Combination treatment with anti-CD20 / anti-CD3 bispecific antibody and chemotherapy

Abstract

The present invention relates to methods of treating B-cell proliferative disorders, such as primary refractory or relapsed diffuse large B-cell lymphoma (DLBCL), by administering an anti-CD20 / anti-CD3 bispecific antibody in combination with an anti-CD20 antibody (e.g., obinutuzumab or rituximab) and one or more chemotherapeutic agents selected from ifosfamide, carboplatin and / or etoposide.

Description

[Technical Field]

[0001] FIELD OF THE INVENTION The present invention relates to methods of treating B-cell proliferative disorders, such as primary refractory or relapsed diffuse large B-cell lymphoma (DLBCL), by administering an anti-CD20 / anti-CD3 bispecific antibody in combination with an anti-CD20 antibody (e.g., obinutuzumab or rituximab) and one or more chemotherapeutic agents selected from ifosfamide, carboplatin, and / or etoposide. [Background technology]

[0002] Background of the Invention Non-Hodgkin lymphoma (NHL) is the most common hematologic malignancy worldwide (Bray et al. 2018). DLBCL, the most common subtype of NHL of B-cell origin (Sun et al. Am. J. Clin. Pathol. 138:429-434, 2012; Al-Hamadani et al. Am. J. Hematol. 24:4785-4797, 2015), is an aggressive form of NHL with a median survival of less than one year in untreated patients (Rovira et al. Ann. Hematol. 94:803-812, 2015). Despite its aggressive disease course, approximately 50% to 70% of patients can be cured with the current standard of care treatment, which consists of rituximab (a monoclonal antibody directed against CD20) combined with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) chemotherapy (Flowers et al. CA Cancer J. Clin. 60:393-408 2010; Tilly et al. Ann. Oncol. 26(Suppl 5):v116-125 2015; NCCN Clinical Practice Guidelines in Oncology, 2020).

[0003] Nevertheless, R-CHOP has been found to be insufficient in 30%–50% of patients due to either primary refractory disease, defined as the inability to achieve complete response (CR) after first-line therapy with rituximab plus anthracycline (Vardhana et al. Br. J. Haematol. 176:591–599, 2017), or relapse after achieving CR. For patients who are not cured by first-line therapy and can medically tolerate intensive therapy, high-dose salvage chemoimmunotherapy followed by ASCT offers a second chance for long-term remission. Approximately half of patients with relapsed DLBCL are refractory to salvage chemoimmunotherapy (Gisselbrecht et al. J. Clin. Oncol. 28:4184–4190, 2010) and therefore are unable to proceed to ASCT. Furthermore, for a subgroup of DLBCL patients, CAR-T therapy is an available treatment option, particularly for those with primary refractory disease or who relapse within 12 months of initial chemoimmunotherapy (Kamdar et al. 2022, Lancet 399, 2294-2308; Locke et al. 2022, N Engl J Med 386, 640-54). Given that the median EFS observed in both studies was less than 1 year, continued opportunities remain for optimizing treatment regimens including CAR-T therapy. Therefore, there is a significant clinical need for improved salvage immunochemotherapy regimens for patients with relapsed or refractory (R / R) DLBCL.

[0004] Combining an anti-CD20 / anti-CD3 bispecific antibody with an anti-CD20 antibody (e.g., obinutuzumab or rituximab) and one or more chemotherapeutic agents selected from ifosfamide, carboplatin, and / or etoposide may result in improved response rates to salvage chemoimmunotherapy, which may ultimately translate into a higher proportion of patients undergoing curative treatment with ASCT or CAR-T therapy and improved survival in this treatment setting.

[0005] Aggressive mature B-NHL accounts for approximately 60% of all cases of pediatric non-Hodgkin's lymphoma (NHL). The major histologic subtypes are Burkitt lymphoma (BL), Burkitt leukemia (BAL; similar to mature B-cell leukemia FAB L3), diffuse large B-cell lymphoma (DLBCL), primary mediastinal large B-cell lymphoma (PMBCL), and aggressive mature B-NHL not further classified. Although frontline therapy with intensive chemotherapy plus rituximab is highly effective in children, with a 3-year event-free survival of 94% (Minard-Colin et al. N. Eng. J. Med. 382:2207-2219, 2020), there remains an urgent and high unmet need for the development of effective salvage regimens for patients with first R / R disease (Pearson et al. Eur. J. Cancer. 110:74-85, 2019). Survival rates for R / R B-NHL in children, adolescents, and young adults are very poor, with 1-year overall survival (OS) rates of less than 30% (Cairo et al. Br. J. Haematol. 182:859-869, 2018; Woessmann et al. Blood. 135:1124-1132, 2020; Burkhardt et al. Cancers. 13:2075, 2021; Crombie and LaCasce Blood. 137:743-750, 2021). Summary of the Invention

[0006] Summary of the Invention In one aspect, the invention features a method of treating a subject having a CD20-positive cell proliferative disorder, comprising administering to the subject an effective amount of: (a) a bispecific antibody that binds to CD20 and CD3; (b) an anti-CD20 antibody; and (c) administering one or more chemotherapeutic agents selected from ifosfamide, carboplatin, and / or etoposide in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle.

[0007] In one embodiment, the subject is 18 years of age or older (e.g., 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, or 110 years of age or older). In one embodiment, the subject is 31 years of age or older.

[0008] In one embodiment, the first administration cycle comprises a first dose of a bispecific antibody that binds CD20 and CD3 (C1D1) and a second dose of the bispecific antibody (C1D2), wherein C1D1 of the bispecific antibody is about 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, or ± 0.25 mg) and C1D2 of the bispecific antibody is about 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, or ± 1 mg); and the second administration cycle comprises and a single dose of bispecific antibody (C2D1), wherein the C2D1 of the bispecific antibody is about 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, or ± 1 mg), about 16 mg (e.g., 16 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, or ± 1.6 mg), or about 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg). In one embodiment, the C2D1 of the bispecific antibody is about 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg).

[0009] In one embodiment, a first dose of a bispecific antibody that binds CD20 and CD3 (C1D1) and a second dose of a bispecific antibody that binds CD20 and CD3 (C1D2) are administered to a subject on days 8 and 15 of a first administration cycle, respectively. In one embodiment, C2D1, a bispecific antibody that binds CD20 and CD3, is administered to a subject on day 8 of a second administration cycle.

[0010] In one embodiment, the anti-CD20 antibody is obinutuzumab and / or rituximab. In one embodiment, the first administration cycle comprises a single dose of obinutuzumab (C1D1); and the second administration cycle comprises a single dose of rituximab (C2D1). In one embodiment, the single dose C1D1 of obinutuzumab is about 1000 mg (e.g., 1000 mg ± 5 mg, ± 10 mg, ± 20 mg, ± 30 mg, ± 50 mg, ± 75 mg, or ± 100 mg), and the single dose of rituximab is about 375 mg / m 2 (e.g., 375 mg / m 2 ±5 mg / m 2 , ±10 mg / m 2 , ±25 mg / m 2 , or ±37.5 mg / m 2 In one embodiment, the anti-CD20 antibody is administered in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein the first dosing cycle comprises a single dose of obinutuzumab on day 1 (C1D1); and the second dosing cycle comprises a single dose of rituximab on day 1 (C2D1).

[0011] In one embodiment, step c) includes all three chemotherapeutic agents. In one embodiment, the first administration cycle includes a single dose of ifosfamide (C1D1), a single dose of carboplatin (C1D1), and the first (C1D1), second (C1D2), and third (C1D3) doses of etoposide; the second cycle includes a single dose of ifosfamide (C2D1), a single dose of carboplatin (C2D1), and the first (C2D1), second (C2D2), and third (C2D3) doses of etoposide, respectively. In one embodiment, ifosfamide is administered at a dose of about 5000 mg / m 2 (e.g., 5000 mg / m 2 ±50 mg / m 2 , ±100 mg / m 2 , ±200 mg / m 2 , ±300 mg / m 2 , ±400 mg / m 2 , or ±500 mg / m 2 ), approx. 4000mg / m 2 (e.g., 4000 mg / m2 ±40 mg / m 2 , ±50 mg / m 2 , ±100 mg / m 2 , ±200 mg / m 2 , ±300 mg / m 2 , or ±400 mg / m 2 ), or approximately 1666 mg / m 2 (e.g., 1666 mg / m 2 ±25 mg / m 2 , ±50 mg / m 2 , ±100 mg / m 2 , or ±166.6 mg / m 2 ), carboplatin is administered at a mg dose targeting an area under the curve (AUC) of about 5 mg / mL / min (e.g., 5 mg / mL / min ±0.05 mg / mL / min, ±0.1 mg / mL / min, ±0.25 mg / mL / min, or ±0.5 mg / mL / min) with a maximum dose of about 750 mg (e.g., 750 mg ±10 mg, ±25 mg, ±50 mg, or ±75 mg), and etoposide is administered at a dose of about 100 mg / m 2 (e.g., 100 mg / m 2 ±1 mg / m 2 , ±2.5 mg / m 2 , ±5 mg / m 2 , or ±10 mg / m 2 ) or 75 mg / m 2 (e.g., 0.5 mg / m 2 ±1 mg / m 2 , ±2.5 mg / m 2 , ±5 mg / m 2 , or ±7.5 mg / m 2 In one embodiment, ifosfamide is administered at a dose of 5000 mg / m 2 , 4000 mg / m 2 or 1666 mg / m 2 carboplatin was administered at a dose of 100 mg / m2 targeting an area under the curve (AUC) of 5 mg / mL / min with a maximum dose of 750 mg; etoposide was administered at a dose of 100 mg / m2 2 or 75 mg / m 2 In one embodiment, ifosfamide is administered at a dose of 5000 mg / m 2carboplatin was administered at a dose of 100 mg / m2 targeting an area under the curve (AUC) of 5 mg / mL / min with a maximum dose of 750 mg; etoposide was administered at a dose of 100 mg / m2 2 In one embodiment, ifosfamide and carboplatin are administered on day 2 of the first administration cycle and the second administration cycle, and etoposide is administered on days 1, 2, and 3 of each of the first administration cycle and the second administration cycle.

[0012] In one embodiment, the first and second dosing cycles are 21 day dosing cycles.

[0013] In one embodiment, the dosing regimen includes one or more additional dosing cycles. In one embodiment, the additional dosing cycles are 21-day dosing cycles. In one embodiment, the dosing regimen includes a total of three dosing cycles.

[0014] In one embodiment, the one or more additional administration cycles include: (a) an additional single dose of a bispecific antibody that binds to CD20 and CD3; (b) an additional single dose of an anti-CD20 antibody, and (c) an additional single dose of ifosfamide, an additional single dose of carboplatin, and an additional first, second, and third dose of etoposide. In one embodiment, the additional single dose of bispecific antibody is about 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg).

[0015] In one embodiment, the anti-CD20 antibody for one or more additional administration cycles is rituximab. In one embodiment, the additional single dose of rituximab is about 375 mg / m 2 (e.g., 375 mg / m 2 ±5 mg / m 2 , ±10 mg / m 2 , ±25 mg / m 2 , or ±37.5 mg / m 2In one embodiment, an additional single dose of rituximab is administered on day 1 of an additional administration cycle.

[0016] In one embodiment, the additional single dose of ifosfamide is about 5000 mg / m 2 (e.g., 5000 mg / m 2 ±50 mg / m 2 , ±100 mg / m 2 , ±200 mg / m 2 , ±300 mg / m 2 , ±400 mg / m 2 , or ±500 mg / m 2 ), approx. 4000mg / m 2 (e.g., 4000 mg / m 2 ±40 mg / m 2 , ±50 mg / m 2 , ±100 mg / m 2 , ±200 mg / m 2 , ±300 mg / m 2 , or ±400 mg / m 2 ), or approximately 1666 mg / m 2 (e.g., 1666 mg / m 2 ±25 mg / m 2 , ±50 mg / m 2 , ±100 mg / m 2 , or ±166.6 mg / m 2 ), the additional single dose of carboplatin is 100 mg / m2 targeting an area under the curve (AUC) of about 5 mg / mL / min (e.g., 5 mg / mL / min ±0.05 mg / mL / min, ±0.1 mg / mL / min, ±0.25 mg / mL / min, or ±0.5 mg / mL / min) at a maximum dose of about 750 mg (e.g., 750 mg ±10 mg, ±25 mg, ±50 mg, or ±75 mg), and the additional first, second, and third doses of etoposide are 100 mg / m2 2 (e.g., 100 mg / m 2 ±1 mg / m 2 , ±2.5 mg / m 2 , ±5 mg / m 2 , or ±10 mg / m 2 ) or 75 mg / m 2 (e.g., 0.5 mg / m 2 ±1 mg / m2 , ±2.5 mg / m 2 , ±5 mg / m 2 , or ±7.5 mg / m 2 In one embodiment, the additional single dose of ifosfamide is 5000 mg / m 2 , 4000 mg / m 2 or 1666 mg / m 2 and the additional single dose of carboplatin is 1 mg targeting an area under the curve (AUC) of 5 mg / mL / min with a maximum dose of 750 mg, and the additional first, second, and third doses of etoposide are 100 mg / m 2 or 75 mg / m 2 In one embodiment, ifosfamide is 5000 mg / m 2 carboplatin was administered at a dose of 100 mg / m2 targeting an area under the curve (AUC) of 5 mg / mL / min with a maximum dose of 750 mg; etoposide was administered at a dose of 100 mg / m2 2 is administered at a dose of

[0017] In one embodiment, ifosfamide and carboplatin are administered on day 2 of the additional administration cycle, and etoposide is administered on each of days 1, 2, and 3 of the additional administration cycle.

[0018] In one embodiment, the method further comprises administering one or more additional therapeutic agents to the subject. In one embodiment, the one or more additional therapeutic agents is tocilizumab. In one embodiment, the subject weighs about 30 kg or more and tocilizumab is administered at a dose of about 8 mg / kg (e.g., 8 mg / kg ± 0.05 mg / kg, ± 0.1 mg / kg, ± 0.25 mg / kg, ± 0.5 mg / kg, or ± 0.8 mg / kg). In one embodiment, the subject weighs less than 30 kg and tocilizumab is administered at a dose of about 12 mg / kg (e.g., 12 mg / kg ± 0.05 mg / kg, ± 0.1 mg / kg, ± 0.25 mg / kg, ± 0.5 mg / kg, ± 0.75 mg / kg, ± 1 mg / kg, or ± 1.2 mg / kg). In some embodiments, the maximum dose of tocilizumab is about 800 mg (e.g., 800 mg ± 10 mg, ± 25 mg, ± 50 mg, or ± 80 mg).

[0019] In one embodiment, the one or more additional therapeutic agents is a corticosteroid. In one embodiment, the corticosteroid comprises prednisone, prednisolone, methylprednisolone, or dexamethasone. In one embodiment, the dexamethasone is administered intravenously at a dose of about 20 mg (e.g., 20 mg ± 0.1 mg, ± 0.25 mg, ± 0.5 mg, ± 1 mg, ± 1.5 mg, or ± 2 mg) at least about 1 hour (i.e., at least 1 hour ± 6 minutes; e.g., at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours, or more) prior to administration of any dose of the bispecific antibody. In one embodiment, dexamethasone is administered intravenously at a dose of about 20 mg (e.g., 20 mg ± 0.1 mg, ± 0.25 mg, ± 0.5 mg, ± 1 mg, ± 1.5 mg, or ± 2 mg) at least about 1 hour (i.e., at least 1 hour ± 6 minutes; e.g., at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours, or more) prior to administration of any dose of obinutuzumab. In one embodiment, methylprednisolone is administered intravenously at a dose of about 80 mg (e.g., 80 mg ± 0.5 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, ± 4 mg, ± 6 mg, or ± 8 mg) at least about 1 hour (i.e., at least 1 hour ± 6 minutes; e.g., at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours, or more) prior to administration of any dose of the bispecific antibody. In one embodiment, methylprednisolone is administered intravenously at a dose of about 80 mg (e.g., 80 mg ±0.5 mg, ±1 mg, ±1.5 mg, ±2 mg, ±4 mg, ±6 mg, or ±8 mg) at least about 1 hour (i.e., at least 1 hour ±6 minutes; e.g., at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours, or more) prior to administration of any dose of obinutuzumab.In one embodiment, prednisone is administered orally at a dose of about 100 mg (e.g., 100 mg ± 0.5 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, ± 4 mg, ± 6 mg, ± 8 mg, or ± 10 mg) at least about 1 hour (i.e., at least 1 hour ± 6 minutes; e.g., at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours, or more) prior to administration of any dose of the bispecific antibody. In one embodiment, prednisolone is administered intravenously at a dose of about 100 mg (e.g., 100 mg ± 0.5 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, ± 4 mg, ± 6 mg, ± 8 mg, or ± 10 mg) at least about 1 hour (i.e., at least 1 hour ± 6 minutes; e.g., at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours, or more) prior to administration of any dose of the bispecific antibody.

[0020] In one embodiment, the one or more additional therapeutic agents is an antihistamine. In one embodiment, the antihistamine is diphenhydramine. In one embodiment, diphenhydramine is administered orally or intravenously at a dose of about 50 mg (e.g., 50 mg ± 0.5 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, ± 3 mg, ± 4 mg, or ± 5 mg) at least about 30 minutes (i.e., at least 30 minutes ± 3 minutes; e.g., at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours, or more) prior to administration of any dose of the bispecific antibody.

[0021] In one embodiment, the one or more additional therapeutic agents comprise granulocyte colony-stimulating factor (G-CSF), hi one embodiment, the G-CSF is administered about 1 to about 2 days (e.g., 24, 26, 28, 30, 32, 36, 38, 40, 42, 44, 46, or 48 hours) after administration of any dose of rituximab, ifosfamide, carboplatin, and / or etoposide.

[0022] In one embodiment, the one or more additional therapeutic agents is an antipyretic. In one embodiment, the antipyretic is acetaminophen or paracetamol. In one embodiment, the acetaminophen or paracetamol is administered orally at a dose of about 500 mg to about 1000 mg (e.g., 1000 mg ± 5 mg, ± 10 mg, ± 20 mg, ± 30 mg, ± 50 mg, ± 75 mg, or ± 100 mg) at least about 30 minutes (i.e., at least 30 minutes ± 3 minutes; e.g., at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours, or more) prior to administration of any dose of the bispecific antibody. In one embodiment, acetaminophen or paracetamol is administered orally at a dose of about 500 mg to about 1000 mg (e.g., 1000 mg ± 5 mg, ± 10 mg, ± 20 mg, ± 30 mg, ± 50 mg, ± 75 mg, or ± 100 mg) at least about 30 minutes (i.e., at least 30 minutes ± 3 minutes; e.g., at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours, or more) prior to administration of any dose of obinutuzumab.

[0023] In one embodiment, the one or more additional therapeutic agents is mesna. In one embodiment, mesna is at about 5000 mg / m 2 (e.g., 5000 mg / m 2 ±50 mg / m 2 , ±100 mg / m 2 , ±200 mg / m 2 , ±300 mg / m 2 , ±400 mg / m 2 , or ±500 mg / m 2 ), approx. 4000mg / m 2 (e.g., 4000 mg / m 2 ±40 mg / m 2 , ±50 mg / m 2 , ±100 mg / m 2 , ±200 mg / m 2 , ±300 mg / m 2 , or ±400 mg / m 2 ), or approximately 1666 mg / m 2 (e.g., 1666 mg / m 2 ±25 mg / m2 , ±50 mg / m 2 , ±100 mg / m 2 , or ±166.6 mg / m 2 ) is administered intravenously.

[0024] In one aspect, the invention features a method of treating a subject 6 months to 17 years of age having a CD20-positive cell proliferative disorder, comprising administering to the subject an effective amount of: (a) a bispecific antibody that binds to CD20 and CD3; (b) an anti-CD20 antibody; and (c) administering one or more chemotherapeutic agents selected from ifosfamide, carboplatin, and / or etoposide in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle.

[0025] In one embodiment, the first administration cycle comprises a first dose of a bispecific antibody (C1D1) and a second dose of a bispecific antibody (C1D2), wherein C1D1 of the bispecific antibody is administered at a dose of about 0.03 mg / kg (e.g., 0.03 mg / kg ± 0.0005 mg / kg, ± 0.001 mg / kg, ± 0.002 mg / kg, or ± 0.003 mg / kg), about 0.04 mg / kg (e.g., 0.04 mg / kg ± 0.0005 mg / kg, ± 0.001 mg / kg, ± 0.002 mg / kg, ± 0.003 mg / kg, or ± 0.004 mg / kg), or about 2 0.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, or ± 0.25 mg), and C1D2 of the bispecific antibody is about 0.15 mg / kg (e.g., 0.15 mg / kg ± 0.001 mg / kg, ± 0.0025 mg / kg, ± 0.005 mg / kg, ± 0.01 mg / kg, or ± 0.015 mg / kg) or about 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, or ± 1 mg); The second administration cycle comprises a single dose of the bispecific antibody (C2D1), wherein the C2D1 of the bispecific antibody is about 0.4 mg / kg (e.g., 0.4 mg / kg ± 0.005 mg / kg, ± 0.01 mg / kg, ± 0.02 mg / kg, ± 0.03 mg / kg, or ± 0.04 mg / kg), about 0.5 mg / kg (e.g., 0.5 mg / kg ± 0.005 mg / kg, ± 0.01 mg / kg, ± 0.02 mg / kg, ± 0.03 mg / kg, ± 0.04 mg / kg, or ± 0.05 mg / kg), or about 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg).

[0026] In one embodiment, (a) the subject weighs at least about 7.5 kg but less than about 13 kg, and the C1D1 of the bispecific antibody is about 0.04 mg / kg (e.g., 0.04 mg / kg ± 0.0005 mg / kg, ± 0.001 mg / kg, ± 0.002 mg / kg, ± 0.003 mg / kg, or ± 0.004 mg / kg), and the C1D2 of the bispecific antibody is about 0.15 mg / kg (e.g., 0.15 mg / kg). g ±0.001 mg / kg, ±0.0025 mg / kg, ±0.005 mg / kg, ±0.01 mg / kg, or ±0.015 mg / kg) and the C2D1 of the bispecific antibody is about 0.5 mg / kg (e.g., 0.5 mg / kg ±0.005 mg / kg, ±0.01 mg / kg, ±0.02 mg / kg, ±0.03 mg / kg, ±0.04 mg / kg, or ±0.05 mg / kg); (b) the subject weighs about 13 kg or more and less than about 45 kg, and C1D1 of the bispecific antibody is about 0.03 mg / kg (e.g., 0.03 mg / kg ± 0.0005 mg / kg, ± 0.001 mg / kg, ± 0.002 mg / kg, or ± 0.003 mg / kg), C1D2 of the bispecific antibody is about 0.15 mg / kg (e.g., 0.15 mg / kg ± 0.001 mg / kg, ± 0.0025 mg / kg, ± 0.005 mg / kg, ± 0.01 mg / kg, or ± 0.015 mg / kg), and C2D1 of the bispecific antibody is about 0.4 mg / kg (e.g., 0.4 mg / kg ± 0.005 mg / kg, ± 0.01 mg / kg, ± 0.02 mg / kg, ± 0.03 mg / kg, or ± 0.04 mg / kg); or (c) the subject weighs about 45 kg or more, C1D1 of the bispecific antibody is about 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, or ± 0.25 mg), C1D2 of the bispecific antibody is about 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, or ± 1 mg), and C2D1 of the bispecific antibody is about 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg).

[0027] In one embodiment, bispecific antibody C1D1 and bispecific antibody C1D2 are administered to a subject on days 8 and 15, respectively, of a first administration cycle. In one embodiment, bispecific antibody C2D1 is administered to a subject on day 1 of a second administration cycle.

[0028] In one embodiment, the anti-CD20 antibody is obinutuzumab and / or rituximab.

[0029] In one embodiment, the first administration cycle comprises a first dose of obinutuzumab (C1D1) and a second dose of obinutuzumab (C1D2). In one embodiment, (a) the subject weighs about 7.5 kg or more and less than about 13 kg and the sum of C1D1 and C1D2 of obinutuzumab is about 38 mg / kg (e.g., 38 mg / kg ± 0.25 mg / kg, ± 0.5 mg / kg, ± 1 mg / kg, ± 2 mg / kg, ± 3 mg / kg, or ± 3.8 mg / kg); (b) the subject weighs about 13 kg or more and less than about 20 kg and the sum of C1D1 and C1D2 of obinutuzumab is about 28 mg / kg (e.g., 28 mg / kg ± 0.25 mg / kg, ± 0.5 mg / kg, ± 1 mg / kg, ± 2 mg / kg, or ± 2.8 mg / kg); (c) the subject weighs about 20 kg or more and less than about 32 kg and the sum of C1D1 and C1D2 of obinutuzumab is about 28 mg / kg (e.g., 28 mg / kg ± 0.25 mg / kg, ± 0.5 mg / kg, ± 1 mg / kg, ± 2 mg / kg, or ± 2.8 mg / kg). (d) the subject weighs about 32 kg or more and less than about 45 kg and the sum of C1D1 and C1D2 of obinutuzumab is about 20 mg / kg (e.g., 23 mg / kg ± 0.25 mg / kg, ± 0.5 mg / kg, ± 1 mg / kg, ± 2 mg / kg, or ± 2.3 mg / kg); or (e) the subject weighs about 45 kg or more and the sum of C1D1 and C1D2 of obinutuzumab is about 1000 mg (e.g., 1000 mg ± 5 mg, ± 10 mg, ± 20 mg, ± 30 mg, ± 50 mg, ± 75 mg, or ± 100 mg).

[0030] In one embodiment, C1D1 of obinutuzumab is in an amount that is about 1 / 10 of the sum of C1D1 and C1D2 of obinutuzumab, and C1D2 of obinutuzumab is in an amount that is about 9 / 10 of the sum of C1D1 and C1D2 of obinutuzumab.In one embodiment, (a) the subject weighs greater than or equal to about 7.5 kg and less than about 13 kg, and the C1D1 of obinutuzumab is about 3.8 mg / kg (e.g., 3.8 mg / kg ± 0.05 mg / kg, 0.1 mg / kg, ± 0.2 mg / kg, ± 0.3 mg / kg, or ± 0.38 mg / kg), and the C1D2 of obinutuzumab is about 34.2 mg / kg (e.g., 34.2 mg / kg ± 0.5 mg / kg, 1 mg / kg, ± 2 mg / kg, ± 3 mg / kg, or ± 3.42 mg / kg); (b) the subject weighs greater than or equal to about 13 kg and less than about 20 kg, and the C1D2 of obinutuzumab is about 34.2 mg / kg (e.g., 34.2 mg / kg ± 0.5 mg / kg, 1 mg / kg, ± 2 mg / kg, ± 3 mg / kg, or ± 3.42 mg / kg); (c) the subject's body weight is greater than or equal to about 20 kg and less than about 32 kg, and the C1D1 of obinutuzumab is about 2.3 mg / kg (e.g., 2.3 mg / kg ± 0.05 mg / kg, 0.1 mg / kg, ± 0.2 mg / kg, or ± 0.28 mg / kg) and the C1D2 of obinutuzumab is about 35.2 mg / kg (e.g., 35.2 mg / kg ± 0.5 mg / kg, 1 mg / kg, ± 2 mg / kg, ± 3 mg / kg, or ± 3.52 mg / kg); (d) the subject's body weight is greater than or equal to about 20 kg and less than about 32 kg, and the C1D1 of obinutuzumab is about 2.3 mg / kg (e.g., 2.3 mg / kg ± 0.05 mg / kg, 0.1 mg / kg, (d) the subject weighs about 32 kg or more and less than about 45 kg, and the C1D1 of obinutuzumab is about 2.0 mg / kg (e.g., 2.0 mg / kg ±0.05 mg / kg, 0.1 mg / kg, or ±0.2 mg / kg) and the C1D2 of obinutuzumab is about 36.0 mg / kg (e.g., 36.0 mg / kg ±0.5 mg / kg, 1 mg / kg, ±2 mg / kg, ±3 mg / kg, or ±3.57 mg / kg); or (e) the subject weighs about 45 kg or more and the C1D1 of obinutuzumab is about 100 mg (e.g., 100 mg ± 0.5 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, ± 4 mg, ± 6 mg, ± 8 mg, or ± 10 mg) and the C1D2 of obinutuzumab is about 900 mg (e.g., 900 mg ± 5 mg, ± 10 mg, ± 20 mg, ± 30 mg, ± 40 mg, ± 50 mg, ± 60 mg, ± 70 mg, ± 80 mg, or ± 90 mg).

[0031] In one embodiment, obinutuzumab C1D1 is administered to the subject on day 1 of the first administration cycle and obinutuzumab C1D2 is administered to the subject on day 2 of the first administration cycle.

[0032] In one embodiment, the second administration cycle comprises a single dose of rituximab (C2D1). In one embodiment, the C2D1 of rituximab is about 375 mg / m 2 (e.g., 375 mg / m 2 ±5 mg / m 2 , ±10 mg / m 2 , ±25 mg / m 2 , or ±37.5 mg / m 2 In one embodiment, rituximab is administered to the subject on day 5 of the second administration cycle.

[0033] In one embodiment, the method comprises administering to the subject ifosfamide, carboplatin, and etoposide.

[0034] In one embodiment, the first administration cycle comprises: (a) first dose of ifosfamide (C1D1), second dose of ifosfamide (C1D2), and third dose of ifosfamide (C1D3); (b) a single dose of carboplatin (C1D1); and (c) a first dose of etoposide (C1D1), a second dose of etoposide (C1D2), and a third dose of etoposide (C1D3); The second cycle is (a) first dose of ifosfamide (C2D1), second dose of ifosfamide (C2D2), and third dose of ifosfamide (C2D3); (b) a single dose of carboplatin (C2D1); and (c) a first dose of etoposide (C2D1), a second dose of etoposide (C2D2), and a third dose of etoposide (C2D3);

[0035] In one embodiment, ifosfamide is administered at a dose of about 3000 mg / m for each dose of ifosfamide. 2 (e.g., 3000 mg / m 2 ±40 mg / m 2 , ±50 mg / m 2 , ±100 mg / m 2 , ±200 mg / m 2 , or ±300 mg / m 2 ) and carboplatin is administered at a dose of approximately 635 mg / m 2 (e.g., 635 mg / m 2 ±5 mg / m 2 , ±10 mg / m 2 , ±25 mg / m 2 , ±50 mg / m 2 , ±60 mg / m 2 , or ±63.5 mg / m 2 ) and etoposide is administered at a dose of about 100 mg / m for each dose of etoposide. 2 (e.g., 100 mg / m 2 ±1 mg / m 2 , ±2.5 mg / m 2 , ±5 mg / m 2 , or ±10 mg / m 2 In one embodiment, (a) ifosfamide C1D1, C1D2, and C1D3 are administered on days 3, 4, and 5, respectively, of the first administration cycle; (b) carboplatin C1D1 is administered on day 3 of the first administration cycle; (c) etoposide C1D1, C1D2, and C1D3 are administered on days 3, 4, and 5, respectively, of the first administration cycle; (d) ifosfamide C2D1, C2D2, and C2D3 are administered on days 6, 7, and 8, respectively, of the second administration cycle; (e) carboplatin C2D1 is administered on day 6 of the second administration cycle; and (f) etoposide C2D1, C2D2, and C2D3 are administered on days 6, 7, and 8, respectively, of the second administration cycle.

[0036] In one embodiment, the first and second administration cycles are each 21-day administration cycles. In one embodiment, the administration regimen includes one or more additional administration cycles. In one embodiment, the one or more additional administration cycles are each 21-day administration cycles. In one embodiment, the administration regimen includes a total of three administration cycles.

[0037] In one embodiment, the one or more additional administration cycles each comprise: (a) an additional single dose of a bispecific antibody that binds to CD20 and CD3; (b) an additional single dose of an anti-CD20 antibody, and (c) an additional first dose, an additional second dose, and an additional third dose of ifosfamide; an additional single dose of carboplatin; and an additional first dose, an additional second dose, and an additional third dose of etoposide. In one embodiment, (a) the subject weighs about 7.5 kg or more and less than about 13 kg and the additional single dose of the bispecific antibody is about 0.5 mg / kg (e.g., 0.5 mg / kg ± 0.005 mg / kg, ± 0.01 mg / kg, ± 0.02 mg / kg, ± 0.03 mg / kg, ± 0.04 mg / kg, or ± 0.05 mg / kg); (b) the subject weighs about 13 kg or more and less than about 45 kg and the additional single dose of the bispecific antibody is about 0.4 mg / kg. g / kg (e.g., 0.4 mg / kg ± 0.005 mg / kg, ± 0.01 mg / kg, ± 0.02 mg / kg, ± 0.03 mg / kg, or ± 0.04 mg / kg); or (c) the subject weighs about 45 kg or more and the additional single dose of bispecific antibody is about 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg).

[0038] In one embodiment, an additional single dose of the bispecific antibody is administered to the subject on day 1 of each of one or more additional administration cycles.

[0039] In one embodiment, the anti-CD20 antibody is rituximab. In one embodiment, the additional single dose of rituximab is about 375 mg / m2 (e.g., 375 mg / m 2 ±5 mg / m 2 , ±10 mg / m 2 , ±25 mg / m 2 , or ±37.5 mg / m 2 In one embodiment, an additional single dose of rituximab is administered on day 5 of each of one or more additional administration cycles.

[0040] In one embodiment, the first additional dose, the second additional dose, and the third additional dose of ifosfamide are each about 3000 mg / m 2 (e.g., 3000 mg / m 2 ±40 mg / m 2 , ±50 mg / m 2 , ±100 mg / m 2 , ±200 mg / m 2 , or ±300 mg / m 2 ) and an additional single dose of carboplatin is approximately 635 mg / m 2 (e.g., 635 mg / m 2 ±5 mg / m 2 , ±10 mg / m 2 , ±25 mg / m 2 , ±50 mg / m 2 , ±60 mg / m 2 , or ±63.5 mg / m 2 ), and the first additional dose, the second additional dose, and the third additional dose of etoposide are each about 100 mg / m 2 (e.g., 100 mg / m 2 ±1 mg / m 2 , ±2.5 mg / m 2 , ±5 mg / m 2 , or ±10 mg / m 2In one embodiment, (a) an additional first dose, an additional second dose, and an additional third dose of ifosfamide are administered to the subject on day 6, day 7, and day 8, respectively, of each of one or more additional administration cycles; (b) an additional single dose of carboplatin is administered on day 6 of each of one or more additional administration cycles; and (c) an additional first dose, an additional second dose, and an additional third dose of etoposide are administered to the subject on day 6, day 7, and day 8, respectively, of each of one or more additional administration cycles.

[0041] In one embodiment, the method further comprises administering one or more additional therapeutic agents to the subject.

[0042] In one embodiment, the one or more additional therapeutic agents is tocilizumab. In one embodiment, the subject weighs about 30 kg or more and tocilizumab is administered at a dose of about 8 mg / kg (e.g., 8 mg / kg ± 0.05 mg / kg, ± 0.1 mg / kg, ± 0.25 mg / kg, ± 0.5 mg / kg, or ± 0.8 mg / kg), or the subject weighs less than 30 kg and tocilizumab is administered at a dose of about 12 mg / kg (e.g., 12 mg / kg ± 0.05 mg / kg, ± 0.1 mg / kg, ± 0.25 mg / kg, ± 0.5 mg / kg, ± 0.75 mg / kg, ± 1 mg / kg, or ± 1.2 mg / kg), with a maximum dose of about 800 mg (e.g., 800 mg ± 10 mg, ± 25 mg, ± 50 mg, or ± 80 mg).

[0043] In one embodiment, the one or more additional therapeutic agents is a corticosteroid, hi one embodiment, the corticosteroid comprises prednisone, prednisolone, methylprednisolone, or dexamethasone.

[0044] In one embodiment, the corticosteroid is dexamethasone. In one embodiment, dexamethasone is administered intravenously at a dose of about 0.15 mg / kg (e.g., 0.15 mg / kg ± 0.001 mg / kg, ± 0.0025 mg / kg, ± 0.005 mg / kg, ± 0.01 mg / kg, or ± 0.015 mg / kg) to about 0.5 mg / kg (e.g., 0.5 mg / kg ± 0.005 mg / kg, ± 0.01 mg / kg, ± 0.02 mg / kg, ± 0.03 mg / kg, ± 0.04 mg / kg, or ± 0.05 mg / kg) at least about 1 hour (i.e., at least 1 hour ± 6 minutes; e.g., at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours, or more) prior to administration of any dose of the bispecific antibody, with a maximum daily dose of 10 mg. In one embodiment, dexamethasone is administered intravenously at a dose of about 0.15 mg / kg (e.g., 0.15 mg / kg ± 0.001 mg / kg, ± 0.0025 mg / kg, ± 0.005 mg / kg, ± 0.01 mg / kg, or ± 0.015 mg / kg) to about 0.5 mg / kg (e.g., 0.5 mg / kg ± 0.005 mg / kg, ± 0.01 mg / kg, ± 0.02 mg / kg, ± 0.03 mg / kg, ± 0.04 mg / kg, or ± 0.05 mg / kg) at least about 1 hour (i.e., at least 1 hour ± 6 minutes; e.g., at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours, or more) prior to administration of any dose of obinutuzumab, with a maximum daily dose of 10 mg.

[0045] In one embodiment, the corticosteroid is methylprednisolone, which is administered intravenously at a dose of about 1 mg / kg to about 2 mg / kg (e.g., 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.9, or 2.0 mg / kg) at least about 1 hour (i.e., at least 1 hour ± 6 minutes; e.g., at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours, or more) prior to administration of any dose of the bispecific antibody. In one embodiment, methylprednisolone is administered intravenously at a dose of about 1 mg / kg to about 2 mg / kg (e.g., 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.9, or 2.0 mg / kg) at least about 1 hour (i.e., at least 1 hour ± 6 minutes; e.g., at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours, or more) prior to administration of any dose of obinutuzumab.

[0046] In one embodiment, the corticosteroid is prednisone or prednisolone, hi one embodiment, the prednisone or prednisolone is administered intravenously at a dose of about 100 mg (e.g., 100 mg ± 0.5 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, ± 4 mg, ± 6 mg, ± 8 mg, or ± 10 mg) or about 2 mg / kg at least about 1 hour (i.e., at least 1 hour ± 6 minutes; e.g., at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours, or more) prior to administration of any dose of the bispecific antibody. In one embodiment, prednisone or prednisolone is administered intravenously at a dose of about 100 mg (e.g., 100 mg ± 0.5 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, ± 4 mg, ± 6 mg, ± 8 mg, or ± 10 mg) or about 2 mg / kg at least about 1 hour (i.e., at least 1 hour ± 6 minutes; e.g., at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours, or more) prior to administration of any dose of obinutuzumab.

[0047] In one embodiment, the one or more additional therapeutic agents is an antihistamine. In one embodiment, the antihistamine is diphenhydramine. In one embodiment, the subject is 2 to 17 years of age, and diphenhydramine is administered intravenously at a dose of about 10 mg to 20 mg (e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 mg), with a maximum single dose of about 1.25 mg / kg. In one embodiment, the subject is under 2 years of age, and diphenhydramine is administered rectally at a dose of about 20 mg (e.g., 20 mg ± 0.1 mg, ± 0.25 mg, ± 0.5 mg, ± 1 mg, ± 1.5 mg, or ± 2 mg). In one embodiment, diphenhydramine is administered at least about 30 minutes (i.e., at least 30 minutes ± 3 minutes; e.g., at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours, or more) prior to administration of any dose of bispecific antibody and / or anti-CD20 antibody.

[0048] In one embodiment, the one or more additional therapeutic agents comprise granulocyte colony-stimulating factor (G-CSF), hi one embodiment, the G-CSF is administered about 1 to about 2 days (e.g., 24, 26, 28, 30, 32, 36, 38, 40, 42, 44, 46, or 48 hours) after administration of any dose of rituximab, ifosfamide, carboplatin, and / or etoposide. In one embodiment, G-CSF is administered intravenously or subcutaneously at a dose of about 5 μg / kg / day (e.g., 5 μg / kg / day ±0.05 μg / kg / day, ±0.1 μg / kg / day, ±0.2 μg / kg / day, ±0.3 μg / kg / day, ±0.4 μg / kg / day, ±0.5 μg / kg / day), or about 10 μg / kg / day (e.g., 10 μg / kg / day ±0.1 μg / kg / day, ±0.2 μg / kg / day, ±0.4 μg / kg / day, ±0.6 μg / kg / day, ±0.8 μg / kg / day, ±1 μg / kg / day). In one embodiment, G-CSF is administered at a dose of about 5 μg / kg / day (e.g., 5 μg / kg / day ±0.05 μg / kg / day, ±0.1 μg / kg / day, ±0.2 μg / kg / day, ±0.3 μg / kg / day, ±0.4 μg / kg / day, ±0.5 μg / kg / day) in the first administration cycle, and about 10 μg / kg / day (e.g., 10 μg / kg / day ±0.1 μg / kg / day, ±0.2 μg / kg / day, ±0.4 μg / kg / day, ±0.6 μg / kg / day, ±0.8 μg / kg / day, ±1 μg / kg / day) in the second administration cycle and / or each additional administration cycle.

[0049] In one embodiment, the one or more additional therapeutic agents is an antipyretic. In one embodiment, the antipyretic is acetaminophen or paracetamol. In one embodiment, the acetaminophen or paracetamol is administered orally or intravenously at a dose of about 500 to about 1000 mg (e.g., 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 mg). In one embodiment, the acetaminophen or paracetamol is administered at least about 30 minutes (i.e., at least 30 minutes ± 3 minutes; e.g., at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours, or more) prior to administration of any dose of the bispecific antibody and / or anti-CD20 antibody.

[0050] In one embodiment, the one or more additional therapeutic agents is mesna. In one embodiment, mesna is administered at a total dose of 3000 mg / m 2 In one embodiment, mesna is administered intravenously daily as five doses in an amount of about 600 mg / m before administration of any dose of ifosfamide. 2 and about 600 mg / m at about 3 hours, about 6 hours, about 9 hours, and about 12 hours, respectively, after the first dose of ifosfamide. 2 In one embodiment, mesna is administered intravenously to a subject daily on days 3, 4, and 5 of a first administration cycle, days 6, 7, and 8 of a second administration cycle, and / or days 6, 7, and 8 of each additional administration cycle.

[0051] In one aspect, the invention features a method of treating a subject aged 18 to 30 years having a CD20-positive cell proliferative disorder, comprising administering to the subject an effective amount of: (a) a bispecific antibody that binds to CD20 and CD3; (b) an anti-CD20 antibody; and (c) administering one or more chemotherapeutic agents selected from ifosfamide, carboplatin, and / or etoposide in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle.

[0052] In one embodiment, the first administration cycle comprises a first dose of bispecific antibody (C1D1) and a second dose of bispecific antibody (C1D2), wherein C1D1 of the bispecific antibody is about 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, or ± 0.25 mg) and C1D2 of the bispecific antibody is about 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, or ± 1 mg); The second administration cycle comprises a single dose of bispecific antibody (C2D1), where the bispecific antibody C2D1 is about 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg).

[0053] In one embodiment, bispecific antibody C1D1 and bispecific antibody C1D2 are administered to a subject on days 8 and 15, respectively, of the first administration cycle.

[0054] In one embodiment, the bispecific antibody C2D1 is administered to the subject on day 1 of the second administration cycle.

[0055] In one embodiment, the anti-CD20 antibody is obinutuzumab and / or rituximab.

[0056] In one embodiment, the first administration cycle comprises a first dose of obinutuzumab (C1D1) and a second dose of obinutuzumab (C1D2). In one embodiment, the sum of C1D1 and C1D2 of obinutuzumab is about 1000 mg (e.g., 1000 mg ± 5 mg, ± 10 mg, ± 20 mg, ± 30 mg, ± 50 mg, ± 75 mg, or ± 100 mg). In one embodiment, C1D1 of obinutuzumab is about 1 / 10 the amount of the sum of C1D1 and C1D2 of obinutuzumab, and C1D2 of obinutuzumab is about 9 / 10 the amount of the sum of C1D1 and C1D2 of obinutuzumab. In one embodiment, C1D1 of obinutuzumab is about 100 mg (e.g., 100 mg ± 0.5 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, ± 4 mg, ± 6 mg, ± 8 mg, or ± 10 mg) and C1D2 of obinutuzumab is about 900 mg (e.g., 900 mg ± 5 mg, ± 10 mg, ± 20 mg, ± 30 mg, ± 40 mg, ± 50 mg, ± 60 mg, ± 70 mg, ± 80 mg, or ± 90 mg). In one embodiment, C1D1 of obinutuzumab is administered to the subject on day 1 of the first administration cycle, and C1D2 of obinutuzumab is administered to the subject on day 2 of the first administration cycle.

[0057] In one embodiment, the second administration cycle comprises a single dose of rituximab (C2D1). In one embodiment, the C2D1 of rituximab is about 375 mg / m 2 (e.g., 375 mg / m 2 ±5 mg / m 2 , ±10 mg / m 2 , ±25 mg / m 2 , or ±37.5 mg / m 2 In one embodiment, the C2D1 of rituximab is administered to the subject on day 5 of the second administration cycle.

[0058] In one embodiment, the method comprises administering to the subject ifosfamide, carboplatin, and etoposide. In one embodiment, the first administration cycle comprises: (a) Single dose of ifosfamide (C1D1); (b) a single dose of carboplatin (C1D1); and (c) a first dose of etoposide (C1D1), a second dose of etoposide (C1D2), and a third dose of etoposide (C1D3); The second cycle is (a) Single dose of ifosfamide (C2D1); (b) a single dose of carboplatin (C2D1); and (c) a first dose of etoposide (C2D1), a second dose of etoposide (C2D2), and a third dose of etoposide (C2D3);

[0059] In one embodiment, ifosfamide is about 5000 mg / m 2 (e.g., 5000 mg / m 2 ±50 mg / m 2 , ±100 mg / m 2 , ±200 mg / m 2 , ±300 mg / m 2 , ±400 mg / m 2 , or ±500 mg / m 2 ), carboplatin is administered at a dose of about 5×(25+creatinine clearance (CrCl)) mg with a maximum dose of about 750 mg (e.g., 750 mg±10 mg, ±25 mg, ±50 mg, or ±75 mg), and etoposide is administered at a dose of about 100 mg / m for each dose of etoposide. 2 (e.g., 100 mg / m 2 ±1 mg / m 2 , ±2.5 mg / m 2 , ±5 mg / m 2 , or ±10 mg / m 2 ) is administered at a dose of

[0060] In one embodiment, (a) the subject is male and CrCl is calculated using the formula CrCl = ([140 - age] x [weight (kg)]) / (72 x [serum creatinine (mg / dL)]); or (b) the subject is female and CrCl is calculated using the formula CrCl = 0.85 x ([140 - age] x [weight (kg)]) / (72 x [serum creatinine (mg / dL)]).

[0061] In one embodiment, (a) the subject has a CrCl of less than about 60 mL / min and each single dose of ifosfamide is 4000 mg / m 2 and / or (b) the subject has a CrCl of less than about 50 mL / min and each dose of etoposide is reduced to about 75 mg / m 2 Reduce to.

[0062] In one embodiment, (a) ifosfamide C1D1 is administered on day 3 of the first administration cycle; (b) carboplatin C1D1 administered on day 3 of the first dosing cycle; (c) etoposide C1D1, C1D2, and C1D3 are administered on days 3, 4, and 5, respectively, of the first dosing cycle; (d) ifosfamide C2D1 administered on day 6 of the second dosing cycle; (e) carboplatin C2D1 administered on day 6 of the second dosing cycle; (f) Etoposide C2D1, C2D2, and C2D3 are administered on days 6, 7, and 8, respectively, of the second administration cycle.

[0063] In one embodiment, the first and second administration cycles are each 21-day administration cycles. In one embodiment, the administration regimen includes one or more additional administration cycles. In one embodiment, the one or more additional administration cycles are each 21-day administration cycles. In one embodiment, the administration regimen includes a total of three administration cycles.

[0064] In one embodiment, the one or more additional administration cycles each comprise: (a) an additional single dose of a bispecific antibody that binds to CD20 and CD3; (b) an additional single dose of an anti-CD20 antibody, and (c) An additional single dose of ifosfamide; an additional single dose of carboplatin; and an additional first dose, an additional second dose, and an additional third dose of etoposide.

[0065] In one embodiment, the additional single dose of the bispecific antibody is about 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg). In one embodiment, the additional single dose of the bispecific antibody is administered to the subject on day 1 of each of one or more additional administration cycles.

[0066] In one embodiment, the anti-CD20 antibody is rituximab. In one embodiment, the additional single dose of rituximab is about 375 mg / m 2 (e.g., 375 mg / m 2 ±5 mg / m 2 , ±10 mg / m 2 , ±25 mg / m 2 , or ±37.5 mg / m 2 In one embodiment, an additional single dose of rituximab is administered on day 5 of each of one or more additional administration cycles.

[0067] In one embodiment, the additional single dose of ifosfamide is about 5000 mg / m 2 (e.g., 5000 mg / m 2 ±50 mg / m 2 , ±100 mg / m 2 , ±200 mg / m 2 , ±300 mg / m 2 , ±400 mg / m 2 , or ±500 mg / m 2 ), the additional single dose of carboplatin is about 5×(25+creatinine clearance (CrCl)) mg, the maximum dose is about 750 mg (e.g., 750 mg±10 mg, ±25 mg, ±50 mg, or ±75 mg), and the additional first dose, additional second dose, and additional third dose of etoposide are each about 100 mg / m 2 (e.g., 100 mg / m 2 ±1 mg / m 2 , ±2.5 mg / m 2 , ±5 mg / m 2 , or ±10 mg / m 2 )

[0068] In one embodiment, (a) the subject is male and CrCl is calculated using the formula CrCl = ([140 - age] x [weight (kg)]) / (72 x [serum creatinine (mg / dL)]); or (b) the subject is female and CrCl is calculated using the formula CrCl = 0.85 x ([140 - age] x [weight (kg)]) / (72 x [serum creatinine (mg / dL)]).

[0069] In one embodiment, (a) the subject has a CrCl of less than about 60 mL / min and the additional single dose of ifosfamide is 4000 mg / m 2 and / or (b) the subject has a CrCl of less than about 50 mL / min and each additional dose of etoposide is reduced to about 75 mg / m 2 Reduce to.

[0070] In one embodiment, (a) an additional single dose of ifosfamide is administered on day 6 of each of one or more additional administration cycles; (b) an additional single dose of carboplatin is administered on day 6 of each of one or more additional administration cycles; (c) An additional first dose, an additional second dose, and an additional third dose of etoposide are administered to the subject on days 6, 7, and 8, respectively, of each of one or more additional administration cycles.

[0071] In one embodiment, the method further comprises administering one or more additional therapeutic agents to the subject.

[0072] In one embodiment, the one or more additional therapeutic agents is tocilizumab. In one embodiment, the subject weighs about 30 kg or more and tocilizumab is administered at a dose of about 8 mg / kg (e.g., 8 mg / kg ± 0.05 mg / kg, ± 0.1 mg / kg, ± 0.25 mg / kg, ± 0.5 mg / kg, or ± 0.8 mg / kg), or the subject weighs less than 30 kg and tocilizumab is administered at a dose of about 12 mg / kg (e.g., 12 mg / kg ± 0.05 mg / kg, ± 0.1 mg / kg, ± 0.25 mg / kg, ± 0.5 mg / kg, ± 0.75 mg / kg, ± 1 mg / kg, or ± 1.2 mg / kg), with a maximum dose of about 800 mg (e.g., 800 mg ± 10 mg, ± 25 mg, ± 50 mg, or ± 80 mg).

[0073] In one embodiment, the one or more additional therapeutic agents is a corticosteroid.

[0074] In one embodiment, the corticosteroid comprises prednisone, prednisolone, methylprednisolone, or dexamethasone.

[0075] In one embodiment, the corticosteroid is dexamethasone. In one embodiment, dexamethasone is administered intravenously at a dose of about 0.15 mg / kg (e.g., 0.15 mg / kg ± 0.001 mg / kg, ± 0.0025 mg / kg, ± 0.005 mg / kg, ± 0.01 mg / kg, or ± 0.015 mg / kg) to about 0.5 mg / kg (e.g., 0.5 mg / kg ± 0.005 mg / kg, ± 0.01 mg / kg, ± 0.02 mg / kg, ± 0.03 mg / kg, ± 0.04 mg / kg, or ± 0.05 mg / kg) at least about 1 hour (i.e., at least 1 hour ± 6 minutes; e.g., at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours, or more) prior to administration of any dose of the bispecific antibody, with a maximum daily dose of 10 mg. In one embodiment, dexamethasone is administered intravenously at a dose of about 0.15 mg / kg (e.g., 0.15 mg / kg ± 0.001 mg / kg, ± 0.0025 mg / kg, ± 0.005 mg / kg, ± 0.01 mg / kg, or ± 0.015 mg / kg) to about 0.5 mg / kg (e.g., 0.5 mg / kg ± 0.005 mg / kg, ± 0.01 mg / kg, ± 0.02 mg / kg, ± 0.03 mg / kg, ± 0.04 mg / kg, or ± 0.05 mg / kg) at least about 1 hour (i.e., at least 1 hour ± 6 minutes; e.g., at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours, or more) prior to administration of any dose of obinutuzumab, with a maximum daily dose of 10 mg.

[0076] In one embodiment, the corticosteroid is methylprednisolone, which is administered intravenously at a dose of about 1 mg / kg to about 2 mg / kg (e.g., 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.9, or 2.0 mg / kg) at least about 1 hour (i.e., at least 1 hour ± 6 minutes; e.g., at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours, or more) prior to administration of any dose of the bispecific antibody. In one embodiment, methylprednisolone is administered intravenously at a dose of about 1 mg / kg to about 2 mg / kg (e.g., 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.9, or 2.0 mg / kg) at least about 1 hour (i.e., at least 1 hour ± 6 minutes; e.g., at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours, or more) prior to administration of any dose of obinutuzumab.

[0077] In one embodiment, the corticosteroid is prednisone or prednisolone, hi one embodiment, the prednisone or prednisolone is administered intravenously at a dose of about 100 mg (e.g., 100 mg ± 0.5 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, ± 4 mg, ± 6 mg, ± 8 mg, or ± 10 mg) or about 2 mg / kg at least about 1 hour (i.e., at least 1 hour ± 6 minutes; e.g., at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours, or more) prior to administration of any dose of the bispecific antibody. In one embodiment, prednisone or prednisolone is administered intravenously at a dose of about 100 mg (e.g., 100 mg ± 0.5 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, ± 4 mg, ± 6 mg, ± 8 mg, or ± 10 mg) or about 2 mg / kg at least about 1 hour (i.e., at least 1 hour ± 6 minutes; e.g., at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours, or more) prior to administration of any dose of obinutuzumab.

[0078] In one embodiment, the one or more additional therapeutic agents is an antihistamine. In one embodiment, the antihistamine is diphenhydramine. In one embodiment, diphenhydramine is administered orally or intravenously at a dose of about 50 mg (e.g., 50 mg ± 0.5 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, ± 3 mg, ± 4 mg, or ± 5 mg). In one embodiment, diphenhydramine is administered at least about 30 minutes (i.e., at least 30 minutes ± 3 minutes; e.g., at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours, or more) prior to administration of any dose of bispecific antibody and / or anti-CD20 antibody.

[0079] In one embodiment, the one or more additional therapeutic agents comprise granulocyte colony-stimulating factor (G-CSF), hi one embodiment, the G-CSF is administered about 1 to about 2 days (e.g., 24, 26, 28, 30, 32, 36, 38, 40, 42, 44, 46, or 48 hours) after administration of any dose of rituximab, ifosfamide, carboplatin, and / or etoposide. In one embodiment, G-CSF is administered intravenously or subcutaneously at a dose of about 5 μg / kg / day (e.g., 5 μg / kg / day ±0.05 μg / kg / day, ±0.1 μg / kg / day, ±0.2 μg / kg / day, ±0.3 μg / kg / day, ±0.4 μg / kg / day, ±0.5 μg / kg / day), or about 10 μg / kg / day (e.g., 10 μg / kg / day ±0.1 μg / kg / day, ±0.2 μg / kg / day, ±0.4 μg / kg / day, ±0.6 μg / kg / day, ±0.8 μg / kg / day, ±1 μg / kg / day). In one embodiment, G-CSF is administered at a dose of about 5 μg / kg / day (e.g., 5 μg / kg / day ±0.05 μg / kg / day, ±0.1 μg / kg / day, ±0.2 μg / kg / day, ±0.3 μg / kg / day, ±0.4 μg / kg / day, ±0.5 μg / kg / day) in the first administration cycle, and about 10 μg / kg / day (e.g., 10 μg / kg / day ±0.1 μg / kg / day, ±0.2 μg / kg / day, ±0.4 μg / kg / day, ±0.6 μg / kg / day, ±0.8 μg / kg / day, ±1 μg / kg / day) in the second administration cycle and / or each additional administration cycle.

[0080] In one embodiment, the one or more additional therapeutic agents is an antipyretic. In one embodiment, the antipyretic is acetaminophen or paracetamol. In one embodiment, the acetaminophen or paracetamol is administered orally or intravenously at a dose of about 500 to about 1000 mg (e.g., 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 mg). In one embodiment, the acetaminophen or paracetamol is administered at least about 30 minutes (i.e., at least 30 minutes ± 3 minutes; e.g., at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours, or more) prior to administration of any dose of the bispecific antibody and / or anti-CD20 antibody.

[0081] In one embodiment, the one or more additional therapeutic agents is mesna. In one embodiment, mesna is at about 5000 mg / m 2 (e.g., 5000 mg / m 2 ±50 mg / m 2 , ±100 mg / m 2 , ±200 mg / m 2 , ±300 mg / m 2 , ±400 mg / m 2 , or ±500 mg / m 2 In one embodiment, mesna is administered intravenously at a dose of 0.1 mg / kg / day. In one embodiment, mesna is administered by continuous infusion over about 24 hours on day 3 of the first dosing cycle, day 6 of the second dosing cycle, and / or day 6 of each additional dosing cycle. In one embodiment, mesna is administered simultaneously with any dose of ifosfamide.

[0082] In one aspect, the invention features a method of treating a subject having a CD20-positive cell proliferative disorder, the method including administering to the subject effective amounts of glofitamab, obinutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen including at least a first dosing cycle and a second dosing cycle; (a) a first administration cycle comprises administering a first dose (C1D1) of glofitamab on day 8 and administering a second dose (C1D2) of glofitamab on day 15, wherein the C1D1 of glofitamab is about 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, or ± 0.25 mg) and the C1D2 of glofitamab is about 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, or ± 1 mg); (b) The second administration cycle comprises administering a single dose of glofitamab (C2D1) on day 8, wherein the C2D1 of glofitamab is about 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg).

[0083] In one aspect, the invention features a method of treating a subject having a CD20-positive cell proliferative disorder, the method including administering to the subject effective amounts of glofitamab, obinutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen including a first dosing cycle, a second dosing cycle, and a third dosing cycle; (a) a first administration cycle comprises administering a first dose (C1D1) of glofitamab on day 8 and administering a second dose (C1D2) of glofitamab on day 15, wherein the C1D1 of glofitamab is about 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, or ± 0.25 mg) and the C1D2 of glofitamab is about 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, or ± 1 mg); (b) the second dosing cycle comprises administering a single dose of glofitamab (C2D1) on day 8, wherein the C2D1 of glofitamab is about 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg); (c) The third administration cycle comprises administering a single dose of glofitamab (C3D1) on day 8, wherein the C3D1 of glofitamab is about 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg).

[0084] In one aspect, the invention features a method of treating a subject having a CD20-positive cell proliferative disorder, the method including administering to the subject effective amounts of glofitamab, obinutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen including at least a first dosing cycle and a second dosing cycle; (a) The first administration cycle comprises: (i) administering a first dose of glofitamab (C1D1) on day 8 and a second dose of glofitamab (C1D2) on day 15 (wherein C1D1 of glofitamab is about 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, or ± 0.25 mg) and C1D2 of glofitamab is about 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, or ± 1 mg)); (ii) administering a first dose (C1D1) of obinutuzumab on day 1 (C1D1 of obinutuzumab is about 1000 mg (e.g., 1000 mg ± 5 mg, ± 10 mg, ± 20 mg, ± 30 mg, ± 50 mg, ± 75 mg, or ± 100 mg)); (iii) administering a single dose of ifosfamide (C1D1) on day 2 (C1D1 of ifosfamide is about 5000 mg / m with a maximum dose of about 800 mg (e.g., 800 mg ± 10 mg, ± 25 mg, ± 50 mg, or ± 80 mg));2 (e.g., 5000 mg / m 2 ±50 mg / m 2 , ±100 mg / m 2 , ±200 mg / m 2 , ±300 mg / m 2 , ±400 mg / m 2 , or ±500 mg / m 2 ) is); (iv) administering a single dose (C1D1) of carboplatin on day 2 (C1D1 of carboplatin is approximately 5 × (25 + creatinine clearance) mg); and (v) administering a first dose of etoposide (C1D1) on day 1, a second dose of etoposide (C1D2) on day 2, and a third dose of etoposide (C1D3) on day 3 (C1D1, C1D2, and C1D3 of etoposide are each about 100 mg / m 2 (e.g., 100 mg / m 2 ±1 mg / m 2 , ±2.5 mg / m 2 , ±5 mg / m 2 , or ±10 mg / m 2 )); (b) the second administration cycle (i) administering a single dose of glofitamab (C2D1) on day 8 (C2D1 of glofitamab is approximately 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg)); (ii) administering the first dose of rituximab (C2D1) on day 1 (C2D1 of rituximab is approximately 375 mg / m 2 (e.g., 375 mg / m 2 ±5 mg / m 2 , ±10 mg / m 2 , ±25 mg / m 2 , or ±37.5 mg / m 2 ) is); (iii) administering a single dose of ifosfamide on day 2 (C2D1) (C2D1 of ifosfamide is about 5000 mg / m with a maximum dose of about 800 mg (e.g., 800 mg ± 10 mg, ± 25 mg, ± 50 mg, or ± 80 mg)); 2 (e.g., 5000 mg / m 2 ±50 mg / m 2 , ±100 mg / m 2 , ±200 mg / m 2 , ±300 mg / m 2 , ±400 mg / m 2 , or ±500 mg / m 2 ) is); (iv) administering a single dose of carboplatin on day 2 (C2D1) (C2D1 of carboplatin is approximately 5 × (25 + creatinine clearance) mg); and (v) administering a first dose of etoposide (C2D1) on day 1, a second dose of etoposide (C2D2) on day 2, and a third dose of etoposide (C2D3) on day 3 (C2D1, C2D2, and C2D3 of etoposide are each about 100 mg / m 2 (e.g., 100 mg / m 2 ±1 mg / m 2 , ±2.5 mg / m 2 , ±5 mg / m 2 , or ±10 mg / m 2 ) is included.

[0085] In one aspect, the invention features a method of treating a subject having a CD20-positive cell proliferative disorder, the method including administering to the subject effective amounts of glofitamab, obinutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen including a first dosing cycle, a second dosing cycle, and a third dosing cycle; (a) The first administration cycle comprises: (i) administering a first dose of glofitamab (C1D1) on day 8 and a second dose of glofitamab (C1D2) on day 15 (wherein C1D1 of glofitamab is about 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, or ± 0.25 mg) and C1D2 of glofitamab is about 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, or ± 1 mg)); (ii) administering a first dose (C1D1) of obinutuzumab on day 1 (C1D1 of obinutuzumab is about 1000 mg (e.g., 1000 mg ± 5 mg, ± 10 mg, ± 20 mg, ± 30 mg, ± 50 mg, ± 75 mg, or ± 100 mg)); (iii) administering a single dose of ifosfamide (C1D1) on day 2 (C1D1 of ifosfamide is about 5000 mg / m with a maximum dose of about 800 mg (e.g., 800 mg ± 10 mg, ± 25 mg, ± 50 mg, or ± 80 mg)); 2 (e.g., 5000 mg / m 2 ±50 mg / m 2 , ±100 mg / m 2 , ±200 mg / m 2 , ±300 mg / m 2 , ±400 mg / m 2 , or ±500 mg / m 2 ) is); (iv) administering a single dose (C1D1) of carboplatin on day 2 (C1D1 of carboplatin is approximately 5 × (25 + creatinine clearance) mg); and (v) administering a first dose of etoposide (C1D1) on day 1, a second dose of etoposide (C1D2) on day 2, and a third dose of etoposide (C1D3) on day 3 (C1D1, C1D2, and C1D3 of etoposide are each about 100 mg / m 2 (e.g., 100 mg / m 2 ±1 mg / m 2 , ±2.5 mg / m 2 , ±5 mg / m 2 , or ±10 mg / m 2)); (b) the second administration cycle (i) administering a single dose of glofitamab (C2D1) on day 8 (C2D1 of glofitamab is approximately 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg)); (ii) administering the first dose of rituximab (C2D1) on day 1 (C2D1 of rituximab is approximately 375 mg / m 2 (e.g., 375 mg / m 2 ±5 mg / m 2 , ±10 mg / m 2 , ±25 mg / m 2 , or ±37.5 mg / m 2 ) is); (iii) administering a single dose of ifosfamide on day 2 (C2D1) (C2D1 of ifosfamide is about 5000 mg / m with a maximum dose of about 800 mg (e.g., 800 mg ± 10 mg, ± 25 mg, ± 50 mg, or ± 80 mg)); 2 (e.g., 5000 mg / m 2 ±50 mg / m 2 , ±100 mg / m 2 , ±200 mg / m 2 , ±300 mg / m 2 , ±400 mg / m 2 , or ±500 mg / m 2 ) is); (iv) administering a single dose of carboplatin on day 2 (C2D1) (C2D1 of carboplatin is approximately 5 × (25 + creatinine clearance) mg); and (v) administering a first dose of etoposide (C2D1) on day 1, a second dose of etoposide (C2D2) on day 2, and a third dose of etoposide (C2D3) on day 3 (C2D1, C2D2, and C2D3 of etoposide are each about 100 mg / m 2 (e.g., 100 mg / m 2 ±1 mg / m 2 , ±2.5 mg / m 2 , ±5 mg / m 2 , or ±10 mg / m2 ) is ) includes; (c) The third administration cycle comprises: (i) administering a single dose of glofitamab (C3D1) on day 8 (C3D1 of glofitamab is about 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg)); (ii) administering the first dose of rituximab (C3D1) on day 1 (C3D1 of rituximab is approximately 375 mg / m 2 (e.g., 375 mg / m 2 ±5 mg / m 2 , ±10 mg / m 2 , ±25 mg / m 2 , or ±37.5 mg / m 2 ) is); (iii) administering a single dose of ifosfamide (C3D1) on day 2 (C3D1 of ifosfamide is about 5000 mg / m with a maximum dose of about 800 mg (e.g., 800 mg ± 10 mg, ± 25 mg, ± 50 mg, or ± 80 mg)); 2 (e.g., 5000 mg / m 2 ±50 mg / m 2 , ±100 mg / m 2 , ±200 mg / m 2 , ±300 mg / m 2 , ±400 mg / m 2 , or ±500 mg / m 2 ) is); (iv) administering a single dose of carboplatin (C3D1) on day 2 (C3D1 of carboplatin is approximately 5 × (25 + creatinine clearance) mg); and (v) administering a first dose of etoposide (C3D1) on day 1, a second dose of etoposide (C3D2) on day 2, and a third dose of etoposide (C3D3) on day 3 (C3D1, C3D2, and C3D3 of etoposide are each about 100 mg / m 2 (e.g., 100 mg / m 2 ±1 mg / m 2 , ±2.5 mg / m 2 , ±5 mg / m 2, or ±10 mg / m 2 ) is included.

[0086] In one embodiment, mesna is administered simultaneously with any dose of ifosfamide. In one embodiment, mesna is administered at about 5000 mg / m 2 (e.g., 5000 mg / m 2 ±50 mg / m 2 , ±100 mg / m 2 , ±200 mg / m 2 , ±300 mg / m 2 , ±400 mg / m 2 , or ±500 mg / m 2 In one embodiment, mesna is administered by continuous infusion over about 24 hours on the second day of each administration cycle.

[0087] In one aspect, the invention features a method of treating a subject 6 months to 17 years of age having a CD20-positive cell proliferative disorder, the method comprising administering to the subject effective amounts of glofitamab, obinutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen including at least a first dosing cycle and a second dosing cycle; (a) The first administration cycle comprises administering a first dose of glofitamab (C1D1) on day 8 and a second dose of glofitamab (C1D2) on day 15, wherein the C1D1 dose of glofitamab is about 0.03 mg / kg (e.g., 0.03 mg / kg ± 0.0005 mg / kg, ± 0.001 mg / kg, ± 0.002 mg / kg, or ± 0.003 mg / kg), about 0.04 mg / kg (e.g., 0.04 mg / kg ± 0.0005 mg / kg, ± 0.001 mg / kg, ± 0.002 mg / kg, ± 0.003 mg / kg, or ± 0.004 mg / kg), g / kg), or about 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, or ± 0.25 mg), and the C1D2 of glofitamab is about 0.15 mg / kg (e.g., 0.15 mg / kg ± 0.001 mg / kg, ± 0.0025 mg / kg, ± 0.005 mg / kg, ± 0.01 mg / kg, or ± 0.015 mg / kg) or about 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, or ± 1 mg); (b) The second administration cycle comprises administering a single dose of glofitamab (C2D1) on day 8, wherein the C2D1 of glofitamab is about 0.4 mg / kg (e.g., 0.4 mg / kg ± 0.005 mg / kg, ± 0.01 mg / kg, ± 0.02 mg / kg, ± 0.03 mg / kg, or ± 0.04 mg / kg), about 0.5 mg / kg (e.g., 0.5 mg / kg ± 0.005 mg / kg, ± 0.01 mg / kg, ± 0.02 mg / kg, ± 0.03 mg / kg, ± 0.04 mg / kg, or ± 0.05 mg / kg), or about 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg).

[0088] In one aspect, the invention features a method of treating a subject 6 months to 17 years of age having a CD20-positive cell proliferative disorder, the method including administering to the subject effective amounts of glofitamab, obinutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen including a first dosing cycle, a second dosing cycle, and a third dosing cycle; (a) The first administration cycle comprises administering a first dose of glofitamab (C1D1) on day 8 and a second dose of glofitamab (C1D2) on day 15, wherein the C1D1 dose of glofitamab is about 0.03 mg / kg (e.g., 0.03 mg / kg ± 0.0005 mg / kg, ± 0.001 mg / kg, ± 0.002 mg / kg, or ± 0.003 mg / kg), about 0.04 mg / kg (e.g., 0.04 mg / kg ± 0.0005 mg / kg, ± 0.001 mg / kg, ± 0.002 mg / kg, ± 0.003 mg / kg, or ± 0.004 mg / kg), g / kg), or about 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, or ± 0.25 mg), and the C1D2 of glofitamab is about 0.15 mg / kg (e.g., 0.15 mg / kg ± 0.001 mg / kg, ± 0.0025 mg / kg, ± 0.005 mg / kg, ± 0.01 mg / kg, or ± 0.015 mg / kg) or about 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, or ± 1 mg); (b) the second dosing cycle comprises administering a single dose of glofitamab (C2D1) on day 8, wherein the C2D1 of glofitamab is about 0.4 mg / kg (e.g., 0.4 mg / kg ± 0.005 mg / kg, ± 0.01 mg / kg, ± 0.02 mg / kg, ± 0.03 mg / kg, or ± 0.04 mg / kg), about 0.5 mg / kg (e.g., 0.5 mg / kg ± 0.005 mg / kg, ± 0.01 mg / kg, ± 0.02 mg / kg, ± 0.03 mg / kg, ± 0.04 mg / kg, or ± 0.05 mg / kg), or about 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg); (c) The third administration cycle comprises administering a single dose of glofitamab (C3D1) on day 8, wherein the C3D1 of glofitamab is about 0.4 mg / kg (e.g., 0.4 mg / kg ± 0.005 mg / kg, ± 0.01 mg / kg, ± 0.02 mg / kg, ± 0.03 mg / kg, or ± 0.04 mg / kg), about 0.5 mg / kg (e.g., 0.5 mg / kg ± 0.005 mg / kg, ± 0.01 mg / kg, ± 0.02 mg / kg, ± 0.03 mg / kg, ± 0.04 mg / kg, or ± 0.05 mg / kg), or about 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg).

[0089] In one aspect, the invention features a method of treating a subject 6 months to 17 years of age having a CD20-positive cell proliferative disorder, the method comprising administering to the subject effective amounts of glofitamab, obinutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen including at least a first dosing cycle and a second dosing cycle; (a) The first administration cycle comprises: (i) administering a first dose of glofitamab (C1D1) on day 8 and a second dose of glofitamab (C1D2) on day 15 (C1D1 of glofitamab may be about 0.03 mg / kg (e.g., 0.03 mg / kg ± 0.0005 mg / kg, ± 0.001 mg / kg, ± 0.002 mg / kg, or ± 0.003 mg / kg), about 0.04 mg / kg (e.g., 0.04 mg / kg ± 0.0005 mg / kg, ± 0.001 mg / kg, ± 0.002 mg / kg, ± 0.003 mg / kg, or ± 0.004 mg / kg), or about 2 0.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, or ± 0.25 mg), and the C1D2 of glofitamab is about 0.15 mg / kg (e.g., 0.15 mg / kg ± 0.001 mg / kg, ± 0.0025 mg / kg, ± 0.005 mg / kg, ± 0.01 mg / kg, or ± 0.015 mg / kg) or about 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, or ± 1 mg); (ii) administering a first dose (C1D1) of obinutuzumab on day 1 and a second dose (C1D2) of obinutuzumab on day 2 (C1D1 of obinutuzumab is about 1 / 10 of the sum of C1D1 and C1D2 of obinutuzumab, and C1D2 of obinutuzumab is about 9 / 10 of the sum of C1D1 and C1D2 of obinutuzumab, and the sum of C1D1 and C1D2 of obinutuzumab is about 38 mg / kg (e.g., 38 mg / kg ± 0.25 mg / kg, ± 0.5 mg / kg, ± 1 mg / kg, ± 2 mg / kg, ± 3 mg / kg) / kg, or ±3.8 mg / kg), about 28 mg / kg (e.g., 28 mg / kg ±0.25 mg / kg, ±0.5 mg / kg, ±1 mg / kg, ±2 mg / kg, or ±2.8 mg / kg), about 23 mg / kg (e.g., 23 mg / kg ±0.25 mg / kg, ±0.5 mg / kg, ±1 mg / kg, ±2 mg / kg, or ±2.3 mg / kg), about 20 mg / kg, or about 1000 mg (e.g., 1000 mg ±5 mg, ±10 mg, ±20 mg, ±30 mg, ±50 mg, ±75 mg, or ±100 mg); (iii) administering a first dose of ifosfamide (C1D1) on day 3, a second dose of ifosfamide (C1D2) on day 4, and a third dose of ifosfamide (C1D3) on day 5 (ifosfamide C1D1, C1D2, and C1D3 are each approximately 3000 mg / m 2 (e.g., 3000 mg / m 2 ±40 mg / m 2 , ±50 mg / m 2 , ±100 mg / m 2 , ±200 mg / m 2 , or ±300 mg / m 2 ) is); (iv) administering a single dose of carboplatin (C1D1) on day 3 (C1D1 of carboplatin is approximately 635 mg / m 2 (e.g., 635 mg / m 2 ±5 mg / m 2 , ±10 mg / m 2 , ±25 mg / m 2 , ±50 mg / m 2 , ±60 mg / m 2 , or ±63.5 mg / m 2 )); and (v) administering a first dose of etoposide (C1D1) on day 3, a second dose of etoposide (C1D2) on day 4, and a third dose of etoposide (C1D3) on day 5 (C1D1, C1D2, and C1D3 of etoposide are each about 100 mg / m 2 (e.g., 100 mg / m 2 ±1 mg / m 2 , ±2.5 mg / m 2 , ±5 mg / m 2 , or ±10 mg / m 2 )); (b) the second administration cycle (i) administering a single dose of glofitamab on day 1 (C2D1) (C2D1 of glofitamab is about 0.4 mg / kg (e.g., 0.4 mg / kg ± 0.005 mg / kg, ± 0.01 mg / kg, ± 0.02 mg / kg, ± 0.03 mg / kg, or ± 0.04 mg / kg), about 0.5 mg / kg (e.g., 0.5 mg / kg ± 0.005 mg / kg, ± 0.01 mg / kg, ± 0.02 mg / kg, ± 0.03 mg / kg, ± 0.04 mg / kg, or ± 0.05 mg / kg), or about 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg)); (ii) administering the first dose of rituximab (C2D1) on day 5 (C2D1 of rituximab is approximately 375 mg / m 2 (e.g., 375 mg / m 2 ±5 mg / m 2 , ±10 mg / m 2 , ±25 mg / m 2 , or ±37.5 mg / m 2 ) is); (iii) administering the first dose of ifosfamide (C2D1) on day 6, the second dose of ifosfamide (C2D2) on day 7, and the third dose of ifosfamide (C2D3) on day 8 (C2D1, C2D2, and C2D3 of ifosfamide are each approximately 3000 mg / m 2 (e.g., 3000 mg / m 2 ±40 mg / m 2 , ±50 mg / m 2 , ±100 mg / m 2 , ±200 mg / m 2 , or ±300 mg / m 2 ) is); (iv) administering a single dose of carboplatin (C2D1) on day 6 (C2D1 of carboplatin is approximately 5 × (25 + creatinine clearance) mg); and (v) administering a first dose of etoposide (C2D1) on day 6, a second dose of etoposide (C2D2) on day 7, and a third dose of etoposide (C2D3) on day 8 (C2D1, C2D2, and C2D3 of etoposide are each about 100 mg / m 2 (e.g., 100 mg / m 2 ±1 mg / m 2 , ±2.5 mg / m 2 , ±5 mg / m 2 , or ±10 mg / m 2 ) is included.

[0090] In one aspect, the invention features a method of treating a subject 6 months to 17 years of age having a CD20-positive cell proliferative disorder, the method including administering to the subject effective amounts of glofitamab, obinutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen including a first dosing cycle, a second dosing cycle, and a third dosing cycle; (a) The first administration cycle comprises: (i) administering a first dose of glofitamab (C1D1) on day 8 and a second dose of glofitamab (C1D2) on day 15 (C1D1 of glofitamab may be about 0.03 mg / kg, about 0.04 mg / kg (e.g., 0.04 mg / kg ± 0.0005 mg / kg, ± 0.001 mg / kg, ± 0.002 mg / kg, ± 0.003 mg / kg, or ± 0.004 mg / kg), or about 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.004 mg / kg). 0.03 mg, ±0.05 mg, ±0.1 mg, ±0.2 mg, or ±0.25 mg), and the C1D2 of glofitamab is about 0.15 mg / kg (e.g., 0.15 mg / kg ±0.001 mg / kg, ±0.0025 mg / kg, ±0.005 mg / kg, ±0.01 mg / kg, or ±0.015 mg / kg) or about 10 mg (e.g., 10 mg ±0.05 mg, ±0.1 mg, ±0.2 mg, ±0.3 mg, ±0.5 mg, ±0.75 mg, or ±1 mg); (ii) administering a first dose (C1D1) of obinutuzumab on day 1 and a second dose (C1D2) of obinutuzumab on day 2 (the C1D1 dose of obinutuzumab is about 1 / 10 of the sum of the C1D1 and C1D2 doses of obinutuzumab, and the C1D2 dose of obinutuzumab is about 9 / 10 of the sum of the C1D1 and C1D2 doses of obinutuzumab, and the sum of the C1D1 and C1D2 doses of obinutuzumab is about 38 mg / kg (e.g., 38 mg / kg ± 0.25 mg / kg, ± 0.5 mg / kg, ± 1 mg / kg, ± 2 mg / kg, ± 3 mg / kg, or ± 3.8 mg / kg), about 28 mg / kg (e.g., 28 mg / kg ± 0.25 mg / kg, ± 0.5 mg / kg, ± 1 mg / kg, ± 2 mg / kg, or ± 2.8 mg / kg), about 23 mg / kg (e.g., 23 mg / kg ± 0.25 mg / kg, ± 0.5 mg / kg, ± 1 mg / kg, ± 2 mg / kg, or ± 2.3 mg / kg), about 20 mg / kg (e.g., 23 mg / kg ± 0.25 mg / kg, ± 0.5 mg / kg, ± 1 mg / kg, or ± 2 mg / kg), or about 1000 mg (e.g., 1000 mg ± 5 mg, ± 10 mg, ± 20 mg, ± 30 mg, ± 50 mg, ± 75 mg, or ± 100 mg)); (iii) administering a first dose of ifosfamide (C1D1) on day 3, a second dose of ifosfamide (C1D2) on day 4, and a third dose of ifosfamide (C1D3) on day 5 (ifosfamide C1D1, C1D2, and C1D3 are each approximately 3000 mg / m 2 (e.g., 3000 mg / m 2 ±40 mg / m 2 , ±50 mg / m 2 , ±100 mg / m 2 , ±200 mg / m 2 , or ±300 mg / m 2 ) is); (iv) administering a single dose of carboplatin (C1D1) on day 3 (C1D1 of carboplatin is approximately 635 mg / m 2 (e.g., 635 mg / m 2 ±5 mg / m 2 , ±10 mg / m 2 , ±25 mg / m 2 , ±50 mg / m 2, ±60 mg / m 2 , or ±63.5 mg / m 2 )); and (v) administering a first dose of etoposide (C1D1) on day 3, a second dose of etoposide (C1D2) on day 4, and a third dose of etoposide (C1D3) on day 5 (C1D1, C1D2, and C1D3 of etoposide are each about 100 mg / m 2 (e.g., 100 mg / m 2 ±1 mg / m 2 , ±2.5 mg / m 2 , ±5 mg / m 2 , or ±10 mg / m 2 ) is); (b) the second administration cycle (i) administering a single dose of glofitamab on day 1 (C2D1) (C2D1 of glofitamab is about 0.4 mg / kg (e.g., 0.4 mg / kg ± 0.005 mg / kg, ± 0.01 mg / kg, ± 0.02 mg / kg, ± 0.03 mg / kg, or ± 0.04 mg / kg), about 0.5 mg / kg (e.g., 0.5 mg / kg ± 0.005 mg / kg, ± 0.01 mg / kg, ± 0.02 mg / kg, ± 0.03 mg / kg, ± 0.04 mg / kg, or ± 0.05 mg / kg), or about 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg)); (ii) administering the first dose of rituximab (C2D1) on day 5 (C2D1 of rituximab is approximately 375 mg / m 2 (e.g., 375 mg / m 2 ±5 mg / m 2 , ±10 mg / m 2 , ±25 mg / m 2 , or ±37.5 mg / m 2 ) is); (iii) administering the first dose of ifosfamide (C2D1) on day 6, the second dose of ifosfamide (C2D2) on day 7, and the third dose of ifosfamide (C2D3) on day 8 (C2D1, C2D2, and C2D3 of ifosfamide are each approximately 3000 mg / m 2(e.g., 3000 mg / m 2 ±40 mg / m 2 , ±50 mg / m 2 , ±100 mg / m 2 , ±200 mg / m 2 , or ±300 mg / m 2 ) is); (iv) administering a single dose of carboplatin (C2D1) on day 6 (C2D1 of carboplatin is approximately 5 × (25 + creatinine clearance) mg); and (v) administering a first dose of etoposide (C2D1) on day 6, a second dose of etoposide (C2D2) on day 7, and a third dose of etoposide (C2D3) on day 8 (C2D1, C2D2, and C2D3 of etoposide are each about 100 mg / m 2 (e.g., 100 mg / m 2 ±1 mg / m 2 , ±2.5 mg / m 2 , ±5 mg / m 2 , or ±10 mg / m 2 ) is ) includes; (c) The third administration cycle comprises: (i) administering a single dose of glofitamab (C3D1) on day 1 (C3D1 of glofitamab is about 0.4 mg / kg (e.g., 0.4 mg / kg ± 0.005 mg / kg, ± 0.01 mg / kg, ± 0.02 mg / kg, ± 0.03 mg / kg, or ± 0.04 mg / kg), about 0.5 mg / kg (e.g., 0.5 mg / kg ± 0.005 mg / kg, ± 0.01 mg / kg, ± 0.02 mg / kg, ± 0.03 mg / kg, ± 0.04 mg / kg, or ± 0.05 mg / kg), or about 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg)); (ii) administering the first dose of rituximab (C3D1) on day 5 (C3D1 of rituximab is approximately 375 mg / m 2 (e.g., 375 mg / m 2 ±5 mg / m 2 , ±10 mg / m 2 , ±25 mg / m 2, or ±37.5 mg / m 2 ) is); (iii) administering a first dose of ifosfamide (C3D1) on day 6, a second dose of ifosfamide (C3D2) on day 7, and a third dose of ifosfamide (C3D3) on day 8 (C3D1, C3D2, and C3D3 of ifosfamide are each approximately 3000 mg / m 2 (e.g., 3000 mg / m 2 ±40 mg / m 2 , ±50 mg / m 2 , ±100 mg / m 2 , ±200 mg / m 2 , or ±300 mg / m 2 ) is); (iv) administering a single dose of carboplatin (C3D1) on day 6 (C3D1 of carboplatin is approximately 5 × (25 + creatinine clearance) mg); and (v) administering a first dose of etoposide (C3D1) on day 6, a second dose of etoposide (C3D2) on day 7, and a third dose of etoposide (C3D3) on day 8 (C3D1, C3D2, and C3D3 of etoposide are each about 100 mg / m 2 (e.g., 100 mg / m 2 ±1 mg / m 2 , ±2.5 mg / m 2 , ±5 mg / m 2 , or ±10 mg / m 2 ) is included.

[0091] In one embodiment, mesna is administered to a subject on days 3, 4, and 5 of a first administration cycle, days 6, 7, and 8 of a second administration cycle, and / or days 6, 7, and 8 of each additional administration cycle. ... 2 In one embodiment, mesna is administered intravenously daily as five doses in an amount of about 600 mg / m before administration of any dose of ifosfamide. 2 and about 600 mg / m at about 3 hours, about 6 hours, about 9 hours, and about 12 hours, respectively, after the first dose of ifosfamide. 2It is administered intravenously in four repeated doses.

[0092] In one aspect, the invention features a method of treating a subject aged 18 to 30 years old having a CD20-positive cell proliferative disorder, the method comprising administering to the subject effective amounts of glofitamab, obinutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen including at least a first dosing cycle and a second dosing cycle; (a) a first administration cycle comprises administering a first dose (C1D1) of glofitamab on day 8 and administering a second dose (C1D2) of glofitamab on day 15, wherein the C1D1 of glofitamab is about 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, or ± 0.25 mg) and the C1D2 of glofitamab is about 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, or ± 1 mg); (b) The second administration cycle comprises administering a single dose of glofitamab (C2D1) on day 1, wherein the C2D1 of glofitamab is about 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg).

[0093] In one aspect, the invention features a method of treating a subject aged 18 to 30 years having a CD20-positive cell proliferative disorder, the method including administering to the subject effective amounts of glofitamab, obinutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen including a first dosing cycle, a second dosing cycle, and a third dosing cycle; (a) a first administration cycle comprises administering a first dose (C1D1) of glofitamab on day 8 and administering a second dose (C1D2) of glofitamab on day 15, wherein the C1D1 of glofitamab is about 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, or ± 0.25 mg) and the C1D2 of glofitamab is about 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, or ± 1 mg); (b) the second dosing cycle comprises administering a single dose of glofitamab on day 1 (C2D1), wherein the C2D1 of glofitamab is about 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg); (c) The third administration cycle comprises administering a single dose of glofitamab (C3D1) on day 1, wherein the C3D1 of glofitamab is about 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg).

[0094] In one aspect, the invention features a method of treating a subject aged 18 to 30 years old having a CD20-positive cell proliferative disorder, the method comprising administering to the subject effective amounts of glofitamab, obinutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen including at least a first dosing cycle and a second dosing cycle; (a) The first administration cycle comprises: (i) administering a first dose of glofitamab (C1D1) on day 8 and a second dose of glofitamab (C1D2) on day 15 (wherein C1D1 of glofitamab is about 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, or ± 0.25 mg) and C1D2 of glofitamab is about 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, or ± 1 mg)); (ii) administering a first dose (C1D1) of obinutuzumab on day 1 and a second dose (C1D2) of obinutuzumab on day 2 (C1D1 of obinutuzumab is about 1 / 10 of the sum of C1D1 and C1D2 of obinutuzumab, C1D2 of obinutuzumab is about 9 / 10 of the sum of C1D1 and C1D2 of obinutuzumab, and the sum of C1D1 and C1D2 of obinutuzumab is about 1000 mg (e.g., 1000 mg ± 5 mg, ± 10 mg, ± 20 mg, ± 30 mg, ± 50 mg, ± 75 mg, or ± 100 mg)); (iii) administering a single dose of ifosfamide (C1D1) on day 3 (C1D1 of ifosfamide is about 5000 mg / m with a maximum dose of about 800 mg (e.g., 800 mg ± 10 mg, ± 25 mg, ± 50 mg, or ± 80 mg)); 2 (e.g., 5000 mg / m 2 ±50 mg / m 2 , ±100 mg / m 2 , ±200 mg / m 2 , ±300 mg / m 2 , ±400 mg / m 2 , or ±500 mg / m 2 ) is); (iv) administering a single dose (C1D1) of carboplatin on day 3 (C1D1 of carboplatin is approximately 5 × (25 + creatinine clearance) mg); and (v) administering a first dose of etoposide (C1D1) on day 3, a second dose of etoposide (C1D2) on day 4, and a third dose of etoposide (C1D3) on day 5 (C1D1, C1D2, and C1D3 of etoposide are each about 100 mg / m2 (e.g., 100 mg / m 2 ±1 mg / m 2 , ±2.5 mg / m 2 , ±5 mg / m 2 , or ±10 mg / m 2 )); (b) the second administration cycle (i) administering a single dose of glofitamab on day 1 (C2D1) (C2D1 of glofitamab is approximately 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg)); (ii) administering the first dose of rituximab (C2D1) on day 5 (C2D1 of rituximab is approximately 375 mg / m 2 (e.g., 375 mg / m 2 ±5 mg / m 2 , ±10 mg / m 2 , ±25 mg / m 2 , or ±37.5 mg / m 2 ) is); (iii) administering a single dose of ifosfamide (C2D1) on day 6 (C2D1 of ifosfamide is about 5000 mg / m with a maximum dose of about 800 mg (e.g., 800 mg ± 10 mg, ± 25 mg, ± 50 mg, or ± 80 mg)); 2 (e.g., 5000 mg / m 2 ±50 mg / m 2 , ±100 mg / m 2 , ±200 mg / m 2 , ±300 mg / m 2 , ±400 mg / m 2 , or ±500 mg / m 2 ) is); (iv) administering a single dose of carboplatin (C2D1) on day 6 (C2D1 of carboplatin is approximately 5 × (25 + creatinine clearance) mg); and (v) administering a first dose of etoposide (C2D1) on day 6, a second dose of etoposide (C2D2) on day 7, and a third dose of etoposide (C2D3) on day 8 (C2D1, C2D2, and C2D3 of etoposide are each about 100 mg / m 2 (e.g., 100 mg / m 2 ±1 mg / m 2 , ±2.5 mg / m 2 , ±5 mg / m 2 , or ±10 mg / m 2 ) is included.

[0095] In one aspect, the invention features a method of treating a subject aged 18 to 30 years having a CD20-positive cell proliferative disorder, the method including administering to the subject effective amounts of glofitamab, obinutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen including a first dosing cycle, a second dosing cycle, and a third dosing cycle; (a) The first administration cycle comprises: (i) administering a first dose of glofitamab (C1D1) on day 8 and a second dose of glofitamab (C1D2) on day 15 (wherein C1D1 of glofitamab is about 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, or ± 0.25 mg) and C1D2 of glofitamab is about 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, or ± 1 mg)); (ii) administering a first dose (C1D1) of obinutuzumab on day 1 and a second dose (C1D2) of obinutuzumab on day 2 (C1D1 of obinutuzumab is about 1 / 10 of the sum of C1D1 and C1D2 of obinutuzumab, C1D2 of obinutuzumab is about 9 / 10 of the sum of C1D1 and C1D2 of obinutuzumab, and the sum of C1D1 and C1D2 of obinutuzumab is about 1000 mg (e.g., 1000 mg ± 5 mg, ± 10 mg, ± 20 mg, ± 30 mg, ± 50 mg, ± 75 mg, or ± 100 mg)); (iii) administering a single dose of ifosfamide (C1D1) on day 3 (C1D1 of ifosfamide is about 5000 mg / m with a maximum dose of about 800 mg (e.g., 800 mg ± 10 mg, ± 25 mg, ± 50 mg, or ± 80 mg)); 2 (e.g., 5000 mg / m 2 ±50 mg / m 2 , ±100 mg / m 2 , ±200 mg / m 2 , ±300 mg / m 2 , ±400 mg / m 2 , or ±500 mg / m 2 ) is); (iv) administering a single dose (C1D1) of carboplatin on day 3 (C1D1 of carboplatin is approximately 5 × (25 + creatinine clearance) mg); and (v) administering a first dose of etoposide (C1D1) on day 3, a second dose of etoposide (C1D2) on day 4, and a third dose of etoposide (C1D3) on day 5 (C1D1, C1D2, and C1D3 of etoposide are each about 100 mg / m 2 (e.g., 100 mg / m 2 ±1 mg / m 2 , ±2.5 mg / m 2 , ±5 mg / m 2 , or ±10 mg / m 2 ) is); (b) the second administration cycle (i) administering a single dose of glofitamab on day 1 (C2D1) (C2D1 of glofitamab is approximately 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg)); (ii) administering the first dose of rituximab (C2D1) on day 5 (C2D1 of rituximab is approximately 375 mg / m 2 (e.g., 375 mg / m 2 ±5 mg / m 2 , ±10 mg / m 2 , ±25 mg / m 2 , or ±37.5 mg / m 2 ) is); (iii) administering a single dose of ifosfamide (C2D1) on day 6 (C2D1 of ifosfamide is about 5000 mg / m with a maximum dose of about 800 mg (e.g., 800 mg ± 10 mg, ± 25 mg, ± 50 mg, or ± 80 mg)); 2 (e.g., 5000 mg / m 2 ±50 mg / m 2 , ±100 mg / m 2 , ±200 mg / m 2 , ±300 mg / m 2 , ±400 mg / m 2 , or ±500 mg / m 2 ) is); (iv) administering a single dose of carboplatin (C2D1) on day 6 (C2D1 of carboplatin is approximately 5 × (25 + creatinine clearance) mg); and (v) administering a first dose of etoposide (C2D1) on day 6, a second dose of etoposide (C2D2) on day 7, and a third dose of etoposide (C2D3) on day 8 (C2D1, C2D2, and C2D3 of etoposide are each about 100 mg / m 2 (e.g., 100 mg / m 2 ±1 mg / m 2 , ±2.5 mg / m 2 , ±5 mg / m 2 , or ±10 mg / m 2 ) is ) includes; (c) The third administration cycle comprises: (i) administering a single dose of glofitamab (C3D1) on day 1 (C3D1 of glofitamab is about 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg)); (ii) administering the first dose of rituximab (C3D1) on day 5 (C3D1 of rituximab is approximately 375 mg / m 2 (e.g., 375 mg / m 2 ±5 mg / m 2 , ±10 mg / m 2 , ±25 mg / m 2 , or ±37.5 mg / m 2 ) is); (iii) administering a single dose of ifosfamide (C3D1) on day 6 (C3D1 of ifosfamide is about 5000 mg / m with a maximum dose of about 800 mg (e.g., 800 mg ± 10 mg, ± 25 mg, ± 50 mg, or ± 80 mg)); 2 (e.g., 5000 mg / m 2 ±50 mg / m 2 , ±100 mg / m 2 , ±200 mg / m 2 , ±300 mg / m 2 , ±400 mg / m 2 , or ±500 mg / m 2 ) is); (iv) administering a single dose of carboplatin (C3D1) on day 6 (C3D1 of carboplatin is approximately 5 × (25 + creatinine clearance) mg); and (v) administering a first dose of etoposide (C3D1) on day 6, a second dose of etoposide (C3D2) on day 7, and a third dose of etoposide (C3D3) on day 8 (C3D1, C3D2, and C3D3 of etoposide are each about 100 mg / m 2 (e.g., 100 mg / m 2 ±1 mg / m 2 , ±2.5 mg / m 2 , ±5 mg / m 2 , or ±10 mg / m 2 ) is included.

[0096] In one embodiment, mesna is administered simultaneously with any dose of ifosfamide. In one embodiment, mesna is administered at about 5000 mg / m 2 (e.g., 5000 mg / m 2 ±50 mg / m 2 , ±100 mg / m 2 , ±200 mg / m 2 , ±300 mg / m 2 , ±400 mg / m 2 , or ±500 mg / m 2) is administered intravenously. In one embodiment, mesna is administered by continuous infusion over about 24 hours on day 3 of the first administration cycle, day 6 of the second administration cycle, and / or day 6 of each additional administration cycle. In one embodiment, the CD20-positive cell proliferative disorder is relapsed and / or refractory DLBCL. In one embodiment, the CD20-positive cell proliferative disorder is relapsed and / or refractory mature B-cell NHL.

[0097] In one embodiment, a bispecific antibody that binds to CD20 and CD3 comprises at least one Fab molecule that specifically binds to CD20 and has the following six hypervariable regions (HVRs): (i) HVR-H1 containing the amino acid sequence of YSWIN (SEQ ID NO: 1); (ii) HVR-H2 comprising the amino acid sequence RIFPGDGDTDYNGKFKG (SEQ ID NO: 2); (iii) HVR-H3 comprising the amino acid sequence NVFDGYWLVY (SEQ ID NO: 3); (iv) HVR-L1 comprising the amino acid sequence RSSKSLLHSNGITYLY (SEQ ID NO: 4); (v) HVR-L2 comprising the amino acid sequence of QMSNLVS (SEQ ID NO: 5); and (vi) HVR-L3 comprising the amino acid sequence of AQNLELPYT (SEQ ID NO: 6) , including Fab molecules.

[0098] In one embodiment, a bispecific antibody that binds to CD20 and CD3 comprises: (a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 7; (b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 8; or (c) at least one Fab molecule that specifically binds CD20, comprising a VH domain similar to (a) and a VL domain similar to (b).

[0099] In one embodiment, a Fab molecule that specifically binds to CD20 comprises (a) a VH domain comprising the amino acid sequence of SEQ ID NO:7 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO:8. In one embodiment, a bispecific antibody that binds CD20 and CD3 comprises at least one Fab molecule that specifically binds CD3, comprising the following six HVRs: (i) HVR-H1 comprising the amino acid sequence of TYAMN (SEQ ID NO: 9); (ii) HVR-H2 comprising the amino acid sequence of RIRSKYNNYATYYADSVKG (SEQ ID NO: 10); (iii) HVR-H3 comprising the amino acid sequence HGNFGNSYVSWFAY (SEQ ID NO: 11); (iv) HVR-L1 comprising the amino acid sequence of GSSTGAVTTSNYAN (SEQ ID NO: 12); (v) HVR-L2 comprising the amino acid sequence of GTNKRAP (SEQ ID NO: 13); and (vi) HVR-L3 comprising the amino acid sequence of ALWYSNLWV (SEQ ID NO: 14).

[0100] In one embodiment, a bispecific antibody that binds to CD20 and CD3 comprises: (a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 15; (b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 16; or (c) at least one Fab molecule that specifically binds CD3, comprising a VH domain similar to (a) and a VL domain similar to (b).

[0101] In one embodiment, a Fab molecule that specifically binds to CD3 comprises (a) a VH domain comprising the amino acid sequence of SEQ ID NO:15 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO:16.

[0102] In one embodiment, a bispecific antibody that binds to CD20 and CD3 is bivalent with respect to CD20 and monovalent with respect to CD3. In one embodiment, a bispecific antibody that binds to CD20 and CD3 comprises two Fab molecules that specifically bind to CD20 and one Fab molecule that specifically binds to CD3. In one embodiment, a bispecific antibody that binds to CD20 and CD3 is a humanized antibody. In one embodiment, a bispecific antibody that binds to CD20 and CD3 is glofitamab.

[0103] In one embodiment, the bispecific antibody that binds to CD20 and CD3 is administered intravenously.

[0104] In one embodiment, the anti-CD20 antibody is administered intravenously.

[0105] In one embodiment, the CD20-positive cell proliferative disorder is a B-cell proliferative disorder. In one embodiment, the B-cell proliferative disorder is non-Hodgkin's lymphoma (NHL) or central nervous system lymphoma (CNSL). In one embodiment, the NHL is diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), high-grade B-cell lymphoma, primary mediastinal (thymic) large B-cell lymphoma (PMLBCL), diffuse B-cell lymphoma, or small lymphocytic lymphoma. In one embodiment, the NHL is Burkitt lymphoma (BL) or Burkitt leukemia (BAL). In one embodiment, the NHL is aggressive and / or mature. In one embodiment, the NHL is relapsed and / or refractory. In one embodiment, the B-cell proliferative disorder is relapsed and / or refractory mature B-cell NHL. In one embodiment, the subject has received one prior systemic therapy. In one embodiment, the subject has received no more than one prior systemic therapy. In one embodiment, the prior systemic therapy comprises an anti-CD20 antibody and an anthracycline.

[0106] In one embodiment, the subject is a human. In one embodiment, the subject is eligible for transplant or CAR-T cell therapy.

[0107] In one embodiment, the subject undergoes autologous stem cell transplantation (ASCT) after completing the above-described administration regimen. In one embodiment, the ASCT is autologous hematopoietic stem cell transplantation. In one embodiment, the subject undergoes allogeneic hematopoietic stem cell transplantation after completing the above-described administration regimen. In one embodiment, the subject undergoes CAR-T cell therapy after completing the above-described administration regimen.

[0108] In one aspect, the invention features a bispecific antibody that binds CD20 and CD3 for use in a method of treating a subject having a CD20-positive cell proliferative disorder, wherein the bispecific antibody that binds CD20 and CD3 is administered in combination with an anti-CD20 antibody and one or more chemotherapeutic agents selected from ifosfamide, carboplatin, and / or etoposide, in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle.

[0109] In one embodiment, the first administration cycle comprises a first dose of a bispecific antibody that binds CD20 and CD3 (C1D1) and a second dose of the bispecific antibody (C1D2), wherein C1D1 of the bispecific antibody is about 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, or ± 0.25 mg) and C1D2 of the bispecific antibody is about 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, or ± 1 mg); The second administration cycle comprises a single dose of bispecific antibody (C2D1), wherein the bispecific antibody C2D1 is about 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, or ± 1 mg), about 16 mg (e.g., 16 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, or ± 1.6 mg), or about 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg). In one embodiment, the bispecific antibody C2D1 is about 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg). In one embodiment, the bispecific antibody C2D1 is administered to the subject on day 8 of the second administration cycle.

[0110] In one embodiment, the anti-CD20 antibody is obinutuzumab and / or rituximab. In one embodiment, the first administration cycle comprises a single dose of obinutuzumab (C1D1); and the second administration cycle comprises a single dose of rituximab (C2D1). In one embodiment, the single dose C1D1 of obinutuzumab is about 1000 mg (e.g., 1000 mg ± 5 mg, ± 10 mg, ± 20 mg, ± 30 mg, ± 50 mg, ± 75 mg, or ± 100 mg), and the single dose of rituximab is about 375 mg / m 2 (e.g., 375 mg / m 2 ±5 mg / m 2 , ±10 mg / m 2 , ±25 mg / m 2 , or ±37.5 mg / m 2 )

[0111] In one embodiment, the anti-CD20 antibody is administered in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein the first dosing cycle comprises a single dose of obinutuzumab on day 1 (C1D1); and the second dosing cycle comprises a single dose of rituximab on day 1 (C2D1).

[0112] In one aspect, the invention features a bispecific antibody that binds CD20 and CD3 for use in a method of treating a subject having a CD20-positive cell proliferative disorder, wherein the bispecific antibody that binds CD20 and CD3 is administered in combination with an anti-CD20 antibody, ifosfamide, carboplatin, and etoposide in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle.

[0113] In one embodiment, the first administration cycle comprises a single dose of ifosfamide (C1D1), a single dose of carboplatin (C1D1), and the first (C1D1), second (C1D2), and third (C1D3) doses of etoposide; the second cycle comprises a single dose of ifosfamide (C2D1), a single dose of carboplatin (C2D1), and the first (C2D1), second (C2D2), and third (C2D3) doses of etoposide, respectively. In one embodiment, ifosfamide is administered at a dose of about 5000 mg / m 2 (e.g., 5000 mg / m 2 ±50 mg / m 2 , ±100 mg / m 2 , ±200 mg / m 2 , ±300 mg / m 2 , ±400 mg / m 2 , or ±500 mg / m 2 ), approx. 4000mg / m 2 (e.g., 4000 mg / m 2 ±40 mg / m 2 , ±50 mg / m 2 , ±100 mg / m 2 , ±200 mg / m 2 , ±300 mg / m 2 , or ±400 mg / m 2 ), or approximately 1666 mg / m 2 (e.g., 1666 mg / m 2 ±25 mg / m 2 , ±50 mg / m 2 , ±100 mg / m 2 , or ±166.6 mg / m 2), carboplatin is administered at a mg dose targeting an area under the curve (AUC) of about 5 mg / mL / min (e.g., 5 mg / mL / min ±0.05 mg / mL / min, ±0.1 mg / mL / min, ±0.25 mg / mL / min, or ±0.5 mg / mL / min) with a maximum dose of about 750 mg (e.g., 750 mg ±10 mg, ±25 mg, ±50 mg, or ±75 mg), and etoposide is administered at a dose of about 100 mg / m 2 (e.g., 100 mg / m 2 ±1 mg / m 2 , ±2.5 mg / m 2 , ±5 mg / m 2 , or ±10 mg / m 2 ) or 75 mg / m 2 (e.g., 0.5 mg / m 2 ±1 mg / m 2 , ±2.5 mg / m 2 , ±5 mg / m 2 , or ±7.5 mg / m 2 In one embodiment, ifosfamide is administered at a dose of 5000 mg / m 2 , 4000 mg / m 2 or 1666 mg / m 2 carboplatin was administered at a dose of 100 mg / m2 targeting an area under the curve (AUC) of 5 mg / mL / min with a maximum dose of 750 mg; etoposide was administered at a dose of 100 mg / m2 2 or 75 mg / m 2 In one embodiment, ifosfamide is administered at a dose of 5000 mg / m 2 carboplatin was administered at a dose of 100 mg / m2 targeting an area under the curve (AUC) of 5 mg / mL / min with a maximum dose of 750 mg; etoposide was administered at a dose of 100 mg / m2 2 In one embodiment, ifosfamide and carboplatin are administered on day 2 of the first administration cycle and the second administration cycle, and etoposide is administered on days 1, 2, and 3 of each of the first administration cycle and the second administration cycle.

[0114] In one embodiment, the first and second dosing cycles are 21 day dosing cycles.

[0115] In one embodiment, the dosing regimen includes one or more additional dosing cycles, hi one embodiment, the additional dosing cycles are 21 day dosing cycles.

[0116] In one embodiment, the dosing regimen comprises a total of three dosing cycles.

[0117] In one embodiment, the one or more additional administration cycles include: (a) an additional single dose of a bispecific antibody that binds to CD20 and CD3; (b) an additional single dose of anti-CD20 antibody (c) An additional single dose of ifosfamide, an additional single dose of carboplatin, and an additional first, second, and third doses of etoposide.

[0118] In one embodiment, the additional single dose of a bispecific antibody that binds CD20 and CD3 is about 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg).

[0119] In one embodiment, the anti-CD20 antibody is rituximab. In one embodiment, the additional single dose of rituximab is about 375 mg / m 2 (e.g., 375 mg / m 2 ±5 mg / m 2 , ±10 mg / m 2 , ±25 mg / m 2 , or ±37.5 mg / m 2 In one embodiment, an additional single dose of rituximab is administered on day 1 of an additional administration cycle.

[0120] In one embodiment, the additional single dose of ifosfamide is about 5000 mg / m 2 (e.g., 5000 mg / m 2 ±50 mg / m 2 , ±100 mg / m 2 , ±200 mg / m 2 , ±300 mg / m2 , ±400 mg / m 2 , or ±500 mg / m 2 ), approx. 4000mg / m 2 (e.g., 4000 mg / m 2 ±40 mg / m 2 , ±50 mg / m 2 , ±100 mg / m 2 , ±200 mg / m 2 , ±300 mg / m 2 , or ±400 mg / m 2 ), or approximately 1666 mg / m 2 (e.g., 1666 mg / m 2 ±25 mg / m 2 , ±50 mg / m 2 , ±100 mg / m 2 , or ±166.6 mg / m 2 ), the additional single dose of carboplatin is 100 mg / m2 targeting an area under the curve (AUC) of about 5 mg / mL / min (e.g., 5 mg / mL / min ±0.05 mg / mL / min, ±0.1 mg / mL / min, ±0.25 mg / mL / min, or ±0.5 mg / mL / min) at a maximum dose of about 750 mg (e.g., 750 mg ±10 mg, ±25 mg, ±50 mg, or ±75 mg), and the additional first, second, and third doses of etoposide are 100 mg / m2 2 (e.g., 100 mg / m 2 ±1 mg / m 2 , ±2.5 mg / m 2 , ±5 mg / m 2 , or ±10 mg / m 2 ) or 75 mg / m 2 (e.g., 0.5 mg / m 2 ±1 mg / m 2 , ±2.5 mg / m 2 , ±5 mg / m 2 , or ±7.5 mg / m 2 In one embodiment, the additional single dose of ifosfamide is 5000 mg / m 2 , 4000 mg / m 2 or 1666 mg / m 2and the additional single dose of carboplatin is 1 mg targeting an area under the curve (AUC) of 5 mg / mL / min with a maximum dose of 750 mg, and the additional first, second, and third doses of etoposide are 100 mg / m 2 or 75 mg / m 2 is.

[0121] In one embodiment, ifosfamide is administered at 5000 mg / m 2 carboplatin was administered at a dose of 100 mg / m2 targeting an area under the curve (AUC) of 5 mg / mL / min with a maximum dose of 750 mg; etoposide was administered at a dose of 100 mg / m2 2 is administered at a dose of

[0122] In one embodiment, ifosfamide and carboplatin are administered on day 2 of the additional administration cycle, and etoposide is administered on each of days 1, 2, and 3 of the additional administration cycle.

[0123] In one embodiment, the method further comprises administering one or more additional therapeutic agents to the subject. In one embodiment, the bispecific antibody is for use in combination with one or more additional therapeutic agents. In one embodiment, the one or more additional therapeutic agents is tocilizumab. In one embodiment, the subject weighs about 30 kg or more and tocilizumab is administered at a dose of about 8 mg / kg (e.g., 8 mg / kg ± 0.05 mg / kg, ± 0.1 mg / kg, ± 0.25 mg / kg, ± 0.5 mg / kg, or ± 0.8 mg / kg). In one embodiment, the subject weighs less than 30 kg and tocilizumab is administered at a dose of about 12 mg / kg (e.g., 12 mg / kg ± 0.05 mg / kg, ± 0.1 mg / kg, ± 0.25 mg / kg, ± 0.5 mg / kg, ± 0.75 mg / kg, ± 1 mg / kg, or ± 1.2 mg / kg). In some embodiments, the maximum dose of tocilizumab is about 800 mg (e.g., 800 mg ± 10 mg, ± 25 mg, ± 50 mg, or ± 80 mg).

[0124] In one embodiment, the one or more additional therapeutic agents is a corticosteroid.

[0125] In one embodiment, the corticosteroid comprises prednisone, prednisolone, methylprednisolone, or dexamethasone. In one embodiment, the dexamethasone is administered intravenously at a dose of about 20 mg (e.g., 20 mg ± 0.1 mg, ± 0.25 mg, ± 0.5 mg, ± 1 mg, ± 1.5 mg, or ± 2 mg) at least about 1 hour (i.e., at least 1 hour ± 6 minutes; e.g., at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours, or more) prior to administration of any dose of the bispecific antibody. In one embodiment, dexamethasone is administered intravenously at a dose of about 20 mg (e.g., 20 mg ± 0.1 mg, ± 0.25 mg, ± 0.5 mg, ± 1 mg, ± 1.5 mg, or ± 2 mg) at least about 1 hour (i.e., at least 1 hour ± 6 minutes; e.g., at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours, or more) prior to administration of any dose of obinutuzumab. In one embodiment, methylprednisolone is administered intravenously at a dose of about 80 mg (e.g., 80 mg ± 0.5 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, ± 4 mg, ± 6 mg, or ± 8 mg) at least about 1 hour (i.e., at least 1 hour ± 6 minutes; e.g., at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours, or more) prior to administration of any dose of the bispecific antibody. In one embodiment, methylprednisolone is administered intravenously at a dose of about 80 mg (e.g., 80 mg ±0.5 mg, ±1 mg, ±1.5 mg, ±2 mg, ±4 mg, ±6 mg, or ±8 mg) at least about 1 hour (i.e., at least 1 hour ±6 minutes; e.g., at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours, or more) prior to administration of any dose of obinutuzumab.In one embodiment, prednisone is administered orally at a dose of about 100 mg (e.g., 100 mg ± 0.5 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, ± 4 mg, ± 6 mg, ± 8 mg, or ± 10 mg) at least about 1 hour (i.e., at least 1 hour ± 6 minutes; e.g., at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours, or more) prior to administration of any dose of the bispecific antibody. In one embodiment, prednisolone is administered intravenously at a dose of about 100 mg (e.g., 100 mg ± 0.5 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, ± 4 mg, ± 6 mg, ± 8 mg, or ± 10 mg) at least about 1 hour (i.e., at least 1 hour ± 6 minutes; e.g., at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours, or more) prior to administration of any dose of the bispecific antibody.

[0126] In one embodiment, the one or more additional therapeutic agents is an antihistamine.

[0127] In one embodiment, the antihistamine is diphenhydramine, which is administered orally or intravenously at a dose of about 50 mg (e.g., 50 mg ± 0.5 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, ± 3 mg, ± 4 mg, or ± 5 mg) at least about 30 minutes (i.e., at least 30 minutes ± 3 minutes; e.g., at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours, or more) prior to administration of any dose of the bispecific antibody.

[0128] In one embodiment, the one or more additional therapeutic agents include G-CSF, hi one embodiment, the G-CSF is administered about 1 to about 2 days (e.g., 24, 26, 28, 30, 32, 36, 38, 40, 42, 44, 46, or 48 hours) after administration of any dose of rituximab, ifosfamide, carboplatin, and / or etoposide.

[0129] In one embodiment, the one or more additional therapeutic agents is an antipyretic. In one embodiment, the antipyretic is acetaminophen or paracetamol. In one embodiment, the acetaminophen or paracetamol is administered orally at a dose of about 500 mg to about 1000 mg at least about 30 minutes (i.e., at least 30 minutes ± 3 minutes; e.g., at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours, or more) prior to administration of any dose of the bispecific antibody. In one embodiment, the acetaminophen or paracetamol is administered orally at a dose of about 500 mg to about 1000 mg at least about 30 minutes (i.e., at least 30 minutes ± 3 minutes; e.g., at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours, or more) prior to administration of any dose of obinutuzumab.

[0130] In one embodiment, the one or more additional therapeutic agents is mesna. In one embodiment, mesna is at about 5000 mg / m 2 , about 4000mg / m 2 , or about 1666 mg / m 2 In one embodiment, mesna is administered intravenously at a dose of 0.01 mg / kg / day. In one embodiment, mesna is administered by continuous infusion over about 24 hours on day 2 of each administration cycle. In one embodiment, mesna is administered simultaneously with any dose of ifosfamide.

[0131] In one aspect, the invention features a bispecific antibody that binds CD20 and CD3 for use in a method of treating a subject 6 months to 17 years of age having a CD20-positive cell proliferative disorder, the bispecific antibody that binds CD20 and CD3 being administered in combination with an anti-CD20 antibody and one or more chemotherapeutic agents selected from ifosfamide, carboplatin, and / or etoposide. The administration is in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle.

[0132] In one embodiment, the first administration cycle comprises a first dose of a bispecific antibody (C1D1) and a second dose of a bispecific antibody (C1D2), wherein C1D1 of the bispecific antibody is administered at a dose of about 0.03 mg / kg (e.g., 0.03 mg / kg ± 0.0005 mg / kg, ± 0.001 mg / kg, ± 0.002 mg / kg, or ± 0.003 mg / kg), about 0.04 mg / kg (e.g., 0.04 mg / kg ± 0.0005 mg / kg, ± 0.001 mg / kg, ± 0.002 mg / kg, ± 0.003 mg / kg, or ± 0.004 mg / kg), or about 2 0.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, or ± 0.25 mg), and C1D2 of the bispecific antibody is about 0.15 mg / kg (e.g., 0.15 mg / kg ± 0.001 mg / kg, ± 0.0025 mg / kg, ± 0.005 mg / kg, ± 0.01 mg / kg, or ± 0.015 mg / kg) or about 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, or ± 1 mg); The second administration cycle comprises a single dose of the bispecific antibody (C2D1), wherein the C2D1 of the bispecific antibody is about 0.4 mg / kg (e.g., 0.4 mg / kg ± 0.005 mg / kg, ± 0.01 mg / kg, ± 0.02 mg / kg, ± 0.03 mg / kg, or ± 0.04 mg / kg), about 0.5 mg / kg (e.g., 0.5 mg / kg ± 0.005 mg / kg, ± 0.01 mg / kg, ± 0.02 mg / kg, ± 0.03 mg / kg, ± 0.04 mg / kg, or ± 0.05 mg / kg), or about 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg).

[0133] In one embodiment, (a) the subject weighs at least about 7.5 kg but less than about 13 kg, and the C1D1 of the bispecific antibody is about 0.04 mg / kg (e.g., 0.04 mg / kg ± 0.0005 mg / kg, ± 0.001 mg / kg, ± 0.002 mg / kg, ± 0.003 mg / kg, or ± 0.004 mg / kg), and the C1D2 of the bispecific antibody is about 0.15 mg / kg (e.g., 0.15 mg / kg). g ±0.001 mg / kg, ±0.0025 mg / kg, ±0.005 mg / kg, ±0.01 mg / kg, or ±0.015 mg / kg) and the C2D1 of the bispecific antibody is about 0.5 mg / kg (e.g., 0.5 mg / kg ±0.005 mg / kg, ±0.01 mg / kg, ±0.02 mg / kg, ±0.03 mg / kg, ±0.04 mg / kg, or ±0.05 mg / kg); (b) the subject weighs about 13 kg or more and less than about 45 kg, and C1D1 of the bispecific antibody is about 0.03 mg / kg (e.g., 0.03 mg / kg ± 0.0005 mg / kg, ± 0.001 mg / kg, ± 0.002 mg / kg, or ± 0.003 mg / kg), C1D2 of the bispecific antibody is about 0.15 mg / kg (e.g., 0.15 mg / kg ± 0.001 mg / kg, ± 0.0025 mg / kg, ± 0.005 mg / kg, ± 0.01 mg / kg, or ± 0.015 mg / kg), and C2D1 of the bispecific antibody is about 0.4 mg / kg (e.g., 0.4 mg / kg ± 0.005 mg / kg, ± 0.01 mg / kg, ± 0.02 mg / kg, ± 0.03 mg / kg, or ± 0.04 mg / kg); or (c) the subject weighs about 45 kg or more, C1D1 of the bispecific antibody is about 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, or ± 0.25 mg), C1D2 of the bispecific antibody is about 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, or ± 1 mg), and C2D1 of the bispecific antibody is about 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg).

[0134] In one embodiment, bispecific antibody C1D1 and bispecific antibody C1D2 will be administered to a subject on days 8 and 15, respectively, of a first administration cycle. In one embodiment, bispecific antibody C2D1 will be administered to a subject on day 1 of a second administration cycle.

[0135] In one embodiment, the anti-CD20 antibody is obinutuzumab and / or rituximab.

[0136] In one embodiment, the first administration cycle comprises a first dose of obinutuzumab (C1D1) and a second dose of obinutuzumab (C1D2). In one embodiment, (a) the subject weighs about 7.5 kg or more and less than about 13 kg and the sum of C1D1 and C1D2 of obinutuzumab is about 38 mg / kg (e.g., 38 mg / kg ± 0.25 mg / kg, ± 0.5 mg / kg, ± 1 mg / kg, ± 2 mg / kg, ± 3 mg / kg, or ± 3.8 mg / kg); (b) the subject weighs about 13 kg or more and less than about 20 kg and the sum of C1D1 and C1D2 of obinutuzumab is about 28 mg / kg (e.g., 28 mg / kg ± 0.25 mg / kg, ± 0.5 mg / kg, ± 1 mg / kg, ± 2 mg / kg, or ± 2.8 mg / kg); (c) the subject weighs about 20 kg or more and less than about 32 kg and the sum of C1D1 and C1D2 of obinutuzumab is about 28 mg / kg (e.g., 28 mg / kg ± 0.25 mg / kg, ± 0.5 mg / kg, ± 1 mg / kg, ± 2 mg / kg, or ± 2.8 mg / kg). (d) the subject weighs about 32 kg or more and less than about 45 kg and the sum of C1D1 and C1D2 of obinutuzumab is about 20 mg / kg (e.g., 23 mg / kg ± 0.25 mg / kg, ± 0.5 mg / kg, ± 1 mg / kg, ± 2 mg / kg, or ± 2.3 mg / kg); or (e) the subject weighs about 45 kg or more and the sum of C1D1 and C1D2 of obinutuzumab is about 1000 mg (e.g., 1000 mg ± 5 mg, ± 10 mg, ± 20 mg, ± 30 mg, ± 50 mg, ± 75 mg, or ± 100 mg).

[0137] In one embodiment, C1D1 of obinutuzumab is in an amount that is about 1 / 10 of the sum of C1D1 and C1D2 of obinutuzumab, and C1D2 of obinutuzumab is in an amount that is about 9 / 10 of the sum of C1D1 and C1D2 of obinutuzumab.In one embodiment, (a) the subject weighs greater than or equal to about 7.5 kg and less than about 13 kg, and the C1D1 of obinutuzumab is about 3.8 mg / kg (e.g., 3.8 mg / kg ± 0.05 mg / kg, 0.1 mg / kg, ± 0.2 mg / kg, ± 0.3 mg / kg, or ± 0.38 mg / kg), and the C1D2 of obinutuzumab is about 34.2 mg / kg (e.g., 34.2 mg / kg ± 0.5 mg / kg, 1 mg / kg, ± 2 mg / kg, ± 3 mg / kg, or ± 3.42 mg / kg); (b) the subject weighs greater than or equal to about 13 kg and less than about 20 kg, and the C1D2 of obinutuzumab is about 34.2 mg / kg (e.g., 34.2 mg / kg ± 0.5 mg / kg, 1 mg / kg, ± 2 mg / kg, ± 3 mg / kg, or ± 3.42 mg / kg); (c) the subject's body weight is greater than or equal to about 20 kg and less than about 32 kg, and the C1D1 of obinutuzumab is about 2.3 mg / kg (e.g., 2.3 mg / kg ± 0.05 mg / kg, 0.1 mg / kg, ± 0.2 mg / kg, or ± 0.28 mg / kg) and the C1D2 of obinutuzumab is about 35.2 mg / kg (e.g., 35.2 mg / kg ± 0.5 mg / kg, 1 mg / kg, ± 2 mg / kg, ± 3 mg / kg, or ± 3.52 mg / kg); (d) the subject's body weight is greater than or equal to about 20 kg and less than about 32 kg, and the C1D1 of obinutuzumab is about 2.3 mg / kg (e.g., 2.3 mg / kg ± 0.05 mg / kg, 0.1 mg / kg, (d) the subject weighs about 32 kg or more and less than about 45 kg, and the C1D1 of obinutuzumab is about 2.0 mg / kg (e.g., 2.0 mg / kg ±0.05 mg / kg, 0.1 mg / kg, or ±0.2 mg / kg) and the C1D2 of obinutuzumab is about 36.0 mg / kg (e.g., 36.0 mg / kg ±0.5 mg / kg, 1 mg / kg, ±2 mg / kg, ±3 mg / kg, or ±3.57 mg / kg); or (e) the subject weighs about 45 kg or more and the C1D1 of obinutuzumab is about 100 mg (e.g., 100 mg ± 0.5 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, ± 4 mg, ± 6 mg, ± 8 mg, or ± 10 mg) and the C1D2 of obinutuzumab is about 900 mg (e.g., 900 mg ± 5 mg, ± 10 mg, ± 20 mg, ± 30 mg, ± 40 mg, ± 50 mg, ± 60 mg, ± 70 mg, ± 80 mg, or ± 90 mg).

[0138] In one embodiment, C1D1 of obinutuzumab will be administered to the subject on day 1 of the first dosing cycle, and C1D2 of obinutuzumab will be administered to the subject on day 2 of the first dosing cycle.

[0139] In one embodiment, the second administration cycle comprises a single dose of rituximab (C2D1). In one embodiment, the C2D1 of rituximab is about 375 mg / m 2 (e.g., 375 mg / m 2 ±5 mg / m 2 , ±10 mg / m 2 , ±25 mg / m 2 , or ±37.5 mg / m 2 In one embodiment, rituximab will be administered to the subject on day 5 of the second administration cycle.

[0140] In one embodiment, the method comprises administering to the subject ifosfamide, carboplatin, and etoposide.

[0141] In one embodiment, the first administration cycle comprises: (a) first dose of ifosfamide (C1D1), second dose of ifosfamide (C1D2), and third dose of ifosfamide (C1D3); (b) a single dose of carboplatin (C1D1); and (c) a first dose of etoposide (C1D1), a second dose of etoposide (C1D2), and a third dose of etoposide (C1D3); The second cycle is (a) first dose of ifosfamide (C2D1), second dose of ifosfamide (C2D2), and third dose of ifosfamide (C2D3); (b) a single dose of carboplatin (C2D1); and (c) a first dose of etoposide (C2D1), a second dose of etoposide (C2D2), and a third dose of etoposide (C2D3);

[0142] In one embodiment, ifosfamide is administered at a dose of about 3000 mg / m for each dose of ifosfamide. 2 (e.g., 3000 mg / m 2 ±40 mg / m 2 , ±50 mg / m 2 , ±100 mg / m 2 , ±200 mg / m 2 , or ±300 mg / m 2 ) and carboplatin will be administered at a dose of approximately 635 mg / m 2 (e.g., 635 mg / m 2 ±5 mg / m 2 , ±10 mg / m 2 , ±25 mg / m 2 , ±50 mg / m 2 , ±60 mg / m 2 , or ±63.5 mg / m 2 ) and etoposide will be administered at a dose of approximately 100 mg / m for each dose of etoposide. 2 (e.g., 100 mg / m 2 ±1 mg / m 2 , ±2.5 mg / m 2 , ±5 mg / m 2 , or ±10 mg / m 2 In one embodiment, (a) ifosfamide C1D1, C1D2, and C1D3 will be administered on days 3, 4, and 5, respectively, of the first administration cycle; (b) carboplatin C1D1 will be administered on day 3 of the first administration cycle; (c) etoposide C1D1, C1D2, and C1D3 will be administered on days 3, 4, and 5, respectively, of the first administration cycle; (d) ifosfamide C2D1, C2D2, and C2D3 will be administered on days 6, 7, and 8, respectively, of the second administration cycle; (e) carboplatin C2D1 will be administered on day 6 of the second administration cycle; and (f) etoposide C2D1, C2D2, and C2D3 will be administered on days 6, 7, and 8, respectively, of the second administration cycle.

[0143] In one embodiment, the first and second administration cycles are each 21-day administration cycles. In one embodiment, the administration regimen includes one or more additional administration cycles. In one embodiment, the one or more additional administration cycles are each 21-day administration cycles. In one embodiment, the administration regimen includes a total of three administration cycles.

[0144] In one embodiment, the one or more additional administration cycles each comprise: (a) an additional single dose of a bispecific antibody that binds to CD20 and CD3; (b) an additional single dose of an anti-CD20 antibody, and (c) an additional first dose, an additional second dose, and an additional third dose of ifosfamide; an additional single dose of carboplatin; and an additional first dose, an additional second dose, and an additional third dose of etoposide. In one embodiment, (a) the subject weighs about 7.5 kg or more and less than about 13 kg and the additional single dose of the bispecific antibody is about 0.5 mg / kg (e.g., 0.5 mg / kg ± 0.005 mg / kg, ± 0.01 mg / kg, ± 0.02 mg / kg, ± 0.03 mg / kg, ± 0.04 mg / kg, or ± 0.05 mg / kg); (b) the subject weighs about 13 kg or more and less than about 45 kg and the additional single dose of the bispecific antibody is about 0.4 mg / kg. g / kg (e.g., 0.4 mg / kg ± 0.005 mg / kg, ± 0.01 mg / kg, ± 0.02 mg / kg, ± 0.03 mg / kg, or ± 0.04 mg / kg); or (c) the subject weighs about 45 kg or more and the additional single dose of bispecific antibody is about 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg).

[0145] In one embodiment, an additional single dose of the bispecific antibody will be administered to the subject on day 1 of each of one or more additional administration cycles.

[0146] In one embodiment, the anti-CD20 antibody is rituximab. In one embodiment, the additional single dose of rituximab is about 375 mg / m2 (e.g., 375 mg / m 2 ±5 mg / m 2 , ±10 mg / m 2 , ±25 mg / m 2 , or ±37.5 mg / m 2 In one embodiment, an additional single dose of rituximab will be administered on day 5 of each of one or more additional administration cycles.

[0147] In one embodiment, the first additional dose, the second additional dose, and the third additional dose of ifosfamide are each about 3000 mg / m 2 (e.g., 3000 mg / m 2 ±40 mg / m 2 , ±50 mg / m 2 , ±100 mg / m 2 , ±200 mg / m 2 , or ±300 mg / m 2 ) and an additional single dose of carboplatin is approximately 635 mg / m 2 (e.g., 635 mg / m 2 ±5 mg / m 2 , ±10 mg / m 2 , ±25 mg / m 2 , ±50 mg / m 2 , ±60 mg / m 2 , or ±63.5 mg / m 2 ), and the first additional dose, the second additional dose, and the third additional dose of etoposide are each about 100 mg / m 2 (e.g., 100 mg / m 2 ±1 mg / m 2 , ±2.5 mg / m 2 , ±5 mg / m 2 , or ±10 mg / m 2In one embodiment, (a) an additional first dose, an additional second dose, and an additional third dose of ifosfamide will be administered to the subject on day 6, day 7, and day 8, respectively, of each of one or more additional administration cycles; (b) an additional single dose of carboplatin will be administered on day 6 of each of one or more additional administration cycles; and (c) an additional first dose, an additional second dose, and an additional third dose of etoposide will be administered to the subject on day 6, day 7, and day 8, respectively, of each of one or more additional administration cycles.

[0148] In one embodiment, the method further comprises administering one or more additional therapeutic agents to the subject.

[0149] In one embodiment, the one or more additional therapeutic agents is tocilizumab. In one embodiment, the subject weighs about 30 kg or more and tocilizumab will be administered at a dose of about 8 mg / kg (e.g., 8 mg / kg ± 0.05 mg / kg, ± 0.1 mg / kg, ± 0.25 mg / kg, ± 0.5 mg / kg, or ± 0.8 mg / kg), or the subject weighs less than 30 kg and tocilizumab will be administered at a dose of about 12 mg / kg (e.g., 12 mg / kg ± 0.05 mg / kg, ± 0.1 mg / kg, ± 0.25 mg / kg, ± 0.5 mg / kg, ± 0.75 mg / kg, ± 1 mg / kg, or ± 1.2 mg / kg), with a maximum dose of about 800 mg (e.g., 800 mg ± 10 mg, ± 25 mg, ± 50 mg, or ± 80 mg).

[0150] In one embodiment, the one or more additional therapeutic agents is a corticosteroid, hi one embodiment, the corticosteroid comprises prednisone, prednisolone, methylprednisolone, or dexamethasone.

[0151] In one embodiment, the corticosteroid is dexamethasone. In one embodiment, dexamethasone will be administered intravenously at a dose of about 0.15 mg / kg (e.g., 0.15 mg / kg ± 0.001 mg / kg, ± 0.0025 mg / kg, ± 0.005 mg / kg, ± 0.01 mg / kg, or ± 0.015 mg / kg) to about 0.5 mg / kg (e.g., 0.5 mg / kg ± 0.005 mg / kg, ± 0.01 mg / kg, ± 0.02 mg / kg, ± 0.03 mg / kg, ± 0.04 mg / kg, or ± 0.05 mg / kg) at least about 1 hour (i.e., at least 1 hour ± 6 minutes; e.g., at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours, or more) prior to administration of any dose of the bispecific antibody, with a maximum daily dose of 10 mg. In one embodiment, dexamethasone will be administered intravenously at a dose of about 0.15 mg / kg (e.g., 0.15 mg / kg ± 0.001 mg / kg, ± 0.0025 mg / kg, ± 0.005 mg / kg, ± 0.01 mg / kg, or ± 0.015 mg / kg) to about 0.5 mg / kg (e.g., 0.5 mg / kg ± 0.005 mg / kg, ± 0.01 mg / kg, ± 0.02 mg / kg, ± 0.03 mg / kg, ± 0.04 mg / kg, or ± 0.05 mg / kg) at least about 1 hour (i.e., at least 1 hour ± 6 minutes; e.g., at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours, or more) prior to administration of any dose of obinutuzumab, with a maximum daily dose of 10 mg.

[0152] In one embodiment, the corticosteroid is methylprednisolone, which is administered intravenously at a dose of about 1 mg / kg to about 2 mg / kg (e.g., 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.9, or 2.0 mg / kg) at least about 1 hour (i.e., at least 1 hour ± 6 minutes; e.g., at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours, or more) prior to administration of any dose of the bispecific antibody. In one embodiment, methylprednisolone will be administered intravenously at a dose of about 1 mg / kg to about 2 mg / kg (e.g., 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.9, or 2.0 mg / kg) at least about 1 hour (i.e., at least 1 hour ± 6 minutes; e.g., at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours, or more) prior to administration of any dose of obinutuzumab.

[0153] In one embodiment, the corticosteroid is prednisone or prednisolone. In one embodiment, the prednisone or prednisolone will be administered intravenously at a dose of about 100 mg (e.g., 100 mg ± 0.5 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, ± 4 mg, ± 6 mg, ± 8 mg, or ± 10 mg) or about 2 mg / kg for at least about 1 hour (i.e., at least 1 hour ± 6 minutes; e.g., at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours, or more) prior to administration of any dose of the bispecific antibody. In one embodiment, prednisone or prednisolone will be administered intravenously at a dose of about 100 mg (e.g., 100 mg ± 0.5 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, ± 4 mg, ± 6 mg, ± 8 mg, or ± 10 mg) or about 2 mg / kg at least about 1 hour (i.e., at least 1 hour ± 6 minutes; e.g., at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours, or more) prior to administration of any dose of obinutuzumab.

[0154] In one embodiment, the one or more additional therapeutic agents is an antihistamine. In one embodiment, the antihistamine is diphenhydramine. In one embodiment, the subject is 2 to 17 years of age, and diphenhydramine will be administered intravenously at a dose of about 10 mg to 20 mg (e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 mg), with a maximum single dose of about 1.25 mg / kg. In one embodiment, the subject is under 2 years of age, and diphenhydramine will be administered rectally at a dose of about 20 mg (e.g., 20 mg ± 0.1 mg, ± 0.25 mg, ± 0.5 mg, ± 1 mg, ± 1.5 mg, or ± 2 mg). In one embodiment, diphenhydramine will be administered at least about 30 minutes (i.e., at least 30 minutes ± 3 minutes; e.g., at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours, or more) prior to administration of any dose of bispecific antibody and / or anti-CD20 antibody.

[0155] In one embodiment, the one or more additional therapeutic agents comprise granulocyte colony-stimulating factor (G-CSF), hi one embodiment, the G-CSF is administered about 1 to about 2 days (e.g., 24, 26, 28, 30, 32, 36, 38, 40, 42, 44, 46, or 48 hours) after administration of any dose of rituximab, ifosfamide, carboplatin, and / or etoposide. In one embodiment, G-CSF will be administered intravenously or subcutaneously at a dose of about 5 μg / kg / day (e.g., 5 μg / kg / day ±0.05 μg / kg / day, ±0.1 μg / kg / day, ±0.2 μg / kg / day, ±0.3 μg / kg / day, ±0.4 μg / kg / day, ±0.5 μg / kg / day), or about 10 μg / kg / day (e.g., 10 μg / kg / day ±0.1 μg / kg / day, ±0.2 μg / kg / day, ±0.4 μg / kg / day, ±0.6 μg / kg / day, ±0.8 μg / kg / day, ±1 μg / kg / day). In one embodiment, G-CSF will be administered at a dose of about 5 μg / kg / day (e.g., 5 μg / kg / day ±0.05 μg / kg / day, ±0.1 μg / kg / day, ±0.2 μg / kg / day, ±0.3 μg / kg / day, ±0.4 μg / kg / day, ±0.5 μg / kg / day) in the first administration cycle, and about 10 μg / kg / day (e.g., 10 μg / kg / day ±0.1 μg / kg / day, ±0.2 μg / kg / day, ±0.4 μg / kg / day, ±0.6 μg / kg / day, ±0.8 μg / kg / day, ±1 μg / kg / day) in the second administration cycle and / or each additional administration cycle.

[0156] In one embodiment, the one or more additional therapeutic agents is an antipyretic. In one embodiment, the antipyretic is acetaminophen or paracetamol. In one embodiment, the acetaminophen or paracetamol will be administered orally or intravenously at a dose of about 500 to about 1000 mg (e.g., 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 mg). In one embodiment, the acetaminophen or paracetamol will be administered at least about 30 minutes (i.e., at least 30 minutes ± 3 minutes; e.g., at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours, or more) prior to administration of any dose of the bispecific antibody and / or anti-CD20 antibody.

[0157] In one embodiment, the one or more additional therapeutic agents is mesna. In one embodiment, mesna is administered at a total dose of 3000 mg / m 2 In one embodiment, mesna is administered intravenously daily as five doses in an amount of about 600 mg / m before the administration of any dose of ifosfamide. 2 and about 600 mg / m at about 3 hours, about 6 hours, about 9 hours, and about 12 hours, respectively, after the first dose of ifosfamide. 2 In one embodiment, mesna will be administered intravenously in four repeat doses of 0.01 mg / kg of mesna. In one embodiment, mesna will be administered daily to a subject on days 3, 4, and 5 of a first administration cycle, days 6, 7, and 8 of a second administration cycle, and / or days 6, 7, and 8 of each additional administration cycle.

[0158] In one aspect, the invention features a bispecific antibody that binds CD20 and CD3 for use in a method of treating a subject aged 18 to 30 years having a CD20-positive cell proliferative disorder, the bispecific antibody that binds CD20 and CD3 being administered in combination with an anti-CD20 antibody and one or more chemotherapeutic agents selected from ifosfamide, carboplatin, and / or etoposide. The administration is in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle.

[0159] In one embodiment, the first administration cycle comprises a first dose of bispecific antibody (C1D1) and a second dose of bispecific antibody (C1D2), wherein C1D1 of the bispecific antibody is about 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, or ± 0.25 mg) and C1D2 of the bispecific antibody is about 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, or ± 1 mg); The second administration cycle comprises a single dose of bispecific antibody (C2D1), where the bispecific antibody C2D1 is about 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg).

[0160] In one embodiment, bispecific antibody C1D1 and bispecific antibody C1D2 will be administered to the subject on days 8 and 15, respectively, of the first administration cycle.

[0161] In one embodiment, the bispecific antibody C2D1 will be administered to the subject on day 1 of the second administration cycle.

[0162] In one embodiment, the anti-CD20 antibody is obinutuzumab and / or rituximab.

[0163] In one embodiment, the first administration cycle comprises a first dose of obinutuzumab (C1D1) and a second dose of obinutuzumab (C1D2). In one embodiment, the sum of C1D1 and C1D2 of obinutuzumab is about 1000 mg (e.g., 1000 mg ± 5 mg, ± 10 mg, ± 20 mg, ± 30 mg, ± 50 mg, ± 75 mg, or ± 100 mg). In one embodiment, C1D1 of obinutuzumab is about 1 / 10 the amount of the sum of C1D1 and C1D2 of obinutuzumab, and C1D2 of obinutuzumab is about 9 / 10 the amount of the sum of C1D1 and C1D2 of obinutuzumab. In one embodiment, C1D1 of obinutuzumab is about 100 mg (e.g., 100 mg ± 0.5 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, ± 4 mg, ± 6 mg, ± 8 mg, or ± 10 mg) and C1D2 of obinutuzumab is about 900 mg (e.g., 900 mg ± 5 mg, ± 10 mg, ± 20 mg, ± 30 mg, ± 40 mg, ± 50 mg, ± 60 mg, ± 70 mg, ± 80 mg, or ± 90 mg). In one embodiment, C1D1 of obinutuzumab will be administered to the subject on day 1 of the first administration cycle, and C1D2 of obinutuzumab will be administered to the subject on day 2 of the first administration cycle.

[0164] In one embodiment, the second administration cycle comprises a single dose of rituximab (C2D1). In one embodiment, the C2D1 of rituximab is about 375 mg / m 2 (e.g., 375 mg / m 2 ±5 mg / m 2 , ±10 mg / m 2 , ±25 mg / m 2 , or ±37.5 mg / m 2 In one embodiment, the C2D1 of rituximab will be administered to the subject on day 5 of the second administration cycle.

[0165] In one embodiment, the method comprises administering to the subject ifosfamide, carboplatin, and etoposide. In one embodiment, the first administration cycle comprises: (a) Single dose of ifosfamide (C1D1); (b) a single dose of carboplatin (C1D1); and (c) a first dose of etoposide (C1D1), a second dose of etoposide (C1D2), and a third dose of etoposide (C1D3); The second cycle is (a) Single dose of ifosfamide (C2D1); (b) a single dose of carboplatin (C2D1); and (c) a first dose of etoposide (C2D1), a second dose of etoposide (C2D2), and a third dose of etoposide (C2D3);

[0166] In one embodiment, ifosfamide is about 5000 mg / m 2 (e.g., 5000 mg / m 2 ±50 mg / m 2 , ±100 mg / m 2 , ±200 mg / m 2 , ±300 mg / m 2 , ±400 mg / m 2 , or ±500 mg / m 2 ), carboplatin will be administered at a dose of about 5×(25+creatinine clearance (CrCl)) mg with a maximum dose of about 750 mg (e.g., 750 mg±10 mg, ±25 mg, ±50 mg, or ±75 mg), and etoposide will be administered at a dose of about 100 mg / m for each dose of etoposide. 2 (e.g., 100 mg / m 2 ±1 mg / m 2 , ±2.5 mg / m 2 , ±5 mg / m 2 , or ±10 mg / m 2 ) will be administered.

[0167] In one embodiment, (a) the subject is male and CrCl is calculated using the formula CrCl = ([140 - age] x [weight (kg)]) / (72 x [serum creatinine (mg / dL)]); or (b) the subject is female and CrCl is calculated using the formula CrCl = 0.85 x ([140 - age] x [weight (kg)]) / (72 x [serum creatinine (mg / dL)]).

[0168] In one embodiment, (a) the subject has a CrCl of less than about 60 mL / min and each single dose of ifosfamide is 4000 mg / m 2 and / or (b) the subject has a CrCl of less than about 50 mL / min and each dose of etoposide is reduced to about 75 mg / m 2 Reduce to.

[0169] In one embodiment, (a) ifosfamide C1D1 will be administered on day 3 of the first administration cycle; (b) Carboplatin C1D1 will be administered on day 3 of the first dosing cycle; (c) etoposide C1D1, C1D2, and C1D3 will be administered on days 3, 4, and 5, respectively, of the first dosing cycle; (d) Ifosfamide C2D1 will be administered on day 6 of the second dosing cycle; (e) Carboplatin C2D1 will be administered on day 6 of the second dosing cycle; (f) Etoposide C2D1, C2D2, and C2D3 will be administered on days 6, 7, and 8, respectively, of the second dosing cycle.

[0170] In one embodiment, the first and second administration cycles are each 21-day administration cycles. In one embodiment, the administration regimen includes one or more additional administration cycles. In one embodiment, the one or more additional administration cycles are each 21-day administration cycles. In one embodiment, the administration regimen includes a total of three administration cycles.

[0171] In one embodiment, the one or more additional administration cycles each comprise: (a) an additional single dose of a bispecific antibody that binds to CD20 and CD3; (b) an additional single dose of an anti-CD20 antibody, and (c) An additional single dose of ifosfamide; an additional single dose of carboplatin; and an additional first dose, an additional second dose, and an additional third dose of etoposide.

[0172] In one embodiment, the additional single dose of the bispecific antibody is about 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg). In one embodiment, the additional single dose of the bispecific antibody will be administered to the subject on day 1 of each of one or more additional administration cycles.

[0173] In one embodiment, the anti-CD20 antibody is rituximab. In one embodiment, the additional single dose of rituximab is about 375 mg / m 2 (e.g., 375 mg / m 2 ±5 mg / m 2 , ±10 mg / m 2 , ±25 mg / m 2 , or ±37.5 mg / m 2 In one embodiment, an additional single dose of rituximab will be administered on day 5 of each of one or more additional administration cycles.

[0174] In one embodiment, the additional single dose of ifosfamide is about 5000 mg / m 2 (e.g., 5000 mg / m 2 ±50 mg / m 2 , ±100 mg / m 2 , ±200 mg / m 2 , ±300 mg / m 2 , ±400 mg / m 2 , or ±500 mg / m 2 ), the additional single dose of carboplatin is about 5×(25+creatinine clearance (CrCl)) mg, the maximum dose is about 750 mg (e.g., 750 mg±10 mg, ±25 mg, ±50 mg, or ±75 mg), and the additional first dose, additional second dose, and additional third dose of etoposide are each about 100 mg / m 2 (e.g., 100 mg / m 2 ±1 mg / m 2 , ±2.5 mg / m 2 , ±5 mg / m 2 , or ±10 mg / m 2 )

[0175] In one embodiment, (a) the subject is male and CrCl is calculated using the formula CrCl = ([140 - age] x [weight (kg)]) / (72 x [serum creatinine (mg / dL)]); or (b) the subject is female and CrCl is calculated using the formula CrCl = 0.85 x ([140 - age] x [weight (kg)]) / (72 x [serum creatinine (mg / dL)]).

[0176] In one embodiment, (a) the subject has a CrCl of less than about 60 mL / min and the additional single dose of ifosfamide is 4000 mg / m 2 and / or (b) the subject has a CrCl of less than about 50 mL / min and each additional dose of etoposide is reduced to about 75 mg / m 2 Reduce to.

[0177] In one embodiment, (a) an additional single dose of ifosfamide is to be administered on day 6 of each of one or more additional administration cycles; (b) an additional single dose of carboplatin is to be administered on day 6 of each of one or more additional administration cycles; (c) An additional first dose, an additional second dose, and an additional third dose of etoposide will be administered to the subject on days 6, 7, and 8, respectively, of each of the one or more additional administration cycles.

[0178] In one embodiment, the method further comprises administering one or more additional therapeutic agents to the subject.

[0179] In one embodiment, the one or more additional therapeutic agents is tocilizumab. In one embodiment, the subject weighs about 30 kg or more and tocilizumab will be administered at a dose of about 8 mg / kg (e.g., 8 mg / kg ± 0.05 mg / kg, ± 0.1 mg / kg, ± 0.25 mg / kg, ± 0.5 mg / kg, or ± 0.8 mg / kg), or the subject weighs less than 30 kg and tocilizumab will be administered at a dose of about 12 mg / kg (e.g., 12 mg / kg ± 0.05 mg / kg, ± 0.1 mg / kg, ± 0.25 mg / kg, ± 0.5 mg / kg, ± 0.75 mg / kg, ± 1 mg / kg, or ± 1.2 mg / kg), with a maximum dose of about 800 mg (e.g., 800 mg ± 10 mg, ± 25 mg, ± 50 mg, or ± 80 mg).

[0180] In one embodiment, the one or more additional therapeutic agents is a corticosteroid.

[0181] In one embodiment, the corticosteroid comprises prednisone, prednisolone, methylprednisolone, or dexamethasone.

[0182] In one embodiment, the corticosteroid is dexamethasone. In one embodiment, dexamethasone will be administered intravenously at a dose of about 0.15 mg / kg (e.g., 0.15 mg / kg ± 0.001 mg / kg, ± 0.0025 mg / kg, ± 0.005 mg / kg, ± 0.01 mg / kg, or ± 0.015 mg / kg) to about 0.5 mg / kg (e.g., 0.5 mg / kg ± 0.005 mg / kg, ± 0.01 mg / kg, ± 0.02 mg / kg, ± 0.03 mg / kg, ± 0.04 mg / kg, or ± 0.05 mg / kg) at least about 1 hour (i.e., at least 1 hour ± 6 minutes; e.g., at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours, or more) prior to administration of any dose of the bispecific antibody, with a maximum daily dose of 10 mg. In one embodiment, dexamethasone will be administered intravenously at a dose of about 0.15 mg / kg (e.g., 0.15 mg / kg ± 0.001 mg / kg, ± 0.0025 mg / kg, ± 0.005 mg / kg, ± 0.01 mg / kg, or ± 0.015 mg / kg) to about 0.5 mg / kg (e.g., 0.5 mg / kg ± 0.005 mg / kg, ± 0.01 mg / kg, ± 0.02 mg / kg, ± 0.03 mg / kg, ± 0.04 mg / kg, or ± 0.05 mg / kg) at least about 1 hour (i.e., at least 1 hour ± 6 minutes; e.g., at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours, or more) prior to administration of any dose of obinutuzumab, with a maximum daily dose of 10 mg.

[0183] In one embodiment, the corticosteroid is methylprednisolone, which is administered intravenously at a dose of about 1 mg / kg to about 2 mg / kg (e.g., 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.9, or 2.0 mg / kg) at least about 1 hour (i.e., at least 1 hour ± 6 minutes; e.g., at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours, or more) prior to administration of any dose of the bispecific antibody. In one embodiment, methylprednisolone will be administered intravenously at a dose of about 1 mg / kg to about 2 mg / kg (e.g., 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.9, or 2.0 mg / kg) at least about 1 hour (i.e., at least 1 hour ± 6 minutes; e.g., at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours, or more) prior to administration of any dose of obinutuzumab.

[0184] In one embodiment, the corticosteroid is prednisone or prednisolone, hi one embodiment, the prednisone or prednisolone will be administered intravenously at a dose of about 100 mg (e.g., 100 mg ± 0.5 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, ± 4 mg, ± 6 mg, ± 8 mg, or ± 10 mg) or about 2 mg / kg at least about 1 hour (i.e., at least 1 hour ± 6 minutes; e.g., at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours, or more) prior to administration of any dose of the bispecific antibody. In one embodiment, prednisone or prednisolone will be administered intravenously at a dose of about 100 mg (e.g., 100 mg ± 0.5 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, ± 4 mg, ± 6 mg, ± 8 mg, or ± 10 mg) or about 2 mg / kg at least about 1 hour (i.e., at least 1 hour ± 6 minutes; e.g., at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours, or more) prior to administration of any dose of obinutuzumab.

[0185] In one embodiment, the one or more additional therapeutic agents is an antihistamine. In one embodiment, the antihistamine is diphenhydramine. In one embodiment, diphenhydramine will be administered orally or intravenously at a dose of about 50 mg (e.g., 50 mg ± 0.5 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, ± 3 mg, ± 4 mg, or ± 5 mg). In one embodiment, diphenhydramine will be administered at least about 30 minutes (i.e., at least 30 minutes ± 3 minutes; e.g., at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours, or more) prior to administration of any dose of bispecific antibody and / or anti-CD20 antibody.

[0186] In one embodiment, the one or more additional therapeutic agents comprise granulocyte colony-stimulating factor (G-CSF), hi one embodiment, the G-CSF is administered about 1 to about 2 days (e.g., 24, 26, 28, 30, 32, 36, 38, 40, 42, 44, 46, or 48 hours) after administration of any dose of rituximab, ifosfamide, carboplatin, and / or etoposide. In one embodiment, G-CSF will be administered intravenously or subcutaneously at a dose of about 5 μg / kg / day (e.g., 5 μg / kg / day ±0.05 μg / kg / day, ±0.1 μg / kg / day, ±0.2 μg / kg / day, ±0.3 μg / kg / day, ±0.4 μg / kg / day, ±0.5 μg / kg / day), or about 10 μg / kg / day (e.g., 10 μg / kg / day ±0.1 μg / kg / day, ±0.2 μg / kg / day, ±0.4 μg / kg / day, ±0.6 μg / kg / day, ±0.8 μg / kg / day, ±1 μg / kg / day). In one embodiment, G-CSF will be administered at a dose of about 5 μg / kg / day (e.g., 5 μg / kg / day ±0.05 μg / kg / day, ±0.1 μg / kg / day, ±0.2 μg / kg / day, ±0.3 μg / kg / day, ±0.4 μg / kg / day, ±0.5 μg / kg / day) in the first administration cycle, and about 10 μg / kg / day (e.g., 10 μg / kg / day ±0.1 μg / kg / day, ±0.2 μg / kg / day, ±0.4 μg / kg / day, ±0.6 μg / kg / day, ±0.8 μg / kg / day, ±1 μg / kg / day) in the second administration cycle and / or each additional administration cycle.

[0187] In one embodiment, the one or more additional therapeutic agents is an antipyretic. In one embodiment, the antipyretic is acetaminophen or paracetamol. In one embodiment, the acetaminophen or paracetamol will be administered orally or intravenously at a dose of about 500 to about 1000 mg (e.g., 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 mg). In one embodiment, the acetaminophen or paracetamol will be administered at least about 30 minutes (i.e., at least 30 minutes ± 3 minutes; e.g., at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours, or more) prior to administration of any dose of the bispecific antibody and / or anti-CD20 antibody.

[0188] In one embodiment, the one or more additional therapeutic agents is mesna. In one embodiment, mesna is at about 5000 mg / m 2 (e.g., 5000 mg / m 2 ±50 mg / m 2 , ±100 mg / m 2 , ±200 mg / m 2 , ±300 mg / m 2 , ±400 mg / m 2 , or ±500 mg / m 2 In one embodiment, mesna will be administered intravenously at a dose of 0.1 mg / kg / day. In one embodiment, mesna will be administered by continuous infusion over about 24 hours on day 3 of the first dosing cycle, day 6 of the second dosing cycle, and / or day 6 of each additional dosing cycle. In one embodiment, mesna will be administered simultaneously with any dose of ifosfamide.

[0189] In one aspect, the invention features glofitamab for use in a method of treating a subject having a CD20-positive cell proliferative disorder, wherein the glofitamab is administered in combination with obinutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle; (a) a first administration cycle comprises administering a first dose (C1D1) of glofitamab on day 8 and administering a second dose (C1D2) of glofitamab on day 15, wherein the C1D1 of glofitamab is about 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, or ± 0.25 mg) and the C1D2 of glofitamab is about 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, or ± 1 mg); (b) The second administration cycle comprises administering a single dose of glofitamab (C2D1) on day 8, wherein the C2D1 of glofitamab is about 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg).

[0190] In one aspect, the invention features glofitamab for use in a method of treating a subject having a CD20-positive cell proliferative disorder, wherein the glofitamab is administered in combination with obinutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen including a first dosing cycle, a second dosing cycle, and a third dosing cycle; (a) a first administration cycle comprises administering a first dose (C1D1) of glofitamab on day 8 and administering a second dose (C1D2) of glofitamab on day 15, wherein the C1D1 of glofitamab is about 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, or ± 0.25 mg) and the C1D2 of glofitamab is about 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, or ± 1 mg); (b) the second dosing cycle comprises administering a single dose of glofitamab (C2D1) on day 8, wherein the C2D1 of glofitamab is about 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg); (c) The third administration cycle comprises administering a single dose of glofitamab (C3D1) on day 8, wherein the C3D1 of glofitamab is about 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg).

[0191] In one aspect, the invention features glofitamab for use in a method of treating a subject having a CD20-positive cell proliferative disorder, wherein the glofitamab is administered in combination with obinutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle; (a) The first administration cycle comprises: (i) administering a first dose of glofitamab (C1D1) on day 8 and a second dose of glofitamab (C1D2) on day 15 (wherein C1D1 of glofitamab is about 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, or ± 0.25 mg) and C1D2 of glofitamab is about 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, or ± 1 mg)); (ii) administering a first dose (C1D1) of obinutuzumab on day 1 (C1D1 of obinutuzumab is about 1000 mg (e.g., 1000 mg ± 5 mg, ± 10 mg, ± 20 mg, ± 30 mg, ± 50 mg, ± 75 mg, or ± 100 mg)); (iii) administering a single dose of ifosfamide (C1D1) on day 2 (C1D1 of ifosfamide is about 5000 mg / m with a maximum dose of about 800 mg (e.g., 800 mg ± 10 mg, ± 25 mg, ± 50 mg, or ± 80 mg)); 2 (e.g., 5000 mg / m 2 ±50 mg / m 2 , ±100 mg / m 2 , ±200 mg / m 2 , ±300 mg / m 2 , ±400 mg / m 2 , or ±500 mg / m 2 ) is); (iv) administering a single dose (C1D1) of carboplatin on day 2 (C1D1 of carboplatin is approximately 5 × (25 + creatinine clearance) mg); and (v) administering a first dose of etoposide (C1D1) on day 1, a second dose of etoposide (C1D2) on day 2, and a third dose of etoposide (C1D3) on day 3 (C1D1, C1D2, and C1D3 of etoposide are each about 100 mg / m 2 (e.g., 100 mg / m 2 ±1 mg / m 2 , ±2.5 mg / m 2 , ±5 mg / m 2 , or ±10 mg / m 2 )); (b) the second administration cycle (i) administering a single dose of glofitamab (C2D1) on day 8 (C2D1 of glofitamab is approximately 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg)); (ii) administering the first dose of rituximab (C2D1) on day 1 (C2D1 of rituximab is approximately 375 mg / m 2 (e.g., 375 mg / m 2 ±5 mg / m 2 , ±10 mg / m 2 , ±25 mg / m 2 , or ±37.5 mg / m 2 ) is); (iii) administering a single dose of ifosfamide on day 2 (C2D1) (C2D1 of ifosfamide is about 5000 mg / m with a maximum dose of about 800 mg (e.g., 800 mg ± 10 mg, ± 25 mg, ± 50 mg, or ± 80 mg)); 2 (e.g., 5000 mg / m 2 ±50 mg / m 2 , ±100 mg / m 2 , ±200 mg / m 2 , ±300 mg / m 2 , ±400 mg / m 2 , or ±500 mg / m 2 ) is); (iv) administering a single dose of carboplatin on day 2 (C2D1) (C2D1 of carboplatin is approximately 5 × (25 + creatinine clearance) mg); and (v) administering a first dose of etoposide (C2D1) on day 1, a second dose of etoposide (C2D2) on day 2, and a third dose of etoposide (C2D3) on day 3 (C2D1, C2D2, and C2D3 of etoposide are each about 100 mg / m 2 (e.g., 100 mg / m 2 ±1 mg / m 2 , ±2.5 mg / m 2 , ±5 mg / m 2 , or ±10 mg / m 2 ) is included.

[0192] In one aspect, the invention features glofitamab for use in a method of treating a subject having a CD20-positive cell proliferative disorder, wherein the glofitamab is administered in combination with obinutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen including a first dosing cycle, a second dosing cycle, and a third dosing cycle; (a) The first administration cycle comprises: (i) administering a first dose of glofitamab (C1D1) on day 8 and a second dose of glofitamab (C1D2) on day 15 (wherein C1D1 of glofitamab is about 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, or ± 0.25 mg) and C1D2 of glofitamab is about 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, or ± 1 mg)); (ii) administering a first dose (C1D1) of obinutuzumab on day 1 (C1D1 of obinutuzumab is about 1000 mg (e.g., 1000 mg ± 5 mg, ± 10 mg, ± 20 mg, ± 30 mg, ± 50 mg, ± 75 mg, or ± 100 mg)); (iii) administering a single dose of ifosfamide (C1D1) on day 2 (C1D1 of ifosfamide is about 5000 mg / m with a maximum dose of about 800 mg (e.g., 800 mg ± 10 mg, ± 25 mg, ± 50 mg, or ± 80 mg)); 2 (e.g., 5000 mg / m 2 ±50 mg / m 2 , ±100 mg / m 2 , ±200 mg / m 2 , ±300 mg / m 2 , ±400 mg / m 2 , or ±500 mg / m 2 ) is); (iv) administering a single dose (C1D1) of carboplatin on day 2 (C1D1 of carboplatin is approximately 5 × (25 + creatinine clearance) mg); and (v) administering a first dose of etoposide (C1D1) on day 1, a second dose of etoposide (C1D2) on day 2, and a third dose of etoposide (C1D3) on day 3 (C1D1, C1D2, and C1D3 of etoposide are each about 100 mg / m 2 (e.g., 100 mg / m 2 ±1 mg / m 2 , ±2.5 mg / m 2 , ±5 mg / m 2 , or ±10 mg / m 2)); (b) the second administration cycle (i) administering a single dose of glofitamab (C2D1) on day 8 (C2D1 of glofitamab is approximately 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg)); (ii) administering the first dose of rituximab (C2D1) on day 1 (C2D1 of rituximab is approximately 375 mg / m 2 (e.g., 375 mg / m 2 ±5 mg / m 2 , ±10 mg / m 2 , ±25 mg / m 2 , or ±37.5 mg / m 2 ) is); (iii) administering a single dose of ifosfamide on day 2 (C2D1) (C2D1 of ifosfamide is about 5000 mg / m with a maximum dose of about 800 mg (e.g., 800 mg ± 10 mg, ± 25 mg, ± 50 mg, or ± 80 mg)); 2 (e.g., 5000 mg / m 2 ±50 mg / m 2 , ±100 mg / m 2 , ±200 mg / m 2 , ±300 mg / m 2 , ±400 mg / m 2 , or ±500 mg / m 2 ) is); (iv) administering a single dose of carboplatin on day 2 (C2D1) (C2D1 of carboplatin is approximately 5 × (25 + creatinine clearance) mg); and (v) administering a first dose of etoposide (C2D1) on day 1, a second dose of etoposide (C2D2) on day 2, and a third dose of etoposide (C2D3) on day 3 (C2D1, C2D2, and C2D3 of etoposide are each about 100 mg / m 2 (e.g., 100 mg / m 2 ±1 mg / m 2 , ±2.5 mg / m 2 , ±5 mg / m 2 , or ±10 mg / m2 ) is ) includes; (c) The third administration cycle comprises: (i) administering a single dose of glofitamab (C3D1) on day 8 (C3D1 of glofitamab is about 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg)); (ii) administering the first dose of rituximab (C3D1) on day 1 (C3D1 of rituximab is approximately 375 mg / m 2 (e.g., 375 mg / m 2 ±5 mg / m 2 , ±10 mg / m 2 , ±25 mg / m 2 , or ±37.5 mg / m 2 ) is); (iii) administering a single dose of ifosfamide (C3D1) on day 2 (C3D1 of ifosfamide is about 5000 mg / m with a maximum dose of about 800 mg (e.g., 800 mg ± 10 mg, ± 25 mg, ± 50 mg, or ± 80 mg)); 2 (e.g., 5000 mg / m 2 ±50 mg / m 2 , ±100 mg / m 2 , ±200 mg / m 2 , ±300 mg / m 2 , ±400 mg / m 2 , or ±500 mg / m 2 ) is); (iv) administering a single dose of carboplatin (C3D1) on day 2 (C3D1 of carboplatin is approximately 5 × (25 + creatinine clearance) mg); and (v) administering a first dose of etoposide (C3D1) on day 1, a second dose of etoposide (C3D2) on day 2, and a third dose of etoposide (C3D3) on day 3 (C3D1, C3D2, and C3D3 of etoposide are each about 100 mg / m 2 (e.g., 100 mg / m 2 ±1 mg / m 2 , ±2.5 mg / m 2 , ±5 mg / m 2, or ±10 mg / m 2 ) is included.

[0193] In one embodiment, mesna will be administered simultaneously with any dose of ifosfamide. In one embodiment, mesna is administered at about 5000 mg / m 2 (e.g., 5000 mg / m 2 ±50 mg / m 2 , ±100 mg / m 2 , ±200 mg / m 2 , ±300 mg / m 2 , ±400 mg / m 2 , or ±500 mg / m 2 In one embodiment, mesna will be administered by continuous infusion over about 24 hours on the second day of each administration cycle.

[0194] In one aspect, the invention features a method of treating a subject 6 months to 17 years of age having a CD20-positive cell proliferative disorder, the method comprising administering to the subject effective amounts of glofitamab, obinutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen including at least a first dosing cycle and a second dosing cycle; (a) The first administration cycle comprises administering a first dose of glofitamab (C1D1) on day 8 and a second dose of glofitamab (C1D2) on day 15, wherein the C1D1 dose of glofitamab is about 0.03 mg / kg (e.g., 0.03 mg / kg ± 0.0005 mg / kg, ± 0.001 mg / kg, ± 0.002 mg / kg, or ± 0.003 mg / kg), about 0.04 mg / kg (e.g., 0.04 mg / kg ± 0.0005 mg / kg, ± 0.001 mg / kg, ± 0.002 mg / kg, ± 0.003 mg / kg, or ± 0.004 mg / kg), g / kg), or about 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, or ± 0.25 mg), and the C1D2 of glofitamab is about 0.15 mg / kg (e.g., 0.15 mg / kg ± 0.001 mg / kg, ± 0.0025 mg / kg, ± 0.005 mg / kg, ± 0.01 mg / kg, or ± 0.015 mg / kg) or about 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, or ± 1 mg); (b) The second administration cycle comprises administering a single dose of glofitamab (C2D1) on day 8, wherein the C2D1 of glofitamab is about 0.4 mg / kg (e.g., 0.4 mg / kg ± 0.005 mg / kg, ± 0.01 mg / kg, ± 0.02 mg / kg, ± 0.03 mg / kg, or ± 0.04 mg / kg), about 0.5 mg / kg (e.g., 0.5 mg / kg ± 0.005 mg / kg, ± 0.01 mg / kg, ± 0.02 mg / kg, ± 0.03 mg / kg, ± 0.04 mg / kg, or ± 0.05 mg / kg), or about 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg).

[0195] In one aspect, the invention features a method of treating a subject 6 months to 17 years of age having a CD20-positive cell proliferative disorder, the method including administering to the subject effective amounts of glofitamab, obinutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen including a first dosing cycle, a second dosing cycle, and a third dosing cycle; (a) The first administration cycle comprises administering a first dose of glofitamab (C1D1) on day 8 and a second dose of glofitamab (C1D2) on day 15, wherein the C1D1 dose of glofitamab is about 0.03 mg / kg (e.g., 0.03 mg / kg ± 0.0005 mg / kg, ± 0.001 mg / kg, ± 0.002 mg / kg, or ± 0.003 mg / kg), about 0.04 mg / kg (e.g., 0.04 mg / kg ± 0.0005 mg / kg, ± 0.001 mg / kg, ± 0.002 mg / kg, ± 0.003 mg / kg, or ± 0.004 mg / kg), g / kg), or about 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, or ± 0.25 mg), and the C1D2 of glofitamab is about 0.15 mg / kg (e.g., 0.15 mg / kg ± 0.001 mg / kg, ± 0.0025 mg / kg, ± 0.005 mg / kg, ± 0.01 mg / kg, or ± 0.015 mg / kg) or about 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, or ± 1 mg); (b) the second dosing cycle comprises administering a single dose of glofitamab (C2D1) on day 8, wherein the C2D1 of glofitamab is about 0.4 mg / kg (e.g., 0.4 mg / kg ± 0.005 mg / kg, ± 0.01 mg / kg, ± 0.02 mg / kg, ± 0.03 mg / kg, or ± 0.04 mg / kg), about 0.5 mg / kg (e.g., 0.5 mg / kg ± 0.005 mg / kg, ± 0.01 mg / kg, ± 0.02 mg / kg, ± 0.03 mg / kg, ± 0.04 mg / kg, or ± 0.05 mg / kg), or about 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg); (c) The third administration cycle comprises administering a single dose of glofitamab (C3D1) on day 8, wherein the C3D1 of glofitamab is about 0.4 mg / kg (e.g., 0.4 mg / kg ± 0.005 mg / kg, ± 0.01 mg / kg, ± 0.02 mg / kg, ± 0.03 mg / kg, or ± 0.04 mg / kg), about 0.5 mg / kg (e.g., 0.5 mg / kg ± 0.005 mg / kg, ± 0.01 mg / kg, ± 0.02 mg / kg, ± 0.03 mg / kg, ± 0.04 mg / kg, or ± 0.05 mg / kg), or about 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg).

[0196] In one aspect, the invention features a method of treating a subject 6 months to 17 years of age having a CD20-positive cell proliferative disorder, the method comprising administering to the subject effective amounts of glofitamab, obinutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen including at least a first dosing cycle and a second dosing cycle; (a) The first administration cycle comprises: (i) administering a first dose of glofitamab (C1D1) on day 8 and a second dose of glofitamab (C1D2) on day 15 (C1D1 of glofitamab may be about 0.03 mg / kg (e.g., 0.03 mg / kg ± 0.0005 mg / kg, ± 0.001 mg / kg, ± 0.002 mg / kg, or ± 0.003 mg / kg), about 0.04 mg / kg (e.g., 0.04 mg / kg ± 0.0005 mg / kg, ± 0.001 mg / kg, ± 0.002 mg / kg, ± 0.003 mg / kg, or ± 0.004 mg / kg), or about 2 0.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, or ± 0.25 mg), and the C1D2 of glofitamab is about 0.15 mg / kg (e.g., 0.15 mg / kg ± 0.001 mg / kg, ± 0.0025 mg / kg, ± 0.005 mg / kg, ± 0.01 mg / kg, or ± 0.015 mg / kg) or about 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, or ± 1 mg); (ii) administering a first dose (C1D1) of obinutuzumab on day 1 and a second dose (C1D2) of obinutuzumab on day 2 (C1D1 of obinutuzumab is about 1 / 10 of the sum of C1D1 and C1D2 of obinutuzumab, and C1D2 of obinutuzumab is about 9 / 10 of the sum of C1D1 and C1D2 of obinutuzumab, and the sum of C1D1 and C1D2 of obinutuzumab is about 38 mg / kg (e.g., 38 mg / kg ± 0.25 mg / kg, ± 0.5 mg / kg, ± 1 mg / kg, ± 2 mg / kg, ± 3 mg / kg) / kg, or ±3.8 mg / kg), about 28 mg / kg (e.g., 28 mg / kg ±0.25 mg / kg, ±0.5 mg / kg, ±1 mg / kg, ±2 mg / kg, or ±2.8 mg / kg), about 23 mg / kg (e.g., 23 mg / kg ±0.25 mg / kg, ±0.5 mg / kg, ±1 mg / kg, ±2 mg / kg, or ±2.3 mg / kg), about 20 mg / kg, or about 1000 mg (e.g., 1000 mg ±5 mg, ±10 mg, ±20 mg, ±30 mg, ±50 mg, ±75 mg, or ±100 mg); (iii) administering a first dose of ifosfamide (C1D1) on day 3, a second dose of ifosfamide (C1D2) on day 4, and a third dose of ifosfamide (C1D3) on day 5 (ifosfamide C1D1, C1D2, and C1D3 are each approximately 3000 mg / m 2 (e.g., 3000 mg / m 2 ±40 mg / m 2 , ±50 mg / m 2 , ±100 mg / m 2 , ±200 mg / m 2 , or ±300 mg / m 2 ) is); (iv) administering a single dose of carboplatin (C1D1) on day 3 (C1D1 of carboplatin is approximately 635 mg / m 2 (e.g., 635 mg / m 2 ±5 mg / m 2 , ±10 mg / m 2 , ±25 mg / m 2 , ±50 mg / m 2 , ±60 mg / m 2 , or ±63.5 mg / m 2 )); and (v) administering a first dose of etoposide (C1D1) on day 3, a second dose of etoposide (C1D2) on day 4, and a third dose of etoposide (C1D3) on day 5 (C1D1, C1D2, and C1D3 of etoposide are each about 100 mg / m 2 (e.g., 100 mg / m 2 ±1 mg / m 2 , ±2.5 mg / m 2 , ±5 mg / m 2 , or ±10 mg / m 2 )); (b) the second administration cycle (i) administering a single dose of glofitamab on day 1 (C2D1) (C2D1 of glofitamab is about 0.4 mg / kg (e.g., 0.4 mg / kg ± 0.005 mg / kg, ± 0.01 mg / kg, ± 0.02 mg / kg, ± 0.03 mg / kg, or ± 0.04 mg / kg), about 0.5 mg / kg (e.g., 0.5 mg / kg ± 0.005 mg / kg, ± 0.01 mg / kg, ± 0.02 mg / kg, ± 0.03 mg / kg, ± 0.04 mg / kg, or ± 0.05 mg / kg), or about 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg)); (ii) administering the first dose of rituximab (C2D1) on day 5 (C2D1 of rituximab is approximately 375 mg / m 2 (e.g., 375 mg / m 2 ±5 mg / m 2 , ±10 mg / m 2 , ±25 mg / m 2 , or ±37.5 mg / m 2 ) is); (iii) administering the first dose of ifosfamide (C2D1) on day 6, the second dose of ifosfamide (C2D2) on day 7, and the third dose of ifosfamide (C2D3) on day 8 (C2D1, C2D2, and C2D3 of ifosfamide are each approximately 3000 mg / m 2 (e.g., 3000 mg / m 2 ±40 mg / m 2 , ±50 mg / m 2 , ±100 mg / m 2 , ±200 mg / m 2 , or ±300 mg / m 2 ) is); (iv) administering a single dose of carboplatin (C2D1) on day 6 (C2D1 of carboplatin is approximately 5 × (25 + creatinine clearance) mg); and (v) administering a first dose of etoposide (C2D1) on day 6, a second dose of etoposide (C2D2) on day 7, and a third dose of etoposide (C2D3) on day 8 (C2D1, C2D2, and C2D3 of etoposide are each about 100 mg / m 2 (e.g., 100 mg / m 2 ±1 mg / m 2 , ±2.5 mg / m 2 , ±5 mg / m 2 , or ±10 mg / m 2 ) is included.

[0197] In one aspect, the invention features a method of treating a subject 6 months to 17 years of age having a CD20-positive cell proliferative disorder, the method including administering to the subject effective amounts of glofitamab, obinutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen including a first dosing cycle, a second dosing cycle, and a third dosing cycle; (a) The first administration cycle comprises: (i) administering a first dose of glofitamab (C1D1) on day 8 and a second dose of glofitamab (C1D2) on day 15 (C1D1 of glofitamab may be about 0.03 mg / kg, about 0.04 mg / kg (e.g., 0.04 mg / kg ± 0.0005 mg / kg, ± 0.001 mg / kg, ± 0.002 mg / kg, ± 0.003 mg / kg, or ± 0.004 mg / kg), or about 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.004 mg / kg). 0.03 mg, ±0.05 mg, ±0.1 mg, ±0.2 mg, or ±0.25 mg), and the C1D2 of glofitamab is about 0.15 mg / kg (e.g., 0.15 mg / kg ±0.001 mg / kg, ±0.0025 mg / kg, ±0.005 mg / kg, ±0.01 mg / kg, or ±0.015 mg / kg) or about 10 mg (e.g., 10 mg ±0.05 mg, ±0.1 mg, ±0.2 mg, ±0.3 mg, ±0.5 mg, ±0.75 mg, or ±1 mg); (ii) administering a first dose (C1D1) of obinutuzumab on day 1 and a second dose (C1D2) of obinutuzumab on day 2 (the C1D1 dose of obinutuzumab is about 1 / 10 of the sum of the C1D1 and C1D2 doses of obinutuzumab, and the C1D2 dose of obinutuzumab is about 9 / 10 of the sum of the C1D1 and C1D2 doses of obinutuzumab, and the sum of the C1D1 and C1D2 doses of obinutuzumab is about 38 mg / kg (e.g., 38 mg / kg ± 0.25 mg / kg, ± 0.5 mg / kg, ± 1 mg / kg, ± 2 mg / kg, ± 3 mg / kg, or ± 3.8 mg / kg), about 28 mg / kg (e.g., 28 mg / kg ± 0.25 mg / kg, ± 0.5 mg / kg, ± 1 mg / kg, ± 2 mg / kg, or ± 2.8 mg / kg), about 23 mg / kg (e.g., 23 mg / kg ± 0.25 mg / kg, ± 0.5 mg / kg, ± 1 mg / kg, ± 2 mg / kg, or ± 2.3 mg / kg), about 20 mg / kg (e.g., 23 mg / kg ± 0.25 mg / kg, ± 0.5 mg / kg, ± 1 mg / kg, or ± 2 mg / kg), or about 1000 mg (e.g., 1000 mg ± 5 mg, ± 10 mg, ± 20 mg, ± 30 mg, ± 50 mg, ± 75 mg, or ± 100 mg)); (iii) administering a first dose of ifosfamide (C1D1) on day 3, a second dose of ifosfamide (C1D2) on day 4, and a third dose of ifosfamide (C1D3) on day 5 (ifosfamide C1D1, C1D2, and C1D3 are each approximately 3000 mg / m 2 (e.g., 3000 mg / m 2 ±40 mg / m 2 , ±50 mg / m 2 , ±100 mg / m 2 , ±200 mg / m 2 , or ±300 mg / m 2 ) is); (iv) administering a single dose of carboplatin (C1D1) on day 3 (C1D1 of carboplatin is approximately 635 mg / m 2 (e.g., 635 mg / m 2 ±5 mg / m 2 , ±10 mg / m 2 , ±25 mg / m 2 , ±50 mg / m 2, ±60 mg / m 2 , or ±63.5 mg / m 2 )); and (v) administering a first dose of etoposide (C1D1) on day 3, a second dose of etoposide (C1D2) on day 4, and a third dose of etoposide (C1D3) on day 5 (C1D1, C1D2, and C1D3 of etoposide are each about 100 mg / m 2 (e.g., 100 mg / m 2 ±1 mg / m 2 , ±2.5 mg / m 2 , ±5 mg / m 2 , or ±10 mg / m 2 ) is); (b) the second administration cycle (i) administering a single dose of glofitamab on day 1 (C2D1) (C2D1 of glofitamab is about 0.4 mg / kg (e.g., 0.4 mg / kg ± 0.005 mg / kg, ± 0.01 mg / kg, ± 0.02 mg / kg, ± 0.03 mg / kg, or ± 0.04 mg / kg), about 0.5 mg / kg (e.g., 0.5 mg / kg ± 0.005 mg / kg, ± 0.01 mg / kg, ± 0.02 mg / kg, ± 0.03 mg / kg, ± 0.04 mg / kg, or ± 0.05 mg / kg), or about 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg)); (ii) administering the first dose of rituximab (C2D1) on day 5 (C2D1 of rituximab is approximately 375 mg / m 2 (e.g., 375 mg / m 2 ±5 mg / m 2 , ±10 mg / m 2 , ±25 mg / m 2 , or ±37.5 mg / m 2 ) is); (iii) administering the first dose of ifosfamide (C2D1) on day 6, the second dose of ifosfamide (C2D2) on day 7, and the third dose of ifosfamide (C2D3) on day 8 (C2D1, C2D2, and C2D3 of ifosfamide are each approximately 3000 mg / m 2(e.g., 3000 mg / m 2 ±40 mg / m 2 , ±50 mg / m 2 , ±100 mg / m 2 , ±200 mg / m 2 , or ±300 mg / m 2 ) is); (iv) administering a single dose of carboplatin (C2D1) on day 6 (C2D1 of carboplatin is approximately 5 × (25 + creatinine clearance) mg); and (v) administering a first dose of etoposide (C2D1) on day 6, a second dose of etoposide (C2D2) on day 7, and a third dose of etoposide (C2D3) on day 8 (C2D1, C2D2, and C2D3 of etoposide are each about 100 mg / m 2 (e.g., 100 mg / m 2 ±1 mg / m 2 , ±2.5 mg / m 2 , ±5 mg / m 2 , or ±10 mg / m 2 ) is ) includes; (c) The third administration cycle comprises: (i) administering a single dose of glofitamab (C3D1) on day 1 (C3D1 of glofitamab is about 0.4 mg / kg (e.g., 0.4 mg / kg ± 0.005 mg / kg, ± 0.01 mg / kg, ± 0.02 mg / kg, ± 0.03 mg / kg, or ± 0.04 mg / kg), about 0.5 mg / kg (e.g., 0.5 mg / kg ± 0.005 mg / kg, ± 0.01 mg / kg, ± 0.02 mg / kg, ± 0.03 mg / kg, ± 0.04 mg / kg, or ± 0.05 mg / kg), or about 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg)); (ii) administering the first dose of rituximab (C3D1) on day 5 (C3D1 of rituximab is approximately 375 mg / m 2 (e.g., 375 mg / m 2 ±5 mg / m 2 , ±10 mg / m 2 , ±25 mg / m 2, or ±37.5 mg / m 2 ) is); (iii) administering a first dose of ifosfamide (C3D1) on day 6, a second dose of ifosfamide (C3D2) on day 7, and a third dose of ifosfamide (C3D3) on day 8 (C3D1, C3D2, and C3D3 of ifosfamide are each approximately 3000 mg / m 2 (e.g., 3000 mg / m 2 ±40 mg / m 2 , ±50 mg / m 2 , ±100 mg / m 2 , ±200 mg / m 2 , or ±300 mg / m 2 ) is); (iv) administering a single dose of carboplatin (C3D1) on day 6 (C3D1 of carboplatin is approximately 5 × (25 + creatinine clearance) mg); and (v) administering a first dose of etoposide (C3D1) on day 6, a second dose of etoposide (C3D2) on day 7, and a third dose of etoposide (C3D3) on day 8 (C3D1, C3D2, and C3D3 of etoposide are each about 100 mg / m 2 (e.g., 100 mg / m 2 ±1 mg / m 2 , ±2.5 mg / m 2 , ±5 mg / m 2 , or ±10 mg / m 2 ) is included.

[0198] In one embodiment, mesna will be administered to a subject on days 3, 4, and 5 of a first dosing cycle, days 6, 7, and 8 of a second dosing cycle, and / or days 6, 7, and 8 of each additional dosing cycle. In one embodiment, mesna is ... 2 In one embodiment, mesna is administered intravenously daily as five doses in an amount of about 600 mg / m before the administration of any dose of ifosfamide. 2 and about 600 mg / m at about 3 hours, about 6 hours, about 9 hours, and about 12 hours, respectively, after the first dose of ifosfamide. 2It will be administered intravenously in four repeated doses.

[0199] In one aspect, the invention features a method of treating a subject aged 18 to 30 years old having a CD20-positive cell proliferative disorder, the method comprising administering to the subject effective amounts of glofitamab, obinutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen including at least a first dosing cycle and a second dosing cycle; (a) a first administration cycle comprises administering a first dose (C1D1) of glofitamab on day 8 and administering a second dose (C1D2) of glofitamab on day 15, wherein the C1D1 of glofitamab is about 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, or ± 0.25 mg) and the C1D2 of glofitamab is about 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, or ± 1 mg); (b) The second administration cycle comprises administering a single dose of glofitamab (C2D1) on day 1, wherein the C2D1 of glofitamab is about 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg).

[0200] In one aspect, the invention features a method of treating a subject aged 18 to 30 years having a CD20-positive cell proliferative disorder, the method including administering to the subject effective amounts of glofitamab, obinutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen including a first dosing cycle, a second dosing cycle, and a third dosing cycle; (a) a first administration cycle comprises administering a first dose (C1D1) of glofitamab on day 8 and administering a second dose (C1D2) of glofitamab on day 15, wherein the C1D1 of glofitamab is about 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, or ± 0.25 mg) and the C1D2 of glofitamab is about 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, or ± 1 mg); (b) the second dosing cycle comprises administering a single dose of glofitamab on day 1 (C2D1), wherein the C2D1 of glofitamab is about 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg); (c) The third administration cycle comprises administering a single dose of glofitamab (C3D1) on day 1, wherein the C3D1 of glofitamab is about 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg).

[0201] In one aspect, the invention features a method of treating a subject aged 18 to 30 years old having a CD20-positive cell proliferative disorder, the method comprising administering to the subject effective amounts of glofitamab, obinutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen including at least a first dosing cycle and a second dosing cycle; (a) The first administration cycle comprises: (i) administering a first dose of glofitamab (C1D1) on day 8 and a second dose of glofitamab (C1D2) on day 15 (wherein C1D1 of glofitamab is about 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, or ± 0.25 mg) and C1D2 of glofitamab is about 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, or ± 1 mg)); (ii) administering a first dose (C1D1) of obinutuzumab on day 1 and a second dose (C1D2) of obinutuzumab on day 2 (C1D1 of obinutuzumab is about 1 / 10 of the sum of C1D1 and C1D2 of obinutuzumab, C1D2 of obinutuzumab is about 9 / 10 of the sum of C1D1 and C1D2 of obinutuzumab, and the sum of C1D1 and C1D2 of obinutuzumab is about 1000 mg (e.g., 1000 mg ± 5 mg, ± 10 mg, ± 20 mg, ± 30 mg, ± 50 mg, ± 75 mg, or ± 100 mg)); (iii) administering a single dose of ifosfamide (C1D1) on day 3 (C1D1 of ifosfamide is about 5000 mg / m with a maximum dose of about 800 mg (e.g., 800 mg ± 10 mg, ± 25 mg, ± 50 mg, or ± 80 mg)); 2 (e.g., 5000 mg / m 2 ±50 mg / m 2 , ±100 mg / m 2 , ±200 mg / m 2 , ±300 mg / m 2 , ±400 mg / m 2 , or ±500 mg / m 2 ) is); (iv) administering a single dose (C1D1) of carboplatin on day 3 (C1D1 of carboplatin is approximately 5 × (25 + creatinine clearance) mg); and (v) administering a first dose of etoposide (C1D1) on day 3, a second dose of etoposide (C1D2) on day 4, and a third dose of etoposide (C1D3) on day 5 (C1D1, C1D2, and C1D3 of etoposide are each about 100 mg / m2 (e.g., 100 mg / m 2 ±1 mg / m 2 , ±2.5 mg / m 2 , ±5 mg / m 2 , or ±10 mg / m 2 )); (b) the second administration cycle (i) administering a single dose of glofitamab on day 1 (C2D1) (C2D1 of glofitamab is approximately 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg)); (ii) administering the first dose of rituximab (C2D1) on day 5 (C2D1 of rituximab is approximately 375 mg / m 2 (e.g., 375 mg / m 2 ±5 mg / m 2 , ±10 mg / m 2 , ±25 mg / m 2 , or ±37.5 mg / m 2 ) is); (iii) administering a single dose of ifosfamide (C2D1) on day 6 (C2D1 of ifosfamide is about 5000 mg / m with a maximum dose of about 800 mg (e.g., 800 mg ± 10 mg, ± 25 mg, ± 50 mg, or ± 80 mg)); 2 (e.g., 5000 mg / m 2 ±50 mg / m 2 , ±100 mg / m 2 , ±200 mg / m 2 , ±300 mg / m 2 , ±400 mg / m 2 , or ±500 mg / m 2 ) is); (iv) administering a single dose of carboplatin (C2D1) on day 6 (C2D1 of carboplatin is approximately 5 × (25 + creatinine clearance) mg); and (v) administering a first dose of etoposide (C2D1) on day 6, a second dose of etoposide (C2D2) on day 7, and a third dose of etoposide (C2D3) on day 8 (C2D1, C2D2, and C2D3 of etoposide are each about 100 mg / m 2 (e.g., 100 mg / m 2 ±1 mg / m 2 , ±2.5 mg / m 2 , ±5 mg / m 2 , or ±10 mg / m 2 ) is included.

[0202] In one aspect, the invention features a method of treating a subject aged 18 to 30 years having a CD20-positive cell proliferative disorder, the method including administering to the subject effective amounts of glofitamab, obinutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen including a first dosing cycle, a second dosing cycle, and a third dosing cycle; (a) The first administration cycle comprises: (i) administering a first dose of glofitamab (C1D1) on day 8 and a second dose of glofitamab (C1D2) on day 15 (wherein C1D1 of glofitamab is about 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, or ± 0.25 mg) and C1D2 of glofitamab is about 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, or ± 1 mg)); (ii) administering a first dose (C1D1) of obinutuzumab on day 1 and a second dose (C1D2) of obinutuzumab on day 2 (C1D1 of obinutuzumab is about 1 / 10 of the sum of C1D1 and C1D2 of obinutuzumab, C1D2 of obinutuzumab is about 9 / 10 of the sum of C1D1 and C1D2 of obinutuzumab, and the sum of C1D1 and C1D2 of obinutuzumab is about 1000 mg (e.g., 1000 mg ± 5 mg, ± 10 mg, ± 20 mg, ± 30 mg, ± 50 mg, ± 75 mg, or ± 100 mg)); (iii) administering a single dose of ifosfamide (C1D1) on day 3 (C1D1 of ifosfamide is about 5000 mg / m with a maximum dose of about 800 mg (e.g., 800 mg ± 10 mg, ± 25 mg, ± 50 mg, or ± 80 mg)); 2 (e.g., 5000 mg / m 2 ±50 mg / m 2 , ±100 mg / m 2 , ±200 mg / m 2 , ±300 mg / m 2 , ±400 mg / m 2 , or ±500 mg / m 2 ) is); (iv) administering a single dose (C1D1) of carboplatin on day 3 (C1D1 of carboplatin is approximately 5 × (25 + creatinine clearance) mg); and (v) administering a first dose of etoposide (C1D1) on day 3, a second dose of etoposide (C1D2) on day 4, and a third dose of etoposide (C1D3) on day 5 (C1D1, C1D2, and C1D3 of etoposide are each about 100 mg / m 2 (e.g., 100 mg / m 2 ±1 mg / m 2 , ±2.5 mg / m 2 , ±5 mg / m 2 , or ±10 mg / m 2 ) is); (b) the second administration cycle (i) administering a single dose of glofitamab on day 1 (C2D1) (C2D1 of glofitamab is approximately 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg)); (ii) administering the first dose of rituximab (C2D1) on day 5 (C2D1 of rituximab is approximately 375 mg / m 2 (e.g., 375 mg / m 2 ±5 mg / m 2 , ±10 mg / m 2 , ±25 mg / m 2 , or ±37.5 mg / m 2 ) is); (iii) administering a single dose of ifosfamide (C2D1) on day 6 (C2D1 of ifosfamide is about 5000 mg / m with a maximum dose of about 800 mg (e.g., 800 mg ± 10 mg, ± 25 mg, ± 50 mg, or ± 80 mg)); 2 (e.g., 5000 mg / m 2 ±50 mg / m 2 , ±100 mg / m 2 , ±200 mg / m 2 , ±300 mg / m 2 , ±400 mg / m 2 , or ±500 mg / m 2 ) is); (iv) administering a single dose of carboplatin (C2D1) on day 6 (C2D1 of carboplatin is approximately 5 × (25 + creatinine clearance) mg); and (v) administering a first dose of etoposide (C2D1) on day 6, a second dose of etoposide (C2D2) on day 7, and a third dose of etoposide (C2D3) on day 8 (C2D1, C2D2, and C2D3 of etoposide are each about 100 mg / m 2 (e.g., 100 mg / m 2 ±1 mg / m 2 , ±2.5 mg / m 2 , ±5 mg / m 2 , or ±10 mg / m 2 ) is ) includes; (c) The third administration cycle comprises: (i) administering a single dose of glofitamab (C3D1) on day 1 (C3D1 of glofitamab is about 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg)); (ii) administering the first dose of rituximab (C3D1) on day 5 (C3D1 of rituximab is approximately 375 mg / m 2 (e.g., 375 mg / m 2 ±5 mg / m 2 , ±10 mg / m 2 , ±25 mg / m 2 , or ±37.5 mg / m 2 ) is); (iii) administering a single dose of ifosfamide (C3D1) on day 6 (C3D1 of ifosfamide is about 5000 mg / m with a maximum dose of about 800 mg (e.g., 800 mg ± 10 mg, ± 25 mg, ± 50 mg, or ± 80 mg)); 2 (e.g., 5000 mg / m 2 ±50 mg / m 2 , ±100 mg / m 2 , ±200 mg / m 2 , ±300 mg / m 2 , ±400 mg / m 2 , or ±500 mg / m 2 ) is); (iv) administering a single dose of carboplatin (C3D1) on day 6 (C3D1 of carboplatin is approximately 5 × (25 + creatinine clearance) mg); and (v) administering a first dose of etoposide (C3D1) on day 6, a second dose of etoposide (C3D2) on day 7, and a third dose of etoposide (C3D3) on day 8 (C3D1, C3D2, and C3D3 of etoposide are each about 100 mg / m 2 (e.g., 100 mg / m 2 ±1 mg / m 2 , ±2.5 mg / m 2 , ±5 mg / m 2 , or ±10 mg / m 2 ) is included.

[0203] In one embodiment, mesna will be administered simultaneously with any dose of ifosfamide. In one embodiment, mesna is administered at about 5000 mg / m 2 (e.g., 5000 mg / m 2 ±50 mg / m 2 , ±100 mg / m 2 , ±200 mg / m 2 , ±300 mg / m 2 , ±400 mg / m 2 , or ±500 mg / m 2) is administered intravenously. In one embodiment, mesna is administered by continuous infusion over about 24 hours on day 3 of the first dosing cycle, day 6 of the second dosing cycle, and / or day 6 of each additional dosing cycle. In one embodiment, the CD20-positive cell proliferative disorder is relapsed and / or refractory DLBCL. In one embodiment, the CD20-positive cell proliferative disorder is relapsed and / or refractory mature B-cell NHL.

[0204] In one embodiment, a bispecific antibody that binds to CD20 and CD3 comprises at least one Fab molecule that specifically binds to CD20 and has the following six hypervariable regions (HVRs): (i) HVR-H1 containing the amino acid sequence of YSWIN (SEQ ID NO: 1); (ii) HVR-H2 comprising the amino acid sequence RIFPGDGDTDYNGKFKG (SEQ ID NO: 2); (iii) HVR-H3 comprising the amino acid sequence NVFDGYWLVY (SEQ ID NO: 3); (iv) HVR-L1 comprising the amino acid sequence RSSKSLLHSNGITYLY (SEQ ID NO: 4); (v) HVR-L2 comprising the amino acid sequence of QMSNLVS (SEQ ID NO: 5); and (vi) HVR-L3 comprising the amino acid sequence of AQNLELPYT (SEQ ID NO: 6) , including Fab molecules.

[0205] In one embodiment, a bispecific antibody that binds to CD20 and CD3 comprises: (a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 7; (b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 8; or (c) at least one Fab molecule that specifically binds to CD20, comprising a VH domain similar to (a) and a VL domain similar to (b). In one embodiment, a Fab molecule that specifically binds to CD20 comprises (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 7 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 8.

[0206] In one embodiment, a bispecific antibody that binds CD20 and CD3 comprises at least one Fab molecule that specifically binds CD3, comprising the following six HVRs: (i) HVR-H1 comprising the amino acid sequence of TYAMN (SEQ ID NO: 9); (ii) HVR-H2 comprising the amino acid sequence of RIRSKYNNYATYYADSVKG (SEQ ID NO: 10); (iii) HVR-H3 comprising the amino acid sequence HGNFGNSYVSWFAY (SEQ ID NO: 11); (iv) HVR-L1 comprising the amino acid sequence of GSSTGAVTTSNYAN (SEQ ID NO: 12); (v) HVR-L2 comprising the amino acid sequence of GTNKRAP (SEQ ID NO: 13); and (vi) HVR-L3 comprising the amino acid sequence of ALWYSNLWV (SEQ ID NO: 14).

[0207] In one embodiment, a bispecific antibody that binds to CD20 and CD3 comprises: (a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 15; (b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 16; or (c) at least one Fab molecule that specifically binds CD3, comprising a VH domain similar to (a) and a VL domain similar to (b).

[0208] In one embodiment, a Fab molecule that specifically binds to CD3 comprises (a) a VH domain comprising the amino acid sequence of SEQ ID NO:15 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO:16.

[0209] In one embodiment, a bispecific antibody that binds to CD20 and CD3 is bivalent with respect to CD20 and monovalent with respect to CD3. In one embodiment, a bispecific antibody that binds to CD20 and CD3 comprises two Fab molecules that specifically bind to CD20 and one Fab molecule that specifically binds to CD3.

[0210] In one embodiment, the bispecific antibody that binds CD20 and CD3 is a humanized antibody. In one embodiment, the bispecific antibody that binds CD20 and CD3 is glofitamab.

[0211] In one embodiment, the bispecific antibody that binds to CD20 and CD3 is administered intravenously.

[0212] In one embodiment, the anti-CD20 antibody is administered intravenously.

[0213] In one embodiment, the CD20-positive cell proliferative disorder is a B-cell proliferative disorder. In one embodiment, the B-cell proliferative disorder is non-Hodgkin's lymphoma (NHL) or central nervous system lymphoma (CNSL). In one embodiment, the NHL is diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), high-grade B-cell lymphoma, primary mediastinal (thymic) large B-cell lymphoma (PMLBCL), diffuse B-cell lymphoma, or small lymphocytic lymphoma. In one embodiment, the NHL is Burkitt lymphoma (BL) or Burkitt leukemia (BAL). In one embodiment, the NHL is aggressive and / or mature. In one embodiment, the NHL is relapsed and / or refractory. In one embodiment, the B-cell proliferative disorder is relapsed and / or refractory mature B-cell NHL. In one embodiment, the subject has received no more than one prior systemic therapy.

[0214] In one embodiment, the prior systemic therapy comprises an anti-CD20 antibody and an anthracycline. In one embodiment, the subject is human. In one embodiment, the subject is eligible for transplantation or CAR-T cell therapy. In one embodiment, the subject undergoes autologous stem cell transplantation (ASCT) after completing the dosing regimen of the method described above. In one embodiment, the ASCT is autologous hematopoietic stem cell transplantation. In one embodiment, the subject undergoes allogeneic hematopoietic stem cell transplantation after completing the dosing regimen described above. In one embodiment, the subject receives CAR-T cell therapy after completing the dosing regimen described above.

[0215] Further aspects of the present invention relate to inventions described herein.

[0216] Any and all embodiments can be combined unless the context clearly indicates otherwise. Any and all embodiments can be applied to any and all aspects of the invention unless the context clearly indicates otherwise.

[0217] Specific embodiments of the present invention will become apparent from the following more detailed description of certain preferred embodiments and the claims. [Brief explanation of the drawings]

[0218] [Figure 1A] FIG. 1A is a schematic diagram showing the structure of an exemplary anti-CD20 / anti-CD3 bispecific antibody. [Figure 1B] FIG. 1B is a schematic diagram showing the structure of an exemplary anti-CD20 / anti-CD3 bispecific antibody. [Figure 1C] FIG. 1C is a schematic diagram showing the structure of an exemplary anti-CD20 / anti-CD3 bispecific antibody. [Figure 1D] FIG. 1D is a schematic diagram showing the structure of an exemplary anti-CD20 / anti-CD3 bispecific antibody. [Figure 1E] FIG. 1E is a schematic diagram showing the structure of an exemplary anti-CD20 / anti-CD3 bispecific antibody. [Figure 1F] FIG. 1F is a schematic diagram showing the structure of an exemplary anti-CD20 / anti-CD3 bispecific antibody. [Figure 1G] FIG. 1G is a schematic diagram showing the structure of an exemplary anti-CD20 / anti-CD3 bispecific antibody. [Figure 1H] FIG. 1H is a schematic diagram showing the structure of an exemplary anti-CD20 / anti-CD3 bispecific antibody. [Figure 1I] FIG. 1I is a schematic diagram showing the structure of an exemplary anti-CD20 / anti-CD3 bispecific antibody. [Figure 1J]FIG. 1J is a schematic diagram showing the structure of an exemplary anti-CD20 / anti-CD3 bispecific antibody. [Figure 1K] FIG. 1K is a schematic diagram showing the structure of an exemplary anti-CD20 / anti-CD3 bispecific antibody. [Figure 1L] FIG. 1L is a schematic diagram showing the structure of an exemplary anti-CD20 / anti-CD3 bispecific antibody. [Figure 1M] FIG. 1M is a schematic diagram showing the structure of an exemplary anti-CD20 / anti-CD3 bispecific antibody. [Figure 1N] FIG. 1N is a schematic diagram showing the structure of an exemplary anti-CD20 / anti-CD3 bispecific antibody. [Figure 2] FIG. 1 is a schematic diagram showing the structure of glofitamab. [Figure 3] FIG. 1 is a schematic diagram outlining the study design as described in Example 1. ASCT = autologous stem cell transplant; CAR-T = chimeric antigen receptor T cells; CR = complete response; DLBCL = diffuse large B-cell lymphoma; EOT = end of treatment; Glofit-R-ICE = glofitamab, carboplatin, etoposide in combination with rituximab + ifosfamide; Gpt = obinutuzumab (GAZYVA®) conditioning; PD = progressive disease; PR = partial response; R / R = relapsed or refractory; SD = stable disease. a: 2-3 cycles according to institutional criteria. b: ASCT conditioning regimen and supportive care according to institutional criteria. [Figure 4] FIG. 1 is a schematic diagram showing the dosing schema of the study as described in Example 1. D = day. a: Carboplatin dose (mg) to target an AUC of 5 mg / mL / min. [Figure 5]Figure 1 is a schematic diagram showing the study schema for Parts 1 and 2 of Example 2. B-NHL = B-cell non-Hodgkin's lymphoma; Glofit = glofitamab; Ped = pediatric; PK = pharmacokinetics; R-ICE = rituximab, ifosfamide, carboplatin, and etoposide; Rec = recommended; R / R = relapsed / refractory; RR = response rate. For Part 1 of the study, safety induction with the starting dose is based on population PK modeling and matching adult exposure with step-up dosing. Safety and pharmacokinetics will be evaluated in at least three participants until the recommended pediatric Part 2 dose is published. Part 2 may begin after at least 10 pediatric participants have been evaluated for early efficacy at the recommended pediatric dose. During Part 2 of the study, young adult participants up to 30 years of age (inclusive) may be enrolled but will not be counted toward the sample size of 45. [Figure 6] FIG. 1 is a schematic diagram showing the dosing schema for glofitamab in combination with R-ICE as described in Example 2. C = cycle; CR = complete response; D = day; G = obinutuzumab; CR = complete response; FD = full dose; G-CSF = granulocyte colony-stimulating factor; Glofit = glofitamab; GpT = obinutuzumab conditioning; HSCT = hematopoietic stem cell transplant; ICE = ifosfamide, carboplatin, and etoposide; PD = progressive disease; R-ICE = rituximab plus ifosfamide, carboplatin, and etoposide; SUD = step-up dose. a Obinutuzumab conditioning is split into 1 / 10 of the total dose on day 1 of the first dosing cycle (cycle 1) and 9 / 10 of the total dose on day 2 of cycle 1. [Figure 7]Figure 2 shows a schematic diagram of the treatment administration schedule for pediatric patients (6 months to 17 years old) in Example 2. *: Arrow indicates mandatory initiation of granulocyte colony-stimulating factor (G-CSF) therapy. **: Participants with any histological type of CNS disease receive intrathecal (IT) therapy on days 3, 10, and 17 of cycle 1 and days 5, 12, and 19 of cycles 2 and 3. Participants with CNS-negative large B-cell lymphoma receive IT therapy only on day 3 of cycle 1. A single dose of obinutuzumab conditioning is divided into 1 / 10 of the full dose on day 1 of cycle 1 and 9 / 10 of the full dose on day 2 of cycle 1. Participants with CNS-negative Burkitt lymphoma (BL) receive IT therapy on day 3 of cycle 1 and day 5 of cycles 2 and 3. Glofitamab is administered as two step-up doses on days 8 and 15 of cycle 1 and as a full dose on day 1 of cycles 2 and 3. [Figure 8] Figure 1 shows a schematic diagram of the treatment administration schedule for young adult patients (18-30 years old) in Example 2. *: Arrow indicates mandatory initiation of G-CSF therapy. **: Participants with any histological type of CNS disease receive IT therapy on days 3, 10, and 17 of cycle 1 and days 5, 12, and 19 of cycles 2 and 3. Participants with CNS-negative large B-cell lymphoma receive IT therapy only on day 3 of cycle 1. A single dose of obinutuzumab conditioning is divided into 1 / 10 of the full dose on day 1 of cycle 1 and 9 / 10 of the full dose on day 2 of cycle 1. Participants with CNS-negative BL receive IT therapy on day 3 of cycle 1 and day 5 of cycles 2 and 3. G-CSF = granulocyte colony-stimulating factor. Glofitamab is administered as two step-up doses on days 8 and 15 of cycle 1 and as a full dose on day 1 of cycles 2 and 3. DETAILED DESCRIPTION OF THE INVENTION

[0219] Detailed Description of the Invention The present invention provides a method of treating a subject with a CD20-positive cell proliferative disorder (e.g., a B-cell proliferative disorder (e.g., non-Hodgkin's lymphoma (NHL) (e.g., relapsed and / or refractory NHL, diffuse large B-cell lymphoma (DLBCL) (e.g., relapsed and / or refractory DLBCL), follicular lymphoma (FL) (e.g., relapsed and / or refractory FL or transformed FL), or mantle cell lymphoma (MCL) (e.g., relapsed or refractory MCL)) or central nervous system lymphoma (CNSL)) comprising administering to the subject an anti-CD20 / anti-CD3 bispecific antibody in combination with an anti-CD20 antibody and one or more chemotherapeutic agents selected from ifosfamide, carboplatin, and / or etoposide.

[0220] (i) General Technology The practice of the present disclosure will employ, unless otherwise indicated, conventional techniques of molecular biology (including recombinant techniques), microbiology, cell biology, biochemistry, and immunology, which are within the skill of one in the art. Such techniques are fully explained in the literature, for example, "Molecular Cloning: A Laboratory Manual," 2nd ed. (Sambrook et al., 1989). "Oligonucleotide Synthesis" (M.J. Gait, ed., 1984); "Animal Cell Culture" (R.I. Freshney, ed., 1987); "Methods in Enzymology" (Academic Press, Inc.); "Current Protocols in Molecular Biology" (F.M.A.usubel et al., eds., 1987, and regularly updated); "PCR: The Polymerase Chain Reaction" (Mullis et al., eds., 1994); "A Practical Guide to Molecular Cloning" (Perbal Bernard V., 1988); and "Phage Display: A Laboratory Manual" (Barbas et al., 2001).

[0221] (ii) Definition Terms are used herein as commonly used in the art unless otherwise defined below.

[0222] As used herein, the term "cluster of differentiation 20" or "CD20" refers to any native CD20 of any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), unless otherwise indicated. CD20 (also known as B lymphocyte antigen CD20, B lymphocyte surface antigen B1, Leu-16, Bp35, BM5, and LF5; the human protein is characterized in UniProt database entry P11836) is a hydrophobic transmembrane protein with a molecular weight of approximately 35 kD expressed on pre-B lymphocytes and mature B lymphocytes (Valentine, MA et al., J. Biol. Chem. 264 (1989) 11282-11287; Tedder, TF, et al., Proc. Natl. Acad. Sci. USA 85 (1988) 208-212; Stamenkovic, I., et al., J. Exp. Med. 167 (1988) 1975-1980; Einfeld, DA, et al., EMBO J. 7 (1988) 711-717; Tedder, T. F., et al., J. Immunol. 142 (1989) 2560-2568). The corresponding human gene is transmembrane 4 domain, subfamily A, member 1, also known as MS4A1. This gene encodes a member of the transmembrane 4A gene family. Members of this emerging protein family are characterized by common structural features and similar intron / exon splice boundaries and display unique expression patterns between hematopoietic cells and non-lymphoid tissues. This gene encodes a B lymphocyte surface molecule that plays a role in the development and differentiation of B cells into plasma cells. This family member is localized to 11q12 within a cluster of family members. The term encompasses "full-length," unprocessed CD20 and any form of CD20 resulting from intracellular processing. The term also encompasses naturally occurring variants of CD20, such as splice variants or allelic variants. Alternative splicing of this gene results in two transcript variants that encode the same protein. In one embodiment, the CD20 is human CD20.

[0223] The terms "anti-CD20 antibody" and "antibody that binds to CD20" refer to an antibody that can bind to CD20 with sufficient affinity so as to be useful as a CD20-targeted diagnostic and / or therapeutic agent. In one embodiment, the binding of an anti-CD20 antibody to an unrelated, non-CD20 protein is less than about 10% of the binding of the antibody to CD20 as measured, for example, by radioimmunoassay (RIA). In certain embodiments, an antibody that binds to CD20 has an affinity of ≦1 μM, ≦100 nM, ≦10 nM, ≦1 nM, ≦0.1 nM, ≦0.01 nM, or ≦0.001 nM (e.g., ≦10 -8 M or less, e.g. 10 -8 M~10 -13 M, e.g. 10 -9 M~10 -13 Dissociation constant (K D In certain embodiments, the anti-CD20 antibody binds to an epitope of CD20 that is conserved among CD20 from different species.

[0224] By "type II anti-CD20 antibody" is meant an anti-CD20 antibody having the binding characteristics and biological activity of type II anti-CD20 antibodies as described in Cragg et al., Blood 103 (2004) 2738-2743; Cragg et al., Blood 101 (2003) 1045-1052, Klein et al., mAbs 5 (2013), 22-33, and summarized in Table 1 below. [Table 1]

[0225] Examples of Type II anti-CD20 antibodies include, for example, obinutuzumab (GA101), tositumomab (B1), humanized B-Ly1 antibody IgG1 (a chimeric humanized IgG1 antibody disclosed in WO 2005 / 044859), 11B8 IgG1 (disclosed in WO 2004 / 035607), and AT80 IgG1.

[0226] Examples of Type I anti-CD20 antibodies include, for example, rituximab, ofatumumab, veltuzumab, ocaratuzumab, ocrelizumab, PRO131921, ublituximab, HI47 IgG3 (ECACC, hybridoma), 2C6 IgG1 (disclosed in WO 2005 / 103081), 2F2 IgG1 (disclosed in WO 2004 / 035607 and WO 2005 / 103081), and 2H7 IgG1 (disclosed in WO 2004 / 056312).

[0227] Unless otherwise specified, "CD3" refers to any native CD3 from any vertebrate source, including mammals such as primates (e.g., humans), non-human primates (e.g., cynomolgus monkeys), and rodents (e.g., mice and rats). The term encompasses "full-length," unprocessed CD3 and any form of CD3 resulting from intracellular processing. The term also encompasses naturally occurring variants of CD3, such as splice variants or allelic variants. In one embodiment, the CD3 is human CD3, particularly the epsilon subunit of human CD3 (CD3ε). The amino acid sequence of human CD3ε is set forth in UniProt (www.uniprot.org) Accession No. P07766 (version 144) or NCBI (www.ncbi.nlm.nih.gov / ) RefSeq NP_000724.1. The amino acid sequence of CD3ε from the cynomolgus monkey [Macaca fascicularis] is shown in NCBI GenBank number BAB71849.1.

[0228] The terms "anti-CD20 antibody / anti-CD3 bispecific antibody" and "bispecific antibody that binds to both CD20 and CD3" refer to a bispecific antibody that is capable of binding to both CD20 and CD3 with sufficient affinity such that the antibody is useful as a diagnostic and / or therapeutic agent in targeting CD20 and / or CD3. In one embodiment, the extent of binding of a bispecific antibody that binds to CD20 and CD3 to an unrelated non-CD3 protein and / or a non-CD20 protein is less than about 10% of the binding of the antibody to CD3 and / or CD20, as measured, for example, by radioimmunoassay (RIA). In certain embodiments, a bispecific antibody that binds to CD20 and CD3 has an affinity of ≦1 μM, ≦100 nM, ≦10 nM, ≦1 nM, ≦0.1 nM, ≦0.01 nM, or ≦0.001 nM (e.g., ≦10 -8 M or less, e.g. 10 -8 M~10 -13 M, e.g. 10 -9 M~10 -13 Dissociation constant (K D In certain embodiments, the bispecific antibody that binds to CD20 and CD3 binds to an epitope of CD3 that is conserved among CD3 from different species and / or an epitope of CD20 that is conserved among CD20 from different species. An example of an anti-CD20 / anti-CD3 bispecific antibody is glofitamab (WHO Drug Information International Nonproprietary Names for Pharmaceutical Substances, Recommended INN: List 83, 2020, vol. 34, no. 1, p. 39; Proposed INN: List 121 WHO Drug Information, Vol. 33, No. 2, 2019, page 276, also known as CD20-TCB, RO7082859, or RG6026; CAS number: 2229047-91-8).

[0229] As used herein, the terms "cytokine release" or "cytokine release" are synonymous with "cytokine storm" or "cytokine release syndrome" (abbreviated "CRS") and refer to increased levels of cytokines, particularly tumor necrosis factor alpha (TNF-α), interferon gamma (IFN-γ), interleukin 6 (IL-6), interleukin 10 (IL-10), interleukin 2 (IL-2), and / or interleukin 8 (IL-8), in a subject's blood during or shortly after (e.g., within one day of) administration of a therapeutic agent, resulting in adverse symptoms. Cytokine release is defined as a supraphysiological response following administration of any immunotherapy that results in the activation or engagement of endogenous or infused T cells and / or other immune effector cells. Symptoms can be progressive, always include fever at onset, and may include hypotension, capillary leak (hypoxia), and end-organ dysfunction (Lee et al. 2019). In some cases, for example, after administration of CAR-T cells, CRS may occur several days after administration as the CAR-T cells proliferate. The incidence and severity typically decrease with subsequent infusions. Symptoms can range from symptomatic discomfort to fatal events and can include fever, chills, dizziness, hypertension, hypotension, dyspnea, restlessness, sweating, flushing, skin rash, tachycardia, tachypnea, headache, tumor pain, nausea, vomiting, and / or organ failure.

[0230] As used herein, the term "amino acid mutation" is intended to encompass amino acid substitution, deletion, insertion, and modification. Any combination of substitution, deletion, insertion, and modification can be performed to arrive at a final construct, as long as the final construct has the desired characteristics, such as reduced binding to Fc receptors. Deletion and insertion of amino acid sequences include deletion and insertion of amino and / or carboxy terminal amino acids. A particular amino acid mutation is an amino acid substitution. Non-conservative amino acid substitutions, i.e., replacing one amino acid with another amino acid having different structure and / or chemical properties, are particularly preferred, for example, to alter the binding characteristics of the Fc region. Amino acid substitutions include substitutions with non-naturally occurring amino acids or substitutions with naturally occurring amino acid derivatives of the 20 common amino acids (e.g., 4-hydroxyproline, 3-methylhistidine, ornithine, homoserine, 5-hydroxylysine). Amino acid mutations can be generated using genetic or chemical methods well known in the art. Genetic methods can include site-directed mutagenesis, PCR, gene synthesis, etc. It is anticipated that methods other than genetic engineering, such as chemical modification, that alter the side chain group of an amino acid may also be useful. Various names may be used herein to indicate the same amino acid mutation. For example, a substitution of proline to glycine at position 329 in the Fc region may be designated as 329G, G329, G 329 , P329G, or Pro329Gly.

[0231] "Affinity" refers to the total strength of non-covalent interactions between a single binding site of a molecule (e.g., a receptor) and its binding partner (e.g., a ligand). As used herein, "binding affinity," unless otherwise indicated, refers to the intrinsic binding affinity that reflects a 1:1 interaction between members of a binding pair (e.g., a receptor and a ligand). The affinity of molecule X for its binding partner Y is generally determined by the dissociation constant (K D ), and the dissociation rate constant and association rate constant (k off and k on) is the ratio of the rate constants. Thus, equivalent affinities can involve different rate constants as long as the ratio of the rate constants remains the same. Affinity can be measured by well-established methods known in the art. A particular method for measuring affinity is surface plasmon resonance (SPR).

[0232] An "affinity matured" antibody refers to an antibody that has one or more alterations in one or more hypervariable regions (HVRs) that improve the affinity of the antibody for antigen, compared to a parent antibody that does not possess such alterations.

[0233] As used herein, the term "antigen-binding moiety" refers to a polypeptide molecule that specifically binds to an antigenic determinant. In one embodiment, an antigen-binding moiety can target an entity to which it is bound (e.g., a cytokine or a second antigen-binding moiety) to a target site, such as a specific type of tumor cell or tumor stroma that bears the antigenic determinant. Antigen-binding moieties include antibodies and fragments thereof, as further defined herein. Preferred antigen-binding moieties include the antigen-binding domain of an antibody, comprising an antibody heavy chain variable region and an antibody light chain variable region. In certain embodiments, antigen-binding moieties comprise antibody constant regions known in the art, as further defined below. Useful heavy chain constant regions include any of the five isotypes: α, δ, ε, γ, or μ. Useful light chain constant regions include any of the two isotypes: κ and λ.

[0234] "Bind," "specifically bind," or "specific for" means that the binding is selective for the antigen and can be distinguished from undesired or nonspecific interactions. The ability of an antigen-binding moiety to bind to a specific antigenic determinant can be measured by enzyme-linked immunosorbent assay (ELISA) or other techniques well known to those skilled in the art, such as surface plasmon resonance technology (analysis on a BIAcore instrument) (Liljeblad et al., Glyco J. 17, 323-329 (2000)) and classical binding assays (Heeley, Endocr Res. 28, 217-229 (2002)). In one embodiment, the binding of the antigen-binding moiety to an unrelated protein is less than about 10% of the binding of the antigen-binding moiety to the antigen, as measured, for example, by SPR. In certain embodiments, the antigen-binding portion that binds to an antigen, or an antigen-binding molecule comprising the antigen-binding portion, has a denaturing activity of ≦1 μM, ≦100 nM, ≦10 nM, ≦1 nM, ≦0.1 nM, ≦0.01 nM, or ≦0.001 nM (e.g., 10 -8 M or less, e.g., 10 -8 M to 10 -13 M, e.g., 10 -9 M to 10 -13 Dissociation constant (K D )

[0235] "Reduced binding," e.g., reduced binding to an Fc receptor, refers to a decrease in affinity for the respective interaction, e.g., as measured by SPR. For clarity, the term also includes a reduction in affinity to zero (or below the detection limit of the analytical method), i.e., a complete cessation of the interaction. Conversely, "increased binding" refers to an increase in binding affinity for the respective interaction.

[0236] As used herein, the term "antigen-binding molecule" refers in the broadest sense to a molecule that specifically binds to an antigenic determinant. Examples of antigen-binding molecules are immunoglobulins and derivatives, such as fragments thereof.

[0237] As used herein, the term "antigenic determinant" is synonymous with "antigen" and "epitope" and refers to a site on a polypeptide macromolecule (e.g., a three-dimensional structure composed of a contiguous stretch of amino acids or distinct regions of non-contiguous amino acids) to which an antigen-binding moiety binds to form an antigen-binding moiety-antigen complex. Useful antigenic determinants can be found, for example, on the surface of tumor cells, on the surface of virus-infected cells, on the surface of other diseased cells, free in serum, and / or in the extracellular matrix (ECM). Unless otherwise specified, proteins (e.g., CD3) referred to herein as antigens are those derived from primates (e.g., humans). The term "antigen" refers to the native form of a protein from any vertebrate source, including mammals such as mice and rodents (e.g., mice and rats). In certain embodiments, the antigen is a human protein. When referring to a particular protein of the invention, the term encompasses the "full-length," unprocessed protein, and any form of the protein obtained from processing of cells. The term also encompasses naturally occurring variants of the protein, such as splice variants or allelic variants. An exemplary human protein useful as an antigen is CD3, particularly the epsilon subunit of CD3 (see UniProt for the human sequence). no. P07766 (version 130), NCBI RefSeq no. NP_000724.1; for the cynomolgus monkey [Macaca fascicularis] sequence see UniProt no. Q95LI5 (version 49), NCBI GenBank no. BAB71849.1). In certain embodiments, the T cell activating bispecific antigen binding molecules described herein bind to an epitope of CD3 or a target cell antigen that is conserved among CD3 or target cell antigens from different species.

[0238] As used herein, the term "polypeptide" refers to a molecule composed of monomers (amino acids) linked in a linear chain by amide bonds (also known as peptide bonds). The term "polypeptide" refers to a chain of two or more amino acids, not a specific length of the product. Thus, peptide, dipeptide, tripeptide, oligopeptide, "protein," "amino acid chain," or any other term used to refer to a chain of two or more amino acids is included within the definition of "polypeptide," and the term "polypeptide" may be used in place of or interchangeably with any of these terms. The term "polypeptide" is also intended to refer to products of post-expression modifications of the polypeptide, including, but not limited to, glycosylation, acetylation, phosphorylation, amidation, derivatization with known protecting / blocking groups, proteolytic cleavage, or modification with non-naturally occurring amino acids. Polypeptides may be derived from natural biological sources or produced by recombinant technology, but are not necessarily translated from a designated nucleic acid sequence. Polypeptides may arise in any manner, including by chemical synthesis. Polypeptides of the invention may be about 3 or more, 5 or more, 10 or more, 20 or more, 25 or more, 50 or more, 75 or more, 100 or more, 200 or more, 500 or more, 1000 or more, or 2000 or more amino acids in size. Polypeptides can have a defined three-dimensional structure, but polypeptides do not necessarily have such a structure. Polypeptides that have a defined three-dimensional structure are referred to as folded, while polypeptides that do not have a defined three-dimensional structure but rather can adopt a number of different conformations are referred to as unfolded.

[0239] By "isolated" polypeptide or variant or derivative thereof is intended a polypeptide that is not in its natural environment. A particular level of purification is not required. For example, an isolated polypeptide can be removed from its native or natural environment. Recombinantly produced polypeptides and proteins expressed in host cells are considered isolated for the purposes of the present invention, as are native or recombinant polypeptides that have been separated, fractionated, or partially or substantially purified by any suitable technique.

[0240] "Percent (%) amino acid sequence identity" to a reference polypeptide sequence is defined as the percentage of amino acid residues in a candidate sequence that are identical to those in the reference polypeptide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, without considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in a variety of ways within the skill of the art, for example, using publicly available computer software such as BLAST, BLAST-2, ALIGN, or Megalign (DNASTAR) software. Those skilled in the art can determine appropriate parameters for sequence alignment, including any algorithms necessary to achieve maximum alignment over the full length of the sequences being compared. However, for purposes herein, percent amino acid sequence identity values ​​are generated using the sequence comparison computer program ALIGN-2. The ALIGN-2 sequence comparison computer program was created by Genentech, Inc., and the source code, together with user documentation, has been filed with the U.S. Copyright Office, Washington, DC 20559, and is registered under U.S. Copyright Registration No. TXU510087. The ALIGN-2 program is publicly available from Genentech, Inc. (South San Francisco, California) or can be compiled from its source code. The ALIGN-2 program should be compiled for use on UNIX operating systems, including digital UNIX V4.0D. All sequence comparison parameters are set by the ALIGN-2 program and do not vary. In situations where ALIGN-2 is used for amino acid sequence comparisons, the percent amino acid sequence identity of a given amino acid sequence A to, with, or relative to a given amino acid sequence B (alternatively, it may be written as a given amino acid sequence A having or containing a certain percent amino acid sequence identity to, with, or relative to a given amino acid sequence B) is calculated as follows: 100 x fraction X / Y

[0241] where X is the number of amino acid residues scored as identical matches by the sequence alignment program ALIGN-2 in that program's alignment of A and B, and Y is the total number of amino acid residues in B. It will be understood that if the length of amino acid sequence A is not equal to the length of amino acid sequence B, then the % amino acid sequence identity of A to B will not equal the % amino acid sequence identity of B to A. Unless otherwise specified, all % amino acid sequence identity values ​​used herein are obtained as described in the immediately preceding paragraph using the ALIGN-2 computer program.

[0242] The term "antibody" as used herein is used in the broadest sense and encompasses a variety of antibody structures, including, but not limited to, monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments, so long as they exhibit the desired antigen-binding activity.

[0243] The terms "full-length antibody," "intact antibody," and "whole antibody" are used interchangeably herein to refer to an antibody having a heavy chain that has a structure substantially similar to a native antibody structure or that contains an Fc region as defined herein.

[0244] An "antibody fragment" refers to a molecule other than an intact antibody that contains a portion of an intact antibody that binds to the antigen to which the intact antibody binds. Examples of antibody fragments include, but are not limited to, Fv, Fab, Fab', Fab'-SH, F(ab'), diabodies, linear antibodies, single-chain antibody molecules (e.g., scFv), and multispecific antibodies formed from antibody fragments. As used herein, the term "antibody fragment" also includes single-domain antibodies.

[0245] The term "immunoglobulin molecule" refers to a protein having the structure of a naturally occurring antibody. For example, immunoglobulins of the IgG class are heterotetrameric glycoproteins of approximately 150,000 daltons, composed of two light chains and two heavy chains disulfide-bonded. From the N-terminus to the C-terminus, each heavy chain has a variable region (VH), also called a variable heavy domain or a heavy chain variable domain, followed by three constant domains (CH1, CH2, and CH3), also called a heavy chain constant region. Similarly, from the N-terminus to the C-terminus, each light chain has a variable region (VL), also called a variable light domain or a light chain variable domain, followed by a constant light (CL) domain, also called a light chain constant region. Immunoglobulin heavy chains are assigned to one of five classes, called α (IgA), δ (IgD), ε (IgE), γ (IgG), or μ (IgM), and some of these classes are further divided into subclasses, e.g., γ1 (IgG1), γ2 (IgG2), γ3 (IgG3), γ4 (IgG4), α1 (IgA1), and α2 (IgA2). Immunoglobulin light chains may be assigned to one of two types, called kappa (κ) and lambda (λ), based on the amino acid sequence of their constant domains. Immunoglobulins essentially consist of two Fab molecules and an Fc domain connected via an immunoglobulin hinge region.

[0246] The term "antigen-binding domain" refers to a part of an antibody that comprises an area that specifically binds to and is complementary to part or all of an antigen. An antigen-binding domain may be provided, for example, by one or more antibody variable domains (also called antibody variable regions). Preferably, the antigen-binding domain comprises an antibody light chain variable region (VL) and an antibody heavy chain variable region (VH).

[0247] The term "variable region" or "variable domain" refers to the domain of an antibody heavy chain or light chain that is involved in binding the antibody to an antigen. The variable domains of the heavy and light chains (VH and VL, respectively) of natural antibodies generally have similar structures, and each domain contains four conserved framework regions (FR) and three hypervariable regions (HVR). See, for example, Kindt et al., Kuby Immunology, 6 th ed., WH Freeman and Co., page 91 (2007). A single VH or VL domain may be sufficient to confer antigen-binding specificity.

[0248] A "human antibody" is an antibody having an amino acid sequence corresponding to an antibody produced by a human or human cell, or an antibody of non-human origin that utilizes human antibody-encoding sequences, such as the human antibody repertoire. This definition of a human antibody specifically excludes humanized antibodies that contain non-human antigen-binding residues.

[0249] A "humanized" antibody refers to a chimeric antibody comprising amino acid residues from non-human HVRs and amino acid residues from human FRs. In certain embodiments, a humanized antibody comprises substantially all of at least one, and typically two, variable domains, in which all or substantially all of the HVRs (e.g., CDRs) correspond to a non-human antibody and all or substantially all of the FRs correspond to a human antibody. A humanized antibody may optionally comprise at least a portion of an antibody constant region derived from a human antibody. A "humanized form" of an antibody, e.g., a non-human antibody, refers to an antibody that has undergone humanization.

[0250] As used herein, the term "hypervariable region" or "HVR" refers to each of the regions of an antibody variable domain that are hypervariable in sequence ("complementarity determining regions" or "CDRs") and / or that form structurally defined loops ("hypervariable loops") and / or contain antigen-contacting residues ("antigen contacts"). Generally, antibodies contain six HVRs: three in the VH (H1, H2, H3) and three in the VL (L1, L2, L3). Exemplary HVRs of the invention include the following: (a) hypervariable loops occurring at amino acid residues 26-32 (L1), 50-52 (L2), 91-96 (L3), 26-32 (H1), 53-55 (H2), and 96-101 (H3) (Chothia and Lesk, J. Mol. Biol. 196:901-917 (1987)); (b) CDRs occurring at amino acid residues 24-34 (L1), 50-56 (L2), 89-97 (L3), 31-35b (H1), 50-65 (H2), and 95-102 (H3) (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD (1991)); (c) antigen contacts occurring at amino acid residues 27c-36 (L1), 46-55 (L2), 89-96 (L3), 30-35b (H1), 47-58 (H2), and 93-101 (H3) (MacCallum et al. J. Mol. Biol. 262:732-745 (1996)); and (d) A combination of (a), (b) and / or (c) comprising HVR amino acid residues 46-56 (L2), 47-56 (L2), 48-56 (L2), 49-56 (L2), 26-35 (H1), 26-35b (H1), 49-65 (H2), 93-102 (H3) and 94-102 (H3).

[0251] Unless otherwise indicated, HVR residues and other residues in the variable domain (e.g., FR residues) are numbered herein according to Kabat et al., supra.

[0252] "Framework" or "FR" refers to variable domain residues other than hypervariable region (HVR) residues. The FR of a variable domain typically consists of four FR domains: FR1, FR2, FR3, and FR4. Thus, the HVR and FR sequences typically appear in VH (or VL) in the following order: FR1-H1(L1)-FR2-H2(L2)-FR3-H3(L3)-FR4.

[0253] A "human consensus framework" is a framework that represents the most commonly occurring amino acid residues in a selection of human immunoglobulin VL or VH framework sequences. Generally, the selection of human immunoglobulin VL or VH sequences is from a subgroup of variable domain sequences. Generally, the subgroup of sequences is a subgroup as set forth in Kabat et al., Sequences of Proteins of Immunological Interest, Fifth Edition, NIH Publication 91-3242, Bethesda, MD (1991), vols. 1-3. In one embodiment, for VL, the subgroup is subgroup kappa I in Kabat et al. (supra). In one embodiment, for VH, the subgroup is subgroup III as set forth in Kabat et al. (supra).

[0254] For purposes herein, an "acceptor human framework" is a framework that comprises the amino acid sequence of a light chain variable domain (VL) framework or a heavy chain variable domain (VH) framework derived from a human immunoglobulin framework or a human consensus framework, as defined below. An acceptor human framework "derived from" a human immunoglobulin framework or a human consensus framework may comprise the same amino acid sequence, or may contain amino acid sequence changes. In some embodiments, the number of amino acid changes is 10 or less, 9 or less, 8 or less, 7 or less, 6 or less, 5 or less, 4 or less, 3 or less, or 2 or less. In some embodiments, the VL acceptor human framework is identical in sequence to the VL human immunoglobulin framework sequence or the human consensus framework sequence.

[0255] The "class" of an antibody refers to the type of constant domain or constant region carried by its heavy chain. There are five major classes of antibodies: IgA, IgD, IgE, IgG, and IgM, and some of these can be further divided into subclasses (isotypes), e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The heavy-chain constant domains that correspond to the different classes of immunoglobulins are called α, δ, ε, γ, and μ, respectively.

[0256] The term IgG "isotype" or "subclass" as used herein means any of the subclasses of immunoglobulins defined by the chemical and antigenic properties of their constant regions.

[0257] The term "Fc domain" or "Fc region" is used herein to define the C-terminal region of an immunoglobulin heavy chain containing at least a portion of the constant region. This term includes native-sequence Fc regions and variant Fc regions. Although the boundaries of the Fc region of an IgG heavy chain may vary slightly, the human IgG heavy chain Fc region is usually defined to stretch from Cys226, or from Pro230, to the carboxy-terminus of the heavy chain. However, antibodies produced by host cells may undergo post-translational cleavage of one or more, particularly one or two, amino acids from the C-terminus of the heavy chain. Thus, antibodies produced by host cells by expression of a specific nucleic acid molecule encoding a full-length heavy chain may comprise a full-length heavy chain or a truncated variant of the full-length heavy chain (also referred to herein as a "truncated variant heavy chain"). This is also true when the last two C-terminal amino acids of the heavy chain are glycine (G446) and lysine (K447, EU numbering). Thus, the C-terminal lysine (Lys447) of the Fc region, or the C-terminal glycine (Gly446) and lysine (K447) may or may not be present. Unless otherwise specified herein, the numbering of amino acid residues in the Fc region or constant region is according to the EU numbering system, also known as the EU index, as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th ed., Public Health Service, National Institutes of Health, Bethesda, MD, 1991 (see also above). As used herein, a "subunit" of an Fc domain refers to one of the two polypeptides that form the dimeric Fc domain, i.e., a polypeptide that comprises the C-terminal constant region of an immunoglobulin heavy chain and is capable of stable self-association. For example, a subunit of an IgG Fc domain comprises the IgG CH2 and IgG CH3 constant domains.

[0258] A "modification that promotes association of a first and second Fc domain subunit" refers to manipulation of the peptide backbone or post-translational modification of an Fc domain subunit that reduces or prevents the association of a polypeptide comprising the Fc domain subunit with an identical polypeptide to form homodimers. As used herein, a modification that promotes association specifically includes separate modifications made to each of the two Fc domain subunits (i.e., the first and second Fc domain subunits) that are desired to associate, where these modifications are complementary to each other to promote the association of the two Fc domain subunits. For example, a modification that promotes association can alter the structure or charge of one or both of the Fc domain subunits to sterically or electrostatically favor their association, respectively. Thus, (hetero)dimerization occurs between a polypeptide comprising a first Fc domain subunit and a polypeptide comprising a second Fc domain subunit, which may not be identical in the sense that the additional components (e.g., antigen-binding moieties) fused to each of the subunits are not the same. In some embodiments, the modification that promotes association comprises an amino acid mutation, particularly an amino acid substitution, within the Fc domain, hi certain embodiments, the modification that promotes association comprises a separate amino acid mutation, particularly an amino acid substitution, in each of the two subunits of the Fc domain.

[0259] An "activating Fc receptor" is an Fc receptor that, following engagement by the Fc region of an antibody, triggers signaling events that stimulate the receptor-bearing cell to carry out an effector function. Activating Fc receptors include FcγRIIIa (CD16a), FcγRI (CD64), FcγRIIa (CD32), and FcαRI (CD89).

[0260] The term "effector function," when used in reference to an antibody, refers to a biological activity attributable to the Fc region of an antibody, which varies depending on the antibody isotype. Examples of antibody effector functions include C1q binding and complement-dependent cytotoxicity (CDC); Fc receptor binding; antibody-dependent cell-mediated cytotoxicity (ADCC); antibody-dependent cellular phagocytosis (ADCP); cytokine secretion; immune complex-mediated antigen uptake by antigen-presenting cells; downregulation of cell surface receptors (e.g., B cell receptors); and B cell activation.

[0261] As used herein, the term "effector cells" refers to a population of lymphocytes that express effector moiety receptors, e.g., cytokine receptors, and / or Fc receptors, on their surface, thereby binding effector moieties, e.g., cytokines, and / or the Fc region of antibodies, and contributing to the destruction of target cells, e.g., tumor cells. Effector cells mediate, for example, cytotoxic or phagocytic effects. Effector cells include CD8 + cytotoxic T cells, CD4 + These include, but are not limited to, effector T cells such as helper T cells, γδ T cells, NK cells, lymphocyte-activated killer (LAK) cells, and macrophages / monocytes.

[0262] As used herein, the terms "engineer," "engineered," and "engineering" are intended to include any manipulation of the peptide backbone or post-translational modification of a naturally occurring or recombinant polypeptide or fragment thereof. Engineering includes modification of the amino acid sequence, modification of the glycosylation pattern, or modification of the side groups of individual amino acids, and combinations of these approaches. In particular, "engineer" with the prefix "glyco," and the term "glycosylation engineering" include metabolic engineering of the glycosylation machinery of a cell, including genetic manipulation of the oligosaccharide synthesis pathway to achieve altered glycosylation of glycoproteins expressed in the cell. Furthermore, glycosylation engineering includes the influence of mutations and the cellular environment on glycosylation. In one embodiment, glycosylation engineering is alteration of glycosyltransferase activity. In certain embodiments, engineering results in altered glucosaminyltransferase activity and / or fucosyltransferase activity. Glycosylation engineering can be used to obtain "host cells with increased GnTIII activity" (e.g., host cells engineered to have increased expression levels of one or more polypeptides having β(1,4)-N-acetylglucosaminyltransferase III (GnTIII) activity), "host cells with increased ManII activity" (e.g., host cells engineered to have increased expression levels of one or more polypeptides having α-mannosidase II (ManII) activity), or "host cells with reduced α(1,6)fucosyltransferase activity" (e.g., host cells engineered to have reduced expression levels of α(1,6)fucosyltransferase).

[0263] The terms "host cell," "host cell line," and "host cell culture" are used interchangeably and refer to cells into which exogenous nucleic acid has been introduced, including the progeny of such cells. Host cells include "transformants" and "transformed cells," which include the original transformed cell and progeny derived from the original transformed cell, regardless of the number of passages. Progeny may not be completely identical in nucleic acid content to the parent cell and may contain mutations. Included herein are progeny of mutants that have the same function or biological activity as screened or selected for in the originally transformed cell. Host cells are any type of cell line that can be used to produce proteins used in the present invention. In one embodiment, the host cells are engineered to enable the production of antibodies with modified oligosaccharides. In certain embodiments, the host cells are engineered to increase the expression level of one or more polypeptides having β(1,4)-N-acetylglucosaminyltransferase III (GnTIII) activity. In certain embodiments, the host cells are further engineered to increase the expression level of one or more polypeptides having α-mannosidase II (ManII) activity. Host cells include cultured cells, e.g., cultured mammalian cells, such as CHO cells, BHK cells, NS0 cells, SP2 / 0 cells, YO myeloma cells, P3X63 mouse bone marrow cells, PER cells, PER.C6 cells or hybridoma cells, yeast cells, insect cells, and plant cells, as well as cells contained within transgenic animals, transgenic plants, or cultured plant or animal tissue.

[0264] As used herein, the term "polypeptide having GnTIII activity" refers to a polypeptide capable of catalyzing the addition of an N-acetylglucosamine (GlcNAc) residue in a β-1,4 linkage to the β-linked mannoside of a trimannosyl core of an N-linked oligosaccharide. This includes fusion polypeptides that exhibit enzymatic activity similar, but not necessarily identical, to the activity of β(1,4)-N-acetylglucosaminyltransferase III, also known as β-1,4-mannosyl-glycoprotein 4-beta-N-acetylglucosaminyltransferase (EC 2.4.1.144) according to the International Union of Biochemistry and Molecular Biology (NC-IUBMB) Commission on Nomenclature, as measured in specific biological assays, with or without dose dependency. If a dose-dependence exists, it need not be identical to that of GnTIII, but rather should be substantially similar to the dose-dependence for a given activity when compared to GnTIII (i.e., the candidate polypeptide will exhibit greater activity or at least about 25-fold, preferably at least about 10-fold, and most preferably at least about 3-fold less activity than GnTIII). In certain embodiments, the polypeptide having GnTIII activity is a fusion polypeptide comprising the catalytic domain of GnTIII and the Golgi localization domain of a heterologous Golgi-resident polypeptide. In particular, the Golgi localization domain is the localization domain of mannosidase II or GnTI, most particularly the localization domain of mannosidase II. Alternatively, the Golgi localization domain is selected from the group consisting of the localization domain of mannosidase I, the localization domain of GnTII, and the localization domain of α1,6 core fucosyltransferase. Methods for making such fusion polypeptides and using them to generate antibodies with increased effector function are disclosed in WO 2004 / 065540, U.S. Provisional Patent No. 60 / 495142, and U.S. Patent Publication No. 2004 / 0241817, the entire contents of which are expressly incorporated herein by reference.

[0265] As used herein, the term "Golgi localization domain" refers to an amino acid sequence of a Golgi-resident polypeptide that is responsible for anchoring the polypeptide to a location within the Golgi complex. Generally, the localization domain constitutes the amino-terminal "tail" of the enzyme.

[0266] As used herein, the term "polypeptide having ManII activity" refers to a polypeptide capable of catalyzing the hydrolysis of terminal 1,3- and 1,6-linked α-D-mannose residues of the branched GlcNAcMan5GlcNAc2 mannose intermediate of N-linked oligosaccharides. This includes polypeptides that exhibit activity similar, but not necessarily identical, to that of Golgi α-mannosidase II, also known as mannosyloligosaccharide 1,3-1,6-α-mannosidase II (EC 3.2.1.114) according to the Nomenclature Committee of the International Union of Biochemistry and Molecular Biology (NC-IUBMB).

[0267] Antibody-dependent cell-mediated cytotoxicity (ADCC) is an immune mechanism that causes immune effector cells to lyse antibody-coated target cells. Target cells are cells to which an Fc region-containing antibody or fragment thereof specifically binds, usually via a protein portion N-terminal to the Fc region. As used herein, the term "increased / decreased ADCC" is defined as either an increase / decrease in the number of target cells lysed in a given time period by the ADCC mechanism as defined above, at a given antibody concentration in the medium surrounding the target cells, and / or a decrease / increase in the antibody concentration in the medium surrounding the target cells required to lyse a given number of target cells in a given time period by the ADCC mechanism. Increased / decreased ADCC is relative to ADCC mediated by the same antibody produced by the same type of host cell, but without manipulation, using the same standard production, purification, formulation, and storage methods (known to those skilled in the art). For example, the increase in ADCC mediated by an antibody produced by a host cell engineered to have an altered glycosylation pattern (e.g., to express a glycosyltransferase, GnTIII, or other glycosyltransferase) by the methods described herein is compared to the ADCC mediated by the same antibody produced by a non-engineered host cell of the same type.

[0268] By "antibody with increased / decreased antibody-dependent cellular cytotoxicity (ADCC)" is meant an antibody with increased / decreased ADCC as determined by any suitable method known to those skilled in the art. One acceptable in vitro ADCC assay is as follows: 1) the assay uses target cells known to express the target antigen recognized by the antigen-binding region of the antibody; 2) the assay uses human peripheral blood mononuclear cells (PBMCs) isolated from the blood of randomly selected healthy donors as effector cells; 3) The assay is performed according to the following protocol. i) PBMCs were isolated using standard density centrifugation procedures and 5×10 6 Suspend in RPMI cell culture medium at 1000 cells / mL; ii) Target cells are grown by standard tissue culture methods, harvested from exponential growth phase with greater than 90% viability, washed with RPMI cell culture medium, and incubated with 100 microcuries of water. 51 Label with Cr, wash twice with cell culture medium, and 5 Resuspend in cell culture medium at a density of 100 cells / mL; iii) Transfer 100 microliters of the final target cell suspension described above into each well of a 96-well microtiter plate. iv) serially diluting the antibody in cell culture medium from 4000 ng / mL to 0.04 ng / mL, and adding 50 microliters of the resulting antibody solution to target cells in a 96-well microtiter plate, testing various antibody concentrations in triplicate to cover the entire concentration range described above; v) As a maximum release (MR) control, three additional wells in the plate containing labeled target cells received 50 microliters of a 2% (V / V) aqueous solution of a non-ionic surfactant (Nonidet, Sigma, St. Louis) instead of the antibody solution (iv above); vi) As a spontaneous release (SR) control, three additional wells in the plate containing labeled target cells receive 50 microliters of RPMI cell culture medium instead of the antibody solution (iv above). vii) The 96-well microtiter plate is then centrifuged at 50×g for 1 minute and incubated at 4° C. for 1 hour; viii) 50 microliters of the PBMC suspension (i above) is added to each well to obtain an effector:target cell ratio of 25:1, and the plate is placed in an incubator in a 5% CO2 atmosphere at 37°C for 4 hours; ix) Recover cell-free supernatant from each well and quantify experimentally released radioactivity (ER) using a gamma counter; x) The percentage of specific lysis is calculated for each antibody concentration according to the formula (ER-MR) / (MR-SR) x 100, where ER is the average radioactivity quantified for that antibody concentration (see ix above), MR is the average radioactivity quantified for the MR control (see v above) (see ix above), and SR is the average radioactivity quantified for the SR control (see vi above) (see ix above); 4) "Increased / decreased ADCC" is defined as either the increase / decrease in the maximum specific lysis rate observed within the antibody concentration range tested above and / or the decrease / increase in the antibody concentration required to achieve half the maximum specific lysis rate observed within the antibody concentration range tested above. The increased / decreased ADCC measured in the above assays is relative to the ADCC mediated by the same antibody produced by the same type of host cell, but without manipulation, using the same standard production, purification, formulation, and storage methods known to those of skill in the art.

[0269] As used herein, the term "monoclonal antibody" refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical and / or bind to the same epitope, with the exception of possible variant antibodies that contain, for example, naturally occurring mutations or that arise during production of the monoclonal antibody preparation, and such variants are generally present in minor amounts. In contrast to polyclonal antibody preparations, which typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody of a monoclonal antibody preparation is directed against a single determinant on an antigen. Thus, the modifier "monoclonal" indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies and should not be construed as requiring production of the antibody by any particular method. For example, monoclonal antibodies used in accordance with the present invention can be produced by a variety of techniques, including, but not limited to, hybridoma methods, recombinant DNA methods, phage display methods, and methods utilizing transgenic animals containing all or part of the human immunoglobulin loci; such methods and other exemplary methods for producing monoclonal antibodies are described herein.

[0270] A "naked antibody" refers to an antibody that is not conjugated to a heterologous moiety (e.g., a cytotoxic moiety) or radiolabel. Naked antibodies may be present in a pharmaceutical formulation.

[0271] "Native antibodies" refer to naturally occurring immunoglobulin molecules with various structures. For example, native IgG antibodies are heterotetrameric glycoproteins of approximately 150,000 daltons composed of two identical light chains and two identical heavy chains that are disulfide-bonded. From the N-terminus to the C-terminus, each heavy chain has a variable region (VH), also called a variable heavy domain or heavy chain variable domain, followed by three constant domains (CH1, CH2, and CH3). Similarly, from the N-terminus to the C-terminus, each light chain has a variable region (VL), also called a variable light domain or light chain variable domain, followed by a constant light (CL) domain. The light chain of an antibody may be assigned to one of two types, called kappa (κ) or lambda (λ), based on the amino acid sequence of its constant domain.

[0272] As used herein, the terms "first," "second," "third," etc., in reference to antigen-binding moieties or domains are used for convenience of distinction when more than one of each type of moiety or domain is present. The use of these terms is not intended to confer a particular order or orientation unless explicitly indicated as such.

[0273] The terms "multispecific" and "bispecific" mean that an antigen-binding molecule can specifically bind to at least two distinct antigenic determinants. Typically, a bispecific antigen-binding molecule contains two antigen-binding sites, each specific for a different antigenic determinant. In certain embodiments, a bispecific antigen-binding molecule can simultaneously bind to two antigenic determinants (particularly, two antigenic determinants expressed on two distinct cells).

[0274] As used herein, the term "valent" or "valency" refers to the presence of a specific number of antigen-binding sites in an antigen-binding molecule. Thus, the term "monovalent binding to an antigen" refers to the presence of one (and not more than one) antigen-binding site specific for the antigen within the antigen-binding molecule.

[0275] "Antigen-binding site" refers to the site of an antigen-binding molecule that interacts with an antigen, i.e., one or more amino acid residues. For example, the antigen-binding site of an antibody comprises amino acid residues from the complementarity-determining region (CDR). A naturally occurring immunoglobulin molecule typically has two antigen-binding sites, while a Fab molecule typically has a single antigen-binding site.

[0276] As used herein, "activating T cell antigen" refers to an antigenic determinant expressed by T lymphocytes, particularly cytotoxic T lymphocytes, which can induce or enhance T cell activation upon interaction with an antigen-binding molecule. Specifically, interaction of an antigen-binding molecule with an activating T cell antigen can induce T cell activation by triggering a signal transduction cascade in the T cell receptor complex. An exemplary activating T cell antigen is CD3. In certain embodiments, the activating T cell antigen is CD3, particularly the epsilon subunit of CD3 (see UniProt No. P07766 (version 130), NCBI RefSeq No. NP_000724.1 for the human sequence; or UniProt No. Q95LI5 (version 49), NCBI GenBank No. BAB71849.1 for the cynomolgus monkey [Macaca fascicularis] sequence).

[0277] As used herein, "T cell activation" refers to one or more cellular responses of T lymphocytes, particularly cytotoxic T lymphocytes, selected from proliferation, differentiation, cytokine secretion, release of cytotoxic effector molecules, cytotoxic activity, and expression of activation markers. T cell activating therapeutic agents used in the present invention are capable of inducing T cell activation. Suitable assays for measuring T cell activation are known in the art and are described herein.

[0278] As used herein, "target cell antigen" refers to an antigenic determinant displayed on the surface of a target cell, e.g., a cell within a tumor, such as a cancer cell or a cell of the tumor stroma. In a specific embodiment, the target cell antigen is CD20, particularly human CD20 (see UniProt No. P11836).

[0279] As used herein, "B cell antigen" refers to an antigenic determinant present on the surface of a B lymphocyte, particularly a malignant B lymphocyte (in which case the antigen is also referred to as a "malignant B cell antigen").

[0280] As used herein, "T cell antigen" refers to an antigenic determinant displayed on the surface of T lymphocytes, particularly cytotoxic T lymphocytes.

[0281] A "Fab molecule" refers to a protein consisting of the VH and CH1 domains of an immunoglobulin heavy chain (a "Fab heavy chain") and the VL and CL domains of a light chain (a "Fab light chain").

[0282] By "fused" is meant that the components (e.g., a Fab molecule and an Fc domain subunit) are linked by peptide bonds, either directly or via one or more peptide linkers.

[0283] An "effective amount" of a drug is the amount necessary to produce a physiological change in the cells or tissue to which it is administered.

[0284] A "therapeutically effective amount" of an agent, e.g., a pharmaceutical composition, refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic or prophylactic result. A therapeutically effective amount of an agent, for example, eliminates, reduces, delays, minimizes, or prevents the side effects of a disease.

[0285] "Therapeutic agent" refers to an active ingredient, e.g., a pharmaceutical composition, that is administered to a subject in an attempt to alter the natural course of a disease in the subject being treated, and can be administered prophylactically or during the course of clinical pathology. "Immunotherapeutic agent" refers to a therapeutic agent that is administered to a subject with the intent of restoring or enhancing the subject's immune response, e.g., against a tumor.

[0286] The term "pharmaceutical composition" refers to a preparation in a form that is effective for the biological activity of the active ingredient contained therein, and that does not contain additional ingredients that are unacceptably toxic to the subject to which the composition is administered.

[0287] A "pharmaceutically acceptable carrier" refers to an ingredient in a pharmaceutical composition, other than an active ingredient, that is not toxic to a subject. Pharmaceutically acceptable carriers include, but are not limited to, buffers, excipients, stabilizers, or preservatives.

[0288] The term "package insert" or "instructions for use" is used to refer to instructions customarily included in the commercial packaging of a therapeutic product, which contain information about the indications, usage, dosage, administration, concomitant therapy, contraindications and / or precautions regarding the use of such therapeutic product.

[0289] The term "combined treatment" as used herein encompasses combined administration (when two or more therapeutic agents are contained in the same or separate formulations) and separate administration, in which the administration of an antibody as reported herein occurs before, simultaneously with, and / or after the administration of one or more additional therapeutic agents, preferably one or more antibodies.

[0290] A "crossover" Fab molecule (also referred to as "Crossfab") refers to a Fab molecule in which the variable or constant domains of a Fab heavy chain have been swapped (i.e., replaced with one another), i.e., the crossover Fab molecule comprises a peptide chain consisting of a light chain variable domain VL and a heavy chain constant domain 1 CH1 (VL-CH1, N-terminal to C-terminal), and a peptide chain consisting of a heavy chain variable domain VH and a light chain constant domain CL (VH-CL, N-terminal to C-terminal). For clarity, in a crossover Fab molecule in which the variable domains of a Fab light chain and a Fab heavy chain have been swapped, the peptide chain comprising the heavy chain constant domain 1 CH1 is referred to herein as the "heavy chain" of the (crossover) Fab molecule. Conversely, in a crossover Fab molecule in which the constant domains of a Fab light chain and a Fab heavy chain have been swapped, the peptide chain comprising the heavy chain variable domain VH is referred to herein as the "heavy chain" of the (crossover) Fab molecule.

[0291] In contrast, a "conventional" Fab molecule refers to a Fab molecule in its native format, i.e., comprising a heavy chain consisting of the heavy chain variable and constant domains (from N- to C-terminus: VH-CH1) and a light chain consisting of the light chain variable and constant domains (from N- to C-terminus: VL-CL).

[0292] The term "polynucleotide" refers to an isolated nucleic acid molecule or construct, e.g., messenger RNA (mRNA), viral-derived RNA, or plasmid DNA (pDNA). A polynucleotide may contain conventional phosphodiester bonds or non-conventional bonds (e.g., amide bonds, such as those found in peptide nucleic acids (PNAs)). The term "nucleic acid molecule" refers to any one or more nucleic acid segments, e.g., DNA or RNA fragments, present in a polynucleotide.

[0293] An "isolated" nucleic acid molecule or polynucleotide refers to a nucleic acid molecule, DNA, or RNA, that has been removed from its natural environment. For example, a recombinant polynucleotide encoding a polypeptide contained in a vector is considered isolated for purposes of the present invention. Further examples of isolated polynucleotides include recombinant polynucleotides maintained in heterologous host cells or purified (partially or substantially) polynucleotides in solution. Isolated polynucleotides include polynucleotide molecules contained in cells that originally contain the polynucleotide molecule, but where the polynucleotide molecule is present extrachromosomally or at a chromosomal location different from its natural chromosomal location. Isolated RNA molecules include in vivo or in vitro RNA transcripts of the present invention, positive- and negative-stranded forms, and double-stranded forms. Isolated polynucleotides or nucleic acids according to the present invention further include such molecules produced synthetically. In addition, polynucleotides or nucleic acids may be or include regulatory elements, such as a promoter, ribosome binding site, or transcription terminator.

[0294] A nucleic acid or polynucleotide having a nucleotide sequence that is, for example, at least 95% "identical" to a reference nucleotide sequence of the present invention means that the nucleotide sequence of the polynucleotide is identical to the reference sequence, except that the nucleotide sequence of the polynucleotide may contain up to five point mutations per 100 nucleotides of the reference nucleotide sequence. In other words, to obtain a polynucleotide having a nucleotide sequence that is at least 95% identical to the reference nucleotide sequence, up to 5% of the nucleotides in the reference sequence may be deleted or substituted with other nucleotides, or up to 5% of the total nucleotides in the reference sequence may be inserted into the reference sequence. Such alterations of the reference sequence may occur at the 5' or 3' terminal positions of the reference nucleotide sequence, or anywhere between these terminal positions, and may be interspersed individually among residues in the reference sequence or interspersed in one or more contiguous groups within the reference sequence. As a practical matter, whether any particular polynucleotide sequence is at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% identical to a nucleotide sequence of the present invention can be determined using computer programs such as those described above for polypeptides (e.g., ALIGN-2).

[0295] The term "expression cassette" refers to a recombinantly or synthetically produced polynucleotide that contains a specific sequence of nucleic acid elements that allows for transcription of a specific nucleic acid in a target cell. Recombinant expression cassettes can be incorporated into plasmids, chromosomes, mitochondrial DNA, plastid DNA, viruses, or nucleic acid fragments. Typically, the recombinant expression cassette portion of an expression vector contains, among other sequences, a nucleic acid sequence to be transcribed and a promoter. In certain embodiments, expression cassettes of the invention comprise a polynucleotide sequence encoding a bispecific antigen-binding molecule of the invention, or a fragment thereof.

[0296] The term "vector" or "expression vector" is synonymous with "expression construct" and refers to a DNA molecule used to introduce and direct the expression of a specific gene with which it is operably associated in a target cell. This term includes not only vectors as self-replicating nucleic acid structures, but also vectors that are integrated into the genome of a host cell into which they are introduced. The expression vector of the present invention comprises an expression cassette. The expression vector enables stable, high-yield transcription of mRNA. Once the expression vector is inside the target cell, the ribonucleic acid molecule or protein encoded by the gene is produced by the cellular transcription and / or translation machinery. In one embodiment, the expression vector of the present invention comprises an expression cassette comprising a polynucleotide sequence encoding a bispecific antibody of the present invention, or a fragment thereof.

[0297] The term "about," as used herein, refers to a normal range of error for the respective value, which would be readily understood by one of ordinary skill in the art. Reference herein to "about" a value or parameter includes (and describes) embodiments that are directed to the value or parameter itself.

[0298] "B cell proliferative disorder" refers to a disease in which the number of B cells in a patient is increased compared to the number of B cells in a healthy subject, particularly a disease in which an increased number of B cells is the cause or evidence of the disease. "CD20-positive B cell proliferative disorder" is a B cell proliferative disorder in which B cells, particularly malignant B cells (in addition to normal B cells), express CD20.

[0299] Exemplary B-cell proliferative disorders include non-Hodgkin's lymphoma (NHL), diffuse large B-cell lymphoma (DLBCL; e.g., relapsed or refractory DLBCL, not otherwise specified (NOS), high-grade B-cell lymphoma (HGBCL; e.g., HGBCL NOS, double-hit HGBCL, and triple-hit HGBCL), primary mediastinal large B-cell lymphoma (PMBCL), and DLBCL arising from FL (transformed FL; trFL); follicular lymphoma (FL) (including grade 1-3b FL); mantle cell lymphoma (MCL); and marginal zone lymphoma (MZL) (including splenic MZL, nodal MZL, or extranodal MZL). In one embodiment, the CD20-positive B-cell proliferative disorder is Burkitt lymphoma (BL); Burkitt leukemia (BAL; mature B-cell leukemia FAB L3); DLBCL, or PMBCL. In one embodiment, the CD20-positive B-cell proliferative disorder is relapsed or refractory NHL (e.g., relapsed or refractory DLBCL, relapsed or refractory FL, or relapsed or refractory MCL). In one embodiment, the BL, BAL, DLBCL, or PMBCL is relapsed and / or refractory. In one embodiment, the BL, BAL, DLBCL, or PMBCL has relapsed after or is refractory to first-line standard of care chemoimmunotherapy.

[0300] "Refractory disease" is defined as the inability to achieve complete remission to first-line therapy, including the following: Progressive disease (PD) as best response to first-line therapy Stable disease (SD) as best response after at least four cycles of first-line therapy (e.g., four cycles of R-CHOP) Partial response (PR) as best response after at least 6 cycles and biopsy-proven residual disease or subsequent disease progression.

[0301] "Relapsed disease" is defined as a complete response to first-line therapy. In one embodiment, disease recurrence is biopsy-proven. In one embodiment, the patient has relapsed after or failed to respond to at least two prior systemic treatment regimens, including at least one prior regimen comprising an anthracycline and at least one prior regimen comprising an anti-CD20-directed therapy.

[0302] An "individual" or "subject" is a mammal. Mammals include, but are not limited to, livestock animals (e.g., cows, sheep, cats, dogs, and horses), primates (e.g., humans and non-human primates such as monkeys), rabbits, and rodents (e.g., mice and rats). Preferably, the individual or subject is a human. In one example, each subject in a population of subjects is a human. In one example, each subject in a reference population of subjects is a human. In one embodiment, a subject is considered to be a pediatric patient if the subject is under 18 years of age (17 years or younger). In one embodiment, a pediatric patient is between 6 months and 17 years of age. In one embodiment, a subject is considered to be a young adult patient if the young adult patient is between 18 and 30 years of age.

[0303] A "transplant-eligible" subject or "eligible for autologous stem cell transplantation (SCT)" is a subject who meets eligibility for, is recommended for, or is able to undergo autologous SCT. In one embodiment, "transplant-eligible" is defined as being medically eligible for intensive platinum-based salvage therapy followed by autologous stem cell transplantation (ASCT). In one embodiment, a transplant-eligible subject achieves an objective response and mobilization of a target dose of at least 2,000,000 CD34+ hematopoietic stem cells / kg. In one embodiment, "transplant-eligible" is defined as being medically eligible for two to three cycles of salvage therapy with R-ICE and glofitamab followed by allogeneic or autologous hematopoietic stem cell transplantation (HSCT) after achieving a CR.

[0304] A "CAR-T cell therapy eligible" or "eligible for CAR-T cell therapy" subject is a subject who meets the eligibility criteria for, is recommended for, or is able to receive chimeric antigen receptor (CAR) T cell therapy.

[0305] As used herein, "treatment" (and its grammatical variants, e.g., "treat" or "treating") refers to clinical intervention in an attempt to alter the natural course of disease in the treated individual and can be carried out prophylactically or during the course of clinical pathology. Desired effects of treatment include preventing the onset or recurrence of disease, alleviating symptoms, attenuating any direct or indirect pathological consequences of the disease, preventing metastasis, reducing the rate of disease progression, remission or palliation of disease symptoms, and improving or improving prognosis. In some embodiments, the methods of the invention are used to delay the onset of disease or slow the progression of disease. In one embodiment, the disease being treated is a CD20-positive B-cell proliferative disorder, such as Burkitt's lymphoma (BL); Burkitt's leukemia (BAL; mature B-cell leukemia FAB L3); DLBCL, or PMBCL.

[0306] As used herein, "delaying the progression" of a disorder or disease means postponing, preventing, slowing, retarding, stabilizing, and / or delaying the development of the disease or disorder (e.g., a CD20-positive B-cell proliferative disorder, e.g., NHL, e.g., DLBCL, e.g., Burkitt's lymphoma (BL); e.g., Burkitt's leukemia (BAL; mature B-cell leukemia FAB L3), or e.g., PMBCL). Such a delay can be of varying duration, depending on the disease being treated and / or the medical history of the individual. As will be apparent to one of skill in the art, a sufficient or significant delay can, in effect, encompass prevention, in that the individual does not develop the disease. For example, in late-stage cancer, the development of central nervous system (CNS) metastases may be delayed.

[0307] "Reducing" or "inhibiting" refers to the ability to cause an overall decrease, e.g., of 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or more. For clarity, the term also includes a reduction to zero (or below the limit of detection of an analytical method), i.e., complete disappearance or elimination. In certain embodiments, reducing or inhibiting refers to a reduction or inhibition of an undesirable event, such as cytokine-induced toxicity (e.g., cytokine release syndrome (CRS)), infusion-related reaction (IRR), macrophage activation syndrome (MAS), neurotoxicity, severe tumor lysis syndrome (TLS), neutropenia, thrombocytopenia, liver enzyme elevation, and / or central nervous system (CNS) toxicity, following treatment with an anti-CD20 / anti-CD3 bispecific antibody using a step-up dosing regimen of the invention, compared to a fixed, preset dose of the bispecific antibody at a target dose. In other embodiments, reducing or inhibiting may refer to antibody effector functions mediated by the antibody Fc region, specifically including complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), and antibody-dependent cellular phagocytosis (ADCP). In other embodiments, reducing or inhibiting may refer to symptoms, the presence or size of metastases, or the size of the primary tumor of the CD20-positive B-cell proliferative disorder being treated (e.g., NHL (e.g., DLBCL), FL (e.g., relapsed and / or refractory FL or transformed FL), MCL, high-grade B-cell lymphoma, or PMLBCL). In one embodiment, the CD20-positive B-cell proliferative disorder being treated is Burkitt's lymphoma (BL); Burkitt's leukemia (BAL; mature B-cell leukemia FAB L3); DLBCL, or PMLBCL.

[0308] As used herein, "administering" refers to a method of providing a subject with a dosage of a compound (e.g., an anti-CD20 / anti-CD3 bispecific antibody) or composition (e.g., a pharmaceutical composition, e.g., a pharmaceutical composition comprising an anti-CD20 / anti-CD3 bispecific antibody). The compounds and / or compositions utilized in the methods described herein can be administered intravenously (e.g., by intravenous infusion).

[0309] A "fixed" or "flat" dose of a therapeutic agent (e.g., a bispecific antibody) herein refers to a dose administered to a patient without regard to the patient's weight or body surface area (BSA). Thus, the fixed or flat dose may be expressed as a mg / kg dose or a mg / m 2 It is not specified as a dose, but rather as an absolute amount (eg, mg) of therapeutic agent.

[0310] As used herein, the term "target dose" refers to the dose of an anti-CD20 / anti-CD3 bispecific antibody that achieves a therapeutic effect, i.e., a desired clinical response. For glofitamab, possible target doses have been found to be 16 mg or 30 mg. In one embodiment, the target dose for pediatric subjects (i.e., 6 months to 17 years of age) is 0.5 mg / kg or 0.4 mg / kg, depending on the subject's weight. In a specific embodiment, the target dose is 0.5 mg / kg for pediatric subjects weighing 7.5 kg to less than 13 kg, 0.4 mg / kg for pediatric subjects weighing 13 kg to less than 45 kg, and a flat dose of 30 mg for pediatric subjects weighing 45 kg or more.

[0311] "Constant or preset dosing at a target dose" and "treatment regimen without a step-up dosing regimen" refer to a dosing schedule that uses the same dose for the first and second cycles, and optionally for subsequent treatment cycles, as opposed to step-up dosing that uses a lower dose for the first few treatment cycles and only reaches the target dose in the second or subsequent treatment cycles.

[0312] As used herein, the term "treatment cycle" or "cycle" (abbreviated "C") refers to a course of one or more doses of an anti-CD20 / anti-CD3 bispecific antibody repeated on a regular schedule, optionally separated by periods of rest (treatment-free). In one aspect of the invention, a first treatment cycle comprises a first administration and a second administration of an anti-CD20 / anti-CD3 bispecific antibody, followed by a rest period. In one such embodiment, a first treatment cycle comprises a first dose of an anti-CD20 / anti-CD3 bispecific antibody on day 8 of the first cycle, a second dose of an anti-CD20 / anti-CD3 bispecific antibody on day 15 of the first cycle, followed by a 6-day rest period. In one embodiment, the second and subsequent cycles comprise a dose of an anti-CD20 / anti-CD3 bispecific antibody on day 8 of the cycle, followed by a 13-day rest period. In one embodiment, a treatment cycle consists of 21 days. In another embodiment, a treatment cycle consists of 14 days. A treatment schedule according to the present invention can consist of two or more treatment cycles, in particular three treatment cycles. In some embodiments, a treatment cycle is referred to as a "dosing cycle."

[0313] An "individual response" or "response" can be assessed using any endpoint that indicates efficacy in a subject, and endpoints include, but are not limited to, (1) some inhibition (including slowing and complete halting) of disease progression (e.g., progression of a CD20-positive B-cell proliferative disorder, e.g., non-Hodgkin's lymphoma (NHL)); (2) reduction in tumor size; (3) inhibition (i.e., reduction, slowing, or complete halt) of cancer cell invasion into adjacent peripheral organs and / or tissues; (4) inhibition (i.e., reduction, slowing, or complete halt) of metastasis; (5) some alleviation of one or more symptoms associated with a CD20-positive B-cell proliferative disorder, e.g., a B-cell proliferative disorder; (6) an increase or prolongation of survival, including overall survival and progression-free survival; and / or (7) a decrease in mortality at a time point following treatment.

[0314] As used herein, "complete response" or "CR" refers to the disappearance of all target lesions. In one embodiment, standard NHL response criteria are assessed to determine CR (Lugano Classification, Cheson et al. J Clin Oncol. 2014 Sep 20;32(27):3059-3067). In one embodiment, the CR rate is defined as the proportion of participants achieving a CR within three cycles of glofit-R-ICE, as determined by the investigator according to the Lugano criteria. In one embodiment, CR is defined as a complete metabolic response as determined by PET / CT of lymph nodes and extralymphatic sites, with a score of 1, 2, or 3, with or without residual masses on the 5PS, where PET 5PS is as follows: 1 = no uptake above background; 2 = uptake > mediastinum; 3 = uptake > mediastinum but ≤ liver; 4 = moderate uptake > liver; 5 = uptake significantly higher than liver and / or new lesions; X = new areas of uptake unlikely to be related to lymphoma. In one embodiment, CR is defined as a complete radiological response as determined by CT of lymph nodes and extralymphatic sites, and the target lymph node / nodal mass must regress to 1.5 cm or less in LDi (longest lateral diameter of the lesion) with no residual extralymphatic sites of disease. For pediatric subjects (<18 years of age), CR is assessed using the International Pediatric NHL Response Criteria (Sandlund JT, Guillerman RP, Perkins SL, et al. International pediatric non-Hodgkin lymphoma response criteria. J. Clin. Oncol. 33:2106-2111, 2015).

[0315] As used herein, "partial response" or "PR" refers to a partial metabolic response determined by PET / CT of lymph nodes and extra-lymphatic sites and / or a partial remission determined by CT of lymph nodes and extra-lymphatic sites. In one embodiment, a partial metabolic response is defined by a score of 4 or 5b with reduced uptake compared to baseline and a residual mass of any size determined by PET / CT of lymph nodes and extra-lymphatic sites, with PET 5PS as follows: 1 = no uptake above background; 2 = uptake > mediastinum; 3 = uptake > mediastinum but ≤ liver; 4 = moderate uptake > liver; 5 = uptake significantly higher than liver and / or new lesions; X = new areas of uptake unlikely to be related to lymphoma. In one embodiment, a partial response is defined as at least a 50% reduction in the product of diameters (SPD) of up to six target measurable lymph nodes and extra-lymphatic sites, referenced to the baseline SPD. For pediatric subjects (under 18 years of age), PR will be assessed using the International Pediatric NHL Response Criteria (Sandlund JT, Guillerman RP, Perkins SL, et al. International pediatric non-Hodgkin lymphoma response criteria. J. Clin. Oncol. 33:2106-2111, 2015).

[0316] A subject's "effective response" or subject "responsiveness" to treatment with a pharmaceutical agent, and similar terms, refers to a clinical or therapeutic benefit conferred on a subject at risk for or suffering from a disease or disorder, such as cancer. In one embodiment, such benefit includes one or more of extending survival (including overall survival and progression-free survival), producing an objective response (including a complete or partial response), or ameliorating the signs or symptoms of cancer.

[0317] "Duration of complete response" (DOCR) is defined as the time from the first occurrence of documented complete response to disease progression or death from any cause (whichever occurs first), as determined by the investigator according to the Lugano criteria (Cheson et al. J Clin Oncol. 2014 Sep 20;32(27):3059-3067.). CR will be assessed by the investigator using the International Pediatric NHL Response Criteria for pediatric subjects under 18 years of age (Sandlund JT, Guillerman RP, Perkins SL, et al. International pediatric non-Hodgkin lymphoma response criteria. J. Clin. Oncol. 33:2106-2111, 2015).

[0318] "Duration of objective response" (DOR) is defined as the time from the first occurrence of documented objective response (CR or PR) to disease progression or death from any cause (whichever occurs first), as determined by the investigator according to the Lugano criteria (Cheson et al. J Clin Oncol. 2014 Sep 20;32(27):3059-3067.). CR and / or PR will be assessed by the investigator using the International Pediatric NHL Response Criteria for pediatric subjects under 18 years of age (Sandlund JT, Guillerman RP, Perkins SL, et al. International pediatric non-Hodgkin lymphoma response criteria. J. Clin. Oncol. 33:2106-2111, 2015).

[0319] "Progression-free survival" (PFS) is defined as the time from the first treatment with an anti-CD20 / anti-CD3 bispecific antibody to the first occurrence of disease progression or death from any cause, whichever occurs first. In one embodiment, PFS is assessed based on the Lugano classification (Cheson et al. J Clin Oncol. 2014 Sep 20;32(27):3059-3067.). PFS is assessed by the investigator using the International Pediatric NHL Response Criteria for pediatric subjects under 18 years of age (Sandlund JT, Guillerman RP, Perkins SL, et al. International pediatric non-Hodgkin lymphoma response criteria. J. Clin. Oncol. 33:2106-2111, 2015).

[0320] "Overall survival" (OS) is defined as the time from first treatment with anti-CD20 / anti-CD3 bispecific antibody to the date of death from any cause.

[0321] As used herein, "event-free survival" (EFS) is defined as the time from initial treatment with an anti-CD20 / anti-CD3 bispecific antibody to the first occurrence of disease progression as determined by the investigator according to the Lugano criteria, the initiation of new anti-lymphoma therapy (excluding planned ASCT), or death from any cause (whichever occurs first). EFS is assessed by the investigator using the International Pediatric NHL Response Criteria for pediatric subjects under 18 years of age (Sandlund JT, Guillerman RP, Perkins SL, et al. International pediatric non-Hodgkin lymphoma response criteria. J. Clin. Oncol. 33:2106-2111, 2015).

[0322] As used herein, "objective response rate" (ORR) is defined as the sum of the partial response (PR) rate and the complete response (CR) rate. In one embodiment, ORR is assessed based on the Lugano classification (Cheson et al. J Clin Oncol. 2014 Sep 20;32(27):3059-3067). In one embodiment, ORR is defined as the proportion of participants who achieve CR or PR within three cycles of the anti-CD20 / anti-CD3 bispecific antibody (e.g., glofitamab) + R-ICE treatment regimen described herein. CR and / or PR are assessed by the investigator using the International Pediatric NHL Response Criteria for pediatric subjects under 18 years of age (Sandlund JT, Guillerman RP, Perkins SL, et al. International pediatric non-Hodgkin lymphoma response criteria. J. Clin. Oncol. 33:2106-2111, 2015).

[0323] As used herein, "stable disease" or "SD" refers to neither sufficient shrinkage of target lesions to qualify as PR nor sufficient increase to qualify as PD, based on the smallest SLD since treatment initiation.

[0324] As used herein, "progressive disease" or "PD" refers to an increase in the SLD of a target lesion by at least 20% from the smallest SLD, or an increase in the SPD of a target lesion by at least 50% from the smallest SPD, or the presence of one or more new lesions documented since the start of treatment.

[0325] As used herein, an "infusion-related reaction," "IRR," or "infusion-related adverse event" is an adverse event that occurs in a patient or subject during or within 24 hours after administration of a drug (e.g., an anti-CD20 / anti-CD3 bispecific antibody, e.g., glofitamab; or an anti-CD20 antibody, e.g., obinutuzumab or rituximab). IRRs can be graded, for example, according to NCI CTCAE v.4, from Grade 1 to 5.

[0326] "Mobilization-adjusted response rate (MARR)" is defined as the percentage of patients who achieved an objective response and mobilization of the target dose of 2,000,000 CD34+ hematopoietic stem cells / kg, the minimum required for ASCT.

[0327] As used herein, the term "R-ICE" refers to rituximab plus ifosfamide, carboplatin, etoposide, or etoposide phosphate. As used herein, the term "ICE" refers to ifosfamide, carboplatin, etoposide, or etoposide phosphate.

[0328] (iii) Combination treatment of anti-CD20 / anti-CD3 bispecific antibody with anti-CD20 antibody and chemotherapy The present invention provides a method of treating a subject with a CD20-positive cell proliferative disorder (e.g., a B-cell proliferative disorder (e.g., non-Hodgkin's lymphoma (NHL) (e.g., relapsed and / or refractory NHL, diffuse large B-cell lymphoma (DLBCL) (e.g., relapsed and / or refractory DLBCL), follicular lymphoma (FL) (e.g., relapsed and / or refractory FL or transformed FL), or mantle cell lymphoma (MCL) (e.g., relapsed or refractory MCL)) or central nervous system lymphoma (CNSL)) comprising administering to the subject an anti-CD20 / anti-CD3 bispecific antibody in combination with an anti-CD20 antibody and one or more chemotherapeutic agents selected from ifosfamide, carboplatin, and / or etoposide.

[0329] In some examples, the method is used to treat a subject with relapsed and / or refractory NHL (e.g., an aggressive NHL (e.g., relapsed and / or refractory DLBCL, relapsed and / or refractory FL, or relapsed and / or refractory MCL)). In some examples, the subject has relapsed after one or more (e.g., one, two, three, four, five, or more) previous therapies (e.g., one or more previous systemic therapies, e.g., one or more previous systemic chemotherapies (e.g., one or more previous systemic therapies comprising administration of an anthracycline), one or more previous stem cell therapies, or one or more previous CAR-T cell therapies) after having a documented history of response (e.g., complete or partial response) for at least six months in the period since completion of the treatment. In some examples, the subject is refractory to any previous treatment (e.g., failed to respond to the previous treatment or progressed within six months of completing the last dose of treatment). Thus, in some embodiments, the dosing regimen is a second-line therapy. In some embodiments, the dosing regimen is a third-line therapy. In some embodiments, the subject has transformed FL that is refractory to standard treatment for transformed FL. In some embodiments, the FL is graded FL (e.g., grade 1, 2, 3a, or 3b FL).

[0330] In one aspect, the invention features a method of treating a subject having a CD20-positive cell proliferative disorder, e.g., a B-cell proliferative disorder (e.g., NHL (e.g., relapsed and / or refractory NHL, DLBCL (e.g., relapsed and / or refractory DLBCL), FL (e.g., relapsed and / or refractory FL or transformed FL), or MCL (e.g., relapsed or refractory MCL)), or CNSL), comprising administering to the subject an effective amount of: (a) a bispecific antibody that binds to CD20 and CD3; (b) an anti-CD20 antibody; and (c) one or more chemotherapeutic agents selected from ifosfamide, carboplatin, and / or etoposide; The method includes administering a dosing regimen comprising at least a first dosing cycle and a second dosing cycle.

[0331] In one embodiment, the first administration cycle comprises a first dose of bispecific antibody (C1D1) and a second dose of bispecific antibody (C1D2), wherein C1D1 of the bispecific antibody is about 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, or ± 0.25 mg) and C1D2 of the bispecific antibody is about 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, or ± 1 mg); and the second administration cycle comprises a first dose of bispecific antibody (C1D1) and a second dose of bispecific antibody (C1D2), wherein C1D1 of the bispecific antibody is about 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, or ± 1 mg). wherein the C2D1 of the bispecific antibody is about 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, or ± 1 mg), about 16 mg (e.g., 16 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, or ± 1.6 mg), or about 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg). In certain embodiments, C1D1 of the bispecific antibody is about 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, or ± 0.25 mg) and C1D2 of the bispecific antibody is about 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, or ± 1 mg). In certain embodiments, C2D1 is about 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, or ± 1 mg). In certain embodiments, the C2D1 of the bispecific antibody is about 16 mg (e.g., 16 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, or ± 1.6 mg). In certain embodiments, the C2D1 of the bispecific antibody is about 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg).

[0332] In one embodiment, the first administration cycle comprises a first dose of bispecific antibody (C1D1) and a second dose of bispecific antibody (C1D2), wherein C1D1 of the bispecific antibody is about 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, or ± 0.25 mg) and C1D2 of the bispecific antibody is about 10 mg (e.g., 10 mg the first administration cycle comprises a single dose of bispecific antibody (C2D1), where the bispecific antibody C2D1 is about 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg); and the second administration cycle comprises a single dose of bispecific antibody (C2D1), where the bispecific antibody C2D1 is about 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg).

[0333] In one embodiment, the first dose of the bispecific antibody (C1D1) and the second dose of the bispecific antibody (C1D2) are administered to the subject on or about day 8 (± 1 day) and on or about day 15 (± 1 day) of the first administration cycle, respectively.

[0334] In one embodiment, the first dose of the bispecific antibody (C1D1) and the second dose of the bispecific antibody (C1D2) are administered to the subject on days 8 and 15, respectively, of the first administration cycle. In some embodiments, the bispecific antibody C2D1 is administered to the subject on or about day 8 (±1 day) of the second administration cycle. In some embodiments, the bispecific antibody C2D1 is administered to the subject on or about day 8 of the second administration cycle.

[0335] In one embodiment, the anti-CD20 antibody is obinutuzumab and / or rituximab. In one embodiment, the first administration cycle comprises a single dose of obinutuzumab (C1D1); and the second administration cycle comprises a single dose of rituximab (C2D1).

[0336] In one embodiment, a single dose of obinutuzumab C1D1 is about 1000 mg (e.g., 1000 mg ± 5 mg, ± 10 mg, ± 20 mg, ± 30 mg, ± 50 mg, ± 75 mg, or ± 100 mg) and a single dose of rituximab is about 375 mg / m 2 (e.g., 375 mg / m 2 ±5 mg / m 2 , ±10 mg / m 2 , ±25 mg / m 2 , or ±37.5 mg / m 2 )

[0337] In one embodiment, the anti-CD20 antibody is administered in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein the first dosing cycle comprises a single dose of obinutuzumab on day 1 (C1D1); and the second dosing cycle comprises a single dose of rituximab on day 1 (C2D1).

[0338] In one aspect, the invention features a method of treating a subject having a CD20-positive cell proliferative disorder, e.g., a B-cell proliferative disorder (e.g., NHL (e.g., relapsed and / or refractory NHL, DLBCL (e.g., relapsed and / or refractory DLBCL), FL (e.g., relapsed and / or refractory FL or transformed FL), or MCL (e.g., relapsed or refractory MCL)), or CNSL), comprising administering to the subject, in a first administration cycle: (a) a first dose of a bispecific antibody that binds CD20 and CD3 (C1D1) of about 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, or ± 0.25 mg) and a second dose of a bispecific antibody that binds CD20 and CD3 (C1D2) of about 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, or ± 1 mg); (b) a single dose of obinutuzumab (C1D1); and (c) administering one or more chemotherapeutic agents selected from ifosfamide, carboplatin, and / or etoposide; and in a second administration cycle, the subject receives: (a) a single dose of a bispecific antibody that binds CD20 and CD3 (C2D1) of about 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg); (b) a single dose of rituximab (C2D1); and (c) administering one or more chemotherapeutic agents selected from ifosfamide, carboplatin, and / or etoposide.

[0339] In one embodiment, a single dose of obinutuzumab C1D1 is about 1000 mg (e.g., 1000 mg ± 5 mg, ± 10 mg, ± 20 mg, ± 30 mg, ± 50 mg, ± 75 mg, or ± 100 mg) and a single dose of rituximab is about 375 mg / m 2 (e.g., 375 mg / m 2 ±5 mg / m 2 , ±10 mg / m 2 , ±25 mg / m 2 , or ±37.5 mg / m 2 )

[0340] In one embodiment, the anti-CD20 antibody is administered in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein the first dosing cycle comprises a single dose of obinutuzumab on day 1 (C1D1); and the second dosing cycle comprises a single dose of rituximab on day 1 (C2D1).

[0341] In one embodiment, the first dose of the bispecific antibody (C1D1) and the second dose of the bispecific antibody (C1D2) are administered to the subject on or about day 8 (± 1 day) and on or about day 15 (± 1 day) of the first administration cycle, respectively.

[0342] In one embodiment, the first dose of the bispecific antibody (C1D1) and the second dose of the bispecific antibody (C1D2) are administered to the subject on days 8 and 15, respectively, of the first administration cycle. In some embodiments, the bispecific antibody C2D1 is administered to the subject on or about day 8 (±1 day) of the second administration cycle. In some embodiments, the bispecific antibody C2D1 is administered to the subject on or about day 8 of the second administration cycle.

[0343] In one embodiment of the method provided above, step c) includes all three chemotherapeutic agents.

[0344] In one embodiment, the first administration cycle comprises a single dose of ifosfamide (C1D1), a single dose of carboplatin (C1D1), and the first (C1D1), second (C1D2), and third (C1D3) doses of etoposide; the second cycle each comprises a single dose of ifosfamide (C2D1), a single dose of carboplatin (C2D1), and the first (C2D1), second (C2D2), and third (C2D3) doses of etoposide.

[0345] In one aspect, the invention features a method of treating a subject having a CD20-positive cell proliferative disorder, e.g., a B-cell proliferative disorder (e.g., NHL (e.g., relapsed and / or refractory NHL, DLBCL (e.g., relapsed and / or refractory DLBCL), FL (e.g., relapsed and / or refractory FL or transformed FL), or MCL (e.g., relapsed or refractory MCL)), or CNSL), comprising administering to the subject, in a first administration cycle: (a) a first dose of a bispecific antibody that binds CD20 and CD3 (C1D1) of about 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, or ± 0.25 mg) and a second dose of a bispecific antibody that binds CD20 and CD3 (C1D2) of about 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, or ± 1 mg); (b) a single dose of obinutuzumab (C1D1); and (c) administering a single dose of ifosfamide (C1D1), a single dose of carboplatin (C1D1), and a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of etoposide; and in a second administration cycle, the subject receives: (a) a single dose of a bispecific antibody that binds CD20 and CD3 (C2D1) of about 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg); (b) a single dose of rituximab (C2D1); and (c) Administering a single dose of ifosfamide (C2D1), a single dose of carboplatin (C2D1), and first (C2D1), second (C2D2), and third (C2D3) doses of etoposide.

[0346] In one embodiment, a single dose of obinutuzumab C1D1 is about 1000 mg (e.g., 1000 mg ± 5 mg, ± 10 mg, ± 20 mg, ± 30 mg, ± 50 mg, ± 75 mg, or ± 100 mg) and a single dose of rituximab is about 375 mg / m 2 (e.g., 375 mg / m 2 ±5 mg / m 2 , ±10 mg / m 2 , ±25 mg / m 2 , or ±37.5 mg / m 2 )

[0347] In one embodiment, the anti-CD20 antibody is administered in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein the first dosing cycle comprises a single dose of obinutuzumab on day 1 (C1D1); and the second dosing cycle comprises a single dose of rituximab on day 1 (C2D1).

[0348] In one embodiment, the first dose of the bispecific antibody (C1D1) and the second dose of the bispecific antibody (C1D2) are administered to the subject on or about day 8 (± 1 day) and on or about day 15 (± 1 day) of the first administration cycle, respectively.

[0349] In one embodiment, the first dose of the bispecific antibody (C1D1) and the second dose of the bispecific antibody (C1D2) are administered to the subject on days 8 and 15, respectively, of the first administration cycle. In some embodiments, the bispecific antibody C2D1 is administered to the subject on or about day 8 (±1 day) of the second administration cycle. In some embodiments, the bispecific antibody C2D1 is administered to the subject on or about day 8 of the second administration cycle.

[0350] In one embodiment of the method provided above, ifosfamide is administered at 5000 mg / m 2 , 4000 mg / m 2 or 1666 mg / m 2 In one embodiment of the method provided above, ifosfamide is administered at a dose of 5000 mg / m 2 In one embodiment of the methods provided above, carboplatin is administered at a dose of 100 mg / mL targeting an area under the curve (AUC) of 5 mg / mL / min with a maximum dose of 750 mg. In one embodiment of the methods provided above, etoposide is administered at a dose of 100 mg / mL 2 or 75 mg / m 2 In one embodiment of the method provided above, etoposide is administered at a dose of 100 mg / m 2 is administered at a dose of

[0351] In one embodiment of the method provided above, ifosfamide is administered at 5000 mg / m 2 , 4000 mg / m 2 or 1666 mg / m 2 carboplatin was administered at a dose of 100 mg / m2 targeting an area under the curve (AUC) of 5 mg / mL / min with a maximum dose of 750 mg; etoposide was administered at a dose of 100 mg / m2 2 or 75 mg / m 2 is administered at a dose of

[0352] In one embodiment of the method provided above, ifosfamide is administered at 5000 mg / m 2 carboplatin was administered at a dose of 100 mg / m2 targeting an area under the curve (AUC) of 5 mg / mL / min with a maximum dose of 750 mg; etoposide was administered at a dose of 100 mg / m2 2 is administered at a dose of

[0353] In one embodiment, ifosfamide is administered at a dose of about 5000 mg / m 2 (e.g., 5000 mg / m 2 ±50 mg / m 2 , ±100 mg / m 2 , ±200 mg / m 2 , ±300 mg / m 2 , ±400 mg / m 2 , or ±500 mg / m 2 ), approx. 4000mg / m 2 (e.g., 4000 mg / m 2 ±40 mg / m 2 , ±50 mg / m 2 , ±100 mg / m 2 , ±200 mg / m 2 , ±300 mg / m 2 , or ±400 mg / m 2 ), or approximately 1666 mg / m 2 (e.g., 1666 mg / m 2 ±25 mg / m 2 , ±50 mg / m 2 , ±100 mg / m 2 , or ±166.6 mg / m 2 ), carboplatin is administered at about 5 × (25 + creatinine clearance (CrCl)) mg with a maximum dose of about 750 mg (e.g., 750 mg ± 10 mg, ± 25 mg, ± 50 mg, or ± 75 mg), and etoposide is administered at about 100 mg / m 2 (e.g., 100 mg / m 2 ±1 mg / m 2 , ±2.5 mg / m 2 , ±5 mg / m 2 , or ±10 mg / m 2 ) or 75 mg / m2 (e.g., 0.5 mg / m 2 ±1 mg / m 2 , ±2.5 mg / m 2 , ±5 mg / m 2 , or ±7.5 mg / m 2 In one embodiment, (a) the subject is male and CrCl is calculated using the formula CrCl = ([140 - age] x [weight (kg)]) / (72 x [serum creatinine (mg / dL)]); or (b) the subject is female and CrCl is calculated using the formula CrCl = 0.85 x ([140 - age] x [weight (kg)]) / (72 x [serum creatinine (mg / dL)]). In one embodiment, (a) the subject has a CrCl of less than about 60 mL / min and each single dose of ifosfamide is 4000 mg / m 2 and / or (b) the subject has a CrCl of less than about 50 mL / min and each dose of etoposide is reduced to about 75 mg / m 2 In one embodiment, the subject is or will be administered ifosfamide in an outpatient setting, and the ifosfamide is reduced to about 1666 mg / m 2 (e.g., 1666 mg / m 2 ±25 mg / m 2 , ±50 mg / m 2 , ±100 mg / m 2 , or ±166.6 mg / m 2 ) is administered at a dose of

[0354] In one embodiment, ifosfamide and carboplatin are administered on day 2 of the first administration cycle and the second administration cycle, and etoposide is administered on days 1, 2, and 3, respectively, of the first administration cycle and the second administration cycle.

[0355] In one aspect, the invention features a method of treating a subject having a CD20-positive cell proliferative disorder, e.g., a B-cell proliferative disorder (e.g., NHL (e.g., relapsed and / or refractory NHL, DLBCL (e.g., relapsed and / or refractory DLBCL), FL (e.g., relapsed and / or refractory FL or transformed FL), or MCL (e.g., relapsed or refractory MCL)), or CNSL), comprising administering to the subject, in a first administration cycle: (a) a first dose of a bispecific antibody that binds CD20 and CD3 (C1D1) of about 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, or ± 0.25 mg) and a second dose of a bispecific antibody that binds CD20 and CD3 (C1D2) of about 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, or ± 1 mg); (b) a single dose of obinutuzumab (C1D1) of about 1000 mg (e.g., 1000 mg ± 5 mg, ± 10 mg, ± 20 mg, ± 30 mg, ± 50 mg, ± 75 mg, or ± 100 mg); and (c) Approximately 5000mg / m 2 (e.g., 5000 mg / m 2 ±50 mg / m 2 , ±100 mg / m 2 , ±200 mg / m 2 , ±300 mg / m 2 , ±400 mg / m 2 , or ±500 mg / m 2 ) single dose of ifosfamide (C1D1), a single dose of carboplatin (C1D1) at a dose of 100 mg targeting an area under the curve (AUC) of 5 mg / mL / min at a maximum dose of 750 mg, and 2 administering a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of etoposide; and in a second administration cycle, the subject receives: (a) a single dose of a bispecific antibody that binds CD20 and CD3 (C2D1) of about 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg); (b) Approximately 375mg / m 2 (e.g., 375 mg / m 2 ±5 mg / m 2 , ±10 mg / m 2 , ±25 mg / m 2 , or ±37.5 mg / m 2 ) a single dose of rituximab (C2D1); and (c) Approximately 5000mg / m 2 (e.g., 5000 mg / m 2 ±50 mg / m 2 , ±100 mg / m 2 , ±200 mg / m 2 , ±300 mg / m 2 , ±400 mg / m 2 , or ±500 mg / m 2 ) single dose of ifosfamide (C1D1), a single dose of carboplatin (C1D1) at a dose of 100 mg targeting an area under the curve (AUC) of 5 mg / mL / min at a maximum dose of 750 mg, and 2 the first dose (C1D1), the second dose (C1D2) and the third dose (C1D3) of etoposide.

[0356] In one aspect, the invention features a method of treating a subject having a CD20-positive cell proliferative disorder, e.g., a B-cell proliferative disorder (e.g., NHL (e.g., relapsed and / or refractory NHL, DLBCL (e.g., relapsed and / or refractory DLBCL), FL (e.g., relapsed and / or refractory FL or transformed FL), or MCL (e.g., relapsed or refractory MCL)), or CNSL), comprising administering to the subject: (a) about 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, or ± 0.25 mg) as a first dose of a bispecific antibody that binds CD20 and CD3 (C1D1) on day 8 of a first administration cycle, and about 10 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, or ± 0.25 mg) as a second dose of a bispecific antibody that binds CD20 and CD3 (C1D2) on day 15 of a first administration cycle; mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, or ± 1 mg), and about 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg) as the first dose on day 8 of the second administration cycle (C2D1); (b) a single dose of about 1000 mg (e.g., 1000 mg ± 5 mg, ± 10 mg, ± 20 mg, ± 30 mg, ± 50 mg, ± 75 mg, or ± 100 mg) of obinutuzumab on day 1 of a first dosing cycle (C1D1) and about 375 mg / m on day 1 of a second dosing cycle 2 (e.g., 375 mg / m 2 ±5 mg / m 2 , ±10 mg / m 2 , ±25 mg / m 2 , or ±37.5 mg / m 2 ) a single dose of rituximab (C2D1); and (c) about 5000 mg / m on day 2 of the first administration cycle and the second administration cycle 2 (e.g., 5000 mg / m 2 ±50 mg / m 2 , ±100 mg / m 2 , ±200 mg / m 2 , ±300 mg / m 2 , ±400 mg / m 2 , or ±500 mg / m 2 a single dose of ifosfamide (C1D1) at a dose of 100 mg / m on days 1, 2, and 3 of the first and second dosing cycles, a single dose of carboplatin (C1D1) at a dose targeting an area under the curve (AUC) of 5 mg / mL / min with a maximum dose of 750 mg on days 1, 2, and 3 of the first and second dosing cycles, and2 the first dose (C1D1), the second dose (C1D2) and the third dose (C1D3) of etoposide.

[0357] In some embodiments, the first and second administration cycles are each 14-day (e.g., 14±3 days) administration cycles. In some embodiments, the first and second administration cycles are each 21-day (e.g., 21±3 days) administration cycles. In certain embodiments, the first and second administration cycles are 21-day administration cycles.

[0358] In some embodiments, the dosing regimen includes one or more additional dosing cycles. In some embodiments, the dosing regimen includes a total of three dosing cycles. In some embodiments, each additional dosing cycle is a 14-day (e.g., 14±3 day) dosing cycle. In some embodiments, each additional dosing cycle is a 21-day (e.g., 21±3 day) dosing cycle. In one embodiment, the methods provided herein include three 21-day dosing cycles.

[0359] In one embodiment, the one or more additional administration cycles comprise: (a) an additional single dose of a bispecific antibody that binds to CD20 and CD3; (b) an additional single dose of an anti-CD20 antibody, and (c) An additional single dose of ifosfamide, an additional single dose of carboplatin, and an additional first, second, and third doses of etoposide.

[0360] In one embodiment, the additional single dose of bispecific antibody is about 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg).

[0361] In one embodiment, the anti-CD20 antibody is rituximab. In one embodiment, the additional single dose of rituximab is about 375 mg / m 2(e.g., 375 mg / m 2 ±5 mg / m 2 , ±10 mg / m 2 , ±25 mg / m 2 , or ±37.5 mg / m 2 In one embodiment, an additional single dose of rituximab is administered on day 1 of an additional administration cycle.

[0362] In one embodiment, the additional single dose of ifosfamide is about 5000 mg / m 2 (e.g., 5000 mg / m 2 ±50 mg / m 2 , ±100 mg / m 2 , ±200 mg / m 2 , ±300 mg / m 2 , ±400 mg / m 2 , or ±500 mg / m 2 ), approx. 4000mg / m 2 (e.g., 4000 mg / m 2 ±40 mg / m 2 , ±50 mg / m 2 , ±100 mg / m 2 , ±200 mg / m 2 , ±300 mg / m 2 , or ±400 mg / m 2 ), or approximately 1666 mg / m 2 (e.g., 1666 mg / m 2 ±25 mg / m 2 , ±50 mg / m 2 , ±100 mg / m 2 , or ±166.6 mg / m 2 ), the additional single dose of carboplatin is 100 mg / m2 targeting an area under the curve (AUC) of about 5 mg / mL / min (e.g., 5 mg / mL / min ±0.05 mg / mL / min, ±0.1 mg / mL / min, ±0.25 mg / mL / min, or ±0.5 mg / mL / min) at a maximum dose of about 750 mg (e.g., 750 mg ±10 mg, ±25 mg, ±50 mg, or ±75 mg), and the additional first, second, and third doses of etoposide are 100 mg / m2 2 (e.g., 100 mg / m 2 ±1 mg / m 2 , ±2.5 mg / m2 , ±5 mg / m 2 , or ±10 mg / m 2 ) or 75 mg / m 2 (e.g., 0.5 mg / m 2 ±1 mg / m 2 , ±2.5 mg / m 2 , ±5 mg / m 2 , or ±7.5 mg / m 2 In one embodiment, the additional single dose of ifosfamide is 5000 mg / m 2 , 4000 mg / m 2 or 1666 mg / m 2 and the additional single dose of carboplatin is 1 mg targeting an area under the curve (AUC) of 5 mg / mL / min with a maximum dose of 750 mg, and the additional first, second, and third doses of etoposide are 100 mg / m 2 or 75 mg / m 2 In one embodiment, ifosfamide is 5000 mg / m 2 carboplatin was administered at a dose of 100 mg / m2 targeting an area under the curve (AUC) of 5 mg / mL / min with a maximum dose of 750 mg; etoposide was administered at a dose of 100 mg / m2 2 is administered at a dose of

[0363] In one embodiment, the additional single dose of ifosfamide is about 5000 mg / m 2 (e.g., 5000 mg / m 2 ±50 mg / m 2 , ±100 mg / m 2 , ±200 mg / m 2 , ±300 mg / m 2 , ±400 mg / m 2 , or ±500 mg / m 2 ), approx. 4000mg / m 2 (e.g., 4000 mg / m 2 ±40 mg / m 2 , ±50 mg / m 2 , ±100 mg / m 2 , ±200 mg / m 2 , ±300 mg / m 2 , or ±400 mg / m 2 ), or approximately 1666 mg / m2 (e.g., 1666 mg / m 2 ±25 mg / m 2 , ±50 mg / m 2 , ±100 mg / m 2 , or ±166.6 mg / m 2 ), an additional single dose of carboplatin is about 5×(25+creatinine clearance (CrCl)) mg with a maximum dose of about 750 mg (e.g., 750 mg±10 mg, ±25 mg, ±50 mg, or ±75 mg), and an additional single dose of etoposide is about 100 mg / m 2 (e.g., 100 mg / m 2 ±1 mg / m 2 , ±2.5 mg / m 2 , ±5 mg / m 2 , or ±10 mg / m 2 ) or 75 mg / m 2 (e.g., 0.5 mg / m 2 ±1 mg / m 2 , ±2.5 mg / m 2 , ±5 mg / m 2 , or ±7.5 mg / m 2 In one embodiment, (a) the subject is male and CrCl is calculated using the formula CrCl = ([140 - age] x [weight (kg)]) / (72 x [serum creatinine (mg / dL)]); or (b) the subject is female and CrCl is calculated using the formula CrCl = 0.85 x ([140 - age] x [weight (kg)]) / (72 x [serum creatinine (mg / dL)]). In one embodiment, (a) the subject has a CrCl of less than about 60 mL / min and the additional single dose of ifosfamide is 4000 mg / m 2 and / or (b) the subject has a CrCl of less than about 50 mL / min and an additional single dose of etoposide of about 75 mg / m 2 In one embodiment, the subject is or will be administered an additional single dose of ifosfamide in an outpatient setting, wherein the additional single dose of ifosfamide is reduced to about 1666 mg / m 2 (e.g., 1666 mg / m 2 ±25 mg / m 2 , ±50 mg / m 2 , ±100 mg / m2 , or ±166.6 mg / m 2 )

[0364] In one embodiment, ifosfamide and carboplatin are administered on day 2 of the additional administration cycle, and etoposide is administered on each of days 1, 2, and 3 of the additional administration cycle.

[0365] In one aspect, the invention features a method of treating a subject having a CD20-positive cell proliferative disorder, e.g., a B-cell proliferative disorder (e.g., NHL (e.g., relapsed and / or refractory NHL, DLBCL (e.g., relapsed and / or refractory DLBCL), FL (e.g., relapsed and / or refractory FL or transformed FL), or MCL (e.g., relapsed or refractory MCL)), or CNSL), comprising administering to the subject, in a first...

Claims

1. A pharmaceutical product for treating subjects with CD20-positive cell proliferation disorders, Medicine, (a) Bispecific antibodies that bind to CD20 and CD3; (b) Anti-CD20 antibody; and (c) One or more chemotherapeutic agents selected from ifosfamide, carboplatin, and / or etoposide. Includes one or more of the following: (a) Bispecific antibodies that bind to CD20 and CD3; (b) Anti-CD20 antibody; and (c) One or more chemotherapeutic agents selected from ifosfamide, carboplatin, and / or etoposide. However, in a dosing regimen including at least a first dosing cycle and a second dosing cycle, the subject is administered Pharmaceuticals.

2. The first administration cycle comprises a first dose (C1D1) of the bispecific antibody and a second dose (C1D2) of the bispecific antibody, wherein the C1D1 of the bispecific antibody is approximately 2.5 mg and the C1D2 of the bispecific antibody is approximately 10 mg; The pharmaceutical product according to claim 1, wherein the second administration cycle comprises a single dose (C2D1) of the bispecific antibody, and the C2D1 of the bispecific antibody is about 10 mg, about 16 mg, or about 30 mg.

3. The pharmaceutical product according to claim 2, wherein the bispecific antibody C1D1 and the bispecific antibody C1D2 are administered to the subject on the 8th and 15th days of the first administration cycle, respectively.

4. The pharmaceutical product according to claim 2 or 3, wherein the C2D1 of the bispecific antibody is administered to the subject on the 8th day of the second administration cycle.

5. The pharmaceutical product according to claim 1 or 2, wherein the anti-CD20 antibody is obinutuzumab and / or rituximab.

6. The pharmacopoeia according to claim 5, wherein the first administration cycle comprises a single dose (C1D1) of obinutuzumab; and the second administration cycle comprises a single dose (C2D1) of rituximab.

7. The C1D1 of obinutuzumab is approximately 1000 mg, and the C2D1 of rituximab is approximately 375 mg / m². ２ The pharmaceutical product according to claim 6.

8. The pharmaceutical product according to claim 6, wherein the anti-CD20 antibody is administered in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, the first dosing cycle comprising administering the C1D1 of obinutuzumab to the subject on day 1; and the second dosing cycle comprising administering the C2D1 of rituximab to the subject on day 1.

9. The pharmaceutical product according to claim 1 or 2, wherein the pharmaceutical product comprises administering ifosfamide, carboplatin, and etoposide to the subject.

10. The pharmacopoeia according to claim 9, wherein the first administration cycle comprises a single dose of ifosfamide (C1D1); a single dose of carboplatin (C1D1); and a first dose of etoposide (C1D1), a second dose of etoposide (C1D2), and a third dose of etoposide (C1D3); and the second administration cycle comprises a single dose of ifosfamide (C2D1); a single dose of carboplatin (C2D1); and a first dose of etoposide (C2D1), a second dose of etoposide (C2D2), and a third dose of etoposide (C2D3).

11. Ifosfamide is approximately 5000 mg / m² ２ , about 4000mg / m ２ , or approximately 1666 mg / m² ２ Carboplatin is administered at a maximum dose of approximately 750 mg, with a target area under the curve (AUC) of approximately 5 mg / mL / min. Etoposide is administered at a dose of approximately 100 mg / m for each dose of etoposide. ２ Or approximately 75 mg / m² ２ The pharmaceutical product according to claim 10, administered in the specified dose.

12. The pharmaceutical product according to claim 10, wherein ifosfamide and carboplatin are administered on the second day of the first and second administration cycles, and the C1D1 to C1D3 and C2D1 to C2D3 of etoposide are administered on the first, second, and third days of the first and second administration cycles, respectively.

13. The pharmaceutical product according to claim 1 or 2, wherein the first administration cycle and the second administration cycle are each 21-day administration cycles.

14. The pharmaceutical product according to claim 1 or 2, wherein the administration regimen includes one or more additional administration cycles.

15. The pharmaceutical product according to claim 14, wherein each of the one or more additional administration cycles is a 21-day administration cycle.

16. The pharmaceutical product according to claim 14, wherein the administration regimen comprises a total of three administration cycles.

17. Each of the aforementioned one or more additional administration cycles is (a) an additional single dose of the bispecific antibody that binds to CD20 and CD3, (b) an additional single dose of the anti-CD20 antibody, and (c) The pharmacopoeia according to claim 14, comprising an additional single dose of ifosfamide, an additional single dose of carboplatin, and an additional first dose, an additional second dose, and an additional third dose of etoposide.

18. The pharmaceutical product according to claim 17, wherein the additional single dose of the bispecific antibody is about 30 mg.

19. The pharmaceutical product according to claim 17, wherein the additional single dose of the bispecific antibody is administered to the subject on the eighth day of each of the one or more additional administration cycles.

20. The pharmaceutical product according to claim 17, wherein the anti-CD20 antibody is rituximab.

21. The aforementioned additional single dose of rituximab is approximately 375 mg / m². ２ The pharmaceutical product according to claim 20.

22. The pharmacopoeia according to claim 20, wherein the additional single dose of rituximab is administered on the first day of each of the one or more additional dosing cycles.

23. The additional single dose of ifosfamide is about 5000 mg / m ２ , about 4000 mg / m ２ , or about 1666 mg / m ２ , and the additional single dose of carboplatin is in mg targeting an area under the curve (AUC) of about 5 mg / mL / min at a maximum dose of about 750 mg, and the additional first dose, the additional second dose, and the additional third dose of etoposide are each about 100 mg / m ２ or about 75 mg / m ２ The medicament according to claim 17.

24. The pharmacopoeia according to claim 17, wherein ifosfamide and carboplatin are administered on the second day of each of the one or more additional dosing cycles, and the additional first dose, the additional second dose, and the additional third dose of etoposide are administered on the first, second, and third days of each of the one or more additional dosing cycles, respectively.

25. A pharmaceutical product for treating subjects aged 6 months to 17 years with CD20-positive cell proliferation disorders, Medicine, (a) Bispecific antibodies that bind to CD20 and CD3; (b) Anti-CD20 antibody; and (c) One or more chemotherapeutic agents selected from ifosfamide, carboplatin, and / or etoposide. Includes one or more of the following: (a) Bispecific antibodies that bind to CD20 and CD3; (b) Anti-CD20 antibody; and (c) One or more chemotherapeutic agents selected from ifosfamide, carboplatin, and / or etoposide. However, in a dosing regimen including at least a first dosing cycle and a second dosing cycle, the subject is administered Pharmaceuticals.

26. The first administration cycle comprises a first dose (C1D1) of the bispecific antibody and a second dose (C1D2) of the bispecific antibody, wherein the C1D1 of the bispecific antibody is approximately 0.03 mg / kg, approximately 0.04 mg / kg, or approximately 2.5 mg, and the C1D2 of the bispecific antibody is approximately 0.15 mg / kg or approximately 10 mg; The pharmaceutical product according to claim 25, wherein the second administration cycle comprises a single dose (C2D1) of the bispecific antibody, and the C2D1 of the bispecific antibody is about 0.4 mg / kg, about 0.5 mg / kg, or about 30 mg.

27. (a) The subject's weight is approximately 7.5 kg or more and less than approximately 13 kg, the C1D1 of the bispecific antibody is approximately 0.04 mg / kg, the C1D2 of the bispecific antibody is approximately 0.15 mg / kg, and the C2D1 of the bispecific antibody is approximately 0.5 mg / kg; (b) The subject's weight is approximately 13 kg or more and less than approximately 45 kg, the C1D1 of the bispecific antibody is approximately 0.03 mg / kg, the C1D2 of the bispecific antibody is approximately 0.15 mg / kg, and the C2D1 of the bispecific antibody is approximately 0.4 mg / kg; or (c) The pharmaceutical product according to claim 26, wherein the weight of the subject is approximately 45 kg or more, the C1D1 of the bispecific antibody is approximately 2.5 mg, the C1D2 of the bispecific antibody is approximately 10 mg, and the C2D1 of the bispecific antibody is approximately 30 mg.

28. The pharmaceutical product according to claim 26 or 27, wherein the bispecific antibody C1D1 and the bispecific antibody C1D2 are administered to the subject on the 8th and 15th days of the first administration cycle, respectively.

29. The pharmaceutical product according to claim 26 or 27, wherein the C2D1 of the bispecific antibody is administered to the subject on the first day of the second administration cycle.

30. The pharmaceutical product according to claim 25 or 26, wherein the anti-CD20 antibody is obinutuzumab and / or rituximab.

31. The pharmacopoeia according to claim 30, wherein the first administration cycle comprises a first dose (C1D1) of obinutuzumab and a second dose (C1D2) of obinutuzumab.

32. (a) The subject's body weight is approximately 7.5 kg or more and less than approximately 13 kg, and the sum of obinutuzumab C1D1 and C1D2 is approximately 38 mg / kg; (b) The subject's weight is approximately 13 kg or more and less than approximately 20 kg, and the sum of obinutuzumab C1D1 and C1D2 is approximately 28 mg / kg; (c) The subject's weight is approximately 20 kg or more and less than approximately 32 kg, and the sum of obinutuzumab C1D1 and C1D2 is approximately 23 mg / kg; (d) The subject's body weight is approximately 32 kg or more and less than approximately 45 kg, and the sum of obinutuzumab C1D1 and C1D2 is approximately 20 mg / kg; or (e) The pharmaceutical product according to claim 31, wherein the subject's weight is approximately 45 kg or more, and the sum of the C1D1 and C1D2 of obinutuzumab is approximately 1000 mg.

33. The pharmaceutical product according to claim 31, wherein the amount of C1D1 of obinutuzumab is about 1 / 10 of the sum of the amounts of C1D1 and C1D2 of obinutuzumab, and the amount of C1D2 of obinutuzumab is about 9 / 10 of the sum of the amounts of C1D1 and C1D2 of obinutuzumab.

34. The pharmaceutical agent according to claim 31, wherein obinutuzumab C1D1 is administered to the subject on day 1 of the first administration cycle, and obinutuzumab C1D2 is administered to the subject on day 2 of the first administration cycle.

35. The pharmaceutical product according to claim 34, wherein the second administration cycle comprises a single dose (C2D1) of rituximab.

36. The C2D1 concentration of rituximab is approximately 375 mg / m². ２ The pharmaceutical product according to claim 35.

37. The pharmaceutical product according to claim 35, wherein rituximab is administered to the subject on the fifth day of the second administration cycle.

38. The pharmaceutical product according to claim 25 or 26, wherein the pharmaceutical product comprises administering ifosfamide, carboplatin, and etoposide to the subject.

39. The first administration cycle described above is (a) Ifosfamide first dose (C1D1), ifosfamide second dose (C1D2), and ifosfamide third dose (C1D3); (b) Single dose of carboplatin (C1D1); and (c) a first dose of etoposide (C1D1), a second dose of etoposide (C1D2), and a third dose of etoposide (C1D3); The second administration cycle described above is (a) Ifosfamide first dose (C2D1), ifosfamide second dose (C2D2), and ifosfamide third dose (C2D3); (b) Single dose of carboplatin (C2D1); and (c) A pharmacopoietic according to claim 38, comprising a first dose of etoposide (C2D1), a second dose of etoposide (C2D2), and a third dose of etoposide (C2D3).

40. Ifosfamide is approximately 3000 mg / m² for each dose of ifosfamide. ２ It is administered at a dose of approximately 635 mg / m² of carboplatin. ２ It is administered in the following doses, with etoposide at approximately 100 mg / m² for each dose of etoposide. ２ The pharmaceutical product according to claim 39, administered in the specified dose.

41. (a) Ifosfamide C1D1, C1D2, and C1D3 are administered on the 3rd, 4th, and 5th days of the first administration cycle, respectively; (b) Carboplatin C1D1 is administered on the third day of the first administration cycle; (c) The C1D1, C1D2, and C1D3 of etoposide are administered on the 3rd, 4th, and 5th days of the first administration cycle, respectively; (d) Ifosfamide C2D1, C2D2, and C2D3 are administered on days 6, 7, and 8 of the second administration cycle, respectively; (e) Carboplatin C2D1 is administered on day 6 of the second administration cycle; (f) The pharmaceutical product according to claim 39, wherein the C2D1, C2D2, and C2D3 of etoposide are administered on the 6th, 7th, and 8th days of the second administration cycle, respectively.

42. The pharmaceutical product according to claim 25 or 26, wherein the first administration cycle and the second administration cycle are each 21-day administration cycles.

43. The pharmaceutical product according to claim 25 or 26, wherein the administration regimen includes one or more additional administration cycles.

44. The pharmaceutical product according to claim 43, wherein each of the one or more additional administration cycles is a 21-day administration cycle.

45. The pharmaceutical product according to claim 43, wherein the administration regimen comprises a total of three administration cycles.

46. Each of the aforementioned one or more additional administration cycles is (a) an additional single dose of the bispecific antibody that binds to CD20 and CD3, (b) an additional single dose of the anti-CD20 antibody, and (c) an additional first dose, an additional second dose, and an additional third dose of ifosfamide; an additional single dose of carboplatin; and an additional first dose, an additional second dose, and an additional third dose of etoposide, according to claim 43.

47. (a) The subject's weight is approximately 7.5 kg or more and less than approximately 13 kg, and the additional single dose of the bispecific antibody is approximately 0.5 mg / kg; (b) The subject's weight is approximately 13 kg or more and less than approximately 45 kg, and the additional single dose of the bispecific antibody is approximately 0.4 mg / kg; or (c) The pharmaceutical product according to claim 46, wherein the subject's weight is approximately 45 kg or more, and the additional single dose of the bispecific antibody is approximately 30 mg.

48. The pharmaceutical product according to claim 46, wherein the additional single dose of the bispecific antibody is administered to the subject on the first day of each of the one or more additional administration cycles.

49. The pharmaceutical product according to claim 46, wherein the anti-CD20 antibody is rituximab.

50. The aforementioned additional single dose of rituximab is approximately 375 mg / m². ２ The pharmaceutical product according to claim 49.

51. The pharmacopoeia according to claim 49, wherein the additional single dose of rituximab is administered on the fifth day of each of the one or more additional administration cycles.

52. The additional first dose, additional second dose, and additional third dose of ifosfamide are each approximately 3000 mg / m². ２ Therefore, the aforementioned additional single dose of carboplatin is approximately 635 mg / m². ２ The additional first dose, additional second dose, and additional third dose of etoposide are each approximately 100 mg / m². ２ The pharmaceutical product according to claim 43.

53. (a) The additional first dose, the additional second dose, and the additional third dose of ifosfamide are administered to the subject on the 6th, 7th, and 8th days of each of the one or more additional dosing cycles; (b) The additional single dose of carboplatin is administered on the sixth day of each of the one or more additional dosing cycles; (c) The pharmacopoeci of claim 43, wherein the additional first dose, the additional second dose, and the additional third dose of etoposide are administered to the subject on the sixth, seventh, and eighth day of each of the one or more additional administration cycles.

54. A pharmaceutical product for treating subjects aged 18 to 30 years with CD20-positive cell proliferation disorders, Medicine, (a) Bispecific antibodies that bind to CD20 and CD3; (b) Anti-CD20 antibody; and (c) One or more chemotherapeutic agents selected from ifosfamide, carboplatin, and / or etoposide. Includes one or more of the following: (a) Bispecific antibodies that bind to CD20 and CD3; (b) Anti-CD20 antibody; and (c) One or more chemotherapeutic agents selected from ifosfamide, carboplatin, and / or etoposide. However, in a dosing regimen including at least a first dosing cycle and a second dosing cycle, the subject is administered Pharmaceuticals.

55. The first administration cycle comprises a first dose (C1D1) of the bispecific antibody and a second dose (C1D2) of the bispecific antibody, wherein the C1D1 of the bispecific antibody is approximately 2.5 mg and the C1D2 of the bispecific antibody is approximately 10 mg; The pharmaceutical product according to claim 54, wherein the second administration cycle comprises a single dose (C2D1) of the bispecific antibody, and the C2D1 of the bispecific antibody is approximately 30 mg.

56. The pharmaceutical product according to claim 55, wherein the bispecific antibody C1D1 and the bispecific antibody C1D2 are administered to the subject on the 8th and 15th days of the first administration cycle, respectively.

57. The pharmaceutical product according to claim 55, wherein the C2D1 of the bispecific antibody is administered to the subject on the first day of the second administration cycle.

58. The pharmaceutical product according to claim 54 or 55, wherein the anti-CD20 antibody is obinutuzumab and / or rituximab.

59. The pharmacopoeia according to claim 58, wherein the first administration cycle comprises a first dose (C1D1) of obinutuzumab and a second dose (C1D2) of obinutuzumab.

60. The pharmaceutical product according to claim 59, wherein the sum of C1D1 and C1D2 of obinutuzumab is approximately 1000 mg.

61. The pharmaceutical product according to claim 59, wherein the amount of C1D1 of obinutuzumab is about 1 / 10 of the sum of the amounts of C1D1 and C1D2 of obinutuzumab, and the amount of C1D2 of obinutuzumab is about 9 / 10 of the sum of the amounts of C1D1 and C1D2 of obinutuzumab.

62. The pharmaceutical product according to claim 59, wherein the C1D1 of obinutuzumab is approximately 100 mg and the C1D2 of obinutuzumab is approximately 900 mg.

63. The pharmaceutical agent according to claim 59, wherein obinutuzumab C1D1 is administered to the subject on day 1 of the first administration cycle, and obinutuzumab C1D2 is administered to the subject on day 2 of the first administration cycle.

64. The pharmaceutical product according to claim 58, wherein the second administration cycle comprises a single dose (C2D1) of rituximab.

65. The C2D1 concentration of rituximab is approximately 375 mg / m². ２ The pharmaceutical product according to claim 64.

66. The pharmaceutical product according to claim 64, wherein the C2D1 of rituximab is administered to the subject on the fifth day of the second administration cycle.

67. The pharmaceutical product according to claim 54 or 55, wherein the pharmaceutical product comprises administering ifosfamide, carboplatin, and etoposide to the subject.

68. The first administration cycle described above is (a) Ifosfamide single dose (C1D1); (b) Single dose of carboplatin (C1D1); and (c) a first dose of etoposide (C1D1), a second dose of etoposide (C1D2), and a third dose of etoposide (C1D3); The second administration cycle described above is (a) Ifosfamide single dose (C2D1); (b) Single dose of carboplatin (C2D1); and (c) A pharmacopoietic according to claim 67, comprising a first dose of etoposide (C2D1), a second dose of etoposide (C2D2), and a third dose of etoposide (C2D3).

69. Ifosfamide is approximately 5000 mg / m² ２ The drugs are administered in the following doses: carboplatin is administered at a maximum dose of approximately 750 mg, at a dose of approximately 5 × (25 + creatinine clearance (CrCl)) mg, and etoposide is administered at approximately 100 mg / m² for each dose of etoposide. ２ The pharmaceutical product according to claim 68, administered in the specified dose.

70. (a) Ifosfamide C1D1 is administered on the third day of the first administration cycle; (b) Carboplatin C1D1 is administered on the third day of the first administration cycle; (c) The C1D1, C1D2, and C1D3 of etoposide are administered on the 3rd, 4th, and 5th days of the first administration cycle, respectively; (d) Ifosfamide C2D1 is administered on day 6 of the second administration cycle; (e) Carboplatin C2D1 is administered on day 6 of the second administration cycle; (f) The pharmaceutical product according to claim 68, wherein the C2D1, C2D2, and C2D3 of etoposide are administered on the 6th, 7th, and 8th days of the second administration cycle, respectively.

71. The pharmaceutical product according to claim 54 or 55, wherein the first administration cycle and the second administration cycle are each 21-day administration cycles.

72. The pharmaceutical product according to claim 54 or 55, wherein the administration regimen includes one or more additional administration cycles.

73. The pharmaceutical product according to claim 72, wherein each of the one or more additional administration cycles is a 21-day administration cycle.

74. The pharmaceutical product according to claim 72, wherein the administration regimen comprises a total of three administration cycles.

75. Each of the aforementioned one or more additional administration cycles is (a) an additional single dose of the bispecific antibody that binds to CD20 and CD3, (b) an additional single dose of the anti-CD20 antibody, and (c) The pharmacopoeia according to claim 72, comprising an additional single dose of ifosfamide; an additional single dose of carboplatin; and an additional first dose, an additional second dose, and an additional third dose of etoposide.

76. The pharmaceutical product according to claim 75, wherein the additional single dose of the bispecific antibody is about 30 mg.

77. The pharmaceutical product according to claim 75, wherein the additional single dose of the bispecific antibody is administered to the subject on the first day of each of the one or more additional administration cycles.

78. The pharmaceutical product according to claim 75, wherein the anti-CD20 antibody is rituximab.

79. The aforementioned additional single dose of rituximab is approximately 375 mg / m². ２ The pharmaceutical product according to claim 78.

80. The pharmacopoeia according to claim 78, wherein the additional single dose of rituximab is administered on the fifth day of each of the one or more additional dosing cycles.

81. The aforementioned additional single dose of ifosfamide is approximately 5000 mg / m². ２ The additional single dose of carboplatin is approximately 750 mg, with a maximum dose of approximately 5 × (25 + creatinine clearance (CrCl)) mg, and the additional first dose, additional second dose, and additional third dose of etoposide are each approximately 100 mg / m². ２ The pharmaceutical product according to claim 75.

82. (a) The additional single dose of ifosfamide is administered on the sixth day of each of the one or more additional dosing cycles; (b) The additional single dose of carboplatin is administered on the sixth day of each of the one or more additional dosing cycles; (c) The pharmacopoeci of claim 75, wherein the additional first dose, the additional second dose, and the additional third dose of etoposide are administered to the subject on the sixth, seventh, and eighth day of each of the one or more additional administration cycles, respectively.

83. The bispecific antibody comprises at least one Fab molecule that specifically binds to CD20, and the Fab molecule is (A) The following six hypervariable regions (HVR): (i) HVR-H1 containing the amino acid sequence of YSWIN (SEQ ID NO: 1); (ii) HVR-H2 containing the amino acid sequence RIFPPGDGDTDYNGKFKG (SEQ ID NO: 2); (iii) HVR-H3 containing the amino acid sequence of NVFDGYWLVY (SEQ ID NO: 3); (iv) HVR-L1 containing the amino acid sequence of RSSKSLLHSNGITYLY (SEQ ID NO: 4); (v) HVR-L2 containing the amino acid sequence of QMSNLVS (SEQ ID NO: 5); and (vi) HVR-L3 containing the amino acid sequence of AQNLELPYT (SEQ ID NO: 6); and / or (B) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 95% sequence identity with respect to the amino acid sequence of SEQ ID NO: 7; (b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity with respect to the amino acid sequence of SEQ ID NO: 8; or (c) a VH domain similar to (a) and a VL domain similar to (b), according to any one of claims 1, 25, and 54.

84. The bispecific antibody comprises at least one Fab molecule that specifically binds to CD3, and the Fab molecule is (A) The following six HVRs: (i) HVR-H1 containing the amino acid sequence of TYAMN (SEQ ID NO: 9); (ii) HVR-H2 containing the amino acid sequence of RIRSKYNNYATYYADSVKG (SEQ ID NO: 10); (iii) HVR-H3 containing the amino acid sequence of HGNFGNSYVSWFAY (SEQ ID NO: 11); (iv) HVR-L1 containing the amino acid sequence of GSSTGAVTTSNYAN (SEQ ID NO: 12); (v) HVR-L2 containing the amino acid sequence of GTNKRAP (SEQ ID NO: 13); and (vi) HVR-L3 containing the amino acid sequence of ALWYSNLWV (SEQ ID NO: 14); and / or (B) a VH domain comprising an amino acid sequence having at least 95% sequence identity with respect to the amino acid sequence of SEQ ID NO: 15; (b) a VL domain comprising an amino acid sequence having at least 95% sequence identity with respect to the amino acid sequence of SEQ ID NO: 16; or (c) a pharmaceutical product according to any one of claims 1, 25, and 54, comprising a VH domain similar to (a) and a VL domain similar to (b).

85. The pharmaceutical product according to any one of claims 1, 25, and 54, wherein the bispecific antibody is grofitamab.

86. The pharmaceutical product according to any one of claims 1, 25, and 54, wherein the CD20-positive cell proliferation disorder is a B-cell proliferation disorder.

87. The pharmaceutical product according to claim 86, wherein the B-cell proliferative disorder is non-Hodgkin lymphoma (NHL) or central nervous system lymphoma (CNSL).

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