Combination therapy of anti-CD20 / anti-CD3 bispecific antibodies with chemotherapy

Abstract

The present invention relates to anti-CD20 / anti-CD3 bispecific antibodies and anti-CD20 antibodies (e.g., anti-CD20 antibodies, anti-CD3 bispecific antibodies). A method of treating a B cell proliferative disorder, such as primary refractory or recurrent diffuse large B cell lymphoma (DLBCL), by administering a chemotherapeutic agent selected from the group consisting of ifosfamide, carboplatin, and / or etoposide, in combination with one or more chemotherapeutic agents selected from the group consisting of ifosfamide, carboplatin, and / or etoposide.

Description

Technical Field

[0001] The present invention relates to a method for treating B-cell proliferative disorders (e.g., 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 Art

[0002] Non-Hodgkin lymphoma (NHL) is the most common hematologic malignancy in the world (Bray et al. 2018). The most common NHL subtype 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), DLBCL is an aggressive NHL with a median survival of <1 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 a combination of rituximab, a monoclonal antibody targeting CD20, and 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] Despite this, R-CHOP was found to be ineffective in 30% to 50% of patients due to primary refractory disease, which is defined as failure to achieve complete remission (CR) after first-line treatment 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 are medically able to tolerate intensive therapy, high-dose salvage chemoimmunotherapy followed by ASCT provides a second chance for long-term remission. About half of patients with relapsed DLBCL are refractory to salvage chemoimmunotherapy (Gisselbrecht et al. J. Clin. Oncol. 28: 4184-4190, 2010) and therefore cannot undergo ASCT. In addition, for a subset of patients with DLBCL, CAR-T therapy is an available treatment option, particularly for patients with primary refractory disease or who have relapsed within 12 months after 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, there is still an opportunity to optimize the treatment regimen involving CAR-T therapy. Therefore, for patients with relapsed or refractory (R / R) DLBCL, there is a significant clinical need to improve salvage immunochemotherapy regimens.

[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 provide improved response rates to salvage chemoimmunotherapy, which may ultimately translate into a higher proportion of patients receiving definitive 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 childhood non-Hodgkin's lymphoma (NHL) cases. The main histological subtypes are Burkitt's lymphoma (BL), Burkitt's 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 that cannot be further classified. Although first-line therapy with intensive chemotherapy plus rituximab is very effective for children, with a 3-year event-free survival rate of 94% (Minard-Colin et al. N. Eng. J. Med. 382: 2207-2219, 2020), the development of effective salvage regimens for patients with R / R disease for the first time remains an urgent and highly unmet need (Pearson et al. Eur. J. Cancer. 110: 74-85, 2019). In children, adolescents, and young adults, the survival probability of R / R B-NHL is very poor, with 1-year overall survival (OS) rates below 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] In one aspect, the invention features a method of treating a subject having a CD20-positive cell proliferative disorder, the method comprising administering to the subject an effective amount of:

[0007] (a) Bispecific antibodies that bind to CD20 and CD3;

[0008] (b) anti-CD20 antibodies; and

[0009] (c) one or more chemotherapeutic agents selected from ifosfamide, carboplatin and / or etoposide.

[0010] 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.

[0011] In one embodiment, a first dosing cycle comprises a first dose (C1D1) of a bispecific antibody that binds to CD20 and CD3 and a second dose (C1D2) of the bispecific antibody, wherein the 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 the 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 a second dosing cycle comprises the bispecific antibody. In some embodiments, the present invention provides a single dose (C2D1) of a bispecific antibody, 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).

[0012] In one embodiment, a first dose (C1D1) of a bispecific antibody that binds to CD20 and CD3 and a second dose (C1D2) of a bispecific antibody that binds to CD20 and CD3 are administered to a subject on days 8 and 15 of a first dosing cycle, respectively. In one embodiment, C2D1 of a bispecific antibody that binds to CD20 and CD3 is administered to a subject on day 8 of a second dosing cycle.

[0013] In one embodiment, the anti-CD20 antibody is obinutuzumab and / or rituximab. In one embodiment, the first dosing cycle includes a single dose of obinutuzumab (C1D1); and the second dosing cycle includes 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 / m2 ±5mg / m 2 ±10mg / m 2 ±25mg / 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).

[0014] 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 a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of etoposide; and the second cycle each includes a single dose of ifosfamide (C2D1), a single dose of carboplatin (C2D1), and a first dose (C2D1), a second dose (C2D2), and a third dose (C2D3) of etoposide. In one embodiment, the dose is about 5000 mg / m 2 (e.g., 5000 mg / m 2 ±50mg / m 2 ±100mg / m 2 ±200mg / m 2 ±300mg / m 2 ±400mg / m 2 or ±500mg / m 2 ), about 4000mg / m 2 (For example, 4000 mg / m 2 ±40mg / m 2 ±50mg / m 2 ±100mg / m 2 ±200mg / m 2 ±300mg / m 2 or ±400 mg / m 2 ) or about 1666 mg / m 2 (e.g., 1666 mg / m 2 ±25mg / m 2 ±50mg / m 2 ±100mg / m 2 or ±166.6 mg / m 2), ifosfamide is administered in a dose in mg to a target 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 carboplatin is administered at a dose of about 100 mg / m 2 (e.g., 100 mg / m 2 ±1mg / m 2 ±2.5mg / m 2 ±5mg / m 2 or ±10 mg / m 2 ) or 75 mg / m 2 (e.g., 0.5 mg / m 2 ±1mg / m 2 ±2.5mg / m 2 ±5mg / m 2 or ±7.5 mg / m 2 In one embodiment, etoposide is administered at a dose of 5000 mg / m 2 4000mg / m 2 or 1666 mg / m 2 Ifosfamide was administered at a dose of 100 mg / mL / min, carboplatin was administered at a dose of 100 mg / mL / min to a target area under the curve (AUC) of 5 mg / mL / min with a maximum dose of 750 mg, and 2 or 75 mg / m 2 In one embodiment, etoposide is administered at a dose of 5000 mg / m 2 Ifosfamide was administered at a dose of 100 mg / mL / min, carboplatin was administered at a dose of 100 mg / mL / min to a target area under the curve (AUC) of 5 mg / mL / min with a maximum dose of 750 mg, and 2 In one embodiment, ifosfamide and carboplatin are administered on day 2 of the first and second dosing cycles, and etoposide is administered on each of days 1, 2, and 3 of the first and second dosing cycles.

[0015] In one embodiment, the first dosing cycle and the second dosing cycle are 21 day dosing cycles.

[0016] In one embodiment, the dosing regimen includes one or more additional dosing cycles. In one embodiment, the additional dosing cycle is a 21-day dosing cycle. In one embodiment, the dosing regimen includes three dosing cycles in total.

[0017] In one embodiment, the one or more additional dosing cycles include:

[0018] (a) an additional single dose of a bispecific antibody that binds to CD20 and CD3,

[0019] (b) an additional single dose of anti-CD20 antibody, and

[0020] (c) an additional single dose of ifosfamide, an additional single dose of carboplatin, and additional first, second, and third doses of etoposide. 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).

[0021] In one embodiment, the one or more additional cycles of administration of 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 ±5mg / m 2 ±10mg / m 2 ±25mg / m 2 or ±37.5 mg / m 2 In one embodiment, the additional single dose of rituximab is administered on day 1 of the additional dosing cycle.

[0022] In one embodiment, the additional single dose of ifosfamide is about 5000 mg / m 2 (e.g., 5000 mg / m 2 ±50mg / m 2 ±100mg / m 2 ±200mg / m 2 ±300mg / m 2 ±400mg / m 2 or ±500mg / m 2 ), about 4000mg / m 2 (For example, 4000 mg / m 2 ±40mg / m 2 ±50mg / m 2 ±100mg / m 2 ±200mg / m 2 ±300mg / m 2 or ±400 mg / m 2 ) or about 1666 mg / m 2 (e.g., 1666 mg / m 2±25mg / m 2 ±50mg / m 2 ±100mg / m 2 or ±166.6 mg / m 2 ), an additional single dose of carboplatin in mg to a target 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 additional first, second, and third doses of etoposide of 100 mg / m 2 (e.g., 100 mg / m 2 ±1mg / m 2 ±2.5mg / m 2 ±5mg / m 2 or ±10 mg / m 2 ) or 75 mg / m 2 (e.g., 0.5 mg / m 2 ±1mg / m 2 ±2.5mg / m 2 ±5mg / m 2 or ±7.5 mg / m 2 In one embodiment, the additional single dose of ifosfamide is 5000 mg / m 2 4000mg / m 2 or 1666 mg / m 2 , additional single doses of carboplatin in mg to a target area under the curve (AUC) of 5 mg / mL / min with a maximum dose of 750 mg, and additional first, second, and third doses of etoposide in mg to 100 mg / mL / min 2 or 75 mg / m 2 In one embodiment, 5000 mg / m 2 Ifosfamide was administered at a dose of 100 mg / mL / min, carboplatin was administered at a dose of 100 mg / mL / min to a target area under the curve (AUC) of 5 mg / mL / min with a maximum dose of 750 mg, and 2 Etoposide was administered at a dose of .

[0023] In one embodiment, ifosfamide and carboplatin are administered on day 2 of an additional dosing cycle, and etoposide is administered on each of days 1, 2, and 3 of an additional dosing cycle.

[0024] 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 are tocilizumab. In one embodiment, the subject's body weight is greater than or equal to about 30 kg, and tocilizumab is administered at a dosage 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's body weight is less than 30 kg, and tocilizumab is administered at a dosage 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).

[0025] In one embodiment, one or more additional therapeutic agents are corticosteroids. In one embodiment, corticosteroids include prednisone, prednisolone, methylprednisolone or dexamethasone. 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 one hour (i.e., at least one 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) before the 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 one hour (i.e., at least one 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, wherein 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 one hour (i.e., at least one 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 one hour (i.e., at least one 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 orally administered 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 one hour (i.e., at least one 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 one hour (i.e., at least one 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.

[0026] In one embodiment, the one or more additional therapeutic agents are antihistamines. 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.

[0027] In one embodiment, the one or more additional therapeutic agents include granulocyte colony stimulating factor (G-CSF). In one embodiment, G-CSF is administered between about one and about two 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.

[0028] In one embodiment, one or more additional therapeutic agents are antipyretics. In one embodiment, the antipyretic is acetaminophen or paracetamol. In one embodiment, acetaminophen or paracetamol is orally administered 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 orally administered at a dose of between 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; for example, 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.

[0029] In one embodiment, the one or more additional therapeutic agents is mesna. In one embodiment, the dosage is about 5000 mg / m 2 (e.g., 5000 mg / m 2 ±50mg / m 2 ±100mg / m 2 ±200mg / m 2 ±300mg / m 2 ±400mg / m 2 or ±500mg / m 2 ), about 4000mg / m 2 (For example, 4000 mg / m 2 ±40mg / m 2 ±50mg / m 2 ±100mg / m 2 ±200mg / m 2 ±300mg / m 2 or ±400 mg / m 2 ) or about 1666 mg / m 2 (e.g., 1666 mg / m 2 ±25mg / m 2 ±50mg / m 2 ±100mg / m 2 or ±166.6 mg / m 2 ) was administered intravenously at a dose of .

[0030] In one aspect, the invention features a method of treating a subject between the ages of 6 months and 17 years old with a CD20-positive cell proliferative disorder, the method comprising administering to the subject an effective amount of:

[0031] (a) Bispecific antibodies that bind to CD20 and CD3;

[0032] (b) anti-CD20 antibodies; and

[0033] (c) one or more chemotherapeutic agents selected from ifosfamide, carboplatin and / or etoposide.

[0034] In one embodiment, the first dosing 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 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 2.5 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 bispecific antibody has a C1D2 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) 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); and

[0035] The second dosing cycle comprises a single dose (C2D1) of the bispecific antibody, 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).

[0036] In one embodiment, (a) the subject weighs greater than or equal to about 7.5 kg and less than about 13 kg, and wherein 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 The bispecific antibody comprises an antibody having a C2D1 of 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);

[0037] (b) the subject weighs greater than or equal to about 13 kg and less than about 45 kg, and wherein the 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), the 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 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); or

[0038] (c) the subject weighs greater than or equal to about 45 kg, and wherein the 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), the 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 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).

[0039] In one embodiment, bispecific antibody C1D1 and bispecific antibody C1D2 are administered to the subject on day 8 and day 15 of the first dosing cycle, respectively. In one embodiment, bispecific antibody C2D1 is administered to the subject on day 1 of the second dosing cycle.

[0040] In one embodiment, the anti-CD20 antibody is obinutuzumab and / or rituximab.

[0041] In one embodiment, the first dosing cycle includes a first dose of inutuzumab (C1D1) and a second dose of inutuzumab (C1D2). In one embodiment, (a) the subject weighs greater than or equal to about 7.5 kg and less than about 13 kg, and wherein the sum of C1D1 and C1D2 of inutuzumab 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 greater than or equal to about 13 kg and less than about 20 kg, and wherein the sum of C1D1 and C1D2 of inutuzumab 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 greater than or equal to about 20 kg and less than about 32 kg, and wherein the C1D1 and C1D2 of inutuzumab are about 38 mg / kg (e.g., 38 mg / kg ± 0.25 mg / kg, ± 0.5 mg / kg, ± 1 mg / kg, ± 2 mg / kg, or ± 3.8 mg / kg); (d) the subject weighs greater than or equal to about 32 kg and less than about 45 kg, and wherein the sum of the C1D1 and the C1D2 of obinutuzumab is 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 (e) the subject weighs greater than or equal to about 45 kg, and wherein the sum of the C1D1 and the 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).

[0042] In one embodiment, C1D1 of obinutuzumab is about one-tenth the amount of the sum of C1D1 and C1D2 of obinutuzumab, and C1D2 of obinutuzumab is about nine-tenths the amount 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 wherein 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 wherein The C1D1 of inutuzumab is about 2.8 mg / kg (e.g., 2.8 mg / kg ± 0.05 mg / kg, 0.1 mg / kg, ± 0.2 mg / kg, or ± 0.28 mg / kg), and the C1D2 of inutuzumab 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); (c) the subject weighs greater than or equal to about 20 kg and less than about 32 kg, and wherein the C1D1 of inutuzumab is about 2.3 mg / kg (e.g., 2.3 mg / kg ± 0.05 mg / kg, 0.1 (d) the subject weighs greater than or equal to about 32 kg and less than about 45 kg, and wherein the C1D1 of inutuzumab 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 inutuzumab is about 35.7 mg / kg (e.g., 35.7 mg / kg ± 0.5 mg / kg, 1 mg / kg, ± 2 mg / kg, ± 3 mg / kg or ± 3.57 mg / kg); .0 mg / kg ± 0.5 mg / kg, 1 mg / kg, ± 2 mg / kg, ± 3 mg / kg, or ± 3.6 mg / kg); or (e) the subject weighs greater than or equal to about 45 kg, and wherein the C1D1 of inutuzumab 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 inutuzumab 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).

[0043] In one embodiment, the subject is administered C1D1 of ibretuzumab on day 1 of the first dosing cycle, and the subject is administered C1D2 of ibretuzumab on day 2 of the first dosing cycle.

[0044] In one embodiment, the second dosing 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 ±5mg / m 2 ±10mg / m 2 ±25mg / m 2 or ±37.5 mg / m 2 In one embodiment, rituximab is administered to the subject on day 5 of the second dosing cycle.

[0045] In one embodiment, the method comprises administering to the subject ifosfamide, carboplatin, and etoposide.

[0046] In one embodiment, the first dosing cycle comprises:

[0047] (a) first dose of ifosfamide (C1D1), second dose of ifosfamide (C1D2), and third dose of ifosfamide (C1D3);

[0048] (b) a single dose of carboplatin (C1D1); and

[0049] (c) a first dose of etoposide (C1D1), a second dose of etoposide (C1D2), and a third dose of etoposide (C1D3);

[0050] And the second cycle includes:

[0051] (a) first dose of ifosfamide (C2D1), second dose of ifosfamide (C2D2), and third dose of ifosfamide (C2D3);

[0052] (b) a single dose of carboplatin (C2D1); and

[0053] (c) A first dose of etoposide (C2D1), a second dose of etoposide (C2D2), and a third dose of etoposide (C2D3).

[0054] In one embodiment, at about 3000 mg / m 2 (For example, 3000 mg / m 2 ±40mg / m 2 ±50mg / m 2 ±100mg / m 2±200mg / m 2 or ±300 mg / m 2 ) for each dose of ifosfamide, at approximately 635 mg / m 2 (e.g., 635 mg / m 2 ±5mg / m 2 ±10mg / m 2 ±25mg / m 2 ±50mg / m 2 ±60mg / m 2 or ±63.5 mg / m 2 Carboplatin was administered at a dose of approximately 100 mg / m 2 (e.g., 100 mg / m 2 ±1mg / m 2 ±2.5mg / m 2 ±5mg / m 2 or ±10 mg / m 2 ) for each dose of etoposide. In one embodiment, (a) C1D1, C1D2, and C1D3 of ifosfamide are administered on days 3, 4, and 5, respectively, of the first dosing cycle; (b) C1D1 of carboplatin is administered on day 3 of the first dosing cycle; (c) C1D1, C1D2, and C1D3 of etoposide are administered on days 3, 4, and 5, respectively, of the first dosing cycle; (d) C2D1, C2D2, and C2D3 of ifosfamide are administered on days 6, 7, and 8, respectively, of the second dosing cycle; (e) C2D1 of carboplatin is administered on day 6 of the second dosing cycle; and (f) C2D1, C2D2, and C2D3 of etoposide are administered on days 6, 7, and 8, respectively, of the second dosing cycle.

[0055] In one embodiment, the first dosing cycle and the second dosing cycle are each a 21-day dosing cycle. In one embodiment, the dosing regimen includes one or more additional dosing cycles. In one embodiment, the one or more additional dosing cycles are each a 21-day dosing cycle. In one embodiment, the dosing regimen includes three dosing cycles in total.

[0056] In one embodiment, the one or more additional dosing cycles each comprise:

[0057] (a) an additional single dose of a bispecific antibody that binds to CD20 and CD3,

[0058] (b) an additional single dose of anti-CD20 antibody, and

[0059] (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 greater than or equal to about 7.5 kg and less than about 13 kg, and wherein 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 greater than or equal to about 13 kg and less than about 45 kg, and wherein the additional single dose of the bispecific antibody is or (c) the subject has a body weight of greater than or equal to about 45 kg, and wherein 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).

[0060] In one embodiment, the subject is administered an additional single dose of the bispecific antibody on day 1 of each of one or more additional dosing cycles.

[0061] 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 ±5mg / m 2 ±10mg / m 2 ±25mg / 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 the one or more additional dosing cycles.

[0062] In one embodiment, the additional first dose, additional second dose, and additional third dose of ifosfamide are each about 3000 mg / m 2 (For example, 3000 mg / m 2 ±40mg / m 2 ±50mg / m 2 ±100mg / m 2 ±200mg / m 2 or ±300 mg / m 2), an additional single dose of carboplatin of approximately 635 mg / m 2 (e.g., 635 mg / m 2 ±5mg / m 2 ±10mg / m 2 ±25mg / m 2 ±50mg / m 2 ±60mg / m 2 or ±63.5 mg / m 2 ), 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 ±1mg / m 2 ±2.5mg / m 2 ±5mg / m 2 or ±10 mg / m 2 In 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 the one or more additional dosing cycles; (b) an additional single dose of carboplatin is administered on day 6 of each of the one or more additional dosing 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 the one or more additional dosing cycles.

[0063] In one embodiment, the method further comprises administering one or more additional therapeutic agents to the subject.

[0064] In one embodiment, the one or more additional therapeutic agents is tocilizumab. In one embodiment, the subject has a body weight greater than or equal to about 30 kg and is administered tocilizumab 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 has a body weight less than 30 kg and is administered tocilizumab 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), and wherein the maximum dose is about 800 mg (e.g., 800 mg ± 10 mg, ± 25 mg, ± 50 mg, or ± 80 mg).

[0065] In one embodiment, the one or more additional therapeutic agents are corticosteroids. In one embodiment, the corticosteroids include prednisone, prednisolone, methylprednisolone, or dexamethasone.

[0066] In one embodiment, the corticosteroid is dexamethasone. In one embodiment, dexamethasone is administered intravenously at a dose between 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 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) prior to administration of any dose of the bispecific antibody, and wherein the maximum daily dose is 10 mg. In one embodiment, dexamethasone is administered intravenously at a dose of between 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 one hour (i.e., at least one 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, and wherein the maximum daily dose is 10 mg.

[0067] In one embodiment, the corticosteroid is methylprednisolone. In one embodiment, methylprednisolone is administered intravenously at a dose of between about 1 mg / kg and 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 one hour (i.e., at least one 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 between 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 one hour (i.e., at least one 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.

[0068] In one embodiment, the corticosteroid is prednisone or prednisolone. 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 one hour (i.e., at least one 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 one hour (i.e., at least one 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.

[0069] In one embodiment, the one or more additional therapeutic agents are antihistamines. In one embodiment, the antihistamine is diphenhydramine. In one embodiment, the subject is between 2 and 17 years old, and wherein diphenhydramine is administered intravenously at a dose of between about 10 mg and 20 mg (e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 mg), wherein the maximum single dose is about 1.25 mg / kg. In one embodiment, the subject is less than two years old, and wherein 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 the bispecific antibody and / or anti-CD20 antibody.

[0070] In one embodiment, the one or more additional therapeutic agents include granulocyte colony stimulating factor (G-CSF). In one embodiment, G-CSF is administered between about one and about two 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 dosing cycle and at a dose of 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 dosing cycle and / or each additional dosing cycle.

[0071] In one embodiment, one or more additional therapeutic agents are antipyretics. In one embodiment, the antipyretic is acetaminophen or paracetamol. In one embodiment, acetaminophen or paracetamol is administered orally or intravenously at a dosage between about 500 and about 1000 mg (e.g., 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 mg). In one embodiment, 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) before the administration of any dose of the bispecific antibody and / or anti-CD20 antibody.

[0072] In one embodiment, the one or more additional therapeutic agents is mesna. In one embodiment, the total amount is 3000 mg / m 2 In one embodiment, mesna is administered intravenously at about 600 mg / m prior to administration of any dose of ifosfamide. 2 The first dose is about 600 mg / m 2 Mesna is administered intravenously in four repeat doses of cyclophosphamide, each of which is about three hours, about six hours, and about 12 hours after the first dose of ifosfamide. In one embodiment, mesna is administered to the subject daily on days 3, 4, and 5 of the first dosing cycle, on days 6, 7, and 8 of the second dosing cycle, and / or on days 6, 7, and 8 of each additional dosing cycle.

[0073] In one aspect, the invention features a method of treating a subject between the ages of 18 and 30 years old with a CD20-positive cell proliferative disorder, the method comprising administering to the subject an effective amount of:

[0074] (a) Bispecific antibodies that bind to CD20 and CD3;

[0075] (b) anti-CD20 antibodies; and

[0076] (c) one or more chemotherapeutic agents selected from ifosfamide, carboplatin and / or etoposide.

[0077] In one embodiment, the first dosing 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 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 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

[0078] The second dosing cycle comprises a single dose of the bispecific antibody (C2D1), wherein 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).

[0079] In one embodiment, the subject is administered bispecific antibody C1D1 and bispecific antibody C1D2 on day 8 and day 15, respectively, of the first dosing cycle.

[0080] In one embodiment, the subject is administered C2D1 of the bispecific antibody on day 1 of the second dosing cycle.

[0081] In one embodiment, the anti-CD20 antibody is obinutuzumab and / or rituximab.

[0082] In one embodiment, the first dosing cycle includes a first dose (C1D1) of Utuzumab and a second dose (C1D2) of Utuzumab. In one embodiment, the sum of C1D1 and C1D2 of Utuzumab 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 Utuzumab is about one-tenth the amount of the sum of C1D1 and C1D2 of Utuzumab, and C1D2 of Utuzumab is about nine-tenths the amount of the sum of C1D1 and C1D2 of Utuzumab. In one embodiment, the C1D1 of Ubinotuzumab 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 Ubinotuzumab 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, the C1D1 of Ubinotuzumab is administered to the subject on day 1 of the first dosing cycle, and the C1D2 of Ubinotuzumab is administered to the subject on day 2 of the first dosing cycle.

[0083] In one embodiment, the second dosing 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 ±5mg / m 2 ±10mg / m 2 ±25mg / m 2 or ±37.5 mg / m 2 In one embodiment, the subject is administered C2D1 of rituximab on day 5 of the second dosing cycle.

[0084] In one embodiment, the method comprises administering to a subject ifosfamide, carboplatin, and etoposide. In one embodiment, a first administration cycle comprises:

[0085] (a) Single dose of ifosfamide (C1D1);

[0086] (b) a single dose of carboplatin (C1D1); and

[0087] (c) a first dose of etoposide (C1D1), a second dose of etoposide (C1D2), and a third dose of etoposide (C1D3);

[0088] And the second cycle includes:

[0089] (a) Single dose of ifosfamide (C2D1);

[0090] (b) a single dose of carboplatin (C2D1); and

[0091] (c) A first dose of etoposide (C2D1), a second dose of etoposide (C2D2), and a third dose of etoposide (C2D3).

[0092] In one embodiment, about 5000 mg / m 2 (e.g., 5000 mg / m 2 ±50mg / m 2 ±100mg / m 2 ±200mg / m 2 ±300mg / m 2 ±400mg / m 2 or ±500mg / m 2 ), ifosfamide 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 carboplatin at a dose of about 100 mg / m 2 (e.g., 100 mg / m 2 ±1mg / m 2 ±2.5mg / m 2 ±5mg / m 2 or ±10 mg / m 2 ) for each dose of etoposide.

[0093] In one embodiment, (a) the subject is male and CrCl is calculated using the formula CrCl = ([140 - age] × [body weight (kg)]) / (72 × [serum creatinine (mg / dL)]); or (b) the subject is female and CrCl is calculated using the formula CrCl = 0.85 × ([140 - age] × [body weight (kg)]) / (72 × [serum creatinine (mg / dL)]).

[0094] In one embodiment, (a) the subject has a CrCl of < about 60 mL / min, and each single dose of ifosfamide is reduced to 4000 mg / m 2 and / or (b) the subject has a CrCl of < about 50 mL / min, and wherein each dose of etoposide is reduced to 75 mg / m 2 .

[0095] In one embodiment, (a) C1D1 ifosfamide is administered on day 3 of the first dosing cycle;

[0096] (b) C1D1 in which carboplatin is administered on day 3 of the first dosing cycle;

[0097] (c) administering C1D1, C1D2, and C1D3 of etoposide on days 3, 4, and 5 of the first dosing cycle, respectively;

[0098] (d) C2D1 with ifosfamide administered on day 6 of the second dosing cycle;

[0099] (e) administering C2D1 of carboplatin on day 6 of the second dosing cycle; and

[0100] (f) C2D1, C2D2, and C2D3 of etoposide were administered on Days 6, 7, and 8 of the second dosing cycle, respectively.

[0101] In one embodiment, the first dosing cycle and the second dosing cycle are each a 21-day dosing cycle. In one embodiment, the dosing regimen includes one or more additional dosing cycles. In one embodiment, the one or more additional dosing cycles are each a 21-day dosing cycle. In one embodiment, the dosing regimen includes three dosing cycles in total.

[0102] In one embodiment, the one or more additional dosing cycles each comprise:

[0103] (a) an additional single dose of a bispecific antibody that binds to CD20 and CD3,

[0104] (b) an additional single dose of anti-CD20 antibody, and

[0105] (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.

[0106] 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 subject is administered an additional single dose of the bispecific antibody on day 1 of each of one or more additional dosing cycles.

[0107] 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 ±5mg / m2 ±10mg / m 2 ±25mg / 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 the one or more additional dosing cycles.

[0108] In one embodiment, the additional single dose of ifosfamide is about 5000 mg / m 2 (e.g., 5000 mg / m 2 ±50mg / m 2 ±100mg / m 2 ±200mg / m 2 ±300mg / m 2 ±400mg / m 2 or ±500mg / m 2 ), an additional single dose of carboplatin 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 an additional first dose, an additional second dose, and an additional third dose of etoposide each of about 100 mg / m 2 (e.g., 100 mg / m 2 ±1mg / m 2 ±2.5mg / m 2 ±5mg / m 2 or ±10 mg / m 2 ).

[0109] In one embodiment, (a) the subject is male, and wherein CrCl is calculated using the formula CrCl = ([140 - age] × [body weight (kg)]) / (72 × [serum creatinine (mg / dL)]); or (b) the subject is female, and wherein CrCl is calculated using the formula CrCl = 0.85 × ([140 - age] × [body weight (kg)]) / (72 × [serum creatinine (mg / dL)]).

[0110] In one embodiment, (a) the subject has a CrCl of < about 60 mL / min and the additional single dose of ifosfamide is reduced to 4000 mg / m 2 and / or (b) the subject has a CrCl of < about 50 mL / min, and wherein each additional dose of etoposide is reduced to 75 mg / m 2 .

[0111] In one embodiment, (a) an additional single dose of ifosfamide is administered on day 6 of each of the one or more additional dosing cycles;

[0112] (b) administering an additional single dose of carboplatin on day 6 of each of the one or more additional dosing cycles; and

[0113] (c) administering to the subject an additional first dose, an additional second dose, and an additional third dose of etoposide on day 6, day 7, and day 8, respectively, of each of the one or more additional dosing cycles.

[0114] In one embodiment, the method further comprises administering one or more additional therapeutic agents to the subject.

[0115] In one embodiment, the one or more additional therapeutic agents is tocilizumab. In one embodiment, the subject has a body weight greater than or equal to about 30 kg and is administered tocilizumab 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 has a body weight less than 30 kg and is administered tocilizumab 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), and wherein the maximum dose is about 800 mg (e.g., 800 mg ± 10 mg, ± 25 mg, ± 50 mg, or ± 80 mg).

[0116] In one embodiment, the one or more additional therapeutic agents is a corticosteroid.

[0117] In one embodiment, the corticosteroid comprises prednisone, prednisolone, methylprednisolone, or dexamethasone.

[0118] In one embodiment, the corticosteroid is dexamethasone. In one embodiment, dexamethasone is administered intravenously at a dose between 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 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) prior to administration of any dose of the bispecific antibody, and wherein the maximum daily dose is 10 mg. In one embodiment, dexamethasone is administered intravenously at a dose of between 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 one hour (i.e., at least one 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, and wherein the maximum daily dose is 10 mg.

[0119] In one embodiment, the corticosteroid is methylprednisolone. In one embodiment, methylprednisolone is administered intravenously at a dose of between about 1 mg / kg and 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 one hour (i.e., at least one 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 between 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 one hour (i.e., at least one 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.

[0120] In one embodiment, the corticosteroid is prednisone or prednisolone. 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 one hour (i.e., at least one 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 one hour (i.e., at least one 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.

[0121] In one embodiment, one or more additional therapeutic agents are antihistamines. 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 the bispecific antibody and / or anti-CD20 antibody.

[0122] In one embodiment, the one or more additional therapeutic agents include granulocyte colony stimulating factor (G-CSF). In one embodiment, G-CSF is administered between about one and about two 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 dosing cycle and at a dose of 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 dosing cycle and / or each additional dosing cycle.

[0123] In one embodiment, one or more additional therapeutic agents are antipyretics. In one embodiment, the antipyretic is acetaminophen or paracetamol. In one embodiment, acetaminophen or paracetamol is administered orally or intravenously at a dosage between about 500 and about 1000 mg (e.g., 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 mg). In one embodiment, 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) before the administration of any dose of the bispecific antibody and / or anti-CD20 antibody.

[0124] In one embodiment, the one or more additional therapeutic agents is mesna. In one embodiment, the dosage is about 5000 mg / m 2 (e.g., 5000 mg / m 2 ±50mg / m 2 ±100mg / m 2 ±200mg / m 2 ±300mg / m 2 ±400mg / m 2 or ±500mg / m 2 ) is administered intravenously at a dose of . In one embodiment, mesna is administered via 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 concurrently with any dose of ifosfamide.

[0125] In one aspect, the invention features a method of treating a subject having a CD20-positive cell proliferative disorder, the method comprising administering to the subject an effective amount of gefiruzumab, obinutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein

[0126] (a) a first dosing cycle comprising administering a first dose of gefizumab (C1D1) on day 8 and administering a second dose of gefizumab (C1D2) on day 15, wherein the C1D1 of gefizumab 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 gefizumab 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

[0127] (b) The second dosing cycle comprises administering a single dose of gefizumab on day 8 (C2D1), wherein the C2D1 of gefizumab 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).

[0128] In one aspect, the invention features a method of treating a subject having a CD20-positive cell proliferative disorder, the method comprising administering to the subject an effective amount of gefiruzumab, obinutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen comprising a first dosing cycle, a second dosing cycle, and a third dosing cycle, wherein

[0129] (a) a first dosing cycle comprising administering a first dose of gefizumab (C1D1) on day 8 and administering a second dose of gefizumab (C1D2) on day 15, wherein the C1D1 of gefizumab 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 gefizumab 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);

[0130] (b) the second dosing cycle comprises administering a single dose of gefizumab on day 8 (C2D1), wherein the C2D1 of gefizumab 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); and

[0131] (c) The third dosing cycle comprises administering a single dose of gefizumab on day 8 (C3D1), wherein the C3D1 of gefizumab 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).

[0132] In one aspect, the invention features a method of treating a subject having a CD20-positive cell proliferative disorder, the method comprising administering to the subject an effective amount of gefiruzumab, obinutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein

[0133] (a) The first dosing cycle includes:

[0134] (i) administering a first dose of gefizumab (C1D1) on day 8 and a second dose of gefizumab (C1D2) on day 15, wherein the C1D1 of gefizumab 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 gefizumab 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);

[0135] (ii) administering a first dose of obinutuzumab on day 1 (C1D1), wherein the 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);

[0136] (iii) administering a single dose of ifosfamide on day 2 (C1D1), wherein the C1D1 of ifosfamide is approximately 5000 mg / m 2 (e.g., 5000 mg / m 2 ±50mg / m 2 ±100mg / m 2 ±200mg / m 2 ±300mg / m 2 ±400mg / m 2 or ±500mg / m 2 ), with a maximum dose of about 800 mg (e.g., 800 mg ± 10 mg, ± 25 mg, ± 50 mg, or ± 80 mg);

[0137] (iv) administering a single dose of carboplatin on day 2 (C1D1), wherein the C1D1 of carboplatin is approximately 5×(25+creatinine clearance) mg; and

[0138] (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, wherein C1D1, C1D2, and C1D3 of etoposide are each about 100 mg / m 2 (e.g., 100 mg / m 2 ±1mg / m 2 ±2.5mg / m 2 ±5mg / m 2 or ±10 mg / m 2 );as well as

[0139] (b) The second dosing cycle includes:

[0140] (i) administering a single dose of gefizumab on day 8 (C2D1), wherein the C2D1 of gefizumab 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);

[0141] (ii) administering the first dose of rituximab on day 1 (C2D1), wherein the C2D1 of rituximab is approximately 375 mg / m 2 (e.g., 375 mg / m 2 ±5mg / m 2 ±10mg / m 2 ±25mg / m 2 or ±37.5 mg / m 2 );

[0142] (iii) administering a single dose of ifosfamide on day 2 (C2D1), wherein the C2D1 of ifosfamide is approximately 5000 mg / m 2 (e.g., 5000 mg / m 2 ±50mg / m 2 ±100mg / m 2 ±200mg / m 2 ±300mg / m 2 ±400mg / m 2 or ±500mg / m 2 ), with a maximum dose of about 800 mg (e.g., 800 mg ± 10 mg, ± 25 mg, ± 50 mg, or ± 80 mg);

[0143] (iv) administering a single dose of carboplatin on day 2 (C2D1), wherein the C2D1 of carboplatin is approximately 5 x (25 + creatinine clearance) mg; and

[0144] (v) administering a first dose of etoposide on day 1 (C2D1), administering a second dose of etoposide on day 2 (C2D2), and administering a third dose of etoposide on day 3 (C2D3), wherein each of C2D1, C2D2, and C2D3 of etoposide is about 100 mg / m 2 (e.g., 100 mg / m 2 ±1mg / m 2 ±2.5mg / m 2 ±5mg / m 2 or ±10 mg / m 2 ).

[0145] In one aspect, the invention features a method of treating a subject having a CD20-positive cell proliferative disorder, the method comprising administering to the subject an effective amount of gefiruzumab, obinutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen comprising a first dosing cycle, a second dosing cycle, and a third dosing cycle, wherein

[0146] (a) The first dosing cycle includes:

[0147] (i) administering a first dose of gefizumab (C1D1) on day 8 and a second dose of gefizumab (C1D2) on day 15, wherein the C1D1 of gefizumab 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 gefizumab 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);

[0148] (ii) administering a first dose of obinutuzumab on day 1 (C1D1), wherein the 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);

[0149] (iii) administering a single dose of ifosfamide on day 2 (C1D1), wherein the C1D1 of ifosfamide is approximately 5000 mg / m 2 (e.g., 5000 mg / m 2 ±50mg / m 2 ±100mg / m 2 ±200mg / m 2 ±300mg / m 2 ±400mg / m 2 or ±500mg / m 2 ), with a maximum dose of about 800 mg (e.g., 800 mg ± 10 mg, ± 25 mg, ± 50 mg, or ± 80 mg);

[0150] (iv) administering a single dose of carboplatin on day 2 (C1D1), wherein the C1D1 of carboplatin is approximately 5×(25+creatinine clearance) mg; and

[0151] (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, wherein C1D1, C1D2, and C1D3 of etoposide are each about 100 mg / m 2 (e.g., 100 mg / m 2 ±1mg / m 2 ±2.5mg / m 2 ±5mg / m 2 or ±10 mg / m 2 );

[0152] (b) The second dosing cycle includes:

[0153] (i) administering a single dose of gefizumab on day 8 (C2D1), wherein the C2D1 of gefizumab 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);

[0154] (ii) administering the first dose of rituximab on day 1 (C2D1), wherein the C2D1 of rituximab is approximately 375 mg / m 2 (e.g., 375 mg / m 2 ±5mg / m 2 ±10mg / m 2 ±25mg / m 2 or ±37.5 mg / m 2 );

[0155] (iii) administering a single dose of ifosfamide on day 2 (C2D1), wherein the C2D1 of ifosfamide is approximately 5000 mg / m 2 (e.g., 5000 mg / m 2 ±50mg / m 2 ±100mg / m 2 ±200mg / m 2 ±300mg / m 2 ±400mg / m 2 or ±500mg / m 2 ), with a maximum dose of about 800 mg (e.g., 800 mg ± 10 mg, ± 25 mg, ± 50 mg, or ± 80 mg);

[0156] (iv) administering a single dose of carboplatin on day 2 (C2D1), wherein the C2D1 of carboplatin is approximately 5 x (25 + creatinine clearance) mg; and

[0157] (v) administering a first dose of etoposide on day 1 (C2D1), administering a second dose of etoposide on day 2 (C2D2), and administering a third dose of etoposide on day 3 (C2D3), wherein each of C2D1, C2D2, and C2D3 of etoposide is about 100 mg / m 2 (e.g., 100 mg / m 2 ±1mg / m 2 ±2.5mg / m 2 ±5mg / m 2 or ±10 mg / m 2 );as well as

[0158] (c) The third dosing cycle includes:

[0159] (i) administering a single dose of gefizumab on day 8 (C3D1), wherein the C3D1 of gefizumab 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] (ii) administering the first dose of rituximab on day 1 (C3D1), wherein the C3D1 of rituximab is approximately 375 mg / m 2 (e.g., 375 mg / m 2 ±5mg / m 2 ±10mg / m 2 ±25mg / m 2 or ±37.5 mg / m 2 );

[0161] (iii) administering a single dose of ifosfamide on day 2 (C3D1), wherein the C3D1 of ifosfamide is approximately 5000 mg / m 2 (e.g., 5000 mg / m 2 ±50mg / m 2 ±100mg / m 2 ±200mg / m 2 ±300mg / m 2 ±400mg / m 2 or ±500mg / m 2 ), with a maximum dose of about 800 mg (e.g., 800 mg ± 10 mg, ± 25 mg, ± 50 mg, or ± 80 mg);

[0162] (iv) administering a single dose of carboplatin on day 2 (C3D1), wherein the C3D1 of carboplatin is approximately 5 x (25 + creatinine clearance) mg; and

[0163] (v) administering a first dose of etoposide on day 1 (C3D1), administering a second dose of etoposide on day 2 (C3D2), and administering a third dose of etoposide on day 3 (C3D3), wherein each of C3D1, C3D2, and C3D3 of etoposide is about 100 mg / m 2 (e.g., 100 mg / m 2 ±1mg / m 2 ±2.5mg / m 2 ±5mg / m 2 or ±10 mg / m 2 ).

[0164] In one embodiment, mesna is administered concurrently with any dose of ifosfamide. In one embodiment, mesna is administered at about 5000 mg / m 2 (e.g., 5000 mg / m 2 ±50mg / m 2 ±100mg / m 2 ±200mg / m 2 ±300mg / m 2 ±400mg / m 2 or ±500mg / m 2 In one embodiment, mesna is administered via continuous infusion over about 24 hours on day 2 of each dosing cycle.

[0165] In one aspect, the invention features a method of treating a subject between the ages of 6 months and 17 years old with a CD20-positive cell proliferative disorder, the method comprising administering to the subject an effective amount of gefiruzumab, obinutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein

[0166] (a) The first dosing cycle comprises administering a first dose of gefizumab (C1D1) on day 8 and administering a second dose of gefizumab (C1D2) on day 15, wherein the C1D1 of gefizumab 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), 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 gefizumab 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); and

[0167] (b) the second dosing cycle comprises administering a single dose of gefizumab on day 8 (C2D1), wherein the C2D1 of gefizumab 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).

[0168] In one aspect, the invention features a method of treating a subject between the ages of 6 months and 17 years old with a CD20-positive cell proliferative disorder, the method comprising administering to the subject an effective amount of gefiruzumab, obinutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen comprising a first dosing cycle, a second dosing cycle, and a third dosing cycle, wherein

[0169] (a) the first dosing cycle comprises administering a first dose of gefizumab (C1D1) on day 8 and administering a second dose of gefizumab (C1D2) on day 15, wherein the C1D1 of gefizumab 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), 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 gefituzumab 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);

[0170] (b) a second dosing cycle comprising administering a single dose of gefizumab on day 8 (C2D1), wherein the C2D1 of gefizumab 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); and

[0171] (c) The third dosing cycle comprises administering a single dose of gefizumab on day 8 (C3D1), wherein the C3D1 of gefizumab 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).

[0172] In one aspect, the invention features a method of treating a subject between the ages of 6 months and 17 years old with a CD20-positive cell proliferative disorder, the method comprising administering to the subject an effective amount of gefiruzumab, obinutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein

[0173] (a) The first dosing cycle includes:

[0174] (i) administering a first dose of gefizumab (C1D1) on day 8 and a second dose of gefizumab (C1D2) on day 15, wherein the C1D1 of gefizumab 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), or about 2.5

[0015] The present invention relates to an oral dosage form of gefizumab 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) 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) wherein the dosage form is 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);

[0175] (ii) administering a first dose of inutuzumab (C1D1) on day 1 and a second dose of inutuzumab (C1D2) on day 2, wherein C1D1 of inutuzumab is about one-tenth the amount of the sum of C1D1 and C1D2 of inutuzumab, and C1D2 of inutuzumab is about nine-tenths the amount of the sum of C1D1 and C1D2 of inutuzumab, and wherein the sum of C1D1 and C1D2 of inutuzumab 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 or about 1000 mg (e.g., 1000 mg ±5 mg, ±10 mg, ±20 mg, ±30 mg, ±50 mg, ±75 mg or ±100 mg);

[0176] (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, wherein each of ifosfamide C1D1, C1D2, and C1D3 is about 3000 mg / m 2 (For example, 3000 mg / m 2 ±40mg / m 2 ±50mg / m 2 ±100mg / m 2 ±200mg / m 2 or ±300 mg / m 2 );

[0177] (iv) administering a single dose of carboplatin on day 3 (C1D1), wherein the C1D1 of carboplatin is approximately 635 mg / m 2 (e.g., 635 mg / m 2 ±5mg / m 2 ±10mg / m 2 ±25mg / m 2 ±50mg / m 2 ±60mg / m 2 or ±63.5 mg / m 2 );as well as

[0178] (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, wherein C1D1, C1D2, and C1D3 of etoposide are each about 100 mg / m 2 (e.g., 100 mg / m 2 ±1mg / m 2 ±2.5mg / m 2 ±5mg / m 2 or ±10 mg / m 2 );as well as

[0179] (b) The second dosing cycle includes:

[0180] (i) administering a single dose of gefizumab on day 1 (C2D1), wherein the C2D1 of gefizumab 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);

[0181] (ii) administering the first dose of rituximab on day 5 (C2D1), wherein the C2D1 of rituximab is approximately 375 mg / m 2 (e.g., 375 mg / m 2 ±5mg / m 2 ±10mg / m 2 ±25mg / m 2 or ±37.5 mg / m 2 );

[0182] (iii) administering a first dose of ifosfamide (C2D1) on day 6, a second dose of ifosfamide (C2D2) on day 7, and a third dose of ifosfamide (C2D3) on day 8, wherein each of ifosfamide in C2D1, C2D2, and C2D3 is about 3000 mg / m 2 (For example, 3000 mg / m 2 ±40mg / m 2 ±50mg / m 2 ±100mg / m 2±200mg / m 2 or ±300 mg / m 2 );

[0183] (iv) administering a single dose of carboplatin on day 6 (C2D1), wherein the C2D1 of carboplatin is approximately 5×(25+creatinine clearance) mg; and

[0184] (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, wherein each of C2D1, C2D2, and C2D3 of etoposide is about 100 mg / m 2 (e.g., 100 mg / m 2 ±1mg / m 2 ±2.5mg / m 2 ±5mg / m 2 or ±10 mg / m 2 ).

[0185] In one aspect, the invention features a method of treating a subject between the ages of 6 months and 17 years old with a CD20-positive cell proliferative disorder, the method comprising administering to the subject an effective amount of gefiruzumab, obinutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen comprising a first dosing cycle, a second dosing cycle, and a third dosing cycle, wherein

[0186] (a) The first dosing cycle includes:

[0187] (i) administering a first dose of gefizumab (C1D1) on day 8 and a second dose of gefizumab (C1D2) on day 15, wherein the C1D1 of gefizumab is 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, ± 0.0 3 mg, ±0.05 mg, ±0.1 mg, ±0.2 mg, or ±0.25 mg), and the C1D2 of gefituzumab 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);

[0188] (ii) administering a first dose of inutuzumab (C1D1) on day 1 and a second dose of inutuzumab (C1D2) on day 2, wherein C1D1 of inutuzumab is about one-tenth the amount of the sum of C1D1 and C1D2 of inutuzumab, and C1D2 of inutuzumab is about nine-tenths the amount of the sum of C1D1 and C1D2 of inutuzumab, and wherein the sum of C1D1 and C1D2 of inutuzumab 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 2 ... g / 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);

[0189] (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, wherein each of ifosfamide C1D1, C1D2, and C1D3 is about 3000 mg / m 2 (For example, 3000 mg / m 2 ±40mg / m 2 ±50mg / m 2 ±100mg / m 2 ±200mg / m 2 or ±300 mg / m 2 );

[0190] (iv) administering a single dose of carboplatin on day 3 (C1D1), wherein the C1D1 of carboplatin is approximately 635 mg / m 2 (e.g., 635 mg / m 2 ±5mg / m 2 ±10mg / m 2 ±25mg / m 2 ±50mg / m 2 ±60mg / m 2or ±63.5 mg / m 2 );as well as

[0191] (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, wherein C1D1, C1D2, and C1D3 of etoposide are each about 100 mg / m 2 (e.g., 100 mg / m 2 ±1mg / m 2 ±2.5mg / m 2 ±5mg / m 2 or ±10 mg / m 2 );

[0192] (b) The second dosing cycle includes:

[0193] (i) administering a single dose of gefizumab on day 1 (C2D1), wherein the C2D1 of gefizumab 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);

[0194] (ii) administering the first dose of rituximab on day 5 (C2D1), wherein the C2D1 of rituximab is approximately 375 mg / m 2 (e.g., 375 mg / m 2 ±5mg / m 2 ±10mg / m 2 ±25mg / m 2 or ±37.5 mg / m 2 );

[0195] (iii) administering a first dose of ifosfamide (C2D1) on day 6, a second dose of ifosfamide (C2D2) on day 7, and a third dose of ifosfamide (C2D3) on day 8, wherein each of ifosfamide in C2D1, C2D2, and C2D3 is about 3000 mg / m 2 (For example, 3000 mg / m 2 ±40mg / m2 ±50mg / m 2 ±100mg / m 2 ±200mg / m 2 or ±300 mg / m 2 );

[0196] (iv) administering a single dose of carboplatin on day 6 (C2D1), wherein the C2D1 of carboplatin is approximately 5×(25+creatinine clearance) mg; and

[0197] (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, wherein each of C2D1, C2D2, and C2D3 of etoposide is about 100 mg / m 2 (e.g., 100 mg / m 2 ±1mg / m 2 ±2.5mg / m 2 ±5mg / m 2 or ±10 mg / m 2 );as well as

[0198] (c) The third dosing cycle includes:

[0199] (i) administering a single dose of gefizumab on day 1 (C3D1), wherein the C3D1 of gefizumab 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);

[0200] (ii) administering the first dose of rituximab on day 5 (C3D1), wherein the C3D1 of rituximab is approximately 375 mg / m 2 (e.g., 375 mg / m 2 ±5mg / m 2 ±10mg / m 2 ±25mg / m 2 or ±37.5 mg / m 2 );

[0201] (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, wherein each of ifosfamide in C3D1, C3D2, and C3D3 is about 3000 mg / m 2 (For example, 3000 mg / m 2 ±40mg / m 2 ±50mg / m 2 ±100mg / m 2 ±200mg / m 2 or ±300 mg / m 2 );

[0202] (iv) administering a single dose of carboplatin on day 6 (C3D1), wherein the C3D1 of carboplatin is approximately 5×(25+creatinine clearance) mg; and

[0203] (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, wherein each of C3D1, C3D2, and C3D3 of etoposide is about 100 mg / m 2 (e.g., 100 mg / m 2 ±1mg / m 2 ±2.5mg / m 2 ±5mg / m 2 or ±10 mg / m 2 ).

[0204] In one embodiment, mesna is administered to a subject on days 3, 4, and 5 of a first dosing cycle, on days 6, 7, and 8 of a second dosing cycle, and / or on days 6, 7, and 8 of each additional dosing cycle. In one embodiment, mesna is administered to a subject in a total amount of 3000 mg / m 2 In one embodiment, mesna is administered intravenously at about 600 mg / m prior to administration of any dose of ifosfamide. 2 The first dose is about 600 mg / m 2 Mesna is administered intravenously in four repeat doses of cyclophosphamide, each of which is about three hours, about six hours, and about 12 hours after the first dose of ifosfamide.

[0205] In one aspect, the invention features a method of treating a subject between the ages of 18 and 30 years old with a CD20-positive cell proliferative disorder, the method comprising administering to the subject an effective amount of gefiruzumab, obinutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein

[0206] (a) a first dosing cycle comprising administering a first dose of gefizumab (C1D1) on day 8 and administering a second dose of gefizumab (C1D2) on day 15, wherein the C1D1 of gefizumab 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 gefizumab 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

[0207] (b) The second dosing cycle comprises administering a single dose of gefizumab on day 1 (C2D1), wherein the C2D1 of gefizumab 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).

[0208] In one aspect, the invention features a method of treating a subject between the ages of 18 and 30 years old with a CD20-positive cell proliferative disorder, the method comprising administering to the subject an effective amount of gefiruzumab, obinutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen comprising a first dosing cycle, a second dosing cycle, and a third dosing cycle, wherein

[0209] (a) a first dosing cycle comprising administering a first dose of gefizumab (C1D1) on day 8 and administering a second dose of gefizumab (C1D2) on day 15, wherein the C1D1 of gefizumab 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 gefizumab 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);

[0210] (b) the second dosing cycle comprises administering a single dose of gefizumab on day 1 (C2D1), wherein the C2D1 of gefizumab 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); and

[0211] (c) The third dosing cycle comprises administering a single dose of gefizumab on day 1 (C3D1), wherein the C3D1 of gefizumab 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).

[0212] In one aspect, the invention features a method of treating a subject between the ages of 18 and 30 years old with a CD20-positive cell proliferative disorder, the method comprising administering to the subject an effective amount of gefiruzumab, obinutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein

[0213] (a) The first dosing cycle includes:

[0214] (i) administering a first dose of gefizumab (C1D1) on day 8 and a second dose of gefizumab (C1D2) on day 15, wherein the C1D1 of gefizumab 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 gefizumab 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);

[0215] (ii) administering a first dose of inutuzumab (C1D1) on day 1 and a second dose of inutuzumab (C1D2) on day 2, wherein the C1D1 of inutuzumab is about one-tenth the amount of the sum of the C1D1 and the C1D2 of inutuzumab, and the C1D2 of inutuzumab is about nine-tenths the amount of the sum of the C1D1 and the C1D2 of inutuzumab, and wherein the sum of the C1D1 and the C1D2 of inutuzumab is about 1000 mg (e.g., 1000 mg ± 5 mg, ± 10 mg, ± 20 mg, ± 30 mg, ± 50 mg, ± 75 mg, or ± 100 mg);

[0216] (iii) administering a single dose of ifosfamide on day 3 (C1D1), wherein the C1D1 of ifosfamide is approximately 5000 mg / m 2 (e.g., 5000 mg / m 2 ±50mg / m 2 ±100mg / m 2 ±200mg / m 2 ±300mg / m 2 ±400mg / m 2 or ±500mg / m 2 ), with a maximum dose of about 800 mg (e.g., 800 mg ± 10 mg, ± 25 mg, ± 50 mg, or ± 80 mg);

[0217] (iv) administering a single dose of carboplatin on day 3 (C1D1), wherein the C1D1 of carboplatin is approximately 5×(25+creatinine clearance) mg; and

[0218] (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, wherein C1D1, C1D2, and C1D3 of etoposide are each about 100 mg / m 2 (e.g., 100 mg / m 2 ±1mg / m 2 ±2.5mg / m 2 ±5mg / m 2 or ±10 mg / m 2 );as well as

[0219] (b) The second dosing cycle includes:

[0220] (i) administering a single dose of gefizumab on day 1 (C2D1), wherein the C2D1 of gefizumab 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);

[0221] (ii) administering the first dose of rituximab on day 5 (C2D1), wherein the C2D1 of rituximab is approximately 375 mg / m 2 (e.g., 375 mg / m 2 ±5mg / m 2 ±10mg / m 2 ±25mg / m 2 or ±37.5 mg / m 2 );

[0222] (iii) administering a single dose of ifosfamide on day 6 (C2D1), wherein the C2D1 of ifosfamide is approximately 5000 mg / m 2 (e.g., 5000 mg / m 2 ±50mg / m 2 ±100mg / m 2 ±200mg / m 2 ±300mg / m 2 ±400mg / m 2 or ±500mg / m 2 ), with a maximum dose of about 800 mg (e.g., 800 mg ± 10 mg, ± 25 mg, ± 50 mg, or ± 80 mg);

[0223] (iv) administering a single dose of carboplatin on day 6 (C2D1), wherein the C2D1 of carboplatin is approximately 5×(25+creatinine clearance) mg; and

[0224] (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, wherein each of C2D1, C2D2, and C2D3 of etoposide is about 100 mg / m 2 (e.g., 100 mg / m 2 ±1mg / m 2 ±2.5mg / m 2 ±5mg / m 2 or ±10 mg / m 2 ).

[0225] In one aspect, the invention features a method of treating a subject between the ages of 18 and 30 years old with a CD20-positive cell proliferative disorder, the method comprising administering to the subject an effective amount of gefiruzumab, obinutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen comprising a first dosing cycle, a second dosing cycle, and a third dosing cycle, wherein

[0226] (a) The first dosing cycle includes:

[0227] (i) administering a first dose of gefizumab (C1D1) on day 8 and a second dose of gefizumab (C1D2) on day 15, wherein the C1D1 of gefizumab 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 gefizumab 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);

[0228] (ii) administering a first dose of inutuzumab (C1D1) on day 1 and a second dose of inutuzumab (C1D2) on day 2, wherein the C1D1 of inutuzumab is about one-tenth the amount of the sum of the C1D1 and the C1D2 of inutuzumab, and the C1D2 of inutuzumab is about nine-tenths the amount of the sum of the C1D1 and the C1D2 of inutuzumab, and wherein the sum of the C1D1 and the C1D2 of inutuzumab is about 1000 mg (e.g., 1000 mg ± 5 mg, ± 10 mg, ± 20 mg, ± 30 mg, ± 50 mg, ± 75 mg, or ± 100 mg);

[0229] (iii) administering a single dose of ifosfamide on day 3 (C1D1), wherein the C1D1 of ifosfamide is approximately 5000 mg / m 2 (e.g., 5000 mg / m 2 ±50mg / m 2 ±100mg / m 2 ±200mg / m 2 ±300mg / m 2 ±400mg / m 2 or ±500mg / m 2 ), with a maximum dose of about 800 mg (e.g., 800 mg ± 10 mg, ± 25 mg, ± 50 mg, or ± 80 mg);

[0230] (iv) administering a single dose of carboplatin on day 3 (C1D1), wherein the C1D1 of carboplatin is approximately 5×(25+creatinine clearance) mg; and

[0231] (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, wherein C1D1, C1D2, and C1D3 of etoposide are each about 100 mg / m 2 (e.g., 100 mg / m2 ±1mg / m 2 ±2.5mg / m 2 ±5mg / m 2 or ±10 mg / m 2 );

[0232] (b) The second dosing cycle includes:

[0233] (i) administering a single dose of gefizumab on day 1 (C2D1), wherein the C2D1 of gefizumab 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);

[0234] (ii) administering the first dose of rituximab on day 5 (C2D1), wherein the C2D1 of rituximab is approximately 375 mg / m 2 (e.g., 375 mg / m 2 ±5mg / m 2 ±10mg / m 2 ±25mg / m 2 or ±37.5 mg / m 2 );

[0235] (iii) administering a single dose of ifosfamide on day 6 (C2D1), wherein the C2D1 of ifosfamide is approximately 5000 mg / m 2 (e.g., 5000 mg / m 2 ±50mg / m 2 ±100mg / m 2 ±200mg / m 2 ±300mg / m 2 ±400mg / m 2 or ±500mg / m 2 ), with a maximum dose of about 800 mg (e.g., 800 mg ± 10 mg, ± 25 mg, ± 50 mg, or ± 80 mg);

[0236] (iv) administering a single dose of carboplatin on day 6 (C2D1), wherein the C2D1 of carboplatin is approximately 5×(25+creatinine clearance) mg; and

[0237] (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, wherein each of C2D1, C2D2, and C2D3 of etoposide is about 100 mg / m 2 (e.g., 100 mg / m 2±1mg / m 2 ±2.5mg / m 2 ±5mg / m 2 or ±10 mg / m 2 );as well as

[0238] (c) The third dosing cycle includes:

[0239] (i) administering a single dose of gefizumab on day 1 (C3D1), wherein the C3D1 of gefizumab 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);

[0240] (ii) administering the first dose of rituximab on day 5 (C3D1), wherein the C3D1 of rituximab is approximately 375 mg / m 2 (e.g., 375 mg / m 2 ±5mg / m 2 ±10mg / m 2 ±25mg / m 2 or ±37.5 mg / m 2 );

[0241] (iii) a single dose of ifosfamide on day 6 (C3D1), wherein the C3D1 of ifosfamide is approximately 5000 mg / m 2 (e.g., 5000 mg / m 2 ±50mg / m 2 ±100mg / m 2 ±200mg / m 2 ±300mg / m 2 ±400mg / m 2 or ±500mg / m 2 ), with a maximum dose of about 800 mg (e.g., 800 mg ± 10 mg, ± 25 mg, ± 50 mg, or ± 80 mg);

[0242] (iv) administering a single dose of carboplatin on day 6 (C3D1), wherein the C3D1 of carboplatin is approximately 5×(25+creatinine clearance) mg; and

[0243] (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, wherein each of C3D1, C3D2, and C3D3 of etoposide is about 100 mg / m 2 (e.g., 100 mg / m 2 ±1mg / m2 ±2.5mg / m 2 ±5mg / m 2 or ±10 mg / m 2 ).

[0244] In one embodiment, mesna is administered concurrently with any dose of ifosfamide. In one embodiment, mesna is administered at about 5000 mg / m 2 (e.g., 5000 mg / m 2 ±50mg / m 2 ±100mg / m 2 ±200mg / m 2 ±300mg / m 2 ±400mg / m 2 or ±500mg / m 2 ) is administered intravenously at a dose of . In one embodiment, mesna is administered via 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.

[0245] In one embodiment, the bispecific antibody that binds to CD20 and CD3 comprises at least one Fab molecule that specifically binds to CD20, wherein the Fab molecule comprises the following six hypervariable regions (HVRs):

[0246] (i) HVR-H1 comprising the amino acid sequence of YSWIN (SEQ ID NO: 1);

[0247] (ii) HVR-H2 comprising the amino acid sequence of RIFPGDGDTDYNGKFKG (SEQ ID NO: 2);

[0248] (iii) HVR-H3 comprising the amino acid sequence of NVFDGYWLVY (SEQ ID NO: 3);

[0249] (iv) HVR-L1 comprising the amino acid sequence of RSSKSLLHSNGITYLY (SEQ ID NO: 4);

[0250] (v) HVR-L2 comprising the amino acid sequence of QMSNLVS (SEQ ID NO: 5); and

[0251] (vi) HVR-L3 comprising the amino acid sequence of AQNLELPYT (SEQ ID NO: 6).

[0252] In one embodiment, the bispecific antibody that binds to CD20 and CD3 includes at least one Fab molecule that specifically binds to CD20, the Fab molecule comprising: (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) the VH domain as in (a) and the VL domain as in (b).

[0253] In one embodiment, the 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.

[0254] In one embodiment, a bispecific antibody that binds to CD20 and CD3 comprises at least one Fab molecule that specifically binds to CD3, wherein the Fab molecule comprises the following six HVRs:

[0255] (i) HVR-H1 comprising the amino acid sequence of TYAMN (SEQ ID NO: 9);

[0256] (ii) HVR-H2 comprising the amino acid sequence of RIRSKYNNYATYYADSVKG (SEQ ID NO: 10);

[0257] (iii) HVR-H3 comprising the amino acid sequence of HGNFGNSYVSWFAY (SEQ ID NO: 11);

[0258] (iv) HVR-L1 comprising the amino acid sequence of GSSTGAVTTSNYAN (SEQ ID NO: 12);

[0259] (v) HVR-L2 comprising the amino acid sequence of GTNCRAP (SEQ ID NO: 13); and

[0260] (vi) HVR-L3 comprising the amino acid sequence of ALWYSNLWV (SEQ ID NO: 14).

[0261] In one embodiment, the bispecific antibody that binds to CD20 and CD3 includes at least one Fab molecule that specifically binds to CD3, the Fab molecule comprising: (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) the VH domain as in (a) and the VL domain as in (b).

[0262] In one embodiment, the 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.

[0263] In one embodiment, the bispecific antibody that binds to CD20 and CD3 is bivalent for CD20 and monovalent for CD3. In one embodiment, the 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, the bispecific antibody that binds to CD20 and CD3 is a humanized antibody. In one embodiment, the bispecific antibody that binds to CD20 and CD3 is gefuzumab.

[0264] In one embodiment, the bispecific antibody that binds to CD20 and CD3 is administered intravenously.

[0265] In one embodiment, the anti-CD20 antibody is administered intravenously.

[0266] 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's lymphoma (BL) or Burkitt's 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, prior systemic therapy includes an anti-CD20 antibody and an anthracycline.

[0267] In one embodiment, the subject is a human. In one embodiment, the subject is eligible for transplantation or CAR-T cell therapy.

[0268] In one embodiment, the subject receives autologous stem cell transplantation (ASCT) after completing the above-described dosing regimen. In one embodiment, ASCT is autologous hematopoietic stem cell transplantation. In one embodiment, the subject receives allogeneic hematopoietic stem cell transplantation after completing the above-described dosing regimen. In one embodiment, the subject receives CAR-T cell therapy after completing the above-described dosing regimen.

[0269] In one aspect, the invention features a bispecific antibody that binds to CD20 and CD3 for use in a method of treating a subject with a CD20-positive cell proliferative disorder, wherein the bispecific antibody that binds to 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 that includes at least a first dosing cycle and a second dosing cycle.

[0270] In one embodiment, the first dosing cycle comprises a first dose (C1D1) of a bispecific antibody that binds to CD20 and CD3 and a second dose (C1D2) of the bispecific antibody, wherein the 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 the 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

[0271] The second dosing cycle comprises a single dose of the 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). In one embodiment, the C2D1 of the bispecific antibody is administered to the subject on day 8 of the second dosing cycle.

[0272] In one embodiment, the anti-CD20 antibody is obinutuzumab and / or rituximab. In one embodiment, the first dosing cycle includes a single dose of obinutuzumab (C1D1); and the second dosing cycle includes 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 ±5mg / m 2 ±10mg / m 2 ±25mg / m 2 or ±37.5 mg / m 2 ).

[0273] 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).

[0274] In one aspect, the invention features a bispecific antibody that binds to CD20 and CD3 for use in a method of treating a subject with a CD20-positive cell proliferative disorder, wherein the bispecific antibody that binds to CD20 and CD3 is administered in combination with an anti-CD20 antibody, ifosfamide, carboplatin, and etoposide in a dosing regimen that includes at least a first dosing cycle and a second dosing cycle.

[0275] In one embodiment, the first administration cycle includes 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 the second cycle each includes a single dose of ifosfamide (C2D1), a single dose of carboplatin (C2D1), and a first dose (C2D1), a second dose (C2D2), and a third dose (C2D3) of etoposide. In one embodiment, the dosage of about 5000 mg / m 2 (e.g., 5000 mg / m 2 ±50mg / m 2 ±100mg / m 2 ±200mg / m 2 ±300mg / m 2 ±400mg / m 2 or ±500mg / m 2 ), about 4000mg / m 2 (For example, 4000 mg / m 2 ±40mg / m 2 ±50mg / m 2 ±100mg / m 2 ±200mg / m 2 ±300mg / m 2 or ±400 mg / m 2 ) or about 1666 mg / m 2 (e.g., 1666 mg / m 2 ±25mg / m 2 ±50mg / m 2 ±100mg / m 2 or ±166.6 mg / m 2), ifosfamide is administered in a dose in mg to a target 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 carboplatin is administered at a dose of about 100 mg / m 2 (e.g., 100 mg / m 2 ±1mg / m 2 ±2.5mg / m 2 ±5mg / m 2 or ±10 mg / m 2 ) or 75 mg / m 2 (e.g., 0.5 mg / m 2 ±1mg / m 2 ±2.5mg / m 2 ±5mg / m 2 or ±7.5 mg / m 2 In one embodiment, etoposide is administered at a dose of 5000 mg / m 2 4000mg / m 2 or 1666 mg / m 2 Ifosfamide was administered at a dose of 100 mg / mL / min, carboplatin was administered at a dose of 100 mg / mL / min to a target area under the curve (AUC) of 5 mg / mL / min with a maximum dose of 750 mg, and 2 or 75 mg / m 2 In one embodiment, etoposide is administered at a dose of 5000 mg / m 2 Ifosfamide was administered at a dose of 100 mg / mL / min, carboplatin was administered at a dose of 100 mg / mL / min to a target area under the curve (AUC) of 5 mg / mL / min with a maximum dose of 750 mg, and 2 In one embodiment, ifosfamide and carboplatin are administered on day 2 of the first and second dosing cycles, and etoposide is administered on each of days 1, 2, and 3 of the first and second dosing cycles.

[0276] In one embodiment, the first dosing cycle and the second dosing cycle are 21 day dosing cycles.

[0277] In one embodiment, the dosing regimen includes one or more additional dosing cycles. In one embodiment, the additional dosing cycle is a 21-day dosing cycle.

[0278] In one embodiment, the dosing regimen comprises three total dosing cycles.

[0279] In one embodiment, the one or more additional dosing cycles include:

[0280] (a) an additional single dose of a bispecific antibody that binds to CD20 and CD3,

[0281] (b) Additional single dose of anti-CD20 antibody

[0282] (c) an additional single dose of ifosfamide, an additional single dose of carboplatin, and additional first, second, and third doses of etoposide.

[0283] In one embodiment, the additional single dose of the bispecific antibody that binds to 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).

[0284] 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 ±5mg / m 2 ±10mg / m 2 ±25mg / m 2 or ±37.5 mg / m 2 In one embodiment, the additional single dose of rituximab is administered on day 1 of the additional dosing cycle.

[0285] In one embodiment, the additional single dose of ifosfamide is about 5000 mg / m 2 (e.g., 5000 mg / m 2 ±50mg / m 2 ±100mg / m 2 ±200mg / m 2 ±300mg / m 2 ±400mg / m 2 or ±500mg / m 2 ), about 4000mg / m 2 (For example, 4000 mg / m 2 ±40mg / m 2 ±50mg / m 2 ±100mg / m 2 ±200mg / m 2 ±300mg / m 2 or ±400 mg / m2 ) or about 1666 mg / m 2 (e.g., 1666 mg / m 2 ±25mg / m 2 ±50mg / m 2 ±100mg / m 2 or ±166.6 mg / m 2 ), an additional single dose of carboplatin in mg to a target 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 additional first, second, and third doses of etoposide of 100 mg / m 2 (e.g., 100 mg / m 2 ±1mg / m 2 ±2.5mg / m 2 ±5mg / m 2 or ±10 mg / m 2 ) or 75 mg / m 2 (e.g., 0.5 mg / m 2 ±1mg / m 2 ±2.5mg / m 2 ±5mg / m 2 or ±7.5 mg / m 2 In one embodiment, the additional single dose of ifosfamide is 5000 mg / m 2 4000mg / m 2 or 1666 mg / m 2 , additional single doses of carboplatin in mg to a target area under the curve (AUC) of 5 mg / mL / min with a maximum dose of 750 mg, and additional first, second, and third doses of etoposide in mg to 100 mg / mL / min 2 or 75 mg / m 2 .

[0286] In one embodiment, 5000 mg / m 2 Ifosfamide was administered at a dose of 100 mg / mL / min, carboplatin was administered at a dose of 100 mg / mL / min to a target area under the curve (AUC) of 5 mg / mL / min with a maximum dose of 750 mg, and 2 Etoposide was administered at a dose of .

[0287] In one embodiment, ifosfamide and carboplatin are administered on day 2 of the additional dosing cycle, and etoposide is administered on each of days 1, 2, and 3 of the additional dosing cycle.

[0288] In one embodiment, the method further comprises: administering one or more additional therapeutic agents to the subject. In one embodiment, the bispecific antibody is used in combination with one or more additional therapeutic agents. In one embodiment, the one or more additional therapeutic agents are tocilizumab. In one embodiment, the subject's body weight is greater than or equal to about 30 kg, and tocilizumab is administered at a dosage 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's body weight is less than 30 kg, and tocilizumab is administered at a dosage 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).

[0289] In one embodiment, the one or more additional therapeutic agents is a corticosteroid.

[0290] In one embodiment, corticosteroids include prednisone, prednisolone, methylprednisolone or dexamethasone. 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 one hour (i.e., at least one 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 one hour (i.e., at least one 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, wherein 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 one hour (i.e., at least one 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 one hour (i.e., at least one 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 orally administered 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 one hour (i.e., at least one 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 one hour (i.e., at least one 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.

[0291] In one embodiment, the one or more additional therapeutic agents is an antihistamine.

[0292] 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.

[0293] In some embodiments, the one or more additional therapeutic agents include G-CSF. In one embodiment, G-CSF is administered between about one and about two 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.

[0294] In one embodiment, one or more additional therapeutic agents are antipyretics. In one embodiment, the antipyretic is acetaminophen or paracetamol. In one embodiment, acetaminophen or paracetamol is orally administered at a dosage of about 500 mg to about 1000 mg for at least about 30 minutes (i.e., at least 30 minutes ± 3 minutes; For example, at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours or more) before the administration of any dose of the bispecific antibody. In one embodiment, acetaminophen or paracetamol is orally administered at a dosage of about 500 mg to about 1000 mg for at least about 30 minutes (i.e., at least 30 minutes ± 3 minutes; For example, at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours or more) before the administration of any dose of obinutuzumab.

[0295] In one embodiment, the one or more additional therapeutic agents is mesna. In one embodiment, the dosage is about 5000 mg / m2 , about 4000mg / m 2 or about 1666 mg / m 2 In one embodiment, mesna is administered intravenously at a dose of 1 mg / dL. In one embodiment, mesna is administered via continuous infusion over about 24 hours on day 2 of each dosing cycle. In one embodiment, mesna is administered concurrently with any dose of ifosfamide.

[0296] In one aspect, the invention features a bispecific antibody that binds to CD20 and CD3 for use in a method of treating a subject between the ages of 6 months and 17 years with a CD20-positive cell proliferative disorder, wherein the bispecific antibody that binds to CD20 and CD3 is to be 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 that includes at least a first dosing cycle and a second dosing cycle.

[0297] In one embodiment, the first dosing 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 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 2.5 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 bispecific antibody has a C1D2 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) 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); and

[0298] The second dosing cycle comprises a single dose (C2D1) of the bispecific antibody, 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).

[0299] In one embodiment, (a) the subject weighs greater than or equal to about 7.5 kg and less than about 13 kg, and wherein 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 The bispecific antibody comprises an antibody having a C2D1 of 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);

[0300] (b) the subject weighs greater than or equal to about 13 kg and less than about 45 kg, and wherein the 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), the 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 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); or

[0301] (c) the subject weighs greater than or equal to about 45 kg, and wherein the 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), the 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 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).

[0302] In one embodiment, bispecific antibody C1D1 and bispecific antibody C1D2 are administered to the subject on day 8 and day 15 of the first dosing cycle, respectively. In one embodiment, bispecific antibody C2D1 is administered to the subject on day 1 of the second dosing cycle.

[0303] In one embodiment, the anti-CD20 antibody is obinutuzumab and / or rituximab.

[0304] In one embodiment, the first dosing cycle includes a first dose of inutuzumab (C1D1) and a second dose of inutuzumab (C1D2). In one embodiment, (a) the subject weighs greater than or equal to about 7.5 kg and less than about 13 kg, and wherein the sum of C1D1 and C1D2 of inutuzumab 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 greater than or equal to about 13 kg and less than about 20 kg, and wherein the sum of C1D1 and C1D2 of inutuzumab 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 greater than or equal to about 20 kg and less than about 32 kg, and wherein the C1D1 and C1D2 of inutuzumab are about 38 mg / kg (e.g., 38 mg / kg ± 0.25 mg / kg, ± 0.5 mg / kg, ± 1 mg / kg, ± 2 mg / kg, or ± 3.8 mg / kg); (d) the subject weighs greater than or equal to about 32 kg and less than about 45 kg, and wherein the sum of the C1D1 and the C1D2 of obinutuzumab is 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 (e) the subject weighs greater than or equal to about 45 kg, and wherein the sum of the C1D1 and the 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).

[0305] In one embodiment, C1D1 of obinutuzumab is about one-tenth the amount of the sum of C1D1 and C1D2 of obinutuzumab, and C1D2 of obinutuzumab is about nine-tenths the amount 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 wherein 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 wherein The C1D1 of inutuzumab is about 2.8 mg / kg (e.g., 2.8 mg / kg ± 0.05 mg / kg, 0.1 mg / kg, ± 0.2 mg / kg, or ± 0.28 mg / kg), and the C1D2 of inutuzumab 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); (c) the subject weighs greater than or equal to about 20 kg and less than about 32 kg, and wherein the C1D1 of inutuzumab is about 2.3 mg / kg (e.g., 2.3 mg / kg ± 0.05 mg / kg, 0.1 (d) the subject weighs greater than or equal to about 32 kg and less than about 45 kg, and wherein the C1D1 of inutuzumab 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 inutuzumab is about 35.7 mg / kg (e.g., 35.7 mg / kg ± 0.5 mg / kg, 1 mg / kg, ± 2 mg / kg, ± 3 mg / kg or ± 3.57 mg / kg); .0 mg / kg ± 0.5 mg / kg, 1 mg / kg, ± 2 mg / kg, ± 3 mg / kg, or ± 3.6 mg / kg); or (e) the subject weighs greater than or equal to about 45 kg, and wherein the C1D1 of inutuzumab 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 inutuzumab 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).

[0306] In one embodiment, C1D1 of inutuzumab is to be administered to the subject on day 1 of the first dosing cycle, and C1D2 of inutuzumab is to be administered to the subject on day 2 of the first dosing cycle.

[0307] In one embodiment, the second dosing 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 ±5mg / m 2 ±10mg / m 2 ±25mg / m 2 or ±37.5 mg / m 2 In one embodiment, rituximab is administered to the subject on day 5 of the second dosing cycle.

[0308] In one embodiment, the method comprises administering to the subject ifosfamide, carboplatin, and etoposide.

[0309] In one embodiment, the first dosing cycle comprises:

[0310] (a) first dose of ifosfamide (C1D1), second dose of ifosfamide (C1D2), and third dose of ifosfamide (C1D3);

[0311] (b) a single dose of carboplatin (C1D1); and

[0312] (c) a first dose of etoposide (C1D1), a second dose of etoposide (C1D2), and a third dose of etoposide (C1D3);

[0313] And the second cycle includes:

[0314] (a) first dose of ifosfamide (C2D1), second dose of ifosfamide (C2D2), and third dose of ifosfamide (C2D3);

[0315] (b) a single dose of carboplatin (C2D1); and

[0316] (c) A first dose of etoposide (C2D1), a second dose of etoposide (C2D2), and a third dose of etoposide (C2D3).

[0317] In one embodiment, the dosage is about 3000 mg / m 2 (For example, 3000 mg / m 2 ±40mg / m 2 ±50mg / m 2 ±100mg / m 2±200mg / m 2 or ±300 mg / m 2 ) for each dose of ifosfamide, to be administered at a dose of approximately 635 mg / m 2 (e.g., 635 mg / m 2 ±5mg / m 2 ±10mg / m 2 ±25mg / m 2 ±50mg / m 2 ±60mg / m 2 or ±63.5 mg / m 2 Carboplatin is administered at a dose of about 100 mg / m 2 (e.g., 100 mg / m 2 ±1mg / m 2 ±2.5mg / m 2 ±5mg / m 2 or ±10 mg / m 2 ) for each dose of etoposide. In one embodiment, (a) C1D1, C1D2, and C1D3 of ifosfamide are to be administered on day 3, day 4, and day 5, respectively, of the first dosing cycle; (b) C1D1 of carboplatin is to be administered on day 3 of the first dosing cycle; (c) C1D1, C1D2, and C1D3 of etoposide are to be administered on day 3, day 4, and day 5, respectively, of the first dosing cycle; (d) C2D1, C2D2, and C2D3 of ifosfamide are to be administered on day 6, day 7, and day 8, respectively, of the second dosing cycle; (e) C2D1 of carboplatin is to be administered on day 6 of the second dosing cycle; and (f) C2D1, C2D2, and C2D3 of etoposide are to be administered on day 6, day 7, and day 8, respectively, of the second dosing cycle.

[0318] In one embodiment, the first dosing cycle and the second dosing cycle are each a 21-day dosing cycle. In one embodiment, the dosing regimen includes one or more additional dosing cycles. In one embodiment, the one or more additional dosing cycles are each a 21-day dosing cycle. In one embodiment, the dosing regimen includes three dosing cycles in total.

[0319] In one embodiment, the one or more additional dosing cycles each comprise:

[0320] (a) an additional single dose of a bispecific antibody that binds to CD20 and CD3,

[0321] (b) an additional single dose of anti-CD20 antibody, and

[0322] (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 greater than or equal to about 7.5 kg and less than about 13 kg, and wherein 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 greater than or equal to about 13 kg and less than about 45 kg, and wherein the additional single dose of the bispecific antibody is or (c) the subject has a body weight of greater than or equal to about 45 kg, and wherein 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).

[0323] In one embodiment, an additional single dose of the bispecific antibody is administered to the subject on day 1 of each of the one or more additional dosing cycles.

[0324] 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 ±5mg / m 2 ±10mg / m 2 ±25mg / 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 the one or more additional dosing cycles.

[0325] In one embodiment, the additional first dose, additional second dose, and additional third dose of ifosfamide are each about 3000 mg / m 2 (For example, 3000 mg / m 2 ±40mg / m 2 ±50mg / m 2 ±100mg / m 2 ±200mg / m 2 or ±300 mg / m 2), an additional single dose of carboplatin of approximately 635 mg / m 2 (e.g., 635 mg / m 2 ±5mg / m 2 ±10mg / m 2 ±25mg / m 2 ±50mg / m 2 ±60mg / m 2 or ±63.5 mg / m 2 ), 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 ±1mg / m 2 ±2.5mg / m 2 ±5mg / m 2 or ±10 mg / m 2 In 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 the one or more additional dosing cycles; (b) an additional single dose of carboplatin is administered on day 6 of each of the one or more additional dosing 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 the one or more additional dosing cycles.

[0326] In one embodiment, the method further comprises administering one or more additional therapeutic agents to the subject.

[0327] In one embodiment, the one or more additional therapeutic agents is tocilizumab. In one embodiment, the subject has a body weight greater than or equal to about 30 kg and is administered tocilizumab 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 has a body weight less than 30 kg and is administered tocilizumab 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), and wherein the maximum dose is about 800 mg (e.g., 800 mg ± 10 mg, ± 25 mg, ± 50 mg, or ± 80 mg).

[0328] In one embodiment, the one or more additional therapeutic agents are corticosteroids. In one embodiment, the corticosteroids include prednisone, prednisolone, methylprednisolone, or dexamethasone.

[0329] In one embodiment, the corticosteroid is dexamethasone. In one embodiment, dexamethasone is administered intravenously at a dose of between 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 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) prior to administration of any dose of the bispecific antibody, and wherein the maximum daily dose is 10 mg. In one embodiment, dexamethasone is administered intravenously at a dose of between 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 one hour (i.e., at least one 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, and wherein the maximum daily dose is 10 mg.

[0330] In one embodiment, the corticosteroid is methylprednisolone. In one embodiment, methylprednisolone is administered intravenously at a dose of between about 1 mg / kg and 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 one hour (i.e., at least one 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 between 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 one hour (i.e., at least one 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.

[0331] In one embodiment, the corticosteroid is prednisone or prednisolone. 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 one hour (i.e., at least one 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) from the 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 one hour (i.e., at least one 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.

[0332] In one embodiment, the one or more additional therapeutic agents are antihistamines. In one embodiment, the antihistamine is diphenhydramine. In one embodiment, the subject is between 2 and 17 years old, and wherein diphenhydramine is to be administered intravenously at a dose of between about 10 mg and 20 mg (e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 mg), wherein the maximum single dose is about 1.25 mg / kg. In one embodiment, the subject is less than two years old, and wherein diphenhydramine is to 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 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.

[0333] In one embodiment, the one or more additional therapeutic agents include granulocyte colony stimulating factor (G-CSF). In one embodiment, G-CSF is administered between about one and about two 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 a first dosing cycle and at a dose of 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 a second dosing cycle and / or each additional dosing cycle.

[0334] In one embodiment, one or more additional therapeutic agents are antipyretics. In one embodiment, the antipyretic is acetaminophen or paracetamol. In one embodiment, 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, 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) before any dose of the bispecific antibody and / or anti-CD20 antibody.

[0335] In one embodiment, the one or more additional therapeutic agents is mesna. In one embodiment, the total amount is 3000 mg / m 2 In one embodiment, mesna is administered intravenously at about 600 mg / m2 before any dose of ifosfamide is administered. 2 The first dose is about 600 mg / m 2 Mesna is administered intravenously for four repeat doses of about 1 hour, about 6 hours, and about 12 hours after the first dose of ifosfamide. In one embodiment, mesna is administered to the subject daily on days 3, 4, and 5 of the first dosing cycle, on days 6, 7, and 8 of the second dosing cycle, and / or on days 6, 7, and 8 of each additional dosing cycle.

[0336] In one aspect, the invention features a bispecific antibody that binds to CD20 and CD3 for use in a method of treating a subject between the ages of 18 and 30 years old with a CD20-positive cell proliferative disorder, wherein the bispecific antibody that binds to CD20 and CD3 is to be 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 that includes at least a first dosing cycle and a second dosing cycle.

[0337] In one embodiment, the first dosing 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 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 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

[0338] The second dosing cycle comprises a single dose of the bispecific antibody (C2D1), wherein 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).

[0339] In one embodiment, bispecific antibody C1D1 and bispecific antibody C1D2 are administered to the subject on day 8 and day 15, respectively, of the first dosing cycle.

[0340] In one embodiment, the bispecific antibody C2D1 is administered to the subject on day 1 of the second dosing cycle.

[0341] In one embodiment, the anti-CD20 antibody is obinutuzumab and / or rituximab.

[0342] In one embodiment, the first dosing cycle includes a first dose (C1D1) of Utuzumab and a second dose (C1D2) of Utuzumab. In one embodiment, the sum of C1D1 and C1D2 of Utuzumab 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 Utuzumab is about one-tenth the amount of the sum of C1D1 and C1D2 of Utuzumab, and C1D2 of Utuzumab is about nine-tenths the amount of the sum of C1D1 and C1D2 of Utuzumab. In one embodiment, the C1D1 of Utuzumab 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 Utuzumab 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, the C1D1 of Utuzumab is administered to the subject on day 1 of the first dosing cycle, and the C1D2 of Utuzumab is administered to the subject on day 2 of the first dosing cycle.

[0343] In one embodiment, the second dosing 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 ±5mg / m 2 ±10mg / m 2 ±25mg / m 2 or ±37.5 mg / m 2 In one embodiment, C2D1 of rituximab is administered to the subject on day 5 of the second dosing cycle.

[0344] In one embodiment, the method comprises administering to a subject ifosfamide, carboplatin, and etoposide. In one embodiment, a first administration cycle comprises:

[0345] (a) Single dose of ifosfamide (C1D1);

[0346] (b) a single dose of carboplatin (C1D1); and

[0347] (c) a first dose of etoposide (C1D1), a second dose of etoposide (C1D2), and a third dose of etoposide (C1D3);

[0348] And the second cycle includes:

[0349] (a) Single dose of ifosfamide (C2D1);

[0350] (b) a single dose of carboplatin (C2D1); and

[0351] (c) A first dose of etoposide (C2D1), a second dose of etoposide (C2D2), and a third dose of etoposide (C2D3).

[0352] In one embodiment, the dosage is about 5000 mg / m 2 (e.g., 5000 mg / m 2 ±50mg / m 2 ±100mg / m 2 ±200mg / m 2 ±300mg / m 2 ±400mg / m 2 or ±500mg / m 2 ), ifosfamide is to 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 carboplatin is to be administered at a dose of about 100 mg / m 2 (e.g., 100 mg / m 2 ±1mg / m 2 ±2.5mg / m 2 ±5mg / m 2 or ±10 mg / m 2 ) for each dose of etoposide.

[0353] In one embodiment, (a) the subject is male and CrCl is calculated using the formula CrCl = ([140 - age] × [body weight (kg)]) / (72 × [serum creatinine (mg / dL)]); or (b) the subject is female and CrCl is calculated using the formula CrCl = 0.85 × ([140 - age] × [body weight (kg)]) / (72 × [serum creatinine (mg / dL)]).

[0354] In one embodiment, (a) the subject has a CrCl of < about 60 mL / min, and each single dose of ifosfamide is reduced to 4000 mg / m 2 and / or (b) the subject has a CrCl of < about 50 mL / min, and wherein each dose of etoposide is reduced to 75 mg / m 2 .

[0355] In one embodiment, (a) C1D1 ifosfamide is administered on day 3 of the first dosing cycle;

[0356] (b) C1D1 in which carboplatin is to be administered on day 3 of the first dosing cycle;

[0357] (c) C1D1, C1D2, and C1D3 to which etoposide is to be administered on days 3, 4, and 5 of the first dosing cycle, respectively;

[0358] (d) C2D1 to be administered with ifosfamide on day 6 of the second dosing cycle;

[0359] (e) C2D1 in which carboplatin is to be administered on day 6 of the second dosing cycle; and

[0360] (f) C2D1, C2D2, and C2D3 to which etoposide is to be administered on Day 6, Day 7, and Day 8 of the second dosing cycle, respectively.

[0361] In one embodiment, the first dosing cycle and the second dosing cycle are each a 21-day dosing cycle. In one embodiment, the dosing regimen includes one or more additional dosing cycles. In one embodiment, the one or more additional dosing cycles are each a 21-day dosing cycle. In one embodiment, the dosing regimen includes three dosing cycles in total.

[0362] In one embodiment, the one or more additional dosing cycles each comprise:

[0363] (a) an additional single dose of a bispecific antibody that binds to CD20 and CD3,

[0364] (b) an additional single dose of anti-CD20 antibody, and

[0365] (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.

[0366] 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 the one or more additional dosing cycles.

[0367] 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 ±5mg / m2 ±10mg / m 2 ±25mg / 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 the one or more additional dosing cycles.

[0368] In one embodiment, the additional single dose of ifosfamide is about 5000 mg / m 2 (e.g., 5000 mg / m 2 ±50mg / m 2 ±100mg / m 2 ±200mg / m 2 ±300mg / m 2 ±400mg / m 2 or ±500mg / m 2 ), an additional single dose of carboplatin 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 an additional first dose, an additional second dose, and an additional third dose of etoposide each of about 100 mg / m 2 (e.g., 100 mg / m 2 ±1mg / m 2 ±2.5mg / m 2 ±5mg / m 2 or ±10 mg / m 2 ).

[0369] In one embodiment, (a) the subject is male, and wherein CrCl is calculated using the formula CrCl = ([140 - age] × [body weight (kg)]) / (72 × [serum creatinine (mg / dL)]); or (b) the subject is female, and wherein CrCl is calculated using the formula CrCl = 0.85 × ([140 - age] × [body weight (kg)]) / (72 × [serum creatinine (mg / dL)]).

[0370] In one embodiment, (a) the subject has a CrCl of < about 60 mL / min and the additional single dose of ifosfamide is reduced to 4000 mg / m 2 and / or (b) the subject has a CrCl of < about 50 mL / min, and wherein each additional dose of etoposide is reduced to 75 mg / m 2 .

[0371] In one embodiment, (a) an additional single dose of ifosfamide is administered on day 6 of each of the one or more additional dosing cycles;

[0372] (b) administering an additional single dose of carboplatin on day 6 of each of the one or more additional dosing cycles; and

[0373] (c) administering to the subject an additional first dose, an additional second dose, and an additional third dose of etoposide on day 6, day 7, and day 8, respectively, of each of the one or more additional dosing cycles.

[0374] In one embodiment, the method further comprises administering one or more additional therapeutic agents to the subject.

[0375] In one embodiment, the one or more additional therapeutic agents is tocilizumab. In one embodiment, the subject has a body weight greater than or equal to about 30 kg and is administered tocilizumab 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 has a body weight less than 30 kg and is administered tocilizumab 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), and wherein the maximum dose is about 800 mg (e.g., 800 mg ± 10 mg, ± 25 mg, ± 50 mg, or ± 80 mg).

[0376] In one embodiment, the one or more additional therapeutic agents is a corticosteroid.

[0377] In one embodiment, the corticosteroid comprises prednisone, prednisolone, methylprednisolone, or dexamethasone.

[0378] In one embodiment, the corticosteroid is dexamethasone. In one embodiment, dexamethasone is administered intravenously at a dose of between 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 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) prior to administration of any dose of the bispecific antibody, and wherein the maximum daily dose is 10 mg. In one embodiment, dexamethasone is administered intravenously at a dose of between 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 one hour (i.e., at least one 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, and wherein the maximum daily dose is 10 mg.

[0379] In one embodiment, the corticosteroid is methylprednisolone. In one embodiment, methylprednisolone is administered intravenously at a dose of between about 1 mg / kg and 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 one hour (i.e., at least one 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 between 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 one hour (i.e., at least one 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.

[0380] In one embodiment, the corticosteroid is prednisone or prednisolone. 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 one hour (i.e., at least one 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 one hour (i.e., at least one 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.

[0381] In one embodiment, the one or more additional therapeutic agents are antihistamines. 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 the bispecific antibody and / or anti-CD20 antibody.

[0382] In one embodiment, the one or more additional therapeutic agents include granulocyte colony stimulating factor (G-CSF). In one embodiment, G-CSF is administered between about one and about two 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 a first dosing cycle and at a dose of 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 a second dosing cycle and / or each additional dosing cycle.

[0383] In one embodiment, one or more additional therapeutic agents are antipyretics. In one embodiment, the antipyretic is acetaminophen or paracetamol. In one embodiment, 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, 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) before any dose of the bispecific antibody and / or anti-CD20 antibody.

[0384] In one embodiment, the one or more additional therapeutic agents is mesna. In one embodiment, the dosage is about 5000 mg / m 2 (e.g., 5000 mg / m 2 ±50mg / m 2 ±100mg / m 2 ±200mg / m 2 ±300mg / m 2 ±400mg / m 2 or ±500mg / m 2 In one embodiment, mesna is administered via 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 concurrently with any dose of ifosfamide.

[0385] In one aspect, the invention features gefizumab for use in a method of treating a subject with a CD20-positive cell proliferative disorder, wherein gefizumab is to be administered in combination with obinutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen that includes at least a first dosing cycle and a second dosing cycle, wherein

[0386] (a) a first dosing cycle comprising administering a first dose of gefizumab (C1D1) on day 8 and administering a second dose of gefizumab (C1D2) on day 15, wherein the C1D1 of gefizumab 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 gefizumab 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

[0387] (b) The second dosing cycle comprises administering a single dose of gefizumab on day 8 (C2D1), wherein the C2D1 of gefizumab 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).

[0388] In one aspect, the invention features gefizumab for use in a method of treating a subject with a CD20-positive cell proliferative disorder, wherein gefizumab is to be administered in combination with obinutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen that includes a first dosing cycle, a second dosing cycle, and a third dosing cycle, wherein

[0389] (a) a first dosing cycle comprising administering a first dose of gefizumab (C1D1) on day 8 and administering a second dose of gefizumab (C1D2) on day 15, wherein the C1D1 of gefizumab 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 gefizumab 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);

[0390] (b) the second dosing cycle comprises administering a single dose of gefizumab on day 8 (C2D1), wherein the C2D1 of gefizumab 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); and

[0391] (c) The third dosing cycle comprises administering a single dose of gefizumab on day 8 (C3D1), wherein the C3D1 of gefizumab 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).

[0392] In one aspect, the invention features gefizumab for use in a method of treating a subject with a CD20-positive cell proliferative disorder, wherein gefizumab is to be administered in combination with obinutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen that includes at least a first dosing cycle and a second dosing cycle, wherein

[0393] (a) The first dosing cycle includes:

[0394] (i) administering a first dose of gefizumab (C1D1) on day 8 and a second dose of gefizumab (C1D2) on day 15, wherein the C1D1 of gefizumab 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 gefizumab 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);

[0395] (ii) administering a first dose of obinutuzumab on day 1 (C1D1), wherein the 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);

[0396] (iii) administering a single dose of ifosfamide on day 2 (C1D1), wherein the C1D1 of ifosfamide is approximately 5000 mg / m 2 (e.g., 5000 mg / m 2 ±50mg / m 2 ±100mg / m 2 ±200mg / m 2 ±300mg / m 2 ±400mg / m 2 or ±500mg / m 2 ), with a maximum dose of about 800 mg (e.g., 800 mg ± 10 mg, ± 25 mg, ± 50 mg, or ± 80 mg);

[0397] (iv) administering a single dose of carboplatin on day 2 (C1D1), wherein the C1D1 of carboplatin is approximately 5×(25+creatinine clearance) mg; and

[0398] (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, wherein C1D1, C1D2, and C1D3 of etoposide are each about 100 mg / m 2 (e.g., 100 mg / m 2 ±1mg / m 2 ±2.5mg / m 2 ±5mg / m 2 or ±10 mg / m 2 );as well as

[0399] (b) The second dosing cycle includes:

[0400] (i) administering a single dose of gefizumab on day 8 (C2D1), wherein the C2D1 of gefizumab 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);

[0401] (ii) administering the first dose of rituximab on day 1 (C2D1), wherein the C2D1 of rituximab is approximately 375 mg / m 2 (e.g., 375 mg / m 2 ±5mg / m 2 ±10mg / m 2 ±25mg / m 2 or ±37.5 mg / m 2 );

[0402] (iii) administering a single dose of ifosfamide on day 2 (C2D1), wherein the C2D1 of ifosfamide is approximately 5000 mg / m 2 (e.g., 5000 mg / m 2 ±50mg / m 2 ±100mg / m 2 ±200mg / m 2 ±300mg / m 2 ±400mg / m 2 or ±500mg / m 2 ), with a maximum dose of about 800 mg (e.g., 800 mg ± 10 mg, ± 25 mg, ± 50 mg, or ± 80 mg);

[0403] (iv) administering a single dose of carboplatin on day 2 (C2D1), wherein the C2D1 of carboplatin is approximately 5 x (25 + creatinine clearance) mg; and

[0404] (v) administering a first dose of etoposide on day 1 (C2D1), administering a second dose of etoposide on day 2 (C2D2), and administering a third dose of etoposide on day 3 (C2D3), wherein each of C2D1, C2D2, and C2D3 of etoposide is about 100 mg / m 2 (e.g., 100 mg / m 2 ±1mg / m 2 ±2.5mg / m 2 ±5mg / m 2 or ±10 mg / m 2 ).

[0405] In one aspect, the invention features gefizumab for use in a method of treating a subject with a CD20-positive cell proliferative disorder, wherein gefizumab is to be administered in combination with obinutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen that includes a first dosing cycle, a second dosing cycle, and a third dosing cycle, wherein

[0406] (a) The first dosing cycle includes:

[0407] (i) administering a first dose of gefizumab (C1D1) on day 8 and a second dose of gefizumab (C1D2) on day 15, wherein the C1D1 of gefizumab 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 gefizumab 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);

[0408] (ii) administering a first dose of obinutuzumab on day 1 (C1D1), wherein the 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);

[0409] (iii) administering a single dose of ifosfamide on day 2 (C1D1), wherein the C1D1 of ifosfamide is approximately 5000 mg / m 2 (e.g., 5000 mg / m 2 ±50mg / m 2 ±100mg / m 2 ±200mg / m 2 ±300mg / m 2 ±400mg / m 2 or ±500mg / m 2 ), with a maximum dose of about 800 mg (e.g., 800 mg ± 10 mg, ± 25 mg, ± 50 mg, or ± 80 mg);

[0410] (iv) administering a single dose of carboplatin on day 2 (C1D1), wherein the C1D1 of carboplatin is approximately 5×(25+creatinine clearance) mg; and

[0411] (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, wherein C1D1, C1D2, and C1D3 of etoposide are each about 100 mg / m 2 (e.g., 100 mg / m 2 ±1mg / m 2 ±2.5mg / m 2 ±5mg / m 2 or ±10 mg / m 2 );

[0412] (b) The second dosing cycle includes:

[0413] (i) administering a single dose of gefizumab on day 8 (C2D1), wherein the C2D1 of gefizumab 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);

[0414] (ii) administering the first dose of rituximab on day 1 (C2D1), wherein the C2D1 of rituximab is approximately 375 mg / m 2 (e.g., 375 mg / m 2 ±5mg / m 2 ±10mg / m 2 ±25mg / m 2 or ±37.5 mg / m 2 );

[0415] (iii) administering a single dose of ifosfamide on day 2 (C2D1), wherein the C2D1 of ifosfamide is approximately 5000 mg / m 2 (e.g., 5000 mg / m 2 ±50mg / m 2 ±100mg / m 2 ±200mg / m 2 ±300mg / m 2 ±400mg / m 2 or ±500mg / m 2 ), with a maximum dose of about 800 mg (e.g., 800 mg ± 10 mg, ± 25 mg, ± 50 mg, or ± 80 mg);

[0416] (iv) administering a single dose of carboplatin on day 2 (C2D1), wherein the C2D1 of carboplatin is approximately 5 x (25 + creatinine clearance) mg; and

[0417] (v) administering a first dose of etoposide on day 1 (C2D1), administering a second dose of etoposide on day 2 (C2D2), and administering a third dose of etoposide on day 3 (C2D3), wherein each of C2D1, C2D2, and C2D3 of etoposide is about 100 mg / m 2 (e.g., 100 mg / m 2 ±1mg / m 2 ±2.5mg / m 2 ±5mg / m 2 or ±10 mg / m 2 );as well as

[0418] (c) The third dosing cycle includes:

[0419] (i) administering a single dose of gefizumab on day 8 (C3D1), wherein the C3D1 of gefizumab 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);

[0420] (ii) administering the first dose of rituximab on day 1 (C3D1), wherein the C3D1 of rituximab is approximately 375 mg / m 2 (e.g., 375 mg / m 2 ±5mg / m 2 ±10mg / m 2 ±25mg / m 2 or ±37.5 mg / m 2 );

[0421] (iii) administering a single dose of ifosfamide on day 2 (C3D1), wherein the C3D1 of ifosfamide is approximately 5000 mg / m 2 (e.g., 5000 mg / m 2 ±50mg / m 2 ±100mg / m 2 ±200mg / m 2 ±300mg / m 2 ±400mg / m 2 or ±500mg / m 2 ), with a maximum dose of about 800 mg (e.g., 800 mg ± 10 mg, ± 25 mg, ± 50 mg, or ± 80 mg);

[0422] (iv) administering a single dose of carboplatin on day 2 (C3D1), wherein the C3D1 of carboplatin is approximately 5 x (25 + creatinine clearance) mg; and

[0423] (v) administering a first dose of etoposide on day 1 (C3D1), administering a second dose of etoposide on day 2 (C3D2), and administering a third dose of etoposide on day 3 (C3D3), wherein each of C3D1, C3D2, and C3D3 of etoposide is about 100 mg / m 2 (e.g., 100 mg / m 2 ±1mg / m 2 ±2.5mg / m 2 ±5mg / m 2 or ±10 mg / m 2 ).

[0424] In one embodiment, mesna is administered concurrently with any dose of ifosfamide. In one embodiment, mesna is administered at about 5000 mg / m 2 (e.g., 5000 mg / m 2 ±50mg / m 2 ±100mg / m 2 ±200mg / m 2 ±300mg / m 2 ±400mg / m 2 or ±500mg / m 2 In one embodiment, mesna is administered via continuous infusion over about 24 hours on day 2 of each dosing cycle.

[0425] In one aspect, the invention features a method of treating a subject between the ages of 6 months and 17 years old with a CD20-positive cell proliferative disorder, the method comprising administering to the subject an effective amount of gefiruzumab, obinutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein

[0426] (a) The first dosing cycle comprises administering a first dose of gefizumab (C1D1) on day 8 and administering a second dose of gefizumab (C1D2) on day 15, wherein the C1D1 of gefizumab 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), 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 gefizumab 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); and

[0427] (b) the second dosing cycle comprises administering a single dose of gefizumab on day 8 (C2D1), wherein the C2D1 of gefizumab 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).

[0428] In one aspect, the invention features a method of treating a subject between the ages of 6 months and 17 years old with a CD20-positive cell proliferative disorder, the method comprising administering to the subject an effective amount of gefiruzumab, obinutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen comprising a first dosing cycle, a second dosing cycle, and a third dosing cycle, wherein

[0429] (a) the first dosing cycle comprises administering a first dose of gefizumab (C1D1) on day 8 and administering a second dose of gefizumab (C1D2) on day 15, wherein the C1D1 of gefizumab 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), 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 gefituzumab 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);

[0430] (b) a second dosing cycle comprising administering a single dose of gefizumab on day 8 (C2D1), wherein the C2D1 of gefizumab 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); and

[0431] (c) The third dosing cycle comprises administering a single dose of gefizumab on day 8 (C3D1), wherein the C3D1 of gefizumab 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).

[0432] In one aspect, the invention features a method of treating a subject between the ages of 6 months and 17 years old with a CD20-positive cell proliferative disorder, the method comprising administering to the subject an effective amount of gefiruzumab, obinutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein

[0433] (a) The first dosing cycle includes:

[0434] (i) administering a first dose of gefizumab (C1D1) on day 8 and a second dose of gefizumab (C1D2) on day 15, wherein the C1D1 of gefizumab 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), or about 2.5

[0015] The present invention relates to an oral dosage form of gefizumab 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) 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) wherein the dosage form is 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);

[0435] (ii) administering a first dose of inutuzumab (C1D1) on day 1 and a second dose of inutuzumab (C1D2) on day 2, wherein C1D1 of inutuzumab is about one-tenth the amount of the sum of C1D1 and C1D2 of inutuzumab, and C1D2 of inutuzumab is about nine-tenths the amount of the sum of C1D1 and C1D2 of inutuzumab, and wherein the sum of C1D1 and C1D2 of inutuzumab 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 or about 1000 mg (e.g., 1000 mg ±5 mg, ±10 mg, ±20 mg, ±30 mg, ±50 mg, ±75 mg or ±100 mg);

[0436] (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, wherein each of ifosfamide C1D1, C1D2, and C1D3 is about 3000 mg / m 2 (For example, 3000 mg / m 2 ±40mg / m 2 ±50mg / m 2 ±100mg / m 2 ±200mg / m 2 or ±300 mg / m 2 );

[0437] (iv) administering a single dose of carboplatin on day 3 (C1D1), wherein the C1D1 of carboplatin is approximately 635 mg / m 2 (e.g., 635 mg / m 2 ±5mg / m 2 ±10mg / m 2 ±25mg / m 2 ±50mg / m 2 ±60mg / m 2 or ±63.5 mg / m 2 );as well as

[0438] (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, wherein C1D1, C1D2, and C1D3 of etoposide are each about 100 mg / m 2 (e.g., 100 mg / m 2 ±1mg / m 2 ±2.5mg / m 2 ±5mg / m 2 or ±10 mg / m 2 );as well as

[0439] (b) The second dosing cycle includes:

[0440] (i) administering a single dose of gefizumab on day 1 (C2D1), wherein the C2D1 of gefizumab 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);

[0441] (ii) administering the first dose of rituximab on day 5 (C2D1), wherein the C2D1 of rituximab is approximately 375 mg / m 2 (e.g., 375 mg / m 2 ±5mg / m 2 ±10mg / m 2 ±25mg / m 2 or ±37.5 mg / m 2 );

[0442] (iii) administering a first dose of ifosfamide (C2D1) on day 6, a second dose of ifosfamide (C2D2) on day 7, and a third dose of ifosfamide (C2D3) on day 8, wherein each of ifosfamide in C2D1, C2D2, and C2D3 is about 3000 mg / m 2 (For example, 3000 mg / m 2 ±40mg / m 2 ±50mg / m 2 ±100mg / m 2±200mg / m 2 or ±300 mg / m 2 );

[0443] (iv) administering a single dose of carboplatin on day 6 (C2D1), wherein the C2D1 of carboplatin is approximately 5×(25+creatinine clearance) mg; and

[0444] (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, wherein each of C2D1, C2D2, and C2D3 of etoposide is about 100 mg / m 2 (e.g., 100 mg / m 2 ±1mg / m 2 ±2.5mg / m 2 ±5mg / m 2 or ±10 mg / m 2 ).

[0445] In one aspect, the invention features a method of treating a subject between the ages of 6 months and 17 years old with a CD20-positive cell proliferative disorder, the method comprising administering to the subject an effective amount of gefiruzumab, obinutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen comprising a first dosing cycle, a second dosing cycle, and a third dosing cycle, wherein

[0446] (a) The first dosing cycle includes:

[0447] (i) administering a first dose of gefizumab (C1D1) on day 8 and a second dose of gefizumab (C1D2) on day 15, wherein the C1D1 of gefizumab is 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, ± 0.0 3 mg, ±0.05 mg, ±0.1 mg, ±0.2 mg, or ±0.25 mg), and the C1D2 of gefituzumab 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);

[0448] (ii) administering a first dose of inutuzumab (C1D1) on day 1 and a second dose of inutuzumab (C1D2) on day 2, wherein C1D1 of inutuzumab is about one-tenth the amount of the sum of C1D1 and C1D2 of inutuzumab, and C1D2 of inutuzumab is about nine-tenths the amount of the sum of C1D1 and C1D2 of inutuzumab, and wherein the sum of C1D1 and C1D2 of inutuzumab 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 2 ... g / 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);

[0449] (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, wherein each of ifosfamide C1D1, C1D2, and C1D3 is about 3000 mg / m 2 (For example, 3000 mg / m 2 ±40mg / m 2 ±50mg / m 2 ±100mg / m 2 ±200mg / m 2 or ±300 mg / m 2 );

[0450] (iv) administering a single dose of carboplatin on day 3 (C1D1), wherein the C1D1 of carboplatin is approximately 635 mg / m 2 (e.g., 635 mg / m 2 ±5mg / m 2 ±10mg / m 2 ±25mg / m 2 ±50mg / m 2 ±60mg / m 2or ±63.5 mg / m 2 );as well as

[0451] (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, wherein C1D1, C1D2, and C1D3 of etoposide are each about 100 mg / m 2 (e.g., 100 mg / m 2 ±1mg / m 2 ±2.5mg / m 2 ±5mg / m 2 or ±10 mg / m 2 );

[0452] (b) The second dosing cycle includes:

[0453] (i) administering a single dose of gefizumab on day 1 (C2D1), wherein the C2D1 of gefizumab 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);

[0454] (ii) administering the first dose of rituximab on day 5 (C2D1), wherein the C2D1 of rituximab is approximately 375 mg / m 2 (e.g., 375 mg / m 2 ±5mg / m 2 ±10mg / m 2 ±25mg / m 2 or ±37.5 mg / m 2 );

[0455] (iii) administering a first dose of ifosfamide (C2D1) on day 6, a second dose of ifosfamide (C2D2) on day 7, and a third dose of ifosfamide (C2D3) on day 8, wherein each of ifosfamide in C2D1, C2D2, and C2D3 is about 3000 mg / m 2 (For example, 3000 mg / m 2 ±40mg / m2 ±50mg / m 2 ±100mg / m 2 ±200mg / m 2 or ±300 mg / m 2 );

[0456] (iv) administering a single dose of carboplatin on day 6 (C2D1), wherein the C2D1 of carboplatin is approximately 5×(25+creatinine clearance) mg; and

[0457] (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, wherein each of C2D1, C2D2, and C2D3 of etoposide is about 100 mg / m 2 (e.g., 100 mg / m 2 ±1mg / m 2 ±2.5mg / m 2 ±5mg / m 2 or ±10 mg / m 2 );as well as

[0458] (c) The third dosing cycle includes:

[0459] (i) administering a single dose of gefizumab on day 1 (C3D1), wherein the C3D1 of gefizumab 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);

[0460] (ii) administering the first dose of rituximab on day 5 (C3D1), wherein the C3D1 of rituximab is approximately 375 mg / m 2 (e.g., 375 mg / m 2 ±5mg / m 2 ±10mg / m 2 ±25mg / m 2 or ±37.5 mg / m 2 );

[0461] (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, wherein each of ifosfamide in C3D1, C3D2, and C3D3 is about 3000 mg / m 2 (For example, 3000 mg / m 2 ±40mg / m 2 ±50mg / m 2 ±100mg / m 2 ±200mg / m 2 or ±300 mg / m 2 );

[0462] (iv) administering a single dose of carboplatin on day 6 (C3D1), wherein the C3D1 of carboplatin is approximately 5×(25+creatinine clearance) mg; and

[0463] (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, wherein each of C3D1, C3D2, and C3D3 of etoposide is about 100 mg / m 2 (e.g., 100 mg / m 2 ±1mg / m 2 ±2.5mg / m 2 ±5mg / m 2 or ±10 mg / m 2 ).

[0464] In one embodiment, mesna is administered to a subject on days 3, 4, and 5 of a first dosing cycle, on days 6, 7, and 8 of a second dosing cycle, and / or on days 6, 7, and 8 of each additional dosing cycle. In one embodiment, mesna is administered to a subject in a total amount of 3000 mg / m 2 In one embodiment, mesna is administered intravenously at about 600 mg / m2 before any dose of ifosfamide is administered. 2 The first dose is about 600 mg / m 2 Mesna is administered intravenously in four repeat doses of cyclophosphamide, each of which is about three hours, about six hours, and about 12 hours after the first dose of ifosfamide.

[0465] In one aspect, the invention features a method of treating a subject between the ages of 18 and 30 years old with a CD20-positive cell proliferative disorder, the method comprising administering to the subject an effective amount of gefiruzumab, obinutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein

[0466] (a) a first dosing cycle comprising administering a first dose of gefizumab (C1D1) on day 8 and administering a second dose of gefizumab (C1D2) on day 15, wherein the C1D1 of gefizumab 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 gefizumab 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

[0467] (b) The second dosing cycle comprises administering a single dose of gefizumab on day 1 (C2D1), wherein the C2D1 of gefizumab 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).

[0468] In one aspect, the invention features a method of treating a subject between the ages of 18 and 30 years old with a CD20-positive cell proliferative disorder, the method comprising administering to the subject an effective amount of gefiruzumab, obinutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen comprising a first dosing cycle, a second dosing cycle, and a third dosing cycle, wherein

[0469] (a) a first dosing cycle comprising administering a first dose of gefizumab (C1D1) on day 8 and administering a second dose of gefizumab (C1D2) on day 15, wherein the C1D1 of gefizumab 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 gefizumab 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);

[0470] (b) the second dosing cycle comprises administering a single dose of gefizumab on day 1 (C2D1), wherein the C2D1 of gefizumab 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); and

[0471] (c) The third dosing cycle comprises administering a single dose of gefizumab on day 1 (C3D1), wherein the C3D1 of gefizumab 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).

[0472] In one aspect, the invention features a method of treating a subject between the ages of 18 and 30 years old with a CD20-positive cell proliferative disorder, the method comprising administering to the subject an effective amount of gefiruzumab, obinutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein

[0473] (a) The first dosing cycle includes:

[0474] (i) administering a first dose of gefizumab (C1D1) on day 8 and a second dose of gefizumab (C1D2) on day 15, wherein the C1D1 of gefizumab 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 gefizumab 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);

[0475] (ii) administering a first dose of inutuzumab (C1D1) on day 1 and a second dose of inutuzumab (C1D2) on day 2, wherein the C1D1 of inutuzumab is about one-tenth the amount of the sum of the C1D1 and the C1D2 of inutuzumab, and the C1D2 of inutuzumab is about nine-tenths the amount of the sum of the C1D1 and the C1D2 of inutuzumab, and wherein the sum of the C1D1 and the C1D2 of inutuzumab is about 1000 mg (e.g., 1000 mg ± 5 mg, ± 10 mg, ± 20 mg, ± 30 mg, ± 50 mg, ± 75 mg, or ± 100 mg);

[0476] (iii) administering a single dose of ifosfamide on day 3 (C1D1), wherein the C1D1 of ifosfamide is approximately 5000 mg / m 2 (e.g., 5000 mg / m 2 ±50mg / m 2 ±100mg / m 2 ±200mg / m 2 ±300mg / m 2 ±400mg / m 2 or ±500mg / m 2 ), with a maximum dose of about 800 mg (e.g., 800 mg ± 10 mg, ± 25 mg, ± 50 mg, or ± 80 mg);

[0477] (iv) administering a single dose of carboplatin on day 3 (C1D1), wherein the C1D1 of carboplatin is approximately 5×(25+creatinine clearance) mg; and

[0478] (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, wherein C1D1, C1D2, and C1D3 of etoposide are each about 100 mg / m 2 (e.g., 100 mg / m 2 ±1mg / m 2 ±2.5mg / m 2 ±5mg / m 2 or ±10 mg / m 2 );as well as

[0479] (b) The second dosing cycle includes:

[0480] (i) administering a single dose of gefizumab on day 1 (C2D1), wherein the C2D1 of gefizumab 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);

[0481] (ii) administering the first dose of rituximab on day 5 (C2D1), wherein the C2D1 of rituximab is approximately 375 mg / m 2 (e.g., 375 mg / m 2 ±5mg / m 2 ±10mg / m 2 ±25mg / m 2 or ±37.5 mg / m 2 );

[0482] (iii) administering a single dose of ifosfamide on day 6 (C2D1), wherein the C2D1 of ifosfamide is approximately 5000 mg / m 2 (e.g., 5000 mg / m 2 ±50mg / m 2 ±100mg / m 2 ±200mg / m 2 ±300mg / m 2 ±400mg / m 2 or ±500mg / m 2 ), with a maximum dose of about 800 mg (e.g., 800 mg ± 10 mg, ± 25 mg, ± 50 mg, or ± 80 mg);

[0483] (iv) administering a single dose of carboplatin on day 6 (C2D1), wherein the C2D1 of carboplatin is approximately 5×(25+creatinine clearance) mg; and

[0484] (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, wherein each of C2D1, C2D2, and C2D3 of etoposide is about 100 mg / m 2 (e.g., 100 mg / m 2 ±1mg / m 2 ±2.5mg / m 2 ±5mg / m 2 or ±10 mg / m 2 ).

[0485] In one aspect, the invention features a method of treating a subject between the ages of 18 and 30 years old with a CD20-positive cell proliferative disorder, the method comprising administering to the subject an effective amount of gefiruzumab, obinutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen comprising a first dosing cycle, a second dosing cycle, and a third dosing cycle, wherein

[0486] (a) The first dosing cycle includes:

[0487] (i) administering a first dose of gefizumab (C1D1) on day 8 and a second dose of gefizumab (C1D2) on day 15, wherein the C1D1 of gefizumab 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 gefizumab 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);

[0488] (ii) administering a first dose of inutuzumab (C1D1) on day 1 and a second dose of inutuzumab (C1D2) on day 2, wherein the C1D1 of inutuzumab is about one-tenth the amount of the sum of the C1D1 and the C1D2 of inutuzumab, and the C1D2 of inutuzumab is about nine-tenths the amount of the sum of the C1D1 and the C1D2 of inutuzumab, and wherein the sum of the C1D1 and the C1D2 of inutuzumab is about 1000 mg (e.g., 1000 mg ± 5 mg, ± 10 mg, ± 20 mg, ± 30 mg, ± 50 mg, ± 75 mg, or ± 100 mg);

[0489] (iii) administering a single dose of ifosfamide on day 3 (C1D1), wherein the C1D1 of ifosfamide is approximately 5000 mg / m 2 (e.g., 5000 mg / m 2 ±50mg / m 2 ±100mg / m 2 ±200mg / m 2 ±300mg / m 2 ±400mg / m 2 or ±500mg / m 2 ), with a maximum dose of about 800 mg (e.g., 800 mg ± 10 mg, ± 25 mg, ± 50 mg, or ± 80 mg);

[0490] (iv) administering a single dose of carboplatin on day 3 (C1D1), wherein the C1D1 of carboplatin is approximately 5×(25+creatinine clearance) mg; and

[0491] (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, wherein C1D1, C1D2, and C1D3 of etoposide are each about 100 mg / m 2 (e.g., 100 mg / m2 ±1mg / m 2 ±2.5mg / m 2 ±5mg / m 2 or ±10 mg / m 2 );

[0492] (b) The second dosing cycle includes:

[0493] (i) administering a single dose of gefizumab on day 1 (C2D1), wherein the C2D1 of gefizumab 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);

[0494] (ii) administering the first dose of rituximab on day 5 (C2D1), wherein the C2D1 of rituximab is approximately 375 mg / m 2 (e.g., 375 mg / m 2 ±5mg / m 2 ±10mg / m 2 ±25mg / m 2 or ±37.5 mg / m 2 );

[0495] (iii) administering a single dose of ifosfamide on day 6 (C2D1), wherein the C2D1 of ifosfamide is approximately 5000 mg / m 2 (e.g., 5000 mg / m 2 ±50mg / m 2 ±100mg / m 2 ±200mg / m 2 ±300mg / m 2 ±400mg / m 2 or ±500mg / m 2 ), with a maximum dose of about 800 mg (e.g., 800 mg ± 10 mg, ± 25 mg, ± 50 mg, or ± 80 mg);

[0496] (iv) administering a single dose of carboplatin on day 6 (C2D1), wherein the C2D1 of carboplatin is approximately 5×(25+creatinine clearance) mg; and

[0497] (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, wherein each of C2D1, C2D2, and C2D3 of etoposide is about 100 mg / m 2 (e.g., 100 mg / m 2±1mg / m 2 ±2.5mg / m 2 ±5mg / m 2 or ±10 mg / m 2 );as well as

[0498] (c) The third dosing cycle includes:

[0499] (i) administering a single dose of gefizumab on day 1 (C3D1), wherein the C3D1 of gefizumab 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);

[0500] (ii) administering the first dose of rituximab on day 5 (C3D1), wherein the C3D1 of rituximab is approximately 375 mg / m 2 (e.g., 375 mg / m 2 ±5mg / m 2 ±10mg / m 2 ±25mg / m 2 or ±37.5 mg / m 2 );

[0501] (iii) a single dose of ifosfamide on day 6 (C3D1), wherein the C3D1 of ifosfamide is approximately 5000 mg / m 2 (e.g., 5000 mg / m 2 ±50mg / m 2 ±100mg / m 2 ±200mg / m 2 ±300mg / m 2 ±400mg / m 2 or ±500mg / m 2 ), with a maximum dose of about 800 mg (e.g., 800 mg ± 10 mg, ± 25 mg, ± 50 mg, or ± 80 mg);

[0502] (iv) administering a single dose of carboplatin on day 6 (C3D1), wherein the C3D1 of carboplatin is approximately 5×(25+creatinine clearance) mg; and

[0503] (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, wherein each of C3D1, C3D2, and C3D3 of etoposide is about 100 mg / m 2 (e.g., 100 mg / m 2 ±1mg / m2 ±2.5mg / m 2 ±5mg / m 2 or ±10 mg / m 2 ).

[0504] In one embodiment, mesna is administered concurrently with any dose of ifosfamide. In one embodiment, mesna is administered at about 5000 mg / m 2 (e.g., 5000 mg / m 2 ±50mg / m 2 ±100mg / m 2 ±200mg / m 2 ±300mg / m 2 ±400mg / m 2 or ±500mg / m 2 ) is administered intravenously at a dose of . In one embodiment, mesna is administered via 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.

[0505] In one embodiment, the bispecific antibody that binds to CD20 and CD3 comprises at least one Fab molecule that specifically binds to CD20, wherein the Fab molecule comprises the following six hypervariable regions (HVRs):

[0506] (i) HVR-H1 comprising the amino acid sequence of YSWIN (SEQ ID NO: 1);

[0507] (ii) HVR-H2 comprising the amino acid sequence of RIFPGDGDTDYNGKFKG (SEQ ID NO: 2);

[0508] (iii) HVR-H3 comprising the amino acid sequence of NVFDGYWLVY (SEQ ID NO: 3);

[0509] (iv) HVR-L1 comprising the amino acid sequence of RSSKSLLHSNGITYLY (SEQ ID NO: 4);

[0510] (v) HVR-L2 comprising the amino acid sequence of QMSNLVS (SEQ ID NO: 5); and

[0511] (vi) HVR-L3 comprising the amino acid sequence of AQNLELPYT (SEQ ID NO: 6).

[0512] In one embodiment, a bispecific antibody that binds to CD20 and CD3 comprises at least one Fab molecule that specifically binds to CD20, the Fab molecule comprising: (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) a VH domain as in (a) and a VL domain as in (b). In one embodiment, the 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.

[0513] In one embodiment, a bispecific antibody that binds to CD20 and CD3 comprises at least one Fab molecule that specifically binds to CD3, wherein the Fab molecule comprises the following six HVRs:

[0514] (i) HVR-H1 comprising the amino acid sequence of TYAMN (SEQ ID NO: 9);

[0515] (ii) HVR-H2 comprising the amino acid sequence of RIRSKYNNYATYYADSVKG (SEQ ID NO: 10);

[0516] (iii) HVR-H3 comprising the amino acid sequence of HGNFGNSYVSWFAY (SEQ ID NO: 11);

[0517] (iv) HVR-L1 comprising the amino acid sequence of GSSTGAVTTSNYAN (SEQ ID NO: 12);

[0518] (v) HVR-L2 comprising the amino acid sequence of GTNCRAP (SEQ ID NO: 13); and

[0519] (vi) HVR-L3 comprising the amino acid sequence of ALWYSNLWV (SEQ ID NO: 14).

[0520] In one embodiment, the bispecific antibody that binds to CD20 and CD3 includes at least one Fab molecule that specifically binds to CD3, the Fab molecule comprising: (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) the VH domain as in (a) and the VL domain as in (b).

[0521] In one embodiment, the 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.

[0522] In one embodiment, the bispecific antibody that binds to CD20 and CD3 is bivalent to CD20 and monovalent to CD3. In one embodiment, the 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.

[0523] In one embodiment, the bispecific antibody that binds to CD20 and CD3 is a humanized antibody. In one embodiment, the bispecific antibody that binds to CD20 and CD3 is gefuzumab.

[0524] In one embodiment, the bispecific antibody that binds to CD20 and CD3 is administered intravenously.

[0525] In one embodiment, the anti-CD20 antibody is administered intravenously.

[0526] 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's lymphoma (BL) or Burkitt's 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.

[0527] In one embodiment, the previous systemic therapy includes an anti-CD20 antibody and an anthracycline. In one embodiment, the subject is human. In one embodiment, the subject meets the conditions for transplantation or CAR-T cell therapy. In one embodiment, the subject receives autologous stem cell transplantation (ASCT) after completing the dosing regimen of the above method. In one embodiment, ASCT is autologous hematopoietic stem cell transplantation. In one embodiment, the subject receives allogeneic hematopoietic stem cell transplantation after completing the dosing regimen as described above. In one embodiment, the subject receives CAR-T cell therapy after completing the dosing regimen as described above.

[0528] Another aspect of the present invention relates to the invention as described herein.

[0529] Unless the context clearly indicates otherwise, each embodiment can be combined.Unless the context clearly indicates otherwise, each embodiment can be applied to various aspects of the invention.

[0530] Certain embodiments of the invention will become apparent from the following more detailed description of certain preferred embodiments and the claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0531] Figure 1 A to Figure 1 N is a schematic diagram showing the configuration of an exemplary anti-CD20 / anti-CD3 bispecific antibody.

[0532] Figure 2 is a schematic diagram showing the structure of Gefituzumab.

[0533] Figure 3is a schematic diagram showing an overview of the study design as described in Example 1. ASCT = autologous stem cell transplantation; CAR-T = chimeric antigen receptor T cells; CR = complete remission; DLBCL = diffuse large B-cell lymphoma; EOT = end of treatment; Glofit-R-ICE = combination of glucagon and rituximab plus ifosfamide, carboplatin, etoposide; Gpt = obinutuzumab Pretreated; PD = progressive disease; PR = partial response; R / R = relapsed or refractory; SD = stable disease. a : 2 to 3 cycles depending on institutional standards. b : ASCT conditioning regimen and supportive care in accordance with institutional standards.

[0534] Figure 4 is a schematic diagram showing the dosing regimen for the study as described in Example 1. D = day. a : Carboplatin dose is in mg for a target AUC of 5 mg / mL / min.

[0535] Figure 5 Schematic diagram showing the study protocol for Parts 1 and 2 of Example 2. B-NHL = B-cell non-Hodgkin's lymphoma; Glofit = gefitinumab; Ped = pediatric; PK = pharmacokinetics; R-ICE = rituximab, ifosfamide, carboplatin, and etoposide; Rec = recommended; R / R = relapsed / refractory; RR = response rate. In Part 1 of the study, the safety lead-in of the starting dose was based on population PK modeling and matched adult exposure with escalating dosing. Safety and pharmacokinetic assessments were performed on at least 3 participants before the recommended pediatric Part 2 dose was announced. Before Part 2 could begin, at least 10 pediatric participants received an early efficacy assessment at the recommended pediatric dose. During Part 2 of the study, open enrollment included young adult participants aged 30 years and under, but they were not counted in the sample size of 45.

[0536] Figure 6 Schematic diagram showing the dosing regimen for the combination of gefiruzumab and R-ICE as described in Example 2. C = cycle; CR = complete remission; D = day; G = obinutuzumab; CR = complete remission; FD = full dose; G-CSF = granulocyte colony-stimulating factor; Glofit = gefiruzumab; GpT = obinutuzumab pretreatment; HSCT = hematopoietic stem cell transplant; ICE = ifosfamide, carboplatin, and etoposide; PD = progressive disease; R-ICE = rituximab plus ifosfamide, carboplatin, etoposide; SUD = escalating dose. aObinutuzumab pretreatment will be divided into one-tenth of the full dose on Day 1 of the first dosing cycle (Cycle 1) and nine-tenths of the full dose on Day 2 of Cycle 1.

[0537] Figure 7 Schematic diagram showing the treatment administration schedule for pediatric patients (aged 6 months to 17 years) in Example 2. *: Arrow indicates mandatory initiation of granulocyte colony-stimulating factor (G-CSF) therapy. **: Participants with CNS disease and any histological features received 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 large B-cell lymphoma and CNS-negative disease received IT therapy only on day 3 of cycle 1. A single dose of pre-treatment with obinutuzumab was divided into one-tenth of the full dose on day 1 of cycle 1 and nine-tenths of the full dose on day 2 of cycle 1. Participants with Burkitt lymphoma (BL) and CNS-negative disease received IT therapy on day 3 of cycle 1 and day 5 of cycle 2 and cycle 3. Gefituzumab was administered in two ascending doses on days 8 and 15 of cycle 1 and at a full dose on day 1 of cycles 2 and 3.

[0538] Figure 8 Schematic diagram showing the treatment administration schedule for young adult patients (aged 18 to 30 years) in Example 2. *: Arrow indicates mandatory initiation of G-CSF therapy. **: Participants with CNS disease and any histological features received IT therapy on days 3, 10, and 17 of cycle 1 and days 5, 12, and 19 of cycles 2 and 3. Participants with large B-cell lymphoma and negative CNS received IT therapy only on day 3 of cycle 1. A single dose of pre-treatment with obinutuzumab was divided into one-tenth of the full dose on day 1 of cycle 1 and nine-tenths of the full dose on day 2 of cycle 1. Participants with BL and negative CNS received IT therapy on day 3 of cycle 1 and day 5 of cycles 2 and 3. G-CSF = granulocyte colony-stimulating factor. Gefituzumab was given in two ascending doses on days 8 and 15 of cycle 1 and at a full dose on day 1 of cycles 2 and 3. DETAILED DESCRIPTION

[0539] The present invention provides a method for treating a subject having 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))), the method 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.

[0540] (i) General Technology

[0541] Unless otherwise noted, the implementation of the present invention will adopt the conventional techniques of molecular biology (including recombinant technology), microbiology, cell biology, biochemistry and immunology, which are within the technical scope of this area. Such techniques are fully explained in the following documents, such as "Molecular Cloning: A Laboratory Manual", Second Edition (Sambrook et al., 1989); "Oligonucleotide Synthesis" (MJ Gait compiles, 1984); "Animal Cell Culture" (RI Freshney compiles, 1987); "Methods in Enzymology" (Academic Press, Inc.); "Current Protocols in Molecular Biology" (FM Ausubel et al. compiles, 1987, and regularly updated); "PCR: The Polymerase Chain Reaction" (Mullis et al. compiles, 1994); "A Practical Guide to Molecular Cloning" (Perbal Bernard V., 1988); "Phage Display: A Laboratory Manual" (Barbas et al., 2001).

[0542] (ii) Definition

[0543] Unless otherwise defined below, the terms used herein are generally as used in the art.

[0544] Unless otherwise indicated, the term "cluster of differentiation 20" or "CD20" as used herein refers to any native CD20 from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats). CD20 (also known as B-lymphocyte antigen CD20, B-lymphocyte surface antigen B1, Leu-16, Bp35, BM5, and LF5; the human protein is described in the UniProt database accession number P11836) is a hydrophobic transmembrane protein with a molecular weight of approximately 35 kD and expressed on pre-B 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, TF 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 family of new proteins are characterized by common structural features and similar intron / exon splicing boundaries and exhibit unique expression patterns in 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 located in a cluster of family members at 11q12. The term encompasses "full-length" unprocessed CD20, as well as any form of CD20 produced by processing in the cell. The term also encompasses naturally occurring variants of CD20, such as splice variants or allelic variants. Alternative splicing of this gene produces two transcript variants encoding the same protein. In one embodiment, CD20 is human CD20.

[0545] The terms "anti-CD20 antibody" and "antibody that binds to CD20" refer to an antibody that binds to CD20 with sufficient affinity to allow the antibody to be used as a diagnostic and / or therapeutic agent targeting CD20. In one embodiment, the extent of binding of the anti-CD20 antibody to unrelated, non-CD20 proteins is less than about 10% of the extent of binding of the antibody to CD20, as measured, for example, by radioimmunoassay (RIA). In certain embodiments, the antibody that binds to CD20 has a binding affinity of ≤1 μM, ≤100 nM, ≤10 nM, ≤1 nM, ≤0.1 nM, ≤0.01 nM, or ≤0.001 nM (e.g., 10 -8M or smaller, for example, 10 -8 M to 10 -13 M, for example, 10 -9 M to 10 -13 The 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.

[0546] "Type II anti-CD20 antibody" refers to an anti-CD20 antibody that has the binding properties and biological activity of a type II anti-CD20 antibody, 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.

[0547] Table 1. Type I and II anti-CD20 antibodies

[0548] Type I anti-CD20 antibodies Type II anti-CD20 antibodies Binds to class I CD20 epitope Binds to class II CD20 epitope Localization of CD20 to lipid rafts CD20 does not localize to lipid rafts High CDC* Low CDC* ADCC activity* ADCC activity* Fully capable of binding to B cells The ability to bind to B cells is approximately halved Weak homotypic aggregation Homopolymerization Low cell death induction Strong cell death induction

[0549] *If IgG1 isotype

[0550] Examples of type II anti-CD20 antibodies include, e.g., obinutuzumab (GA101), tositumumab (B1), humanized B-Ly1 antibody IgG1 (a chimeric humanized IgG1 antibody as disclosed in WO 2005 / 044859), 11B8 IgG1 (as disclosed in WO 2004 / 035607), and AT80 IgG1.

[0551] Examples of type I anti-CD20 antibodies include, e.g., rituximab, ofatumumab, veltuzumab, okatuzumab, oreluzumab, PRO131921, urituximab, HI47 IgG3 (ECACC, hybridoma), 2C6 IgG1 (as disclosed in WO 2005 / 103081), 2F2 IgG1 (as disclosed in WO 2004 / 035607 and WO 2005 / 103081), and 2H7 IgG1 (as disclosed in WO 2004 / 056312).

[0552] Unless otherwise indicated, "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, as well as any form of CD3 produced by processing in cells. The term also encompasses naturally occurring variants of CD3, such as splice variants or allelic variants. In one embodiment, CD3 is human CD3, particularly the epsilon subunit (CD3 epsilon) of human CD3. The amino acid sequence of human CD3 epsilon is shown in UniProt (www.uniprot.org) accession number P07766 (version 144) or NCBI (www.ncbi.nlm.nih.gov / ) RefSeq NP_000724.1. The amino acid sequence of cynomolgus monkey [Macaca fascicularis] CD3 epsilon is shown in NCBI GenBank number BAB71849.1.

[0553] The terms "anti-CD20 / anti-CD3 bispecific antibody" and "bispecific antibody that binds to CD20 and CD3" refer to a bispecific antibody that binds to both CD20 and CD3 with sufficient affinity such that the antibody is useful as a diagnostic and / or therapeutic agent targeting CD20 and / or CD3. In one embodiment, the extent of binding of the bispecific antibody that binds to CD20 and CD3 to unrelated, non-CD3 proteins and / or non-CD20 proteins 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, the dissociation constant (K) of the bispecific antibody that binds to CD20 and CD3 is less than about 10%. D ) is ≤1 μM, ≤100 nM, ≤10 nM, ≤1 nM, ≤0.1 nM, ≤0.01 nM, or ≤0.001 nM (e.g., 10 -8 M or lower, e.g., 10 -8 M to 10 -13 M, for example, 10 -9 to 10 -13M). In certain embodiments, the bispecific antibody that binds to CD20 and CD3 binds to a CD3 antigen epitope conserved between CD3 from different species and / or a CD20 antigen epitope conserved between CD20 from different species. An example of an anti-CD20 / anti-CD3 bispecific antibody is gefuzumab (WHO Drug Information (International Nonproprietary Name of the Drug), Recommended INN: List 83, 2020, Vol. 34, No. 1, p. 39; Proposed INN: List 121 WHO Drug Information, Vol. 33, No. 2, 2019, p. 276, also known as CD20-TCB, RO7082859 or RG6026; CAS#: 2229047-91-8).

[0554] As used herein, the term "cytokine release" or "cytokine release" is synonymous with "cytokine storm" or "cytokine release syndrome" (abbreviated as "CRS") and refers to an increase in the 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 the blood of a subject during or shortly after administration of a therapeutic agent (e.g., within 1 day), leading to adverse symptoms. Cytokine release is defined as a supraphysiological response that results in the activation or engagement of endogenous or infused T cells and / or other immune effector cells following the administration of any immunotherapy. Symptoms may be progressive, always include fever at the 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 also occur several days after administration as the CAR-T cells expand. The incidence and severity generally decrease with subsequent infusions. Symptoms may range from symptomatic discomfort to fatal events and may include fever, chills, dizziness, hypertension, hypotension, dyspnea, irritability, sweating, flushing, rash, tachycardia, shortness of breath, headache, tumor pain, nausea, vomiting, and / or organ failure.

[0555] As used herein, the term "amino acid mutation" refers to amino acid substitutions, deletions, insertions, and modifications. Any combination of substitutions, deletions, insertions, and modifications can be implemented to obtain the final construct, provided that the final construct has the desired properties, for example, reduced binding to Fc receptors. Amino acid sequence deletions and insertions include amino-terminal and / or carboxyl-terminal deletions and insertions of the amino acid. Specific amino acid mutations are amino acid substitutions. For the purpose of changing the binding characteristics of, for example, the Fc region, non-conservative amino acid substitutions, i.e., replacing one amino acid with another amino acid having different structural and / or chemical properties, are particularly preferred. Amino acid substitutions include substitutions with non-naturally occurring amino acids or with amino acid derivatives of the twenty naturally occurring standard amino acids (e.g., 4-hydroxyproline, 3-methylhistidine, ornithine, homoserine, 5-hydroxylysine). Amino acid mutations can be produced using genetic or chemical methods well known in the art. Genetic methods can include site-directed mutagenesis, PCR, gene synthesis, etc. It is also useful to envision methods for changing amino acid side chain groups by methods other than genetic engineering (such as chemical modification). Various names can be used herein to indicate the same amino acid mutation. For example, substitution of proline at position 329 of the Fc domain with glycine can be represented as 329G, G329, G 329 , P329G or Pro329Gly.

[0556] "Affinity" refers to the strength of the sum of non-covalent interactions between a single binding site of a molecule (e.g., a receptor) and its binding partner (e.g., a ligand). Unless otherwise indicated, as used herein, "binding affinity" refers to intrinsic binding affinity, which reflects a 1:1 interaction between members of a binding pair (e.g., a receptor and a ligand). The affinity of a molecule X for its partner Y can generally be expressed in terms of the dissociation constant (K D ) indicates that the dissociation constant is the dissociation rate constant and the association rate constant (k off and k on ). Thus, equivalent affinities can include different rate constants as long as the ratio of the rate constants remains the same. Affinity can be measured by established methods known in the art. A particular method for measuring affinity is surface plasmon resonance (SPR).

[0557] An "affinity matured" antibody is one with one or more alterations in one or more hypervariable regions (HVRs) which result in an improvement in the affinity of the antibody for antigen, compared to a parent antibody which does not possess such alteration(s).

[0558] As used herein, the term "antigen binding portion" refers to a polypeptide molecule that specifically binds to an antigenic determinant. In one embodiment, the antigen binding portion is capable of directing the entity to which it is attached (e.g., a cytokine or a second antigen binding portion) to a target site, for example, to a specific type of tumor cell or tumor stroma with an antigenic determinant. The antigen binding portion includes antibodies and fragments thereof as further defined herein. Preferred antigen binding portions include the antigen binding domains of antibodies, which include antibody heavy chain variable regions and antibody light chain variable regions. In certain embodiments, the antigen binding portion may include antibody constant regions as further defined herein and as known in the art. Available heavy chain constant regions include any one of the following five isotypes: α, δ, ε, γ or μ. Available light chain constant regions include any one of the following two isotypes: κ and λ.

[0559] "Binding", "specific binding" or "specific for..." means that the binding is selective for the antigen and can distinguish undesired or non-specific interactions. The ability of the antigen binding portion to bind to a specific antigenic determinant can be measured by enzyme-linked immunosorbent assay (ELISA) or other techniques familiar to those skilled in the art, for example, surface plasmon resonance (analyzed on a BIAcore instrument) (Liljeblad et al., Glyco J.17, 323-329 (2000)) and traditional binding assays (Heeley, EEndocr Res.28, 217-229 (2002)). In one embodiment, the degree of binding of the antigen binding portion to an unrelated protein, as measured, for example, by SPR, is less than about 10% of the degree of binding of the antigen binding portion to the antigen. In certain embodiments, the antigen binding portion that binds to the antigen, or the antigen binding molecule comprising the antigen binding portion, has the following dissociation constant (K D ): ≤1 μM, ≤100 nM, ≤10 nM, ≤1 nM, ≤0.1 nM, ≤0.01 nM or ≤0.001 nM (e.g., 10 -8 M or smaller, for example, from 10 -8 M to 10 -13 M, for example, from 10 -9 M to 10 -13 M).

[0560] "Decreased binding" (e.g., reduced binding to an Fc receptor) refers to a decrease in affinity for the corresponding interaction, as measured, for example, by SPR. For clarity, the term also includes a decrease in affinity to zero (or below the detection limit of the analytical method), i.e., complete elimination of the interaction. Conversely, "increased binding" refers to an increase in binding affinity for the corresponding interaction.

[0561] As used herein, the term "antigen binding molecule" in its broadest sense refers to a molecule that specifically binds to an antigenic determinant. Examples of antigen binding molecules are immunoglobulins and their derivatives, such as fragments thereof.

[0562] 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 stretch of continuous amino acids or a conformational configuration consisting of different regions of non-continuous amino acids) to which an antigen-binding portion binds, thereby forming an antigen-binding portion-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, in free matter and / or in the extracellular matrix (ECM) in serum. Unless otherwise indicated, proteins referred to herein as antigens (e.g., CD3) can be proteins in any natural form from any vertebrate source, including mammals, such as primates (e.g., humans) and rodents (e.g., mice and rats). In a specific embodiment, the antigen is a human protein. When referring to a specific protein herein, the term encompasses "full length", unprocessed proteins, and any form of protein produced by intracellular processing. The term also encompasses naturally occurring protein variants, such as splice variants or allelic variants. An exemplary human protein that can be used as an antigen is CD3, in particular the epsilon subunit of CD3 (see UniProt No. P07766 (version 130), NCBI RefSeq No. NP_000724.1 for human sequences; or UniProt No. Q95LI5 (version 49), NCBI GenBank No. BAB71849.1 for macaque [Macaca fascicularis] sequences). In certain embodiments, the T cell activating bispecific antigen binding molecules disclosed herein bind to an epitope of CD3 or a target cell antigen that is conserved between CD3 or target cell antigens from different species.

[0563] As used herein, the term "polypeptide" refers to a molecule consisting of monomers (amino acids) linearly connected by amide bonds (also referred to as peptide bonds). The term "polypeptide" refers to any chain with two or more amino acids, rather than the specific length of the product. Therefore, peptides, dipeptides, tripeptides, oligopeptides, "proteins," "amino acid chains," or any other terms used to refer to chains with two or more amino acids are included in the definition of "polypeptide," and the term "polypeptide" can be used in place of any of these terms, or interchangeably with any of these terms. The term "polypeptide" is also intended to refer to post-expression modification products of the polypeptide, which include but are not limited to glycosylation, acetylation, phosphorylation, amidation, derivatization with known protection / blocking groups, proteolytic cleavage, or modification with non-naturally occurring amino acids. The polypeptide can be derived from a natural biological source or produced by recombinant technology, and is not necessarily translated from a specified nucleic acid sequence. It can be generated in any way, including by chemical synthesis. The size of the polypeptides of the present invention can 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, 1,000 or more, or 2,000 or more amino acids. Polypeptides can have a defined three-dimensional structure, but they do not necessarily have such a structure. Polypeptides with a defined three-dimensional structure are referred to as folded; and polypeptides that do not have a defined three-dimensional structure, but can adopt a large number of different conformations, are referred to as unfolded.

[0564] An "isolated" polypeptide or variant or derivative thereof is intended to mean a polypeptide that is not in its native environment. No particular level of purification is 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.

[0565] " amino acid sequence identity percentage (%) " relative to a reference polypeptide sequence is defined as after comparing candidate sequence with reference polypeptide sequence and introducing room (if necessary) to realize maximum sequence identity percentage, and without considering any conservative substitution as a component of sequence identity, the percentage that the amino acid residue in the candidate sequence is identical with the amino acid residue in the reference polypeptide sequence. The comparison for determining amino acid sequence identity percentage can be realized in a variety of ways within the scope 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 the appropriate parameters for aligning sequences, including any algorithm required for realizing maximum alignment on the full length of the compared sequence. However, for purposes herein, sequence comparison computer program ALIGN-2 is used to generate amino acid sequence identity %. ALIGN-2 sequence comparison computer program is written by Genentech, Inc., and source code has been submitted to US Copyright Office, Washington DC, 20559, with user documentation, where it is registered with 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 source code. The ALIGN-2 program should be compiled for use on a UNIX operating system, including digital UNIX V4.0D. All sequence comparison parameters are set by the ALIGN-2 program and do not change. When ALIGN-2 is used for amino acid sequence comparison, the % amino acid sequence identity between a given amino acid sequence A and a given amino acid sequence B (which can alternatively be expressed as the % that a given amino acid sequence A has or comprises a certain amino acid sequence identity with a given amino acid sequence B) is calculated as follows:

[0566] Multiply 100 by the fraction X / Y

[0567] 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 where Y is the total number of amino acid residues in B. It will be understood that where the length of amino acid sequence A is not equal to the length of amino acid sequence B, the % amino acid sequence identity of A to B will not equal the % amino acid sequence identity of B to A. Unless specifically stated otherwise, all % amino acid sequence identity values ​​used herein are obtained using the ALIGN-2 computer program as described in the preceding paragraph.

[0568] The term "antibody" herein is used in the broadest sense and encompasses various 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.

[0569] The terms "full length antibody," "intact antibody," and "whole antibody" are used interchangeably herein to refer to an antibody that has a structure substantially similar to a native antibody structure or has heavy chains that contain an Fc region as defined herein.

[0570] "Antibody fragment" refers to a molecule other than an intact antibody that comprises 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')2; 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 encompasses single-domain antibodies.

[0571] The term "immunoglobulin molecule" refers to a protein with the structure of a naturally occurring antibody. For example, the IgG class immunoglobulin is a heterotetrameric glycoprotein of approximately 150,000 daltons, consisting of two light chains and two heavy chains bonded by disulfide bonds. From the N-terminus to the C-terminus, each heavy chain has a variable region (VH) (also referred to as a variable heavy chain domain or a heavy chain variable domain), followed by three constant domains (CH1, CH2, and CH3) (also referred to as a heavy chain constant region). Similarly, from the N-terminus to the C-terminus, each light chain has a variable region (VL) (also referred to as a variable light chain domain or a light chain variable domain), followed by a constant light chain (CL) domain (also referred to as a light chain constant region). The heavy chains of immunoglobulins can be assigned to one of five classes: α (IgA), δ (IgD), ε (IgE), γ (IgG), or μ (IgM), some of which can be further divided into subclasses, such as γ1 (IgG1), γ2 (IgG2), γ3 (IgG3), γ4 (IgG4), α1 (IgA1), and α2 (IgA2). The light chains of immunoglobulins can be assigned to one of two types based on the amino acid sequence of their constant domains: kappa (κ) and lambda (λ). Immunoglobulins are essentially composed of two Fab molecules and an Fc domain connected by the immunoglobulin hinge region.

[0572] The term "antigen binding domain" refers to a portion of an antibody that includes a region that specifically binds to and is complementary to part or all of an antigen. The antigen binding domain can be provided by, for example, one or more antibody variable domains (also referred to as antibody variable regions). Preferably, the antigen binding domain comprises an antibody light chain variable region (VL) and an antibody heavy chain variable region (VH).

[0573] The term "variable region" or "variable domain" refers to the domain of an antibody heavy or light chain that participates in binding an antibody to an antigen. The variable domains of the heavy and light chains of natural antibodies (VH and VL, respectively) generally have similar structures, with each domain comprising four conserved framework regions (FRs) and three hypervariable regions (HVRs). See, e.g., Kindt et al., Kuby Immunology, 6th ed., WH Freeman and Co., p. 91 (2007). A single VH or VL domain may be sufficient to confer antigen-binding specificity.

[0574] A "human antibody" is an antibody having an amino acid sequence that corresponds to the amino acid sequence of an antibody produced by a human or human cell, or derived from a non-human source utilizing a repertoire of human antibodies or other human antibody coding sequences. This definition of a human antibody specifically excludes humanized antibodies comprising non-human antigen-binding residues.

[0575] "Humanized" antibodies refer to chimeric antibodies comprising amino acid residues from non-human HVRs and amino acid residues from human FRs. In certain embodiments, a humanized antibody will comprise substantially all of at least one, typically two, variable domains, wherein all or substantially all of the HVRs (e.g., CDRs) correspond to the HVRs of a non-human antibody, and all or substantially all of the FRs correspond to the FRs of a human antibody. A humanized antibody optionally may 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 been humanized.

[0576] As used herein, the term "hypervariable region" or "HVR" refers to the regions of an antibody variable domain that are hypervariable in sequence ("complementarity determining regions" or "CDRs") and / or form structurally defined loops ("hypervariable loops") and / or contain antigen contact residues ("antigen contact points"). Typically, an antibody comprises six HVRs: three in VH (H1, H2, H3) and three in VL (L1, L2, L3). Exemplary HVRs herein include:

[0577] (a) Hypervariable loops occurring at the following amino acid residues: 26-32 (L1), 50-52

[0578] (L2), 91-96 (L3), 26-32 (H1), 53-55 (H2), and 96-101 (H3) (Chothia and Lesk, J. Mol. Biol. 196:901-917 (1987));

[0579] (b) CDRs occurring at the following amino acid residues: 24 to 34 (L1), 50 to 56

[0580] (L2), 89 to 97 (L3), 31 to 35b (H1), 50 to 65 (H2), and 95 to 102 (H3)

[0581] (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Edition Public Health Service, National Institutes of Health, Bethesda, MD (1991));

[0582] (c) Antigenic contact points 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.

[0583] J. Mol. Biol. 262:732-745 (1996); and

[0584] (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

[0585] (H2), 93-102(H3) and 94-102(H3).

[0586] 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.

[0587] "Framework" or "FR" refers to the variable domain residues excluding the hypervariable region (HVR) residues. The FR of a variable domain is typically composed of the following four FR domains: FR1, FR2, FR3, and FR4. Thus, the HVR and FR sequences typically appear in the following sequence in VH (or VL): FR1-H1(L1)-FR2-H2(L2)-FR3-H3(L3)-FR4.

[0588] "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. Typically, the selection of human immunoglobulin VL or VH sequences is from a subset of variable domain sequences. Typically, the subset of sequences is a subset as described in Kabat et al., Sequences of Proteins of Immunological Interest, Fifth Edition, NIH Publication 91-3242, Bethesda MD (1991), Volumes 1 to 3. In one embodiment, for VL, the subgroup is subgroup κI as in Kabat et al., supra. In one embodiment, for VH, the subgroup is subgroup III as in Kabat et al. (supra).

[0589] For the purposes of this paper, an "acceptor human framework" is a framework comprising an 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 an amino acid sequence identical to that of the human immunoglobulin framework or the human consensus framework, or it may comprise 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.

[0590] The "class" of an antibody refers to the type of constant domain or region possessed by its heavy chain. There are five major classes of antibodies: IgA, IgD, IgE, IgG, and IgM, and some of these antibodies can be further divided into subclasses (isotypes), such as IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The heavy chain constant domains corresponding to the different classes of immunoglobulins are called α, δ, ε, γ, and μ, respectively.

[0591] As used herein, the term IgG "isotype" or "subclass" refers to any subclass of immunoglobulins defined by the chemical and antigenic characteristics of the immunoglobulin constant region.

[0592] The term "Fc domain" or "Fc region" herein is used to define the C-terminal region of an immunoglobulin heavy chain, which contains at least a portion of a constant region. The term includes native sequence Fc regions and variant Fc regions. Although the boundaries of the IgG heavy chain Fc region may be slightly different, the human IgG heavy chain Fc region is generally defined as extending from Cys226 or from Pro230 to the carboxyl terminus of the heavy chain. However, the antibody produced by the host cell can undergo post-translational cleavage of one or more (particularly one or two) amino acids from the heavy chain C-terminus. Therefore, the antibody produced by the host cell by expressing a specific nucleic acid molecule encoding a full-length heavy chain can include a full-length heavy chain, or the antibody can include a cleavage variant (also referred to herein as "cleaved variant heavy chain") of the full-length heavy chain. This may be a situation where the last two C-terminal amino acids of the heavy chain are glycine (G446) and lysine (K447, EU numbering). Therefore, the C-terminal lysine (Lys447) or C-terminal glycine (Gly446) and lysine (K447) of the Fc region may be present or may not be present. Unless otherwise indicated herein, the numbering of amino acid residues in the Fc region or constant region is according to the EU numbering system, also referred to as the EU index, as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Edition Public Health Service, National Institutes of Health, Bethesda, MD, 1991 (see also above). As used herein, the "subunit" of the Fc domain refers to one of the two polypeptides that form the dimeric Fc domain, i.e., a polypeptide including the C-terminal constant region of an immunoglobulin heavy chain, which is capable of stabilizing self-association. For example, the subunit of the IgG Fc domain comprises IgG CH2 and IgG CH3 constant domains.

[0593] "Modifications that promote the association of the first and second subunits of the Fc domain" are manipulations of the peptide backbone or post-translational modifications of the Fc domain subunits that reduce or prevent the association of a polypeptide comprising the Fc domain subunit with the same polypeptide to form a homodimer. As used herein, modifications that promote association particularly include separate modifications to each of the two Fc domain subunits (i.e., the first and second subunits of the Fc domain) that are desired to associate, wherein the modifications complement each other to promote the association of the two Fc domain subunits. For example, modifications that promote association may alter the structure or charge of one or both of the Fc domain subunits so as to favor their association sterically or electrostatically, respectively. Thus, (hetero) dimerization occurs between a polypeptide comprising the first Fc domain subunit and a polypeptide comprising the second Fc domain subunit, which may be different in the sense that the additional components (e.g., antigen binding moieties) fused to each subunit are inconsistent. In some embodiments, modifications that promote association include amino acid mutations, particularly amino acid substitutions, in the Fc domain. In a specific embodiment, the association-promoting modifications comprise individual amino acid mutations, particularly amino acid substitutions, of each of the two subunits of the Fc domain.

[0594] "Activating Fc receptors" are Fc receptors that, upon engagement by the Fc region of an antibody, trigger signaling events that stimulate cells bearing the receptor to perform effector functions. Activating Fc receptors include FcγRIIIa (CD16a), FcγRI (CD64), FcγRIIa (CD32), and FcαRI (CD89).

[0595] When used in reference to antibodies, the term "effector function" refers to those biological activities attributable to the Fc region of an antibody, which vary with 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 receptor), and B cell activation.

[0596] As used herein, the term "effector cell" refers to a population of lymphocytes that display effector moiety receptors (e.g., cytokine receptors) and / or Fc receptors on their surface, through which they bind to effector moieties (e.g., cytokines) and / or the Fc region of antibodies and contribute to the destruction of target cells, e.g., tumor cells. Effector cells can, for example, mediate cytotoxic or phagocytic responses. Effector cells include, but are not limited to, effector T cells, such as CD8 T cells. + Cytotoxic T cells, CD4 +Helper T cells, γδ T cells, NK cells, lymphokine-activated killer (LAK) cells and macrophages / monocytes.

[0597] As used herein, the terms "engineering, engineered, engineered" are considered to include any manipulation of the peptide backbone, or post-translational modification of a naturally occurring or recombinant polypeptide or fragment thereof. Engineering includes modifications to the amino acid sequence, glycosylation pattern, or side chain groups of individual amino acids, as well as combinations of these methods. "Engineering" (particularly with the prefix "glycosyl") and the term "glycosylation engineering" include metabolic engineering of the cellular glycosylation machinery, including genetic manipulation of oligosaccharide synthesis pathways to achieve altered glycosylation of glycoproteins expressed in cells. In addition, glycosylation engineering includes the effects of mutations and the cellular environment on glycosylation. In one embodiment, glycosylation engineering is a change in glycosyltransferase activity. In a specific embodiment, 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 that have been manipulated to express increased 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 that have been manipulated to express increased 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 that have been manipulated to express reduced levels of α(1,6) glycofucosyltransferase).

[0598] The terms "host cell," "host cell line," and "host cell culture" are used interchangeably and refer to cells into which exogenous nucleic acids have been introduced, including the progeny of such cells. Host cells include "transformants" and "transformed cells," which include primary transformed cells and progeny derived from the primary transformed cells, regardless of the number of passages. Progeny may not be completely identical to the nucleic acid content of the parent cell, but may contain mutations. This document includes mutant progeny with the same function or biological activity as screened or selected in the original transformed cells. A host cell is a cell system that can be used to generate any type of protein for the present invention. In one embodiment, the host cell is modified to allow the production of antibodies with modified oligosaccharides. In certain embodiments, the host cell has been manipulated to express increased levels of one or more polypeptides having β(1,4)-N-acetylglucosaminyltransferase III (GnTIII) activity. In certain embodiments, the host cell has been further manipulated to express increased levels 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, NSO cells, SP2 / 0 cells, YO myeloma cells, P3X63 mouse myeloma cells, PER cells, PER.C6 cells or hybridoma cells, yeast cells, insect cells and plant cells, as well as cells included in transgenic animals, transgenic plants or cultured plant or animal tissues, to name a few.

[0599] As used herein, the term "polypeptide having GnTIII activity" refers to a β-linked mannoside capable of catalyzing the addition of an N-acetylglucosamine (GlcNAc) residue in a β-1,4 linkage to a trimannosyl core of an N-linked oligosaccharide. The term includes fusion polypeptides that exhibit enzymatic activity (as measured in a specific bioassay and with or without dose dependence) similar to, but not necessarily identical to, the activity of β(1,4)-N-acetylglucosaminyltransferase III (also known as β-1,4-mannosyl-glycoprotein 4-β-N-acetylglucosaminyl-transferase (EC 2.4.1.144), according to the Nomenclature Committee of the International Union of Biochemistry and Molecular Biology (NC-IUBMB)). Where dose dependence does exist, it need not be identical to that of GnTIII, but rather substantially similar to the dose dependence of a given activity compared to GnTIII (i.e., the candidate polypeptide will exhibit greater activity or no more than about 25-fold less activity, preferably no more than about ten-fold less activity, and most preferably no more than about three-fold less activity relative to 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 of producing this fusion polypeptide and using it to generate antibodies with increased effector function are disclosed in WO 2004 / 065540, US Provisional Patent Application No. 60 / 495,142, and US Patent Application Publication No. 2004 / 0241817, the entire contents of which are expressly incorporated herein by reference.

[0600] As used herein, the term "Golgi localization domain" refers to the amino acid sequence of a Golgi-resident polypeptide that is responsible for anchoring the polypeptide to its location in the Golgi complex. Typically, the localization domain includes the amino terminal "tail" of the enzyme.

[0601] As used herein, the term "polypeptide having ManII activity" refers to a polypeptide that is capable of catalyzing the hydrolysis of terminal 1,3- and 1,6-linked α-D-mannose residues in branched GlcNAcMan5GlcNAc2 mannose intermediates of N-linked oligosaccharides. The term includes polypeptides that exhibit enzymatic activity similar to, but not necessarily identical to, the activity of Golgi α-mannosidase II (also known as mannosyl oligosaccharide 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)).

[0602] 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 that specifically bind to antibodies or derivatives thereof including Fc regions, and this specific binding is typically carried out via the protein portion of the N-terminus of the Fc region. As used herein, the term "increased / decreased ADCC" is defined as an increase / decrease in the number of target cells lysed with a given concentration of antibody in the culture medium surrounding the target cells within a given time by the ADCC mechanism defined above, and / or a decrease / increase in the antibody concentration in the culture medium surrounding the target cells required for the lysis of a given number of target cells achieved within a given time by the ADCC mechanism. The increase / decrease in ADCC is relative to the ADCC mediated by the same antibody (but not yet transformed) produced by the same type of host cells using the same standard production, purification, formulation and storage methods (methods known to those skilled in the art). For example, ADCC mediated by an antibody produced by a host cell engineered using the methods disclosed herein to have an altered glycosylation pattern (e.g., to express a glycosyltransferase, GnTIII or other glycosyltransferase) is increased relative to ADCC mediated by the same antibody produced by an unengineered host cell of the same type.

[0603] "Antibody with increased antibody-dependent cell-mediated cytotoxicity (ADCC)" means an antibody as defined herein that has increased / decreased ADCC as determined by any suitable method known to those of ordinary skill in the art. One recognized in vitro ADCC assay is as follows:

[0604] 1) The assay uses target cells known to express the target antigen recognized by the antigen-binding region of the antibody;

[0605] 2) The assay uses human peripheral blood mononuclear cells (PBMCs) isolated from the blood of randomly selected healthy donors as effector cells;

[0606] 3) The assay was performed according to the following protocol:

[0607] i) PBMCs were isolated using standard density centrifugation procedures and centrifuged at 5 × 10 6 The cells were suspended in RPMI cell culture medium at a density of 10 cells / mL;

[0608] ii) Target cells were grown by standard tissue culture methods, harvested from the exponential growth phase, and cell viability was above 90%, washed in RPMI cell culture medium, and treated with 100 μCi 51 Cr labeling, washed twice with cell culture medium, and 5 Resuspend in cell culture medium at a density of 10 cells / mL;

[0609] iii) transferring 100 μl of the final target cell suspension into each well of a 96-well microtiter plate;

[0610] iv) serially diluting the antibody from 4000 ng / mL to 0.04 ng / mL in cell culture medium and adding 50 μL of the resulting antibody solution to target cells in a 96-well microtiter plate, testing various antibody concentrations covering the entire concentration range in triplicate;

[0611] v) For the maximum release (MR) control, add 50 μl of 2% (v / v) non-ionic detergent in water (Nonidet, Sigma, St. Louis) to the other three wells of the plate containing labeled target cells to replace the antibody solution (point iv above);

[0612] vi) For spontaneous release (SR) controls, three additional wells in the plate containing labeled target cells received 50 μl of RPMI cell culture medium instead of the antibody solution (point iv above);

[0613] vii) the 96-well microtiter plate was then centrifuged at 50×g for 1 minute and incubated at 4° C. for 1 hour;

[0614] viii) 50 μl of the PBMC suspension (point i above) was added to each well to obtain an effector:target cell ratio of 25:1, and the plate was placed in a 5% CO2 atmosphere and a 37°C incubator for 4 hours;

[0615] ix) harvesting the cell-free supernatant from each well and quantifying the experimentally released radioactivity (ER) using a gamma counter;

[0616] x) Calculate the percentage of specific lysis at each antibody concentration according to the formula (ER-MR) / (MR-SR)×100, where ER is the mean radioactivity quantified for that antibody concentration (see point ix above), MR is the mean radioactivity quantified for the MR control (see point v above) (see point ix above), and SR is the mean radioactivity quantified for the SR control (see point vi above) (see point ix above);

[0617] 4) "Increased / decreased ADCC" is defined as an increase / decrease in the maximum percentage of specific lysis observed within the antibody concentration range tested above, and / or a decrease / increase in the antibody concentration required to achieve half the maximum percentage of specific lysis observed within the antibody concentration range tested above. The increase / decrease in ADCC is relative to the ADCC mediated by the same antibody (but not modified) produced by the same type of host cell using the same standard production, purification, formulation, and storage methods (methods known to those skilled in the art) (measured using the above assay).

[0618] As used herein, term " monoclonal antibody " refers to the antibody obtained from substantially homogeneous antibody colony, that is, except possible variant antibody (for example, containing naturally occurring mutation or producing in the production process of monoclonal antibody preparation, such variant is usually presented in a small amount of form), each antibody comprising this colony is identical and / or combines identical epi-position.Contrary to the polyclonal antibody preparation that generally includes the different antibodies for different determinants (epi-positions), every kind of monoclonal antibody in monoclonal antibody preparation is for the single determinant on antigen.Therefore, the modifier " monoclonal " represents that the feature of antibody is obtained from substantially homogeneous antibody colony, and should not be interpreted as needing to produce antibody by any ad hoc method.For example, the monoclonal antibody for use according to the present invention can be prepared by various techniques, including but not limited to hybridoma method, recombinant DNA method, phage display method and the method for utilizing the transgenic animal containing all or part of human immunoglobulin locus, such method and other exemplary methods for preparing monoclonal antibody are described herein.

[0619] A "naked antibody" is an antibody that is not conjugated to a heterologous moiety (eg, a cytotoxic moiety) or a radiolabel. Naked antibodies can be present in pharmaceutical formulations.

[0620] "Natural antibodies" refer to naturally occurring immunoglobulin molecules with different structures. For example, natural IgG antibodies are heterotetrameric glycoproteins of approximately 150,000 daltons, consisting of two identical light chains and two identical heavy chains bound by disulfide bonds. From the N-terminus to the C-terminus, each heavy chain has a variable region (VH), also referred to as a variable heavy chain domain or a 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 referred to as a variable light chain domain or a light chain variable domain, followed by a constant light chain (CL) domain. The light chain of an antibody can be classified into one of two types, called kappa (κ) and lambda (λ), based on the amino acid sequence of its constant domain.

[0621] As used herein, the terms "first," "second," or "third," etc., with respect to antigen-binding portions or domains, are used to conveniently distinguish each type of portion or domain when more than one portion or domain is present. Unless explicitly stated, the use of these terms is not intended to confer a particular order or orientation.

[0622] The terms "multispecific" and "bispecific" refer to the ability of an antigen-binding molecule to specifically bind to at least two different antigenic determinants. Typically, a bispecific antigen-binding molecule comprises two antigen-binding sites, each of which is specific for a different antigenic determinant. In certain embodiments, a bispecific antigen-binding molecule is capable of simultaneously binding to two antigenic determinants, particularly two antigenic determinants expressed on two distinct cells.

[0623] As used herein, the term "valence" or "valency" indicates that a specified number of antigen binding sites are present in an antigen binding molecule. Thus, the term "monovalently binds to an antigen" indicates that there is one (and no more than one) antigen binding site specific for the antigen in an antigen binding molecule.

[0624] "Antigen binding site" refers to the site, i.e., one or more amino acid residues, of an antigen-binding molecule that provides interaction with an antigen. For example, the antigen-binding site of an antibody comprises amino acid residues from the complementarity determining region (CDR). Natural immunoglobulin molecules typically have two antigen-binding sites, while Fab molecules typically have a single antigen-binding site.

[0625] As used herein, " activated T cell antigen " refers to an antigenic determinant expressed by T lymphocytes (particularly cytotoxic T lymphocytes), which can induce or enhance T cell activation when interacting with antigen binding molecules. Specifically, the interaction of antigen binding molecules with activated T cell antigens can induce T cell activation by triggering the signal transduction cascade of the T cell receptor complex. Exemplary activated T cell antigens are CD3. In a specific embodiment, activated T cell antigens are CD3, particularly the epsilon subunit of CD3 (see UniProt numbering P07766 (130th edition), NCBI RefSeq numbering NP_000724.1, which are directed to human sequences; or UniProt numbering Q95LI5 (49th edition), NCBI GenBank number BAB71849.1, which are directed to macaque [long-tailed macaque] sequences).

[0626] As used herein, "T cell activation" refers to one or more cellular responses of T lymphocytes (particularly cytotoxic T lymphocytes) selected from the group consisting of proliferation, differentiation, cytokine secretion, cytotoxic effector molecule release, cytotoxic activity, and expression of activation markers. The T cell activation 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.

[0627] As used herein, "target cell antigen" refers to an antigenic determinant present on the surface of a target cell, such as a cell in 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).

[0628] As used herein, "B cell antigen" refers to an antigenic determinant presented on the surface of B lymphocytes, particularly malignant B lymphocytes (in which case the antigen is also referred to as a "malignant B cell antigen").

[0629] As used herein, "T cell antigen" refers to an antigenic determinant present on the surface of T lymphocytes, particularly cytotoxic T lymphocytes.

[0630] "Fab molecule" refers to a protein composed of the VH and CH1 domains of an immunoglobulin heavy chain ("Fab heavy chain") and the VL and CL domains of a light chain ("Fab light chain").

[0631] By "fused" is meant that the components (eg, a Fab molecule and an Fc domain subunit) are linked by peptide bonds, either directly or via one or more peptide linkers.

[0632] An "effective amount" of an agent is that amount required to produce a physiological change in the cells or tissues to which it is administered.

[0633] A "therapeutically effective amount" of an agent (e.g., a pharmaceutical composition) is an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic or preventive result. A therapeutically effective amount of an agent, for example, eliminates, reduces, delays, minimizes, or prevents the adverse effects of a disease.

[0634] "Therapeutic agent" means an active ingredient, such as a pharmaceutical composition, that is administered to a subject in an attempt to alter the natural course of the subject's disease and can be used prophylactically or performed during the course of clinical pathology. "Immunotherapeutic agent" refers to a therapeutic agent that is administered to a subject in an attempt to restore or enhance the subject's immune response (e.g., an immune response to a tumor).

[0635] The term "pharmaceutical composition" refers to a preparation that is in such form that the biological activity of the active ingredient contained therein is effective, and that contains no additional components that are unacceptably toxic to a subject to which the composition would be administered.

[0636] "Pharmaceutically acceptable carrier" refers to a component of a pharmaceutical composition other than the active ingredient that is non-toxic to the subject. Pharmaceutically acceptable carriers include, but are not limited to, buffers, excipients, stabilizers, or preservatives.

[0637] The terms "package insert" or "instructions for use" are used to refer to instructions customarily included in commercial packages of therapeutic products, that contain information about the indications, usage, dosage, administration, combination therapy, contraindications and / or warnings concerning the use of such therapeutic products.

[0638] The term "combination therapy" as used herein encompasses combined administration, in which two or more therapeutic agents are included in the same or separate formulations, as well as separate administration, in which case administration of an antibody as reported herein can occur before, simultaneously with, and / or after administration of one or more additional therapeutic agents, preferably one or more antibodies.

[0639] "Crossfab" refers to a Fab molecule in which the variable or constant domains of the Fab heavy and light chains are exchanged (i.e., replaced with each other), i.e., a crossover Fab molecule comprises a peptide chain (VL-CH1, in the N-terminal to C-terminal direction) consisting of a light chain variable domain VL and a heavy chain constant domain 1CH1, and a peptide chain (VH-CL, in the N-terminal to C-terminal direction) consisting of a heavy chain variable domain VH and a light chain constant domain CL. For clarity, in crossover Fab molecules in which the variable domains of the Fab light chain and the variable domains of the Fab heavy chain are exchanged, the peptide chain comprising the heavy chain constant domain 1CH1 is referred to herein as the "heavy chain" of the (crossover) Fab molecule. Conversely, in crossover Fab molecules in which the constant domains of the Fab light chain and the constant domains of the Fab heavy chain are exchanged, the peptide chain comprising the heavy chain variable domain VH is referred to herein as the "heavy chain" of the (crossover) Fab molecule.

[0640] In contrast, a "conventional" Fab molecule is intended to be a Fab molecule in its native form, i.e., comprising a heavy chain consisting of a heavy chain variable domain and a constant domain (VH-CH1, in N-terminal to C-terminal direction), and a light chain consisting of a light chain variable domain and a constant domain (VL-CL, in N-terminal to C-terminal direction).

[0641] The term "polynucleotide" refers to an isolated nucleic acid molecule or construct, such as messenger RNA (mRNA), virally derived RNA, or plasmid DNA (pDNA). A polynucleotide may contain conventional phosphodiester bonds or unconventional bonds (e.g., amide bonds, such as those found in peptide nucleic acids (PNA)). The term "nucleic acid molecule" refers to any one or more nucleic acid segments, e.g., DNA or RNA fragments, present in a polynucleotide.

[0642] "Isolated" nucleic acid molecules or polynucleotides refer to nucleic acid molecules, DNA or RNA that have been taken out of their natural environment. For example, recombinant polynucleotides encoding polypeptides contained in vectors are considered to be isolated for the purposes of the present invention. Other examples of isolated polynucleotides include recombinant polynucleotides maintained in heterologous host cells or purified (partially or substantially purified) polynucleotides in solution. Isolated polynucleotides include polynucleotide molecules that are contained in cells that typically contain polynucleotide molecules, but that are present outside the chromosome or in a chromosomal position different from their natural chromosomal position. Isolated RNA molecules include in vivo or in vitro RNA transcripts of the present invention, as well as positive and negative strand forms and double-stranded forms. Isolated polynucleotides or nucleic acids according to the present invention also include such molecules produced by synthesis. In addition, polynucleotides or nucleic acids can be or can include regulatory elements, such as promoters, ribosome binding sites or transcription terminators.

[0643] In the case of a nucleic acid or polynucleotide having a nucleotide sequence that is at least, for example, 95% "identical" to a reference nucleotide sequence of the present invention, it is meant that the nucleotide sequence of the polynucleotide is identical to the reference sequence, except that the polynucleotide sequence may include 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 a reference nucleotide sequence, up to 5% of the nucleotides in the reference sequence may be deleted or substituted with additional nucleotides, or up to 5% of the total nucleotides in the reference sequence may be inserted into the reference sequence. These changes in the reference sequence may occur at the 5' or 3' terminal positions of the reference nucleotide sequence or anywhere between those terminal positions, or may be interspersed individually among the residues in the reference sequence or 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 routinely determined using known computer programs, such as those discussed below for polypeptides (e.g., ALIGN-2).

[0644] The term "expression cassette" refers to a polynucleotide produced by recombination or synthesis, which has a series of specific nucleic acid elements that allow a specific nucleic acid to be transcribed in a target cell. The recombinant expression cassette can be incorporated into a plasmid, chromosome, mitochondrial DNA, plastid DNA, virus or nucleic acid fragment. Typically, the recombinant expression cassette portion of the expression vector also includes a nucleic acid sequence to be transcribed and a promoter in addition to other sequences. In certain embodiments, the expression cassette of the present invention comprises a polynucleotide sequence encoding a bispecific antigen binding molecule of the present invention or a fragment thereof.

[0645] The term "vector" or "expression vector" is synonymous with "expression construct" and refers to a DNA molecule used to introduce a specific gene into a target cell operably associated therewith and to direct the expression of the gene. The term includes vectors that are self-replicating nucleic acid structures, as well as vectors that are incorporated into the genome of the host cell into which it has been introduced. The expression vector of the present invention comprises an expression cassette. The expression vector allows for the transcription of a large amount of stable mRNA. Once the expression vector is inside the target cell, the ribonucleic acid molecule or protein encoded by the gene is produced by the cell's transcription and / or translation machinery. In one embodiment, the expression vector of the present invention comprises an expression cassette comprising a polynucleotide sequence encoding the bispecific antigen binding molecule of the present invention or a fragment thereof.

[0646] As used herein, the term "about" refers to the common error range of the corresponding value that is readily known to those skilled in the art. References to "about" values ​​or parameters herein include (and describe) embodiments involving the value or parameter itself.

[0647] "B-cell proliferative disorder" means a disorder in which the number of B cells in a patient is greater than the number of B cells in healthy subjects, and particularly wherein the increase in the number of B cells is the cause or hallmark of the disorder. A "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.

[0648] Exemplary B-cell proliferative disorders include non-Hodgkin 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, lymph node, 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 a relapsed or refractory NHL (e.g., relapsed or refractory DLBCL, relapsed or refractory FL, or relapsed or refractory MCL). In one embodiment, BL, BAL, DLBCL, or PMBCL is relapsed and / or refractory. In one embodiment, BL, BAL, DLBCL, or PMBCL has relapsed or is refractory after first-line standard of care chemoimmunotherapy.

[0649] "Refractory disease" is defined as failure to achieve a complete response to first-line therapy, including:

[0650] Progressive disease (PD) as best response to first-line therapy

[0651] Stable disease (SD) as best response after at least 4 cycles of first-line therapy (e.g., 4 cycles of R-CHOP)

[0652] Partial response (PR) as best response after at least 6 cycles with biopsy-proven residual disease or subsequent disease progression.

[0653] "Relapsed disease" is defined as complete remission to first-line therapy. In one embodiment, disease recurrence is documented by biopsy. In one embodiment, the patient has relapsed or had no remission after at least two prior systemic treatment regimens, including at least one prior regimen containing anthracyclines and at least one prior regimen containing anti-CD20 directed therapy.

[0654] "Individual" or "subject" is a mammal. Mammals include, but are not limited to, domesticated animals (e.g., cattle, 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 case, each subject in the subject population is a human. In one case, each subject in the subject reference population is a human. In one embodiment, a subject is considered to be a pediatric patient if the patient is less than 18 years of age (i.e., 17 years of age or younger). In one embodiment, the age of 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 patient is between 18 and 30 years of age.

[0655] A "transplant eligible" subject or an "autologous stem cell transplant (SCT) eligible" subject is a subject who is eligible for, recommended for, or eligible for SCT. In one embodiment, "transplant eligible" is defined as being medically eligible for intensive platinum-based salvage therapy followed by autologous stem cell transplant (ASCT). In one embodiment, a transplant eligible subject achieves an objective remission and a target dose of at least 2,000,000 CD34+ hematopoietic stem cells / kg mobilized. In one embodiment, "transplant eligible" is defined as being medically eligible for two to three cycles of salvage therapy with R-ICE and gefizumab to achieve CR, followed by allogeneic or autologous hematopoietic stem cell transplant (HSCT).

[0656] A "CAR-T cell therapy eligible" subject or a "CAR-T cell therapy eligible" subject is a subject who meets the conditions for, is recommended for, or can receive chimeric antigen receptor (CAR) T cell therapy.

[0657] As used herein, "treatment" (and grammatical variations thereof) refers to an attempt to change the natural course of the disease in the individual being treated, and can be performed for prevention or clinical interventions that can be performed during clinical pathology. The desired effects of treatment include, but are not limited to, preventing the occurrence or recurrence of the disease, alleviating symptoms, weakening any direct or indirect pathological consequences of the disease, preventing metastasis, reducing the rate of disease progression, improving or alleviating the disease state, and alleviating or improving prognosis. In some embodiments, the methods of the present invention are used to delay the development of the disease or slow the progression of the disease. In one embodiment, the disease being treated is a CD20-positive B-cell proliferative disorder, for example, Burkitt's lymphoma (BL); Burkitt's leukemia (BAL; mature B-cell leukemia FAB L3); DLBCL or PMBCL.

[0658] As used herein, "delaying progression" of a disorder or disease means postponing, hindering, slowing, delaying, stabilizing, and / or delaying the development of a 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). This delay can be of varying lengths of time, depending on the medical history and / or the individual being treated. It will be apparent to one skilled in the art that a sufficient or significant delay can actually encompass prevention, as the individual will not develop the disease. For example, in advanced cancer, the development of central nervous system (CNS) metastases may be delayed.

[0659] "Reduce" or "inhibit" means the ability to cause an overall reduction, for example, 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 detection limit of the analytical method), i.e., complete abolition or elimination. In certain embodiments, reduction or inhibition can refer to reducing or inhibiting undesirable events, for example, cytokine-driven toxicity (e.g., cytokine release syndrome (CRS)), infusion-related reaction (IRR), macrophage activation syndrome (MAS), neurotoxicity, severe tumor lysis syndrome (TLS), neutropenia, thrombocytopenia, elevated liver enzymes, and / or central nervous system (CNS) toxicity, relative to the invariant scheduled dosing of the target dose using the bispecific antibody, following treatment with the anti-CD20 / anti-CD3 bispecific antibody using the ascending dosing regimen of the present invention. In other embodiments, reduction or inhibition can refer to the effector functions of the antibody mediated by the Fc region of the antibody, such effector functions specifically include complement dependent cytotoxicity (CDC), antibody dependent cellular cytotoxicity (ADCC) and antibody dependent cellular phagocytosis (ADCP). In other embodiments, reduction or inhibition can refer to the symptoms 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), the presence or size of metastases or the size of the primary tumor. 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 PMBCL.

[0660] As used herein, "administering" refers to a method of administering a dose 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) to a subject. The compounds and / or compositions utilized in the methods described herein can be administered intravenously (e.g., by intravenous infusion).

[0661] A "fixed" or "flat" dose of a therapeutic agent (e.g., a bispecific antibody) herein refers to a dose that is administered to a patient without regard to the patient's weight or body surface area (BSA). Thus, a fixed dose is not a mg / kg dose or mg / m 2 The dosage is not provided in units of units, but rather in absolute doses of the therapeutic agent (eg, mg).

[0662] "Target dose" herein refers to the dose of the anti-CD20 / anti-CD3 bispecific antibody that achieves a therapeutic effect, i.e., achieves the desired clinical efficacy. It was found that for Gefituzumab, a possible target dose was 16 mg or 30 mg. In one embodiment, the target dose for pediatric subjects (i.e., aged 6 months to 17 years) is 0.5 mg / kg or 0.4 mg / kg, depending on the weight of the subject. In a specific embodiment, the target dose is 0.5 mg / kg for pediatric subjects weighing 7.5 kg to <13 kg, 0.4 mg / kg for pediatric subjects weighing ≥13 kg to <45 kg, and 30 mg uniform dose for pediatric subjects weighing ≥45 kg.

[0663] "Unchanged or predetermined dosing with a target dose" and "a treatment regimen that does not use an escalating dosing regimen" refer to a dosing regimen in which the same dose is used in the first and second cycles and, optionally, in any subsequent treatment cycles, as opposed to escalating dosing, in which lower doses are used in the first few treatment cycles and the target dose is reached only in the second or subsequent treatment cycles.

[0664] As used herein, the term "treatment cycle" or "cycle" (abbreviated as: "C") means a course of one or more doses of an anti-CD20 / anti-CD3 bispecific antibody repeated on a regular schedule, optionally with a rest period (no treatment) in between. In one aspect of the invention, a first treatment cycle comprises a first dose and a second dose of an anti-CD20 / anti-CD3 bispecific antibody, followed by a rest period. In one such embodiment, the first treatment cycle comprises a first dose of an anti-CD20 / anti-CD3 bispecific antibody on day 8 of the first cycle and 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 cycle and any subsequent cycles comprise a dose of an anti-CD20 / anti-CD3 bispecific antibody given on day 8 of the cycle, followed by a 13-day rest period. In one embodiment, one treatment cycle comprises 21 days. In another embodiment, one treatment cycle comprises 14 days. The treatment regimen according to the present invention may comprise 2 or more treatment cycles, in particular 3 treatment cycles. In some embodiments, a treatment cycle is referred to as a "dosing cycle."

[0665] "Individual remission" or "remission" can be assessed using any endpoint indicative of benefit to the subject, including but not limited to (1) inhibition of disease progression (e.g., progression of a CD20-positive B-cell proliferative disorder, e.g., non-Hodgkin's lymphoma (NHL)) to some extent, including slowing and complete arrest; (2) reduction in tumor size; (3) inhibition (i.e., reduction, slowing, or complete cessation) of cancer cell infiltration into adjacent peripheral organs and / or tissues; (4) inhibition (i.e., reduction, slowing, or complete cessation) of metastasis; (5) alleviation to some extent of one or more symptoms associated with a CD20-positive B-cell proliferative disorder, e.g., a B-cell proliferative disorder; (6) increase or prolongation of the period of survival (including overall survival and progression-free survival); and / or (7) reduction in mortality at a given time point after treatment.

[0666] As used herein, "complete remission" or "CR" refers to the disappearance of all target lesions. In one embodiment, standard NHL remission 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 who achieve 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 complete metabolic remission as determined by PET / CT of lymph nodes and extralymphatic sites, with a score of 1, 2, or 3, with or without residual mass on 5PS, where PET 5PS: 1 = no uptake above background; 2 = uptake > mediastinum; 3 = uptake > mediastinum, but ≤ liver; 4 = uptake moderate > liver; 5 = uptake significantly above liver and / or new lesions; X = new area of ​​uptake unlikely to be related to lymphoma. In one embodiment, CR is defined as complete radiographic response as determined by CT of lymph nodes and extralymphatic sites, wherein the target node / nodular mass must shrink to ≤1.5 cm in LDi (the longest transverse diameter of the lesion) and no extralymphatic disease sites remain. For pediatric subjects (age <18 years), 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).

[0667] As used herein, "partial response" or "PR" refers to a partial metabolic response as determined by PET / CT of lymph nodes and extralymphatic sites and / or a partial response as determined by CT of lymph nodes and extralymphatic sites. In one embodiment, a partial metabolic response is defined by a score of 4 or 5b, decreased uptake compared to baseline, and a residual mass of any size as determined by PET / CT of lymph nodes and extralymphatic sites, where PET 5PS: 1 = no uptake above background; 2 = uptake > mediastinum; 3 = uptake > mediastinum, but ≤ liver; 4 = moderate uptake > liver; 5 = uptake significantly above liver and / or new lesions; X = new area of ​​uptake unlikely to be related to lymphoma. In one embodiment, a partial response is defined as a reduction of at least 50% in the product of the diameters (SPD) of up to 6 target measurable nodules and extranodal sites, with baseline SPD as reference. For pediatric subjects (age <18 years), PR was 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).

[0668] An "effective response" of a subject to a drug or treatment, or "responsiveness" of a subject, and similar terms, refers to a clinical or therapeutic benefit conferred on a subject at risk for or suffering from a disease or condition, such as cancer. In one embodiment, such benefit includes one or more of: prolonging survival (including overall survival and progression-free survival); resulting in an objective response (including complete or partial response); or ameliorating signs or symptoms of cancer.

[0669] Duration of complete response (DOCR) was defined as the time from the first documented complete response to disease progression or death from any cause, whichever occurred 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 was assessed by the investigator using the International Pediatric NHL Response Criteria for pediatric subjects <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).

[0670] "Duration of objective response (DOR)" was defined as the time from the first documented objective response (CR or PR) to disease progression or death from any cause (whichever occurred 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 were assessed by the investigator using the International Pediatric NHL Response Criteria for pediatric subjects <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).

[0671] "Progression-free survival" (PFS) is defined as the time from the first treatment with anti-CD20 / anti-CD3 bispecific antibodies 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 researchers using the international pediatric NHL remission criteria for pediatric subjects aged <18 years (Sandlund JT, Guillerman RP, Perkins SL et al. International pediatric non-Hodgkin lymphoma response criteria. J. Clin Oncol. 33: 2106-2111, 2015).

[0672] "Overall survival" (OS) was defined as the time from the first anti-CD20 / anti-CD3 bispecific antibody treatment to death from any cause.

[0673] As used herein, "event-free survival" (EFS) is defined as the time from the first treatment with anti-CD20 / anti-CD3 bispecific antibodies to the first appearance of disease progression as determined by the investigator according to the Lugano criteria, the start of a 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 remission criteria for pediatric subjects <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).

[0674] As used herein, " objective response rate (ORR) " is defined as the sum of partial remission (PR) rate and complete remission (CR) rate. In one embodiment, ORR is evaluated based on Lugano classification (Cheson et al. J Clin Oncol. 2014 Sep 20; 32 (27): 3059-3067). In one embodiment, ORR is defined as the ratio of participants who achieve CR or PR within three cycles of the anti-CD20 / anti-CD3 bispecific antibody (e.g., Gefituzumab)+R-ICE treatment regimen described therein. CR and / or PR are evaluated by researchers using the international pediatric NHL remission criteria for pediatric subjects aged <18 years (Sandlund JT, Guillerman RP, Perkins SL et al. International pediatric non-Hodgkin lymphoma response criteria. J. Clin. Oncol. 33: 2106-2111, 2015).

[0675] As used herein, "stable disease" or "SD" means that the target lesion has neither shrunk sufficiently to qualify as a PR nor increased sufficiently to qualify as a PD, taking as reference the smallest SLD since the start of treatment.

[0676] As used herein, "progressive disease" or "PD" refers to an increase in the SLD of the target lesion by at least 20% based on the minimum SLD recorded since the start of treatment, or an increase in the SPD of the target lesion by at least 50% based on the minimum SPD recorded since the start of treatment, or the appearance of one or more new lesions.

[0677] 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., gefuzumab; or an anti-CD20 antibody, e.g., obinutuzumab or rituximab). IRRs can be graded, for example, on a scale of 1-5 according to NCI CTCAE v.4.

[0678] The mobilization-adjusted response rate (MARR) was defined as the percentage of patients who achieved an objective response and a target mobilization dose of 2 million CD34+ hematopoietic stem cells / kg (usually the minimum requirement for ASCT).

[0679] 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.

[0680] (iii) Combination therapy of anti-CD20 / anti-CD3 bispecific antibodies with anti-CD20 antibodies and chemotherapy

[0681] The present invention provides a method for treating a subject having 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))), the method 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.

[0682] In some cases, the present method is used to treat a subject with relapsed and / or refractory NHL (e.g., aggressive NHL (e.g., relapsed and / or refractory DLBCL, relapsed and / or refractory FL, or relapsed and / or refractory MCL)). In some cases, the subject relapses after one or more (e.g., one, two, three, four, five or more) prior therapies (e.g., one or more prior systemic therapies, e.g., one or more prior systemic chemotherapies (e.g., one or more prior systemic therapies comprising administration of anthracyclines), one or more prior stem cell therapies, or one or more prior CAR-T cell therapies) following a documented history of remission (e.g., complete remission or partial remission) for at least 6 months from the end of the therapy. In some cases, the subject is refractory to any prior therapy (e.g., did not respond to the prior therapy, or progressed within 6 months of completing the last dose of therapy). Thus, in some embodiments, the present dosing regimen is a second-line therapy. In some embodiments, the present dosing regimen is a third-line therapy. In some embodiments, the subject has transformed FL that is refractory to standard therapy for transformed FL. In some embodiments, the FL is a graded FL (eg, a grade 1, 2, 3a, or 3b FL).

[0683] 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), the method comprising administering to the subject an effective amount of:

[0684] (a) Bispecific antibodies that bind to CD20 and CD3;

[0685] (b) anti-CD20 antibodies; and

[0686] (c) one or more chemotherapeutic agents selected from ifosfamide, carboplatin and / or etoposide.

[0687] In one embodiment, a first dosing 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 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 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 a second dosing cycle comprises a single dose of the bispecific antibody 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, or ±1.6 mg) of the bispecific antibody. In certain embodiments, the 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 the 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).

[0688] In one embodiment, the first dosing 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 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 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 dosing cycle comprises a single dose (C2D1) of the bispecific antibody, wherein 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).

[0689] In one embodiment, the subject is administered a first dose (C1D1) of the bispecific antibody and a second dose (C1D2) of the bispecific antibody on or around day 8 (±1 day) and day 15 (±1 day) of the first dosing cycle, respectively.

[0690] In one embodiment, the first dose (C1D1) and the second dose (C1D2) of the bispecific antibody are administered to the subject on day 8 and day 15 of the first dosing cycle, respectively. In some embodiments, C2D1 of the bispecific antibody is administered to the subject on or around day 8 (±1 day) of the second dosing cycle. In some embodiments, C2D1 of the bispecific antibody is administered to the subject on or around day 8 of the second dosing cycle.

[0691] In one embodiment, the anti-CD20 antibody is obinutuzumab and / or rituximab. In one embodiment, the first dosing cycle includes a single dose of obinutuzumab (C1D1); and the second dosing cycle includes a single dose of rituximab (C2D1).

[0692] In one embodiment, a 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 a single dose of rituximab is about 375 mg / m 2 (e.g., 375 mg / m 2 ±5mg / m 2 ±10mg / m 2 ±25mg / m 2 or ±37.5 mg / m 2 ).

[0693] 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).

[0694] 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 dosing cycle:

[0695] (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 (C1D1) of the bispecific antibody that binds to CD20 and CD3 and 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) as a second dose (C1D2) of the bispecific antibody that binds to CD20 and CD3;

[0696] (b) a single dose of obinutuzumab (C1D1); and

[0697] (c) one or more chemotherapeutic agents selected from ifosfamide, carboplatin and / or etoposide;

[0698] In the second dosing cycle, the subjects were administered:

[0699] (a) a single dose (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) of a bispecific antibody that binds to CD20 and CD3;

[0700] (b) a single dose of rituximab (C2D1); and

[0701] (c) one or more chemotherapeutic agents selected from ifosfamide, carboplatin and / or etoposide.

[0702] In one embodiment, a 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 a single dose of rituximab is about 375 mg / m 2 (e.g., 375 mg / m 2 ±5mg / m 2 ±10mg / m 2 ±25mg / m 2 or ±37.5 mg / m 2 ).

[0703] 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).

[0704] In one embodiment, the subject is administered a first dose (C1D1) of the bispecific antibody and a second dose (C1D2) of the bispecific antibody on or around day 8 (±1 day) and day 15 (±1 day) of the first dosing cycle, respectively.

[0705] In one embodiment, the first dose (C1D1) and the second dose (C1D2) of the bispecific antibody are administered to the subject on day 8 and day 15 of the first dosing cycle, respectively. In some embodiments, C2D1 of the bispecific antibody is administered to the subject on or around day 8 (±1 day) of the second dosing cycle. In some embodiments, C2D1 of the bispecific antibody is administered to the subject on or around day 8 of the second dosing cycle.

[0706] In one embodiment of the methods provided above, step c) includes all three chemotherapeutic agents.

[0707] In one embodiment, the first dosing cycle includes 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 the second cycles each include a single dose of ifosfamide (C2D1), a single dose of carboplatin (C2D1), and a first dose (C2D1), a second dose (C2D2), and a third dose (C2D3) of etoposide.

[0708] 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 dosing cycle:

[0709] (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 (C1D1) of the bispecific antibody that binds to CD20 and CD3 and 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) as a second dose (C1D2) of the bispecific antibody that binds to CD20 and CD3;

[0710] (b) a single dose of obinutuzumab (C1D1); and

[0711] (c) a single dose of ifosfamide (C1D1), a single dose of carboplatin (C1D1), and the first dose (C1D1), second dose (C1D2), and third dose (C1D3) of etoposide;

[0712] In the second dosing cycle, the subjects were administered:

[0713] (a) a single dose (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) of a bispecific antibody that binds to CD20 and CD3;

[0714] (b) a single dose of rituximab (C2D1); and

[0715] (c) A single dose of ifosfamide (C2D1), a single dose of carboplatin (C2D1), and the first dose (C2D1), second dose (C2D2), and third dose (C2D3) of etoposide.

[0716] In one embodiment, a 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 a single dose of rituximab is about 375 mg / m2 (e.g., 375 mg / m 2 ±5mg / m 2 ±10mg / m 2 ±25mg / m 2 or ±37.5 mg / m 2 ).

[0717] 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).

[0718] In one embodiment, the subject is administered a first dose (C1D1) of the bispecific antibody and a second dose (C1D2) of the bispecific antibody on or around day 8 (±1 day) and day 15 (±1 day) of the first dosing cycle, respectively.

[0719] In one embodiment, the first dose (C1D1) and the second dose (C1D2) of the bispecific antibody are administered to the subject on day 8 and day 15 of the first dosing cycle, respectively. In some embodiments, C2D1 of the bispecific antibody is administered to the subject on or around day 8 (±1 day) of the second dosing cycle. In some embodiments, C2D1 of the bispecific antibody is administered to the subject on or around day 8 of the second dosing cycle.

[0720] In one embodiment of the method provided above, 5000 mg / m 2 4000mg / 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 / min to a target area under the curve (AUC) of 5 mg / mL / min, with a maximum dose of 750 mg. 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 Etoposide was administered at a dose of .

[0721] In one embodiment of the method provided above, 5000 mg / m 2 4000mg / m 2 or 1666 mg / m2 Ifosfamide was administered at a dose of 100 mg / mL / min, carboplatin was administered at a dose of 100 mg / mL / min to a target area under the curve (AUC) of 5 mg / mL / min with a maximum dose of 750 mg, and 2 or 75 mg / m 2 Etoposide was administered at a dose of .

[0722] In one embodiment of the method provided above, 5000 mg / m 2 Ifosfamide was administered at a dose of 100 mg / mL / min, carboplatin was administered at a dose of 100 mg / mL / min to a target area under the curve (AUC) of 5 mg / mL / min with a maximum dose of 750 mg, and 2 Etoposide was administered at a dose of .

[0723] In one embodiment, about 5000 mg / m 2 (e.g., 5000 mg / m 2 ±50mg / m 2 ±100mg / m 2 ±200mg / m 2 ±300mg / m 2 ±400mg / m 2 or ±500mg / m 2 ), about 4000mg / m 2 (For example, 4000 mg / m 2 ±40mg / m 2 ±50mg / m 2 ±100mg / m 2 ±200mg / m 2 ±300mg / m 2 or ±400 mg / m 2 ) or about 1666 mg / m 2 (e.g., 1666 mg / m 2 ±25mg / m 2 ±50mg / m 2 ±100mg / m 2 or ±166.6 mg / m 2 ), ifosfamide 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 carboplatin at a dose of about 100 mg / m 2 (e.g., 100 mg / m 2 ±1mg / m 2 ±2.5mg / m 2 ±5mg / m2 or ±10 mg / m 2 ) or 75 mg / m 2 (e.g., 0.5 mg / m 2 ±1mg / m 2 ±2.5mg / m 2 ±5mg / m 2 or ±7.5 mg / m 2 ) dose of etoposide. In one embodiment, (a) the subject is male and CrCl is calculated using the formula CrCl = ([140 - age] × [body weight (kg)]) / (72 × [serum creatinine (mg / dL)]); or (b) the subject is female and CrCl is calculated using the formula CrCl = 0.85 × ([140 - age] × [body weight (kg)]) / (72 × [serum creatinine (mg / dL)]). In one embodiment, (a) the subject has a CrCl of < about 60 mL / min and each single dose of ifosfamide is reduced to 4000 mg / m 2 and / or (b) the subject has a CrCl of < about 50 mL / min, and wherein each dose of etoposide is reduced to 75 mg / m 2 In one embodiment, the subject is or will be administered ifosfamide in an outpatient setting at a dose of about 1666 mg / m 2 (e.g., 1666 mg / m 2 ±25mg / m 2 ±50mg / m 2 ±100mg / m 2 or ±166.6 mg / m 2 ) was administered at a dose of ifosfamide.

[0724] In one embodiment, ifosfamide and carboplatin are administered on day 2 of the first and second dosing cycles, and etoposide is administered on each of days 1, 2, and 3 of the first and second dosing cycles.

[0725] 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 dosing cycle:

[0726] (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 (C1D1) of the bispecific antibody that binds to CD20 and CD3 and 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) as a second dose (C1D2) of the bispecific antibody that binds to CD20 and CD3;

[0727] (b) a single dose (C1D1) 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; and

[0728] (c) Ifosfamide, approximately 5000 mg / m 2 (e.g., 5000 mg / m 2 ±50mg / m 2 ±100mg / m 2 ±200mg / m 2 ±300mg / m 2 ±400mg / m 2 or ±500mg / m 2 ), a single dose (C1D1) of carboplatin in mg to a target area under the curve (AUC) of 5 mg / mL / min, with a maximum dose of 750 mg (C1D1), and approximately 100 mg / m 2 the first dose (C1D1), second dose (C1D2), and third dose (C1D3) of

[0729] In the second dosing cycle, the subjects were administered:

[0730] (a) a single dose (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) of a bispecific antibody that binds to CD20 and CD3;

[0731] (b) Rituximab at approximately 375 mg / m 2 (e.g., 375 mg / m 2 ±5mg / m 2 ±10mg / m 2 ±25mg / m 2 or ±37.5 mg / m 2) a single dose (C2D1); and

[0732] (c) Ifosfamide, approximately 5000 mg / m 2 (e.g., 5000 mg / m 2 ±50mg / m 2 ±100mg / m 2 ±200mg / m 2 ±300mg / m 2 ±400mg / m 2 or ±500mg / m 2 ), a single dose (C1D1) of carboplatin in mg to a target area under the curve (AUC) of 5 mg / mL / min, with a maximum dose of 750 mg (C1D1), and approximately 100 mg / m 2 The first dose (C1D1), the second dose (C1D2) and the third dose (C1D3) of the drug were measured.

[0733] 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:

[0734] (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 the bispecific antibody that binds to CD20 and CD3 on day 8 of the first dosing cycle (C1D1), 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) as a second dose of the bispecific antibody that binds to CD20 and CD3 on day 15 (C1D2), 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 a first dose on day 8 of the second dosing cycle (C2D1);

[0735] (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 / m2 of rituximab on day 1 of a second dosing cycle (C1D1). 2 (e.g., 375 mg / m 2 ±5mg / m 2 ±10mg / m 2 ±25mg / m 2 or ±37.5 mg / m 2 ) a single dose (C2D1); and

[0736] (c) Ifosfamide at approximately 5000 mg / m2 on day 2 of the first and second cycles 2 (e.g., 5000 mg / m 2 ±50mg / m 2 ±100mg / m 2 ±200mg / m 2 ±300mg / m 2 ±400mg / m 2 or ±500mg / m 2 ), a single dose (C1D1) of carboplatin in mg to a target area under the curve (AUC) of 5 mg / mL / min on Day 2 of Cycle 1 and Cycle 2, with a maximum dose of 750 mg (C1D1), and etoposide at approximately 100 mg / m2 on Days 1, 2, and 3 of Cycle 1 and Cycle 2. 2 The first dose (C1D1), the second dose (C1D2) and the third dose (C1D3) of the drug were measured.

[0737] In some embodiments, the first dosing cycle and the second dosing cycle are 14 day (e.g., 14 ± 3 day) dosing cycles. In some embodiments, the first dosing cycle and the second dosing cycle are 21 day (e.g., 21 ± 3 day) dosing cycles. In a specific embodiment, the first dosing cycle and the second dosing cycle are 21 day dosing cycles.

[0738] In certain embodiments, the dosage regimen includes one or more additional dosing cycles. In certain embodiments, the dosage regimen includes three dosing cycles in total. In certain embodiments, the additional dosing cycle is a 14-day (e.g., 14 ± 3 day) dosing cycle. In certain embodiments, the additional dosing cycle is a 21-day (e.g., 21 ± 3 day) dosing cycle. In one embodiment, the method provided herein includes three 21-day dosing cycles.

[0739] In one embodiment, the one or more additional dosing cycles include:

[0740] (a) an additional single dose of a bispecific antibody that binds to CD20 and CD3,

[0741] (b) an additional single dose of anti-CD20 antibody, and

[0742] (c) an additional single dose of ifosfamide, an additional single dose of carboplatin, and additional first, second, and third doses of etoposide.

[0743] 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).

[0744] 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 ±5mg / m 2 ±10mg / m 2 ±25mg / m 2 or ±37.5 mg / m 2 In one embodiment, the additional single dose of rituximab is administered on day 1 of the additional dosing cycle.

[0745] In one embodiment, the additional single dose of ifosfamide is about 5000 mg / m 2 (e.g., 5000 mg / m 2 ±50mg / m 2 ±100mg / m 2 ±200mg / m 2 ±300mg / m 2 ±400mg / m 2 or ±500mg / m 2 ), about 4000mg / m 2 (For example, 4000 mg / m 2 ±40mg / m 2 ±50mg / m 2 ±100mg / m 2 ±200mg / m 2 ±300mg / m 2 or ±400 mg / m 2 ) or about 1666 mg / m 2 (e.g., 1666 mg / m 2±25mg / m 2 ±50mg / m 2 ±100mg / m 2 or ±166.6 mg / m 2 ), an additional single dose of carboplatin in mg to a target 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 additional first, second, and third doses of etoposide of 100 mg / m 2 (e.g., 100 mg / m 2 ±1mg / m 2 ±2.5mg / m 2 ±5mg / m 2 or ±10 mg / m 2 ) or 75 mg / m 2 (e.g., 0.5 mg / m 2 ±1mg / m 2 ±2.5mg / m 2 ±5mg / m 2 or ±7.5 mg / m 2 In one embodiment, the additional single dose of ifosfamide is 5000 mg / m 2 4000mg / m 2 or 1666 mg / m 2 , additional single doses of carboplatin in mg to a target area under the curve (AUC) of 5 mg / mL / min with a maximum dose of 750 mg, and additional first, second, and third doses of etoposide in mg to 100 mg / mL / min 2 or 75 mg / m 2 In one embodiment, 5000 mg / m 2 Ifosfamide was administered at a dose of 100 mg / mL / min, carboplatin was administered at a dose of 100 mg / mL / min to a target area under the curve (AUC) of 5 mg / mL / min with a maximum dose of 750 mg, and 2 Etoposide was administered at a dose of .

[0746] In one embodiment, the additional single dose of ifosfamide is about 5000 mg / m 2 (e.g., 5000 mg / m 2 ±50mg / m 2 ±100mg / m 2 ±200mg / m2 ±300mg / m 2 ±400mg / m 2 or ±500mg / m 2 ), about 4000mg / m 2 (For example, 4000 mg / m 2 ±40mg / m 2 ±50mg / m 2 ±100mg / m 2 ±200mg / m 2 ±300mg / m 2 or ±400 mg / m 2 ) or about 1666 mg / m 2 (e.g., 1666 mg / m 2 ±25mg / m 2 ±50mg / m 2 ±100mg / m 2 or ±166.6 mg / m 2 ), an additional single dose of carboplatin 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 an additional single dose of etoposide of about 100 mg / m 2 (e.g., 100 mg / m 2 ±1mg / m 2 ±2.5mg / m 2 ±5mg / m 2 or ±10 mg / m 2 ) or 75 mg / m 2 (e.g., 0.5 mg / m 2 ±1mg / m 2 ±2.5mg / m 2 ±5mg / 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] × [weight (kg)]) / (72 × [serum creatinine (mg / dL)]); or (b) the subject is female and CrCl is calculated using the formula CrCl = 0.85 × ([140 - age] × [weight (kg)]) / (72 × [serum creatinine (mg / dL)]). In one embodiment, (a) the subject has a CrCl of < about 60 mL / min and the additional single dose of ifosfamide is reduced to 4000 mg / m 2and / or (b) the subject has a CrCl of < about 50 mL / min and the additional single dose of etoposide is reduced to 75 mg / m 2 In one embodiment, the subject is or will be administered an additional single dose of ifosfamide in an outpatient setting, and the additional single dose of ifosfamide is about 1666 mg / m 2 (e.g., 1666 mg / m 2 ±25mg / m 2 ±50mg / m 2 ±100mg / m 2 or ±166.6 mg / m 2 ).

[0747] In one embodiment, ifosfamide and carboplatin are administered on day 2 of an additional dosing cycle, and etoposide is administered on each of days 1, 2, and 3 of an additional dosing cycle.

[0748] 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 dosing cycle:

[0749] (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 (C1D1) of the bispecific antibody that binds to CD20 and CD3 and about 10 mg (e.g., 10 mg...

Claims

1. A method for treating a subject having a CD20-positive cell proliferative disorder, the method comprising administering to the subject an effective amount of: (a) a bispecific antibody that binds to CD20 and CD3; (b) anti-CD20 antibodies; and (c) one or more chemotherapeutic agents selected from ifosfamide, carboplatin and / or etoposide.

2. The method according to claim 1, wherein The first dosing 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 about 2.5 mg, and the C1D2 of the bispecific antibody is about 10 mg; and The second dosing cycle comprises a single dose (C2D1) of the bispecific antibody, wherein the C2D1 of the bispecific antibody is about 10 mg, about 16 mg, or about 30 mg. 3 . The method according to claim 2 , wherein the C1D1 of the bispecific antibody and the C1D2 of the bispecific antibody are administered to the subject on day 8 and day 15 of the first dosing cycle, respectively. 4 . The method according to claim 2 or 3 , wherein the C2D1 of the bispecific antibody is administered to the subject on day 8 of the second dosing cycle.

5. The method according to any one of claims 1 to 4, wherein the anti-CD20 antibody is obinutuzumab and / or rituximab.

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

7. The method of claim 6, wherein the C1D1 of obinutuzumab is about 1000 mg and the C2D1 of rituximab is about 375 mg / m 2 .

8. The method of claim 6 or 7, wherein 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 administering the C1D1 of obinutuzumab to the subject on day 1; and the second dosing cycle comprises administering the C2D1 of rituximab to the subject on day 1.

9. The method of any one of claims 1 to 8, wherein the method comprises administering to the subject ifosfamide, carboplatin, and etoposide.

10. The method of claim 9, wherein the first dosing 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 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. The method of claim 10, wherein the dosage is about 5000 mg / m 2 , about 4000mg / m 2 or about 1666 mg / m 2 Ifosfamide was administered in doses of about 10 mg / mL / min, carboplatin was administered in doses of about 750 mg maximum with a target area under the curve (AUC) of about 5 mg / mL / min, and carboplatin was administered in doses of about 100 mg / mL / min. 2 or about 75 mg / m 2 Etoposide is administered at a dose of for each dose of etoposide.

12. The method according to claim 10 or 11, wherein ifosfamide and carboplatin are administered on day 2 of the first dosing cycle and the second dosing cycle, and the C1D1 to C1D3 and C2D1 to C2D3 of etoposide are administered on day 1, day 2, and day 3 of the first dosing cycle and the second dosing cycle, respectively.

13. The method according to any one of claims 1 to 12, wherein the first dosing cycle and the second dosing cycle are each a 21-day dosing cycle.

14. The method of any one of claims 1 to 13, wherein the dosing regimen comprises one or more additional dosing cycles.

15. The method of claim 14, wherein the one or more additional dosing cycles are each a 21 day dosing cycle.

16. The method of claim 14 or 15, wherein the dosing regimen comprises a total of three dosing cycles.

17. The method according to any one of claims 14 to 16, wherein the one or more additional dosing cycles each comprise: (a) an additional single dose of said bispecific antibody that binds to CD20 and CD3, (b) an additional single dose of said 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.

18. The method of claim 17, wherein the additional single dose of the bispecific antibody is about 30 mg.

19. The method of claim 17 or 18, wherein the additional single dose of the bispecific antibody is administered to the subject on day 8 of each of the one or more additional dosing cycles.

20. The method of any one of claims 17 to 19, wherein the anti-CD20 antibody is rituximab.

21. The method of claim 20, wherein the additional single dose of rituximab is about 375 mg / m 2 .

22. The method of claim 20 or 21, wherein the additional single dose of rituximab is administered on day 1 of each of the one or more additional dosing cycles.

23. The method of any one of claims 17 to 22, wherein the additional single dose of ifosfamide is about 5000 mg / m 2 , about 4000mg / m 2 or about 1666 mg / m 2 , the additional single dose of carboplatin is a maximum dose of about 750 mg with a target area under the curve (AUC) in mg to about 5 mg / mL / min, 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 .

24. The method of any one of claims 17 to 23, wherein ifosfamide and carboplatin are administered on day 2 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 day 1, day 2, and day 3, respectively, of each of the one or more additional dosing cycles.

25. A method of treating a subject between the ages of 6 months and 17 years old having a CD20-positive cell proliferative disorder, the method comprising administering to the subject an effective amount of: (a) a bispecific antibody that binds to CD20 and CD3; (b) anti-CD20 antibodies; and (c) one or more chemotherapeutic agents selected from ifosfamide, carboplatin and / or etoposide.

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

27. The method of claim 26, wherein: (a) the subject has a body weight of greater than or equal to about 7.5 kg and less than about 13 kg, and wherein the C1D1 of the bispecific antibody is about 0.04 mg / kg, the C1D2 of the bispecific antibody is about 0.15 mg / kg, and the C2D1 of the bispecific antibody is about 0.5 mg / kg; (b) the subject has a body weight of greater than or equal to about 13 kg and less than about 45 kg, and wherein the C1D1 of the bispecific antibody is about 0.03 mg / kg, the C1D2 of the bispecific antibody is about 0.15 mg / kg, and the C2D1 of the bispecific antibody is about 0.4 mg / kg; or (c) the subject has a body weight of greater than or equal to about 45 kg, and wherein the C1D1 of the bispecific antibody is about 2.5 mg, the C1D2 of the bispecific antibody is about 10 mg, and the C2D1 of the bispecific antibody is about 30 mg.

28. The method of claim 26 or 27, wherein the C1D1 of the bispecific antibody and the C1D2 of the bispecific antibody are administered to the subject on day 8 and day 15 of the first dosing cycle, respectively.

29. The method of any one of claims 26 to 28, wherein the C2D1 of the bispecific antibody is administered to the subject on day 1 of the second dosing cycle.

30. The method according to any one of claims 25 to 29, wherein the anti-CD20 antibody is obinutuzumab and / or rituximab.

31. The method of claim 30, wherein the first dosing cycle comprises a first dose of inutuzumab (C1D1) and a second dose of inutuzumab (C1D2).

32. The method of claim 31, wherein: (a) the subject has a body weight greater than or equal to about 7.5 kg and less than about 13 kg, and wherein the sum of the C1D1 and the C1D2 of obinutuzumab is about 38 mg / kg; (b) the subject has a body weight greater than or equal to about 13 kg and less than about 20 kg, and wherein the sum of the C1D1 and the C1D2 of obinutuzumab is about 28 mg / kg; (c) the subject has a body weight greater than or equal to about 20 kg and less than about 32 kg, and wherein the sum of the C1D1 and the C1D2 of obinutuzumab is about 23 mg / kg; (d) the subject has a body weight greater than or equal to about 32 kg and less than about 45 kg, and wherein the sum of the C1D1 and the C1D2 of obinutuzumab is about 20 mg / kg; or (e) the subject has a body weight greater than or equal to about 45 kg, and wherein the sum of the C1D1 and the C1D2 of obinutuzumab is about 1000 mg.

33. The method of claim 31 or 32, wherein the C1D1 of inutuzumab is about one-tenth the amount of the sum of the C1D1 and the C1D2 of inutuzumab, and the C1D2 of inutuzumab is about nine-tenths the amount of the sum of the C1D1 and the C1D2 of inutuzumab.

34. The method according to any one of claims 31 to 33, wherein the C1D1 of Ulcetumab is administered to the subject on day 1 of the first dosing cycle, and the C1D2 of Ulcetumab is administered to the subject on day 2 of the first dosing cycle.

35. The method of claim 34, wherein the second dosing cycle comprises a single dose of rituximab (C2D1).

36. The method of claim 35, wherein the C2D1 of rituximab is about 375 mg / m 2 .

37. The method of claim 35 or 36, wherein rituximab is administered to the subject on day 5 of the second dosing cycle.

38. The method of any one of claims 25 to 37, wherein the method comprises administering to the subject ifosfamide, carboplatin, and etoposide.

39. The method of claim 38, wherein the first dosing cycle comprises: (a) a first dose of ifosfamide (C1D1), a second dose of ifosfamide (C1D2), and a 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); And the second cycle includes: (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).

40. The method of claim 39, wherein the dosage is about 3000 mg / m 2 Ifosfamide is administered at a dose of approximately 635 mg / m 2 Carboplatin was administered at a dose of about 100 mg / m 2 Etoposide is administered at a dose of for each dose of etoposide.

41. The method of claim 39 or 40, wherein: (a) administering the C1D1, C1D2 and C1D3 containing ifosfamide on the 3rd day, 4th day and 5th day of the first administration cycle, respectively; (b) administering carboplatin to said C1D1 on day 3 of said first dosing cycle; (c) administering said C1D1, C1D2 and C1D3 of etoposide on day 3, day 4 and day 5 of said first dosing cycle, respectively; (d) administering said C2D1, C2D2 and C2D3 with ifosfamide on day 6, day 7 and day 8 of said second dosing cycle, respectively; (e) administering said C2D1 with carboplatin on day 6 of said second dosing cycle; and (f) administering said C2D1, C2D2 and C2D3 of etoposide on day 6, day 7 and day 8 of said second dosing cycle, respectively.

42. The method of any one of claims 25 to 41, wherein the first dosing cycle and the second dosing cycle are each 21 day dosing cycles.

43. The method of any one of claims 25 to 42, wherein the dosing regimen comprises one or more additional dosing cycles.

44. The method of claim 43, wherein the one or more additional dosing cycles are each a 21 day dosing cycle.

45. The method of claim 43 or 44, wherein the dosing regimen comprises a total of three dosing cycles.

46. ​​The method of any one of claims 43 to 45, wherein each of the one or more additional dosing cycles comprises: (a) an additional single dose of said bispecific antibody that binds to CD20 and CD3, (b) an additional single dose of said 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.

47. The method of claim 46, wherein: (a) the subject has a body weight greater than or equal to about 7.5 kg and less than about 13 kg, and wherein the additional single dose of the bispecific antibody is about 0.5 mg / kg; (b) the subject has a body weight greater than or equal to about 13 kg and less than about 45 kg, and wherein the additional single dose of the bispecific antibody is about 0.4 mg / kg; or (c) the subject has a body weight greater than or equal to about 45 kg, and wherein the additional single dose of the bispecific antibody is about 30 mg.

48. The method of claim 46 or 47, wherein the additional single dose of the bispecific antibody is administered to the subject on day 1 of each of the one or more additional dosing cycles.

49. The method of any one of claims 46 to 48, wherein the anti-CD20 antibody is rituximab.

50. The method of claim 49, wherein the additional single dose of rituximab is about 375 mg / m 2 .

51. The method of claim 49 or 50, wherein the additional single dose of rituximab is administered on day 5 of each of the one or more additional dosing cycles.

52. The method of any one of claims 43 to 51, wherein the additional first dose, additional second dose, and additional third dose of ifosfamide are each about 3000 mg / m 2 The additional single dose of carboplatin is about 635 mg / m 2 , and the additional first dose, the additional second dose, and the additional third dose of etoposide are each about 100 mg / m 2 .

53. A method according to any one of claims 43 to 52, wherein: (a) administering to the subject the additional first dose, the additional second dose, and the additional third dose of ifosfamide on day 6, day 7, and day 8, respectively, of each of the one or more additional dosing cycles; (b) administering said additional single dose of carboplatin on day 6 of each of said one or more additional dosing cycles; and (c) administering to the subject the additional first dose, the additional second dose, and the additional third dose of etoposide on day 6, day 7, and day 8, respectively, of each of the one or more additional dosing cycles.

54. A method of treating a subject between the ages of 18 and 30 years old suffering from a CD20-positive cell proliferative disorder, the method comprising administering to the subject an effective amount of: (a) a bispecific antibody that binds to CD20 and CD3; (b) anti-CD20 antibodies; and (c) one or more chemotherapeutic agents selected from ifosfamide, carboplatin and / or etoposide.

55. The method of claim 54, wherein The first dosing 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 about 2.5 mg, and the C1D2 of the bispecific antibody is about 10 mg; and The second dosing cycle comprises a single dose (C2D1) of the bispecific antibody, wherein the C2D1 of the bispecific antibody is about 30 mg.

56. The method of claim 55, wherein the C1D1 of the bispecific antibody and the C1D2 of the bispecific antibody are administered to the subject on day 8 and day 15 of the first dosing cycle, respectively.

57. The method of claim 55 or 56, wherein the C2D1 of the bispecific antibody is administered to the subject on day 1 of the second dosing cycle.

58. The method of any one of claims 54 to 57, wherein the anti-CD20 antibody is obinutuzumab and / or rituximab.

59. The method of claim 58, wherein the first dosing cycle comprises a first dose of inutuzumab (C1D1) and a second dose of inutuzumab (C1D2).

60. The method of claim 59, wherein the sum of the C1D1 and the C1D2 of obinutuzumab is about 1000 mg.

61. The method of claim 59 or 60, wherein the C1D1 of Invitrofoam is about one-tenth the amount of the sum of the C1D1 and the C1D2 of Invitrofoam, and the C1D2 of Invitrofoam is about nine-tenths the amount of the sum of the C1D1 and the C1D2 of Invitrofoam.

62. The method of any one of claims 59 to 61, wherein the C1D1 of Inutuzumab is about 100 mg and the C1D2 of Inutuzumab is about 900 mg.

63. The method of any one of claims 59 to 62, wherein the C1D1 of Ulcetumab is administered to the subject on day 1 of the first dosing cycle, and the C1D2 of Ulcetumab is administered to the subject on day 2 of the first dosing cycle.

64. The method of claim 58, wherein the second dosing cycle comprises a single dose of rituximab (C2D1).

65. The method of claim 64, wherein the C2D1 of rituximab is about 375 mg / m 2 .

66. The method of claim 64 or 65, wherein the C2D1 of rituximab is administered to the subject on day 5 of the second dosing cycle.

67. The method of any one of claims 54 to 66, wherein the method comprises administering to the subject ifosfamide, carboplatin, and etoposide.

68. The method of claim 67, wherein the first dosing cycle comprises: (a) Single dose of ifosfamide (C1D1); (b) single dose of carboplatin (C1D1); as well as (c) a first dose of etoposide (C1D1), a second dose of etoposide (C1D2), and a third dose of etoposide (C1D3); And the second cycle includes: (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).

69. The method of claim 68, wherein the dosage is about 5000 mg / m 2 Ifosfamide is administered at a dose of about 5 × (25 + creatinine clearance (CrCl)) mg to a maximum dose of about 750 mg, and carboplatin is administered at a dose of about 100 mg / m 2 Etoposide is administered at a dose of for each dose of etoposide.

70. The method of claim 68 or 69, wherein: (a) administering said C1D1 with ifosfamide on day 3 of said first dosing cycle; (b) administering carboplatin to said C1D1 on day 3 of said first dosing cycle; (c) administering said C1D1, C1D2 and C1D3 of etoposide on day 3, day 4 and day 5 of said first dosing cycle, respectively; (d) administering said C2D1 with ifosfamide on day 6 of said second dosing cycle; (e) administering said C2D1 with carboplatin on day 6 of said second dosing cycle; and (f) administering said C2D1, C2D2 and C2D3 of etoposide on day 6, day 7 and day 8 of said second dosing cycle, respectively.

71. The method of any one of claims 54 to 70, wherein the first dosing cycle and the second dosing cycle are each 21 day dosing cycles.

72. The method of any one of claims 54 to 71, wherein the dosing regimen comprises one or more additional dosing cycles.

73. The method of claim 72, wherein the one or more additional dosing cycles are each a 21 day dosing cycle.

74. The method of claim 72 or 73, wherein the dosing regimen comprises a total of three dosing cycles.

75. The method of any one of claims 72 to 74, wherein each of the one or more additional dosing cycles comprises: (a) an additional single dose of said bispecific antibody that binds to CD20 and CD3, (b) an additional single dose of said 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.

76. The method of claim 75, wherein the additional single dose of the bispecific antibody is about 30 mg.

77. The method of claim 75 or 76, wherein the additional single dose of the bispecific antibody is administered to the subject on day 1 of each of the one or more additional dosing cycles.

78. The method of any one of claims 75 to 77, wherein the anti-CD20 antibody is rituximab.

79. The method of claim 78, wherein the additional single dose of rituximab is about 375 mg / m 2 .

80. The method of claim 78 or 79, wherein the additional single dose of rituximab is administered on day 5 of each of the one or more additional dosing cycles.

81. The method of any one of claims 75 to 80, wherein the additional single dose of ifosfamide is about 5000 mg / m 2 The additional single dose of carboplatin is about 5 The maximum dose of about 750 mg of the dose of etoposide is about 100 mg / m 2 .

82. The method of any one of claims 75 to 81, wherein: (a) administering said additional single dose of ifosfamide on day 6 of each of said one or more additional dosing cycles; (b) administering said additional single dose of carboplatin on day 6 of each of said one or more additional dosing cycles; and (c) administering to the subject the additional first dose, the additional second dose, and the additional third dose of etoposide on day 6, day 7, and day 8, respectively, of each of the one or more additional dosing cycles.

83. The method of any one of claims 1 to 82, wherein the bispecific antibody comprises at least one Fab molecule that specifically binds to CD20, the Fab molecule comprising: (A) The following six hypervariable regions (HVRs): (i) HVR-H1 comprising the amino acid sequence of YSWIN (SEQ ID NO: 1); (ii) HVR-H2 comprising the amino acid sequence of RIFPGDGDTDYNGKFKG (SEQ ID NO: 2); (iii) HVR-H3 comprising the amino acid sequence of NVFDGYWLVY (SEQ ID NO: 3); (iv) HVR-L1 comprising the amino acid sequence of 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); and / or (B) (a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 95% sequence identity with 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 the amino acid sequence of SEQ ID NO:8; or (c) a VH domain as in (a) and a VL domain as in (b).

84. The method of any one of claims 1 to 83, wherein the bispecific antibody comprises at least one Fab molecule that specifically binds to CD3, the Fab molecule comprising: (A) 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 of 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 GTNCRAP (SEQ ID NO: 13); and (vi) HVR-L3 comprising the amino acid sequence of ALWYSNLWV (SEQ ID NO: 14); and / or (B) (a) a VH domain comprising an amino acid sequence having at least 95% sequence identity with 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 the amino acid sequence of SEQ ID NO: 16; or (c) a VH domain as in (a) and a VL domain as in (b).

85. The method of any one of claims 1 to 84, wherein the bispecific antibody is Gefituzumab.

86. The method of any one of claims 1 to 85, wherein the CD20-positive cell proliferative disorder is a B-cell proliferative disorder.

87. The method of claim 86, wherein the B-cell proliferative disorder is non-Hodgkin's lymphoma (NHL) or central nervous system lymphoma (CNSL).

88. A bispecific antibody that binds to 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 to CD20 and CD3 is to be 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.

89. Use of a bispecific antibody that binds to CD20 and CD3 in the manufacture of a medicament for treating a subject suffering from a CD20-positive cell proliferative disorder, wherein in said treatment, said bispecific antibody that binds to CD20 and CD3 is to be 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.

90. A bispecific antibody that binds to CD20 and CD3 for use in a method of treating a subject between the ages of 6 months and 17 years suffering from a CD20-positive cell proliferative disorder, wherein the bispecific antibody that binds to CD20 and CD3 is to be 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.

91. Use of a bispecific antibody that binds to CD20 and CD3 in the manufacture of a medicament for treating a subject between the ages of 6 months and 17 years old suffering from a CD20-positive cell proliferative disorder, wherein in said treatment, said bispecific antibody that binds to CD20 and CD3 is to be 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.

92. A bispecific antibody that binds to CD20 and CD3 for use in a method of treating a subject between the ages of 18 and 30 years old suffering from a CD20-positive cell proliferative disorder, wherein the bispecific antibody that binds to CD20 and CD3 is to be 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.

93. Use of a bispecific antibody that binds to CD20 and CD3 in the manufacture of a medicament for treating a subject between the ages of 18 and 30 years old suffering from a CD20-positive cell proliferative disorder, wherein in said treatment, said bispecific antibody that binds to CD20 and CD3 is to be 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.

94. The invention as hereinbefore described.

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