criteria apply:

[0163] 1. Be able to give signed informed consent: regulatory, ethical, and trial oversight considerations, including compliance with the requirements and restrictions stated in the Informed Consent Form (ICF) and this protocol. 2. Patients must be aged between 18 and 80 years (18-70 years in the Czech Republic) at the time of signing the informed consent. 3. Histologically confirmed diagnosis of one of the following: ·DLBCL NOS(DLBCL not otherwise specified) ·T-cell / histiocyte-rich large B-cell lymphoma (THRLBCL) Elderly Epstein-Barr virus (EBV)-positive DLBCL (EBV-positive DLBCL) Follicular lymphoma grade 3b Composite lymphoma with DLBCL components according to the Revised European American Lymphoma / World Health Organization (REAL / WHO) classification with subsequent relapse of DLBCL. In addition, patients with evidence of histologic transformation to DLBCL from an initial diagnosis of indolent lymphoma (i.e., indolent disease, e.g., follicular lymphoma, marginal zone lymphoma, chronic lymphocytic leukemia) with subsequent relapse of DLBCL are also eligible. 4. Tumor tissue for retrospective central pathology review must be provided to support participation in this study. If archival paraffin-embedded tumor tissue obtained within 3 years prior to screening is not available, a fresh tumor tissue specimen will be obtained from the patient. 5. The patient shall have: a. Appendix 3: Study Specific Definitions Relapsed and / or refractory disease as defined in the Appendix. b. At least one bidimensionally measurable site of disease. Lesions must have a maximum transverse diameter of ≥1.5 cm and a maximum perpendicular diameter of ≥1.0 cm at baseline. Lesions must be positive on positron emission tomography (PET) scans (for definition, see Juweid et al., 2007). c. Received at least one, but no more than three, prior systemic regimens for the treatment of DLBCL, with one line of treatment including cluster of differentiation-20 (CD20)-targeted therapy (e.g., rituximab [RTX]). Eastern Cooperative Oncology Group (ECOG) performance status 0–2. 6. Patients who are ineligible or do not wish to undergo intensive salvage therapy such as autologous stem cell transplantation (ASCT). The reason a patient is ineligible must meet one of the following criteria explained below and listed in the patient's source data: a. Unsatisfactory performance status (Karnofsky performance status ≤ 80%, see Karnofsky Performance Status Scale) b. Disease unresponsive to salvage chemotherapy. Responsiveness is defined as tumors showing either a complete response (CR) or partial response (PR) to salvage chemotherapy. c. Inadequate function of major organs (any of the following): i. Symptomatic congestive heart failure ii. Pulmonary function - forced vital capacity (FVC), forced vital capacity in 1 second (FEV-1), and corrected diffusion capacity of the lung for carbon monoxide (DLCO) ≦60% iii. Liver function - Total serum bilirubin and transaminases >2x upper limit of normal (ULN) d. History or evidence of significant comorbid medical or psychiatric illness that seriously impairs the patient's clinical care and chances of survival. e. Inability to collect suitable stem cell grafts (e.g., 1-2 x 10 cells without tumor contamination) 6 CD34+ cells per kg of recipient body weight 7. Patients must meet the following laboratory criteria at screening: Absolute neutrophil count (ANC) ≥ 1.5 x 10 9 / L (unless secondary to bone marrow involvement due to DLBCL as demonstrated by recent bone marrow aspirate and bone marrow biopsy). B. Platelet count ≥ 75x10 9 / L (unless secondary to bone marrow involvement due to DLBCL as demonstrated by recent bone marrow aspirate and bone marrow biopsy). c. Total serum bilirubin ≤ 2.5xULN, unless secondary to Gilbert's syndrome or with documented hepatic involvement due to lymphoma. Patients with Gilbert's syndrome with documented hepatic involvement due to lymphoma may be included if their total bilirubin is ≤ 5xULN (see Exclusion Criterion 6g). d. Alanine transaminase (ALT), aspartate transaminase (AST) and alkaline phosphatase (ALP) ≤ 3xULN or < 5xULN (if liver disease is demonstrated). e. Serum creatinine CL should be ≥ 50 mL / min, either measured or calculated using the standard Cockcroft and Gault formula.

[0164] Exclusion criteria Patients will be excluded from the study if they meet any of the following criteria: 1. General provisions: A patient who is lawfully institutionalized or under legal custody. b. Concurrently enrolled in another interventional clinical trial. 2. Patients with: A. Other histological lymphomas, such as primary mediastinal (thymic) large cell (PMBL) or Burkitt lymphoma. b. Primary refractory DLBCL (see Appendix 3: Study Specific Definitions for definition). c. Known "double / triple hit" genetics (high-grade B-cell lymphoma) characterized by co-detection of MYC with BCL2 and / or BCL6 translocation(s) defined by fluorescent in situ hybridization. Testing of MYC, BCL2, BCL6 prior to study enrollment is not required. 3. Patients with the following within 14 days prior to dosing on Day 1: a. Ongoing CD20-targeted therapy, chemotherapy, radiation therapy, investigational anticancer therapy, or other lymphoma-specific therapy. b. Have had major surgery (within the last 4 weeks) or significant trauma. c. Have received a live vaccine (see Appendix 7: Covid-19: Prevention of infectious diseases and vaccines). d. Have parenteral antimicrobial therapy as required for active intercurrent infections. 4.Patients with: a. In the opinion of the investigator, has not adequately recovered from the adverse toxic effects of prior therapy. b. Previously treated with CD19 targeted therapy or IMiDs® (e.g., thalidomide, LEN). c. History of hypersensitivity to compounds with similar biological or chemical composition to tafasitamab, IMiDs®, and / or excipients contained in the study therapeutic formulation. d. Having undergone ASCT within 3 months prior to signing the ICF. Patients with prior ASCT must have achieved complete hematologic recovery prior to study enrollment. e. Previous allogeneic stem cell transplant. f. Deep vein thrombosis / embolism, threatening thromboembolism or known history of thrombophilia, or in the opinion of the investigator, is at high risk for thromboembolic events and is unwilling / unable to receive venous thromboembolism (VTE) prophylaxis during the entire treatment period. g. Concurrent use of other anti-cancer or experimental therapies. 5. History of other malignancies that may affect compliance with the protocol or interpretation of results. exception: a. Patients with any malignancy who have been adequately treated with curative intent and who have been in treatment-free remission of the malignancy for more than 2 years prior to enrollment are eligible. b. Patients with low-grade early stage prostate cancer (Gleason score ≤ 6 or stage 1 or 2) not requiring treatment at any time prior to the study are eligible. 6.Patients with: Positive hepatitis B and / or hepatitis C serology (see 12.8 Appendix 8: Hepatitis virus serology for further information). b. Known seropositivity or history of active viral infection with human immunodeficiency virus (HIV). c. Concurrent central nervous system (CNS) lymphoma - current or past history. d. History or evidence of clinically significant cardiovascular disease, central nervous system disease, and / or other systemic disease which, in the investigator's opinion, either precludes participation in the study or impairs the patient's ability to give informed consent. e. History or evidence of the rare inherited problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption. f. Gastrointestinal (GI) abnormalities (problems with absorption), such as inability to take oral medications. g. Severe liver impairment (total serum bilirubin >3 mg / dL), history or evidence of jaundice (unless secondary to Gilbert's syndrome) or documented liver involvement due to lymphoma (see inclusion criterion 7c). h. History of hypersensitivity to the study treatment or any of its excipients, or to drugs of a similar chemical class. i. Any other medical condition that, in the opinion of the Investigator, makes the patient unsuitable for the study. 7. Contraception Clause: Females: Due to the teratogenic potential of LEN, FCBP should be: Applicable to all countries except the United States: a. Negative serum pregnancy test at screening and not pregnant as confirmed by a medically controlled urine pregnancy test prior to starting study therapy. b. Abstain from breast-feeding and egg donation during the study period and for 3 months after the last dose of study drug, or in accordance with LEN national guidelines, whichever is longer. c. Agrees to continue pregnancy testing during the study and after completion of study therapy, even if the patient applies complete sexual abstinence. d. Promise to continue abstaining from heterosexual intercourse if following the lifestyle of eligible women (which must be reviewed monthly) or agree to use highly effective contraception and be able to adhere to its use without interruption, for at least 4 weeks prior to the start of the study drug, during study treatment and for 3 months after the last dose of study drug, or in the case of LEN, in accordance with national guidelines, whichever is longer. Applicable in the United States: e. Not pregnant (even if true abstinence is the chosen birth control method) as confirmed by a pregnancy test taken within 10-14 days prior to starting treatment and again within 24 hours. f. Abstain from breast-feeding and oocyte donation during the study period and for 3 months after the last dose of study drug, or in the case of LEN, in accordance with US guidelines, whichever is longer. g. Agree to continue pregnancy testing throughout the study (every 3 weeks for women with regular menstrual cycles and every 2 weeks for women with irregular menstrual cycles) and after completion of study therapy (even if the birth control method chosen is truly foreclosed). h. Have received study treatment and have not been pregnant for at least 3 months after the last dose of study treatment by using two effective methods of contraception, at least one highly effective method and one additional effective method, simultaneously during each sexual act with a man, beginning at least 4 weeks prior to receiving study treatment and continuing through study treatment, during drug holidays (interruptions of medication), and for at least 3 months after discontinuing study treatment, or in the case of LEN, in accordance with U.S. guidelines, whichever is longer. True abstinence from heterosexual intercourse is also an acceptable method of contraception. Use of emergency contraception is also permitted. 8. Male participants shall: Applicable in all countries except the United States: Patients will use uninterrupted, effective barrier contraception if they are sexually active with FCBP. Male patients will abstain from semen donation during study participation and for 3 months after the last dose of study treatment, or according to LEN national guidelines, whichever is longer. Applicable in the United States: b. Use a latex or synthetic condom each time the patient has sexual intercourse with the FCBP. True abstinence from heterosexual intercourse is also an acceptable method of contraception. Use of emergency contraception is also permitted. Male patients will abstain from semen donation during study participation and for 3 months after the last dose of study drug, or in accordance with LEN US guidelines, whichever is longer.

[0165] statistical analysis The primary analysis will be performed when all enrolled patients have completed C3D28 or have discontinued the study for any reason prior to C3D28. The final analysis will be performed at the end of the study.

[0166] Any deviations from the statistical analysis outlined in this protocol, and the reasons for deviations will be listed, will be described in the clinical trial report.

[0167] Details of the analyses to be performed on the data from this study will be provided in a separate SAP.

[0168] End of exam The end of the study will be defined as the date when the last patient completed their last visit (approximately 3 years after the last patient received their first study treatment).

[0169] Upon completion of the study, MorphoSys will notify the applicable regulatory authorities, in accordance with local country requirements.

[0170] Patient End-of-Study Visit: A patient's end-of-study visit is defined as the visit that occurs when a patient completes the 90-day safety follow-up after receiving their last dose of tafasitamab.

[0171] Appendix 3: Study Specific Definitions For the purposes of this protocol, primary refractory disease is defined as disease that progresses over the course of first-line treatment according to the International Working Group response criteria (Cheson et al., 2007) and / or disease that demonstrates less than a PR response to first-line treatment or disease relapse / progression within less than 6 months after completing first-line treatment.

[0172] Disease refractory to last therapy was defined as less than PR to the most recent systemic therapy.

[0173] Relapsed / progressive / recurrent disease reflects the appearance of any new lesions or a 50% or greater increase from the nadir of previously involved sites according to the International Working Group response criteria (Cheson et al., 2007) after the most recent systemic therapy.

[0174] End of Treatment: End of treatment is defined as the date the patient received their last dose of tafasitamab. End of treatment visits will occur within 14 days of the decision to discontinue treatment.

[0175] End of Study: End of study will be defined as the date when the last patient completed their last visit (approximately 3 years after the last patient received their first study treatment).

[0176] Patient End-of-Study Visit: A patient's end-of-study visit is defined as when the patient completes the 90-day safety follow-up after their last dose of tafasitamab.

[0177] Study Initiation: "Clinical Trial Initiation" means the initial act of recruiting potential subjects for a particular clinical trial, unless defined differently in the protocol.

[0178] Appendix 7: Covid-19: Infection prevention and vaccines Live vaccines must not be administered to patients in this study. Killed, inactivated vaccines, such as injectable annual influenza vaccines, are permitted. Investigators will adhere to institutional guidelines regarding infectious chemoprophylaxis for patients considered at high risk for infection.

[0179] Whenever possible, relapsed / refractory patients treated with immunosuppressive therapy, including tafasitamab-containing regimens, should begin vaccination against COVID-19 as soon as possible, with at least the first dose, and ideally approximately 2 weeks before the start of study treatment.

[0180] Based on current safety / benefit considerations, and in the absence of data or guidance to the contrary, we propose that all patients with lymphoma (unless explicitly contraindicated) should receive a COVID-19 vaccine, accepting that full protection may not be achieved due to impaired humoral and / or cellular immunity.

[0181] For patients already receiving a tafasitamab-containing regimen, the advantages and disadvantages of delaying vaccination or interrupting treatment to allow for immune recovery should be carefully considered on a case-by-case basis. The recommendation is to vaccinate these patients despite their possible inability to mount a fully protective immune response to a COVID-19 vaccine.

[0182] Appendix 8: Hepatitis virus serology Patients are tested according to the SoA for viral hepatitis B and C. Hepatitis B biomarkers include HbsAg, total anti-hepatitis B core antibody (anti-HBc) and anti-HBsAb.

[0183] Anti-HBc positive patients may be included only if HBV DNA is undetectable. Only in these patients should HBV DNA be assessed at various subsequent visits as outlined in the SoA.

[0184] With regard to the exclusion criteria, seropositivity or active viral infection with HBV means: ·HBV surface antigen positive HBV surface antigen negative, HBV surface antibody positive and / or HBV core antibody positive, and detectable viral DNA. Note: HBV surface antigen negative and viral DNA negative patients are eligible. Patients who present with the classical vaccination profile of HBV surface antibody positivity, HBV core antibody negativity, and HBV surface antigen negativity are eligible.

[0185] If HBV-DNA becomes detectable during treatment, patients shall be treated prophylactically and followed up for potential hepatitis B reactivation according to national medical practice or institutional guidelines for CD20 antibodies such as RTX. If the HBV-DNA assay is positive, patients may continue on study only if evaluated by a physician experienced in treating hepatitis B and preemptive treatment is initiated if deemed appropriate and / or according to national practice / guidelines.

[0186] Hepatitis C serology should be performed at screening only. Hepatitis C biomarkers include anti-HCV antibodies. For patients who are anti-HCV antibody positive, HCV-RNA should be measured. 1. A positive hepatitis C test is defined as a positive HCV antibody test and a positive HCV RNA test.

Claims

1. 1. A pharmaceutical composition comprising an anti-CD19 antibody for the treatment of cancer, wherein said anti-CD19 antibody is administered at a dose of at least 24 mg / kg.

2. 2. The pharmaceutical composition of claim 1, wherein the anti-CD19 antibody comprises a heavy chain variable region comprising an HCDR1 region comprising the sequence SYVMH (SEQ ID NO: 1), an HCDR2 region comprising the sequence NPYNDG (SEQ ID NO: 2), and an HCDR3 region comprising the sequence GTYYYGTRVFDY (SEQ ID NO: 3), and a light chain variable region comprising an LCDR1 region comprising the sequence RSSKSLQNVNGNTYLY (SEQ ID NO: 4), an LCDR2 region comprising the sequence RMSNLNS (SEQ ID NO: 5), and an LCDR3 region comprising the sequence MQHLEYPIT (SEQ ID NO: 6).

3. 2. The pharmaceutical composition of claim 1, wherein the anti-CD19 antibody comprises a heavy chain variable region comprising an HCDR1 region of SYVMH (SEQ ID NO: 1), an HCDR2 region of NPYNDG (SEQ ID NO: 2), and an HCDR3 region of GTYYYGTRVFDY (SEQ ID NO: 3), and a light chain variable region comprising an LCDR1 region of RSSKSLQNVNGNTYLY (SEQ ID NO: 4), an LCDR2 region of RMSNLNS (SEQ ID NO: 5), and an LCDR3 region of MQHLEYPIT (SEQ ID NO: 6).

4. the anti-CD19 antibody has a heavy chain variable region of EVQLVESGGGLVKPGGSLKLSCAASGYTFTSYVMHWVRQAPGKGLEWIGYINPYNDGTKYNEKFQGRVTISSDKSISTAYMELSSLRSEDTAMYYCARGTYYYGTRVFDYWGQGTLVTVSS (SEQ ID NO: 7); , and a light chain variable region of: DIVMTQSPATLSLSPGERATLSCRSSKSLQNVNGNTYLYWFQQKPGQSPQLLIYRMSNLNSGVPDRFSGSGSGTEFTLTISSLEPEDFAVYYCMQHLEYPITFGAGTKLEIK (SEQ ID NO: 8).

5. 2. The pharmaceutical composition of claim 1, wherein the anti-CD19 antibody comprises an Fc domain comprising an amino acid substitution at positions S239 and / or I332, wherein numbering is according to the EU index as in Kabat.

6. 2. The pharmaceutical composition of claim 1, wherein the anti-CD19 antibody comprises an Fc domain comprising an amino acid substitution of S239D and an amino acid substitution of I332E, wherein numbering is according to the EU index as in Kabat.

7. The anti-CD19 antibody is ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPDVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKALPAPEEKTISKTKGQPREPQVYTLPPSR 2. The pharmaceutical composition of claim 1, comprising a heavy chain constant region of EEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 9) and a light chain constant region of RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 10).

8. The anti-CD19 antibody is EVQLVESGGGLVKPGGSLKLSCAASGYTFTSYVMHWVRQAPGKGLEWIGYINPYNDGTKYNEKFQGRVTISSDKSISTAYMELSSLRSEDTAMYYCARGTYYYGTRVFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGV HTFPAVLQSSGLYSLSSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPDVFLFPPKPKDTLMISRTPE VTCVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKALPAPEEKTISKTKGQPREPQVY TLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 11), and the heavy chain region of DIVMTQSPATTLSLSPGERATLSCRSSKSLQNVNGNTYLYWFQQKPGQSPQLLIYRMSNLNSGVPDRFSG and a light chain region of SGSGTEFTLTISSLEPEDFAVYYCMQHLEYPITFGAGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 12).

9. The pharmaceutical composition of claim 1, wherein the anti-CD19 antibody is administered intravenously or subcutaneously by intravenous infusion.

10. 10. The pharmaceutical composition of claim 1, wherein said dosage reduces the dosing frequency from once a week to at least once every two weeks.

11. The pharmaceutical composition of claim 1 , wherein the cancer is a hematological malignancy.

12. The pharmaceutical composition of claim 1 , wherein the cancer is lymphoma or leukemia.

13. 2. The pharmaceutical composition of claim 1, wherein the cancer is non-Hodgkin's lymphoma (NHL), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), or acute lymphoblastic leukemia (ALL).

14. 2. The pharmaceutical composition of claim 1, wherein the cancer is diffuse large B-cell lymphoma (DLBCL) or relapsed or refractory diffuse large B-cell lymphoma (r / r DLBCL).

15. The pharmaceutical composition of claim 1, wherein the anti-CD19 antibody is administered once a week, once every two weeks, or once every four weeks.

16. The pharmaceutical composition of claim 1, wherein the anti-CD19 antibody is administered at a dose ranging from 24 mg / kg to 30 mg / kg.

17. The pharmaceutical composition of claim 1, wherein the anti-CD19 antibody is administered at a dose of 24 mg / kg.

18. The pharmaceutical composition of claim 1, wherein the anti-CD19 antibody is administered at a dose of 30 mg / kg.

19. 2. The pharmaceutical composition of claim 1, wherein the anti-CD19 antibody is administered in 28-day cycles, wherein a) a 12 mg / kg dose is administered on days 1, 4, and 9 of a first cycle and a dose of at least 24 mg / kg is administered on day 15 of the first cycle; b) a 24 mg / kg dose is administered on days 1 and 15 of cycles 2-3; and c) a dose of at least 24 mg / kg is administered on day 1 of additional subsequent cycles.

20. 10. The pharmaceutical composition of claim 1, wherein the anti-CD19 antibody is administered in 28-day cycles, wherein a) a dose of 12 mg / kg is administered on days 1, 4, and 9 of a first cycle and a dose ranging from 24 mg / kg to 30 mg / kg is administered on day 15 of the first cycle; b) a dose ranging from 24 mg / kg to 30 mg / kg is administered on days 1 and 15 of cycles 2-3; and c) a dose ranging from 24 mg / kg to 30 mg / kg is administered on day 1 of additional subsequent cycles.

21. 2. The pharmaceutical composition of claim 1, wherein the anti-CD19 antibody is administered in 28-day cycles, wherein a) a 12 mg / kg dose is administered on days 1, 4, and 9 of a first cycle and a 24 mg / kg dose is administered on day 15 of the first cycle; b) a 24 mg / kg dose is administered on days 1 and 15 of cycles 2-3; and c) a 24 mg / kg dose is administered on day 1 of additional subsequent cycles.

22. 10. The pharmaceutical composition of claim 1, wherein the anti-CD19 antibody is administered in 28-day cycles, wherein a) a 12 mg / kg dose is administered on days 1, 4, and 9 of a first cycle and a 30 mg / kg dose is administered on day 15 of the first cycle; b) a 30 mg / kg dose is administered on days 1 and 15 of cycles 2-3; and c) a 30 mg / kg dose is administered on day 1 of additional subsequent cycles.

23. A pharmaceutical composition described in any one of claims 1 to 22, wherein the anti-CD19 antibody is administered in combination with lenalidomide.

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