Dosing regimens for the reduction of cytokine release syndrome

Abstract

A dosing regimen for anti-CD3 x anti-CD20 bispecific antibodies that reduces cytokine release syndrome and infusion-associated reactions is disclosed. The method employs split doses over several weeks of treatment, along with administration of steroids and antihistamines.

Description

[Technical field]

[0001] Sequence Listing Reference This application incorporates by reference a computer readable sequence listing in ST.26 XML format entitled 11150WO01_Sequence, created on February 17, 2023, which contains 26,237 bytes.

[0002] The present invention is in the medical field and relates to a dosing regimen of a bispecific anti-CD3 x anti-CD20 antibody that reduces the prevalence and severity of cytokine release syndrome or infusion-associated reactions in patients undergoing immunotherapy. [Background technology]

[0003] Cytokine release syndrome (CRS) is a systemic inflammatory response that can be triggered by a variety of factors, including certain drugs. T cell-activated cancer immunotherapy is particularly at risk for CRS, which is usually due to an on-target effect triggered by the binding of bispecific antibody or chimeric antigen receptor (CAR) T cells to their antigen and the subsequent activation of bystander immune cells and non-immune cells, such as endothelial cells. Activation of bystander cells results in a massive release of various cytokines. IL-6, IL-10, and interferon (IFN)-γ belong to the core cytokines that are consistently found to be elevated in the serum of CRS patients. In T cell-activated therapy against tumor cells, CRS is caused by a massive release of IFN-γ by activated T cells or the tumor cells themselves. The secreted IFN-γ induces the activation of other immune cells, most importantly macrophages, which then produce excessive amounts of additional cytokines, such as IL-6, TNF-α, and IL-10. In particular, IL-6 contributes to many of the major symptoms of CRS, including vascular leakage and activation of the complement and coagulation cascades that induce disseminated intravascular coagulation. In addition, IL-6 likely contributes to cardiomyopathy by promoting myocardial dysfunction. Shimabukaro-Vornhagen et al., Journal for Immunotherapy of Cancer, 6:56, pp.1-14, 2018. In some cases, symptoms related to CRS are referred to as infusion-related reactions (IRR) if they occur within six hours of infusion initiation, and as CRS if they occur more than six hours after infusion initiation.

[0004] Managing the toxicity of cancer immunotherapy is a challenging clinical problem. Mitigation of CRS or IRR is an indication for administering certain therapeutic modalities, e.g., CAR T cells and T cell-targeting bispecific antibodies. Low-grade CRS is generally treated symptomatically with antihistamines, antipyretics, and fluids. Severe CRS may represent a life-threatening adverse event that requires prompt and aggressive treatment. Reduction of tumor burden, limiting the dose of administered therapy, and premedication with steroids have reduced the incidence of severe CRS, as has the use of anti-cytokine therapy. Tocilizumab, an anti-IL-6 antibody, has become the standard initial treatment for severe CRS in some settings. Alternative strategies to mitigate the potentially life-threatening effects of CRS without adversely affecting the therapeutic benefits of immunotherapy remain needed. Summary of the Invention

[0005] In one aspect, the disclosure provides a dosing regimen for administering an anti-CD3 x anti-CD20 bispecific antibody to a subject to treat a B cell malignancy, the regimen comprising: (a) administering to the subject an initial dose of 0.7 mg of the bispecific antibody, the initial dose being divided into a first dose fraction comprising 0.2 mg of the bispecific antibody and a second dose fraction comprising 0.5 mg of the bispecific antibody, the first dose fraction being administered to the subject followed by the second dose fraction over two days in the first week of the dosing regimen; and (b) administering to the subject an initial dose of 0.7 mg of the bispecific antibody, the initial dose being divided into a first dose fraction comprising 0.2 mg of the bispecific antibody and a second dose fraction comprising 0.5 mg of the bispecific antibody over two days in the first week of the dosing regimen. (c) administering to the subject a first intermediate dose of 4 mg of the bispecific antibody, the first intermediate dose being divided into two equal fractions (a first fraction and a second fraction) each containing 2 mg of the bispecific antibody, the two fractions of the first intermediate dose being administered over two days in the second week of the dosing regimen; and (d) administering to the subject a second intermediate dose of 20 mg of the bispecific antibody, the second intermediate dose being divided into two equal fractions (a first fraction and a second fraction) each containing 10 mg of the bispecific antibody, the second intermediate dose being administered over two days in the second week of the dosing regimen. (d) administering a full dose of the bispecific antibody to the subject every week between weeks 4 and 12 of the dosing regimen; and (e) administering a maintenance dose of the bispecific antibody to the subject in week 14 of the dosing regimen, wherein the bispecific antibody comprises a first antigen-binding region that binds human CD20 and a second antigen-binding region that binds human CD3, the first antigen-binding region comprising three heavy chain complementarity determinants comprising the amino acid sequences of SEQ ID NOs: 7, 8, and 9, respectively. the first antigen-binding region comprises three heavy chain complementarity determining regions HCDR1, HCDR2, and HCDR3 comprising the amino acid sequences of SEQ ID NOs: 10, 11, and 12, respectively, and three light chain complementarity determining regions LCDR1, LCDR2, and LCDR3 comprising the amino acid sequences of SEQ ID NOs: 13, 14, and 15, respectively; and the second antigen-binding region comprises three heavy chain complementarity determining regions HCDR1, HCDR2, and HCDR3 comprising the amino acid sequences of SEQ ID NOs: 10, 11, and 12, respectively, and three light chain complementarity determining regions LCDR1, LCDR2, and LCDR3 comprising the amino acid sequences of SEQ ID NOs: 13, 14, and 15, respectively.In some embodiments, the initial dose (0.7 mg) may be divided into other fractions, such as 0.1 mg and 0.6 mg, 0.15 mg and 0.55 mg, 0.25 mg and 0.45 mg, or 0.3 mg and 0.4 mg.

[0006] In some embodiments, the entire dose is administered to the subject as a single dose between weeks 4 and 12 of the dosing regimen.

[0007] In some embodiments, if the subject experiences a grade 3 event of cytokine release syndrome when administered the initial dose, the first intermediate dose, or the second intermediate dose, then the full dose of the bispecific antibody administered to the subject in week 4 is divided into two equal fractions, the two fractions of the full dose are administered over two days in week 4 of the dosing regimen, and the full dose is administered to the subject as a single dose between weeks 5 and 12 of the dosing regimen.

[0008] In some embodiments, a maintenance dose is administered to the subject every two weeks beginning on week 14 of the dosing regimen.

[0009] In some embodiments, the maintenance dose is administered to the subject every four or eight weeks beginning on a subsequent week of the dosing regimen, where this subsequent week is at least week 36 of the dosing regimen.

[0010] In some embodiments, the second dose fraction of the first dose is administered to the subject 18-96 hours after the first dose fraction of the first dose. In some embodiments, the two fractions of the first intermediate dose are administered to the subject 18-96 hours apart. In some embodiments, the two fractions of the second intermediate dose are administered to the subject 18-96 hours apart. In some embodiments, the two fractions of the total dose are administered to the subject 18-96 hours apart.

[0011] In some embodiments, the two days are consecutive days. In some embodiments, the two days are no more than three days apart.

[0012] In some embodiments, the B cell malignancy is a B cell non-Hodgkin's lymphoma. In some cases, the B cell malignancy is a follicular lymphoma, a diffuse large B cell lymphoma, a mantle cell lymphoma, or a marginal zone lymphoma.

[0013] In some embodiments, the total dose of the bispecific antibody is between 80 mg and 320 mg.

[0014] In some embodiments, the maintenance dose of the bispecific antibody is between 160 mg and 320 mg.

[0015] In some embodiments, the B cell malignancy is follicular lymphoma and the total dose is 80 mg and the maintenance dose is 160 mg or 320 mg. In some cases, the follicular lymphoma is grade 1-3a.

[0016] In some embodiments, the B cell malignancy is diffuse large B cell lymphoma, the total dose is 160 mg, and the maintenance dose is 320 mg. In some embodiments, the B cell malignancy is diffuse large B cell lymphoma, the total dose is 320 mg, and the maintenance dose is 320 mg. In some cases, the subject has failed a previous CAR-T therapy.

[0017] In some embodiments, the B cell malignancy is mantle cell lymphoma, the total dose is 160 mg, and the maintenance dose is 320 mg. In some cases, the subject has failed previous Bruton's tyrosine kinase (BTK) inhibitor therapy.

[0018] In some embodiments, the B cell malignancy is marginal zone lymphoma, the total dose is 80 mg, and the maintenance dose is 160 mg.

[0019] In some embodiments, the B cell malignancy is follicular lymphoma, diffuse large B cell lymphoma, mantle cell lymphoma, or non-Hodgkin's lymphoma other than marginal zone lymphoma, and the total dose is 160 mg and the maintenance dose is 320 mg.

[0020] In some embodiments, the B cell malignancy is aggressive lymphoma, the total dose is 160 mg, and the maintenance dose is 320 mg.

[0021] In some embodiments, the subject has a documented CD20+ B-cell malignancy with active disease unresponsive to prior therapy, for which no standard treatment options exist and for which treatment with an anti-CD20 antibody may be appropriate. In some embodiments, the subject has documented progressive B-NHL that has relapsed within one year of frontline therapy and intends to proceed with autologous stem cell transplant (ASCT).

[0022] In some embodiments, the subject has not been previously treated with a systemic anti-lymphoma therapy, hi some embodiments, the subject has relapsed or refractory disease.

[0023] In some embodiments, the subject has relapsed or is refractory to at least two prior lines of systemic therapy including an anti-CD20 antibody and an alkylating agent.

[0024] In some embodiments, the subject is refractory to an anti-CD20 antibody in any previous line of therapy.

[0025] In some embodiments, the subject is dual refractory to an alkylating agent and an anti-CD20 antibody in any previous lines of therapy.

[0026] In some embodiments, the subject is a human aged 18 years or older.

[0027] In any of the various embodiments discussed in the above aspects of this disclosure, the bispecific antibody may be administered intravenously.

[0028] In one aspect, the disclosure provides a dosing regimen for administering to a subject an anti-CD3 x anti-CD20 bispecific antibody to treat a B cell malignancy, the regimen comprising: administering to the subject an initial dose of 1 mg or 2 mg of the bispecific antibody in week 1 of the dosing regimen; administering to the subject a first intermediate dose of 10 mg or 26 mg of the bispecific antibody in week 2 of the dosing regimen; administering to the subject a second intermediate dose of 50 mg or 100 mg of the bispecific antibody in week 3 of the dosing regimen; and administering to the subject a full dose of the bispecific antibody in week 4 and subsequent weeks of the dosing regimen, wherein the bispecific antibody comprises a first antigen-binding region that binds human CD20; and a second antigen-binding region that binds to human CD3, the first antigen-binding region comprising three heavy chain complementarity determining regions HCDR1, HCDR2, and HCDR3 comprising the amino acid sequences of SEQ ID NOs: 7, 8, and 9, respectively, and three light chain complementarity determining regions LCDR1, LCDR2, and LCDR3 comprising the amino acid sequences of SEQ ID NOs: 13, 14, and 15, respectively, and the second antigen-binding region comprising three heavy chain complementarity determining regions HCDR1, HCDR2, and HCDR3 comprising the amino acid sequences of SEQ ID NOs: 10, 11, and 12, and three light chain complementarity determining regions LCDR1, LCDR2, and LCDR3 comprising the amino acid sequences of SEQ ID NOs: 13, 14, and 15, respectively.

[0029] In some embodiments, the initial dose is 2 mg. In some embodiments, the first intermediate dose is 26 mg. In some embodiments, the second intermediate dose is 100 mg. In some embodiments, the total dose is 200 mg, 400 mg, or 600 mg. In some cases, the total dose is 400 mg. In some cases, the total dose is 600 mg.

[0030] In some embodiments, the full dose is administered to the subject once every three weeks. In some embodiments, the full dose is administered to the subject weekly. In some cases, the full dose is administered to the subject weekly for three weeks, and then the full dose is administered to the subject once every three weeks.

[0031] In some embodiments, the subject has relapsed or refractory disease, hi some embodiments, the subject is refractory to an anti-CD20 antibody in any previous line of therapy.

[0032] In some embodiments, the B cell malignancy is follicular lymphoma. In some embodiments, the B cell malignancy is diffuse large B cell lymphoma.

[0033] In some embodiments, the subject is a human aged 18 years or older.

[0034] In any of the various embodiments discussed in the above aspects of this disclosure, the bispecific antibody may be administered subcutaneously.

[0035] In one aspect, the disclosure provides a dosing regimen for administering an anti-CD3 x anti-CD20 bispecific antibody to a subject to treat a B-cell malignancy, comprising administering to the subject an initial dose of the bispecific antibody, the initial dose being split into a first dose fraction of the bispecific antibody and a second dose fraction of the bispecific antibody, the first dose fraction being administered to the subject followed by the second dose fraction over two days in a first week of the dosing regimen; administering to the subject a first intermediate dose of the bispecific antibody, the first intermediate dose being split into two equal fractions of the bispecific antibody (a first fraction and a second fraction), the two fractions of the first intermediate dose being administered over two days in a second week of the dosing regimen; administering to the subject a second intermediate dose of the bispecific antibody, the second intermediate dose being split into two equal fractions of the bispecific antibody (a first fraction and a second fraction), the two fractions of the second intermediate dose being administered over two days in a third week of the dosing regimen; administering a full dose of the bispecific antibody to the subject weekly during weeks 4-12 of the dosing regimen; and administering a maintenance dose of the bispecific antibody to the subject during week 14 of the dosing regimen, wherein the initial dose, first intermediate dose, second intermediate dose, full dose, and maintenance dose are dependent on the subject's body weight, and (i) if the subject has a body weight of 40 kg to less than 165 kg (e.g., 40-164 kg), the initial dose is 0.7 mg, the first dose fraction of the initial dose is 0.2 mg, the second dose fraction of the initial dose is 0.3 mg, and the third dose fraction of the initial dose is 0.4 mg. the first intermediate dose is 0.5 mg, the first intermediate dose is 4 mg, two equal fractions of the first intermediate dose each contain 2 mg, the second intermediate dose is 20 mg, two equal fractions of the second intermediate dose each contain 10 mg, the total dose is 160 mg, and the maintenance dose is 320 mg; or (ii) if the subject has a body weight of 20 kg to less than 40 kg (e.g., 20 to 39 kg), the initial dose is 0.4 mg, the first dose fraction of the initial dose is 0.1 mg, and the second dose fraction of the initial dose is 0.3 mg, the first intermediate dose is 2 mg, two equal fractions of the first intermediate dose each contain 1 mg, the second intermediate dose is 12 mg, two equal fractions of the second intermediate dose each contain 6 mg, the upper total dose is 90 mg, and the maintenance dose is 150 mg; or (iii) if the subject has a body weight of 10 kg to less than 20 kg (e.g., 10 to 19 kg), the initial dose is 0.3 mg, the first dose fraction of the initial dose is 0.1 mg, and the second dose fraction of the initial dose is 0.2 mg. wherein the first intermediate dose is 1.6 mg, two equal fractions of the first intermediate dose each contain 0.8 mg, the second intermediate dose is 8 mg, and two equal fractions of the second intermediate dose each contain 4 mg, the total dose is 60 mg, and the maintenance dose is 100 mg; or (iv) if the subject has a body weight of between 6 kg and less than 10 kg (e.g., between 6 and 9 kg), the initial dose is 0.24 mg, the first dose fraction of the initial dose is 0.07 mg, and the second dose fraction of the initial dose is 0.17 mg; The first intermediate dose is 1.2 mg, two equal fractions of the first intermediate dose each contain 0.6 mg, the second intermediate dose is 6 mg, and two equal fractions of the second intermediate dose each contain 3 mg, the total dose is 45 mg, and the maintenance dose is 75 mg, and the bispecific antibody comprises a first antigen-binding region that binds to human CD20 and a second antigen-binding region that binds to human CD3, and the first antigen-binding region comprises three heavy chain complementarity determining regions (HCDRs) that comprise the amino acid sequences of SEQ ID NOs: 7, 8, and 9, respectively. The first antigen-binding region comprises three heavy chain complementarity determining regions HCDR1, HCDR2, and HCDR3 comprising the amino acid sequences of SEQ ID NOs: 13, 14, and 15, respectively, and the second antigen-binding region comprises three heavy chain complementarity determining regions HCDR1, HCDR2, and HCDR3 comprising the amino acid sequences of SEQ ID NOs: 10, 11, and 12, respectively, and three light chain complementarity determining regions LCDR1, LCDR2, and LCDR3 comprising the amino acid sequences of SEQ ID NOs: 13, 14, and 15, respectively.

[0036] In some embodiments, the full dose is administered to the subject as a single dose between weeks 4 and 12 of the dosing regimen. In some embodiments, a maintenance dose is administered to the subject every two weeks beginning at week 14 of the dosing regimen.

[0037] In some embodiments, the second dose fraction of the first dose is administered to the subject 18-96 hours after the first dose fraction of the first dose. In some embodiments, the two fractions of the first intermediate dose are administered to the subject 18-96 hours apart. In some embodiments, the two fractions of the second intermediate dose are administered to the subject 18-96 hours apart.

[0038] In some embodiments, the two days are consecutive days. In some embodiments, the two days are no more than three days apart.

[0039] In some embodiments, the B cell malignancy is a B cell non-Hodgkin's lymphoma. In some embodiments, the B cell malignancy is a follicular lymphoma, a diffuse large B cell lymphoma, a mantle cell lymphoma, or a marginal zone lymphoma.

[0040] In some embodiments, the subject is a human under the age of 18.

[0041] In any of the various embodiments discussed in the above aspects of this disclosure, the bispecific antibody may be administered intravenously.

[0042] In one aspect, the disclosure provides a dosing regimen for administering an anti-CD3 x anti-CD20 bispecific antibody to a subject to treat follicular lymphoma, the regimen comprising: (a) administering to the subject an initial dose of 0.7 mg of the bispecific antibody, the initial dose being divided into a first dose fraction comprising 0.2 mg of the bispecific antibody and a second dose fraction comprising 0.5 mg of the bispecific antibody, the first dose fraction being administered to the subject followed by the second dose fraction over two days in the first week of the dosing regimen; and (b) administering to the subject a first dose of 0.7 mg of the bispecific antibody. (c) administering to the subject a first intermediate dose of 4 mg of the bispecific antibody, the first intermediate dose being divided into two equal fractions (a first fraction and a second fraction) each containing 2 mg of the bispecific antibody, the two fractions of the first intermediate dose being administered over two days in the second week of the administration regimen; and (b) administering to the subject a second intermediate dose of 20 mg of the bispecific antibody, the second intermediate dose being divided into two equal fractions (a first fraction and a second fraction) each containing 10 mg of the bispecific antibody, the two fractions of the second intermediate dose being administered over two days in the second week of the administration regimen. (d) administering a total dose of 40 mg or 80 mg of the bispecific antibody to the subject weekly during weeks 4-12 of the dosing regimen; and (e) administering a maintenance dose of 80 mg or 160 mg of the bispecific antibody to the subject during week 14 of the dosing regimen, wherein the bispecific antibody comprises a first antigen-binding region that binds human CD20 and a second antigen-binding region that binds human CD3, the first antigen-binding region comprising a triplet comprising the amino acid sequences of SEQ ID NOs: 7, 8, and 9, respectively. the first antigen-binding region comprises three heavy chain complementarity determining regions HCDR1, HCDR2, and HCDR3 and three light chain complementarity determining regions LCDR1, LCDR2, and LCDR3 comprising the amino acid sequences of SEQ ID NOs: 13, 14, and 15, respectively; and the second antigen-binding region comprises three heavy chain complementarity determining regions HCDR1, HCDR2, and HCDR3 comprising the amino acid sequences of SEQ ID NOs: 10, 11, and 12, respectively, and three light chain complementarity determining regions LCDR1, LCDR2, and LCDR3 comprising the amino acid sequences of SEQ ID NOs: 13, 14, and 15, respectively.In some embodiments, the initial dose (0.7 mg) may be divided into other fractions, such as 0.1 mg and 0.6 mg, 0.15 mg and 0.55 mg, 0.25 mg and 0.45 mg, or 0.3 mg and 0.4 mg.

[0043] In one aspect, the disclosure provides a dosing regimen for administering an anti-CD3 x anti-CD20 bispecific antibody to a subject to treat diffuse large B-cell lymphoma, the regimen comprising: (a) administering to the subject an initial dose of 0.7 mg of the bispecific antibody, the initial dose being divided into a first dose fraction comprising 0.2 mg of the bispecific antibody and a second dose fraction comprising 0.5 mg of the bispecific antibody, the first dose fraction being administered to the subject followed by the second dose fraction over two days in the first week of the dosing regimen; and (b) administering to the subject an initial dose of 0.7 mg of the bispecific antibody, the initial dose being divided into a first dose fraction comprising 0.2 mg of the bispecific antibody and a second dose fraction comprising 0.5 mg of the bispecific antibody over two days in the first week of the dosing regimen. (c) administering to the subject a first intermediate dose of 4 mg of the bispecific antibody, the first intermediate dose being divided into two equal fractions (a first fraction and a second fraction) each containing 2 mg of the bispecific antibody, the two fractions of the first intermediate dose being administered over two days in the second week of the dosing regimen; and (b) administering to the subject a second intermediate dose of 20 mg of the bispecific antibody, the second intermediate dose being divided into two equal fractions (a first fraction and a second fraction) each containing 10 mg of the bispecific antibody, the two fractions of the second intermediate dose being administered over two days in the second week of the dosing regimen. (d) administering a total dose of 80 mg or 160 mg of the bispecific antibody weekly to the subject during weeks 4-12 of the dosing regimen; and (e) administering a maintenance dose of 160 mg or 320 mg of the bispecific antibody to the subject during weeks 13 or 14 of the dosing regimen, wherein the bispecific antibody comprises a first antigen-binding region that binds human CD20 and a second antigen-binding region that binds human CD3, wherein the first antigen-binding region comprises the amino acid sequence of SEQ ID NOs: 7, 8, and 9, respectively. the first antigen-binding region comprises three heavy chain complementarity determining regions HCDR1, HCDR2, and HCDR3 comprising the amino acid sequences of SEQ ID NOs: 13, 14, and 15, respectively, and three light chain complementarity determining regions LCDR1, LCDR2, and LCDR3 comprising the amino acid sequences of SEQ ID NOs: 10, 11, and 12, respectively, and three light chain complementarity determining regions LCDR1, LCDR2, and LCDR3 comprising the amino acid sequences of SEQ ID NOs: 13, 14, and 15, respectively;In some embodiments, the initial dose (0.7 mg) may be divided into other fractions, such as 0.1 mg and 0.6 mg, 0.15 mg and 0.55 mg, 0.25 mg and 0.45 mg, or 0.3 mg and 0.4 mg.

[0044] In some embodiments, the entire dose is administered to the subject as a single dose between weeks 4 and 12 of the dosing regimen.

[0045] In some embodiments, a maintenance dose is administered to a subject every two weeks beginning on week 13 of the dosing regimen. In some embodiments, a maintenance dose is administered to a subject every two weeks beginning on week 14 of the dosing regimen.

[0046] In some embodiments, the total dose is 40 mg. In some embodiments, the total dose is 80 mg. In some embodiments, the total dose is 160 mg. In some embodiments, the maintenance dose is 80 mg. In some embodiments, the maintenance dose is 160 mg. In some embodiments, the maintenance dose is 320 mg.

[0047] In some embodiments, the second dose fraction of the first dose is administered to the subject 18-96 hours after the first dose fraction of the first dose. In some embodiments, the two fractions of the first intermediate dose are administered to the subject 18-96 hours apart. In some embodiments, the two fractions of the second intermediate dose are administered to the subject 18-96 hours apart.

[0048] In some embodiments, the dosing regimen further comprises administering a combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). In some embodiments, the dosing regimen further comprises administering a combination of cyclophosphamide, vincristine, and prednisone (CVP). In some cases, CHOP / CVP is administered the week prior to week 1 of the dosing regimen, and again at weeks 3, 6, 9, 12, and 15 of the dosing regimen. In some cases, cyclophosphamide is administered at a dose of 750 mg / m 2and doxorubicin was administered at a dose of 50 mg / m 2 and vincristine was administered at a dose of 1.4 mg / m 2 prednisone is administered at a dose of 100 mg, cyclophosphamide, doxorubicin, and vincristine are administered once during the week prior to week 1 of the dosing regimen and once during each of weeks 3, 6, 9, 12, and 15 of the dosing regimen, and prednisone is administered for five consecutive days during the week prior to week 1 of the dosing regimen and for five consecutive days during each of weeks 3, 6, 9, 12, and 15 of the dosing regimen.

[0049] In some embodiments, the subject has relapsed or refractory disease. In some cases, the subject is refractory to anti-CD20 antibodies in any previous line of therapy. In some cases, the subject is double refractory to alkylating agents and anti-CD20 antibodies.

[0050] In some embodiments, the subject has not been previously treated with a systemic anti-lymphoma therapy (ie, the subject is previously untreated).

[0051] In some embodiments, the subject has previously undergone an autologous stem cell transplant.

[0052] In some embodiments, the bispecific antibody is administered to a subject intravenously.

[0053] In some embodiments, a first antigen-binding region of the bispecific antibody comprises a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO:4 and a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO:6, and a second antigen-binding region of the bispecific antibody comprises a HCVR comprising the amino acid sequence of SEQ ID NO:5 and a LCVR comprising the amino acid sequence of SEQ ID NO:6.

[0054] In some embodiments, the bispecific antibody comprises a human IgG heavy chain constant region. In some cases, the human IgG heavy chain constant region is of isotype IgG1. In some cases, the human IgG heavy chain constant region is of isotype IgG4.

[0055] In some embodiments, the bispecific antibody comprises a first heavy chain constant region comprising the amino acid sequence of SEQ ID NO:16 and a second heavy chain constant region comprising the amino acid sequence of SEQ ID NO:17.

[0056] In some embodiments, the bispecific antibody comprises a first heavy chain constant region comprising the amino acid sequence of SEQ ID NO:18 and a second heavy chain constant region comprising the amino acid sequence of SEQ ID NO:19.

[0057] In some embodiments, the bispecific antibody comprises a first heavy chain comprising amino acid residues 1-452 of SEQ ID NO:1 paired with a common light chain comprising the amino acid sequence of SEQ ID NO:3, and a second heavy chain comprising amino acid residues 1-448 of SEQ ID NO:2 paired with a common light chain comprising the amino acid sequence of SEQ ID NO:3.

[0058] In some embodiments, the bispecific antibody comprises a first heavy chain comprising the amino acid sequence of SEQ ID NO:1 paired with a common light chain comprising the amino acid sequence of SEQ ID NO:3, and a second heavy chain comprising the amino acid sequence of SEQ ID NO:2 paired with a common light chain comprising the amino acid sequence of SEQ ID NO:3.

[0059] In any of the various embodiments described above or discussed herein, the dosing regimen further comprises administering to the subject a dose of steroid 12 to 24 hours prior to administration of the first dose fraction of the initial dose, 12 to 24 hours prior to administration of the first fraction of the first intermediate dose, and 12 to 24 hours prior to administration of the first fraction of the second intermediate dose.

[0060] In some embodiments, if the first dose fraction of the first dose and the second dose fraction of the first dose are not administered to the subject on consecutive days, the dosing regimen further comprises administering to the subject a dose of a steroid 12-24 hours prior to administration of the second dose fraction of the first dose of the bispecific antibody. In some embodiments, if the first fraction of the first intermediate dose and the second fraction of the first intermediate dose are not administered to the subject on consecutive days, the dosing regimen further comprises administering to the subject a dose of a steroid 12-24 hours prior to administration of the second fraction of the first intermediate dose of the bispecific antibody. In some embodiments, if the first fraction of the second intermediate dose and the second fraction of the second intermediate dose are not administered to the subject on consecutive days, the dosing regimen further comprises administering to the subject a dose of a steroid 12-24 hours prior to administration of the second fraction of the second intermediate dose of the bispecific antibody.

[0061] In some embodiments, the dosing regimen further comprises administering to the subject a dose of a steroid 1 to 3 hours prior to administration of the first dose fraction of the first dose, 1 to 3 hours prior to administration of the second dose fraction of the first dose, and 1 to 3 hours prior to administration of each of the first intermediate dose and second intermediate dose fractions, and administering to the subject a dose of an antihistamine 30 to 60 minutes prior to administration of the first dose fraction of the first dose, 30 to 60 minutes prior to administration of the second dose fraction of the first dose, and 30 to 60 minutes prior to administration of each of the first intermediate dose and second intermediate dose fractions.

[0062] In some embodiments, the dosing regimen further includes administering to the subject a dose of acetaminophen 30 to 60 minutes prior to administration of the first dose fraction of the initial dose, 30 to 60 minutes prior to administration of the second dose fraction of the initial dose, and 30 to 60 minutes prior to administration of each fraction of the first intermediate dose and the second intermediate dose.

[0063] In some embodiments, the dosing regimen further comprises administering to the subject a dose of steroid 20 to 28 hours after the end of administration of the second dose fraction of the first dose, 20 to 28 hours after the end of administration of the second fraction of the first intermediate dose, and 20 to 28 hours after the end of administration of the second fraction of the second intermediate dose.

[0064] In some embodiments, the dosing regimen further includes administering to the subject a dose of a steroid 1-3 hours prior to administration of all doses in week 4 of the dosing regimen, and administering to the subject a dose of an antihistamine 30-60 minutes prior to administration of all doses in week 4 of the dosing regimen.

[0065] In some embodiments, the dosing regimen further comprises administering to the subject a dose of acetaminophen 30-60 minutes prior to administration of the entire dose in week 4 of the dosing regimen.

[0066] In some embodiments, the dosing regimen further comprises administering to the subject a dose of steroid 20-28 hours after completion of administration of all doses during week 4 of the dosing regimen.

[0067] In some embodiments, if the subject experiences a grade 3 event of cytokine release syndrome when administered the initial dose, the first intermediate dose, or the second intermediate dose, then the full dose of the bispecific antibody administered to the subject in week 4 is split into two equal fractions (a first fraction and a second fraction), and the two fractions of the full dose are administered over two days in week 4 of the dosing regimen, and the dosing regimen further comprises administering to the subject a dose of a steroid 12-24 hours prior to administration of the first fraction of the full dose. In some cases, if the first fraction of the full dose and the second fraction of the full dose are not administered to the subject on consecutive days, the dosing regimen further comprises administering to the subject a dose of a steroid 12-24 hours prior to administration of the second fraction of the full dose of the bispecific antibody. In some cases, the dosing regimen further comprises administering to the subject a dose of a steroid 1-3 hours prior to administration of the first fraction of the full dose, and administering to the subject a dose of an antihistamine 30-60 minutes prior to administration of the first fraction of the full dose. In some cases, the dosing regimen further comprises administering to the subject a dose of acetaminophen 30-60 minutes prior to administration of the first fraction of the full dose. In some cases, the dosing regimen further comprises administering to the subject a dose of a steroid 1-3 hours prior to administration of the full dose in week 5 of the dosing regimen, and administering to the subject a dose of an antihistamine 30-60 minutes prior to administration of the full dose in week 5 of the dosing regimen. In some embodiments, the dosing regimen further comprises administering to the subject a dose of acetaminophen 30-60 minutes prior to administration of the full dose in week 5 of the dosing regimen. In some embodiments, the dosing regimen further comprises administering to the subject a dose of steroid 20-28 hours after completion of administration of all doses during week 5 of the dosing regimen.

[0068] In some embodiments, administering a dose of a steroid, administering a dose of an antihistamine, or administering a dose of acetaminophen comprises instructing the subject to take a dose of a steroid, a dose of an antihistamine, or a dose of acetaminophen, respectively.

[0069] In some embodiments, administering a dose of a steroid or administering a dose of an antihistamine comprises administering a dose of a steroid or a dose of an antihistamine intravenously.

[0070] In some embodiments, the steroid is dexamethasone. In some instances, the dose of the steroid is 20 mg.

[0071] In some embodiments, the antihistamine is diphenhydramine. In some instances, the dose of the antihistamine is 25 mg.

[0072] In some embodiments, the dose of acetaminophen is 650 mg.

[0073] In any of the various embodiments described above or discussed herein, the dosing regimen further comprises administering an anti-IL-6 receptor antibody. In some cases, the anti-IL-6 receptor antibody is tocilizumab or sarilumab.

[0074] In one aspect, the disclosure provides a method of treating B cell cancer in a subject, the method comprising selecting a subject diagnosed with B cell cancer and administering a bispecific antibody to the subject according to a dosing regimen described above or discussed herein.

[0075] In various embodiments of the method of treatment, (a) the subject has been diagnosed with follicular lymphoma, (b) the subject has been diagnosed with grade 1-3a follicular lymphoma, (c) the subject has been diagnosed with relapsed or refractory follicular lymphoma after at least two prior lines of systemic therapy, (d) the subject has been diagnosed with follicular lymphoma and has not been previously treated with systemic anti-lymphoma therapy, (e) the subject has been diagnosed with follicular lymphoma and the total dose is 80 mg, and / or (f) the subject has been diagnosed with follicular lymphoma and the maintenance dose is 160 mg or 320 mg.

[0076] In various embodiments of the method of treatment, (a) the subject has been diagnosed with diffuse large B-cell lymphoma (DLBCL), (b) the subject has been diagnosed with DLBCL and the DLBCL is de novo or has transformed from a lower grade neoplasm, (c) the subject has been diagnosed with DLBCL and is refractory to at least two prior lines of systemic therapy, (d) the subject has been diagnosed with relapsed or refractory DLBCL after at least two prior lines of systemic therapy, including CAR-T therapy, (e) the subject has been diagnosed with DLBCL and has not been previously treated with systemic anti-lymphoma therapy, (f) the subject has been diagnosed with DLBCL and the total dose is 160 mg, and / or (g) the subject has been diagnosed with DLBCL and the maintenance dose is 320 mg.

[0077] The present disclosure also contemplates the use of an anti-CD20 x anti-CD3 antibody (e.g., odronextamab) for use in the methods described above or discussed herein, as well as the use of an anti-CD20 x anti-CD3 antibody (e.g., odronextamab) in the manufacture of a medicament for treating a B cell cancer (e.g., FL or DLBCL) in a subject according to the methods described above or discussed herein.

[0078] In one aspect, the disclosure provides a pharmaceutical kit comprising: (i) a container containing a bispecific antibody; and (ii) a label comprising instructions for administering the bispecific antibody according to the dosing regimen described above or discussed herein.

[0079] In some embodiments, the label further includes instructions for administering the steroid and antihistamine according to the dosing regimen described above or discussed herein.

[0080] In various embodiments, any feature or component of any embodiment discussed above or herein may be combined, and such combinations are encompassed within the scope of the present disclosure. Any specific value discussed above or herein may be combined with another related value discussed above or herein to describe a range with values ​​representing the upper and lower limits of the range, and such ranges are encompassed within the scope of the present disclosure. Therapeutic proteins for use in any method discussed herein, or the use of therapeutic proteins in the manufacture of a medicament for use in any method discussed herein, are also encompassed within the scope of the present disclosure.

[0081] Other embodiments will become apparent from consideration of the following detailed description. [Brief description of the drawings]

[0082] [Figure 1] FIG. 1 illustrates an odronextamab dosing regimen for the treatment of patients with follicular lymphoma according to an embodiment of the invention. *Dexamethasone 20 mg IV 1-3 hours prior to each split or first single infusion; †Dexamethasone 10 mg orally 12-24 hours prior to the first split infusion. On each day of the split or single infusion, dexamethasone 20 mg IV 1-3 hours prior to infusion, diphenhydramine 25 mg IV or orally 30-60 minutes prior to infusion, and acetaminophen 650 mg orally. CRS: cytokine release syndrome, D: day, IV: intravenous, Q2W: every 2 weeks. [Diagram 2] Figure 2 shows that the majority of relapsed / refractory follicular lymphoma patients who were efficacy evaluable (N=121) had substantial tumor shrinkage after odronextamab monotherapy. The plot shows the best change (%) from baseline in tumor SPD (sum of products of diameters). PD: progressive disease, CR / PR: complete response, partial response, NE: not estimable, SD: stable disease. [Diagram 3]Figure 3 shows the antitumor efficacy of odronextamab monotherapy in efficacy-evaluable patients with relapsed / refractory follicular lymphoma (N=121) and subgroups. ASCT: autologous stem cell transplant, CR: complete response, FLIPI: Follicular Lymphoma International Prognostic Index, ORR: objective response rate, POD24: disease progression within 24 months of initiating first-line therapy. [Figure 4-1] Figure 4 shows the durability of responses and complete responses in patients with relapsed / refractory follicular lymphoma treated with odronextamab monotherapy. CI: confidence interval, DOCR: duration of complete response, DOR: duration of response, NE: not estimable. [Figure 4-2] Same as above. [Figure 5-1] Figure 5 shows progression-free survival and overall survival of patients with relapsed / refractory follicular lymphoma treated with odronextamab monotherapy. CI: confidence interval, NE: not estimable, OS: overall survival, PFS: progression-free survival. [Figure 5-2] Same as above. [Figure 6] FIG. 6 illustrates an odronectamab dosing regimen for the treatment of patients with diffuse large B-cell lymphoma according to an embodiment of the invention. *Dexamethasone 20 mg IV 1-3 hours prior to each fraction or first single infusion; †Dexamethasone 10 mg orally 12-24 hours prior to first fraction infusion. On each day of the fraction or single infusion, dexamethasone 20 mg IV 1-3 hours prior to infusion, diphenhydramine 25 mg IV or orally 30-60 minutes prior to infusion, and acetaminophen 650 mg orally. CRS: cytokine release syndrome, D: day, IV: intravenous, Q2W: every two weeks. [Figure 7] Figure 7 shows the antitumor efficacy of odronextamab monotherapy in efficacy-evaluable DLBCL patients (N=130) and subgroups. ASCT=autologous stem cell transplant, CI=confidence interval, CR=complete response, DLBCL=diffuse large B-cell lymphoma, ORR=objective response rate. [Figure 8-1]Figure 8 shows the durability of responses and complete responses in relapsed / refractory DLBCL patients treated with odronextamab monotherapy. CI: confidence interval, DOCR: duration of complete response, DOR: duration of response, NE: not evaluable. [Figure 8-2] Same as above. [Figure 9] Figure 9 shows progression free survival of relapsed / refractory DLBCL patients treated with odronextamab monotherapy. CI: confidence interval, NE: not evaluable, PFS: progression free survival. [Figure 10] Figure 10 illustrates the dosing scheme of odronextamab + chemotherapy by cycle. The DLT observation period is defined as the first 35 days starting from C1D8 (first odronextamab administration) to the administration of two full doses of odronextamab, whichever occurs later. [Figure 11] FIG. 11 illustrates the dosing scheme of rituximab plus chemotherapy per cycle, used as a comparator. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0083] In describing the present invention, it is to be understood that the present invention is not limited to the specific methods and experimental conditions described, since such methods and conditions may vary. It is also to be understood that the terminology used herein is for the purpose of describing only specific embodiments, and is not intended to be limiting, since the scope of the present invention is limited only by the appended claims.

[0084] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which the present invention belongs.The term "about" when used in relation to a specific referenced numerical value means that the value may vary from the referenced value by 1% or less.For example, the expression "about 100" includes 99 and 101, and all values ​​therebetween (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

[0085] Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are described below. All patents, patent applications, and non-patent publications mentioned herein are incorporated by reference in their entirety.

[0086] definition All references herein to proteins, polypeptides, and protein fragments are intended to refer to the human version of the respective protein, polypeptide, or protein fragment, unless expressly specified as being from a non-human species. Thus, for example, the terms "CD3" and "CD20" refer to human CD3 and human CD20, respectively, unless specified as being from a non-human species.

[0087] The term "CD3" refers to an antigen expressed on T cells as part of the multimolecular T cell receptor (TCR) and consisting of a homodimer or heterodimer formed from the association of two of the four receptor chains: CD3-epsilon, CD3-delta, CD3-zeta, and CD3-gamma.

[0088] An "antigen-binding domain that binds CD3", "antigen-binding region that binds CD3", "antibody that binds CD3", or "anti-CD3 antibody" includes antibodies and antigen-binding fragments thereof that specifically recognize a single CD3 subunit (e.g., epsilon, delta, gamma, or zeta), as well as antibodies and antigen-binding fragments thereof that specifically recognize a dimeric complex of two CD3 subunits (e.g., gamma / epsilon, delta / epsilon, and zeta / zeta CD3 dimers). The antibodies and antigen-binding fragments of the invention may bind to soluble CD3 and / or cell surface expressed CD3. Soluble CD3 includes native CD3 protein as well as recombinant CD3 protein variants that lack a transmembrane domain or are otherwise not associated with a cell membrane, such as, for example, monomeric and dimeric CD3 constructs.

[0089] The term "CD20" refers to a non-glycosylated phosphoprotein expressed on the cell membrane of mature B cells. CD20 is expressed by more than 95% of B cell non-Hodgkin's lymphomas (NHL) and other B cell malignancies, but is absent from precursor B cells, dendritic cells, and plasma cells, and is therefore considered a B cell tumor-associated antigen.

[0090] An "antigen-binding domain that binds CD20," "antigen-binding region that binds CD20," "antibody that binds CD20," or "antibody" includes antibodies and antigen-binding fragments thereof that specifically recognize CD20.

[0091] "Cytokine release syndrome" (CRS) refers to a disorder characterized by fever, tachypnea, headache, tachycardia, hypertension, rash, and / or hypoxia, and is defined as an event occurring 6 hours or more after the start of a bispecific antibody infusion or 2 hours or more after the completion of a bispecific antibody infusion (whichever is later). CRS grades are defined in Tables 5, 6, and 11 in the Examples.

[0092] "Infusion-related reaction" (IRR) refers to an adverse event occurring within 6 hours of the start of bispecific antibody infusion and associated with typical signs and symptoms including, but not limited to, flushing, tachycardia, hypertension, dyspnea, bronchospasm, back pain, fever, urticaria, edema, nausea, and rash. As used herein, signs and symptoms of an IRR occurring 6 hours or more after the start of the infusion are defined as cytokine release syndrome (CRS).

[0093] Non-Hodgkin's lymphomas can be divided into two main prognostic groups: indolent (low-grade, slow-growing) lymphomas, and aggressive (high-grade, fast-growing) lymphomas. "Aggressive lymphoma" is a lymphoma characterized by one of the following subtypes based on the World Health Organization classification: diffuse large B-cell lymphoma (DLBCL) not otherwise specified by WHO classification (NOS), germline center B-cell type, activated B-cell type, primary mediastinal (thymic) large B-cell lymphoma, T-cell / histiocyte-rich large B-cell lymphoma, Epstein-Barr virus (EBV)+ DLBCL, high-grade B-cell lymphoma with NOS, MYC and BCL2 and / or BCL6 rearrangements, NOS high-grade B-cell lymphoma, B-cell lymphoma unclassifiable and with features intermediate between DLBCL and classical Hodgkin lymphoma, grade 3b follicular lymphoma. Grades 1-3a follicular lymphoma are the most common forms of indolent lymphoma.

[0094] As used herein, the term "antibody" refers to any antigen-binding molecule or molecular complex that contains at least one complementarity determining region (CDR) that specifically binds to or interacts with a particular antigen (e.g., CD20 or CD3). The term "antibody" encompasses immunoglobulin molecules that contain four polypeptide chains, i.e., two heavy (H) chains and two light (L) chains, interconnected by disulfide bonds, as well as multimers thereof (e.g., IgM). The term "antibody" also includes immunoglobulin molecules that consist of four polypeptide chains, i.e., two heavy (H) chains and two light (L) chains, interconnected by disulfide bonds. Each heavy chain contains a heavy chain variable region (referred to herein as HCVR or VVR). H The heavy chain constant region comprises a C H 1. C H 2, and C H Each light chain comprises three domains: a light chain variable region (herein referred to as LCVR or V L The light chain constant region comprises one domain (C L 1) is included. HArea and V L The regions can be further subdivided into regions of hypervariability, called complementarity determining regions (CDRs), separated by regions that are relatively conserved, called framework regions (FRs). H and V L is composed of three CDRs and four FRs arranged from amino terminus to carboxy terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In different embodiments of the invention, the FRs of the antibody (or antigen-binding portion thereof) may be identical to human germline sequences or may be naturally or artificially modified. An amino acid consensus sequence may be defined based on the parallel analysis of two or more CDRs. The term "antibody" includes "bispecific antibodies" unless otherwise specified.

[0095] As used herein, the term "antibody" also includes antigen-binding fragments of a complete antibody molecule. The terms "antigen-binding portion" of an antibody, "antigen-binding fragment" of an antibody, and the like include any naturally occurring, enzymatically obtainable, synthetic, or genetically engineered polypeptide or glycoprotein that specifically binds to an antigen to form a complex. Antigen-binding fragments of antibodies may be obtained from complete antibody molecules using any suitable standard method, such as, for example, proteolytic digestion, or recombinant genetic engineering techniques, including the manipulation and expression of DNA encoding antibody variable regions and, optionally, constant domains. Such DNA is known and / or readily available, for example, from commercial sources, DNA libraries (including, for example, phage antibody libraries), or can be synthesized. The DNA may be sequenced and manipulated chemically or by the use of molecular biology techniques, for example, to place one or more variable and / or constant domains in the appropriate configuration, or to introduce codons, create cysteine ​​residues, modify, add, or delete amino acids, and the like.

[0096] The term "bispecific antigen-binding molecule" refers to a protein, polypeptide, or molecular complex that comprises at least a first antigen-binding domain and a second antigen-binding domain. Each antigen-binding domain in a bispecific antigen-binding molecule comprises at least one CDR that specifically binds to a particular antigen, either alone or in combination with one or more additional CDRs and / or FRs. Bispecific antigen-binding molecules include bispecific antibodies.

[0097] Non-limiting examples of antibody-binding fragments include (i) Fab fragments, (ii) F(ab')2 fragments, (iii) Fd fragments, (iv) Fv fragments, (v) single chain Fv (scFv) molecules, (vi) dAb fragments, and (vii) minimal recognition units consisting of amino acid residues mimicking a hypervariable region of an antibody (e.g., an isolated complementarity determining region (CDR) such as a CDR3 peptide), or a constrained FR3-CDR3-FR4 peptide. Domain-specific antibodies, single domain antibodies, domain deleted antibodies, chimeric antibodies, CDR-grafted antibodies, diabodies, triabodies, tetrabodies, minibodies, nanobodies (e.g., monovalent nanobodies, bivalent nanobodies, etc.), small modular immunopharmaceuticals (SMIPs), and other engineered molecules such as shark variable IgNAR domains are also encompassed by the term "antigen-binding fragment".

[0098] Antigen-binding fragments of antibodies typically contain at least one variable domain, which may be of any size or amino acid composition and generally contains at least one CDR adjacent to, or in frame with, one or more framework sequences. L Domain-associated V H For antigen-binding fragments containing domains, V H Domains and V L The domains may be positioned relative to each other in any suitable configuration. For example, the variable region may be a dimer and may have a V H -V H Dimer, V H -V L Dimer or V L -V LAlternatively, the antigen-binding fragment of the antibody may comprise a monomeric V H or V L It may contain domains.

[0099] In certain embodiments, an antigen-binding fragment of an antibody may comprise at least one variable domain covalently linked to at least one constant domain. Non-limiting exemplary configurations of variable and constant domains that may be found within an antigen-binding fragment of an antibody of the invention include: (i) a V H -C H 1, (ii) V H -C H 2. (iii) V H -C H 3. (iv) V H -C H 1-C H 2. (v) V H -C H 1-C H 2-C H 3. (vi) V H -C H 2-C H 3. (vii) V H -C L , (viii) V L -C H 1, (ix) V L -C H 2. (x)V L -C H 3. (xi) V L -C H 1-C H 2. (xii) V L -C H 1-C H 2-C H 3. (xiii) V L -C H 2-C H 3, and (xiv) V L -C LIn any configuration of variable and constant domains, including any of the exemplary configurations listed above, the variable and constant domains may be directly linked to each other or may be linked by a complete or partial hinge or linker region. The hinge region may be comprised of at least two (e.g., 5, 10, 15, 20, 40, 60 or more) amino acids that provide a flexible or semi-flexible linkage between adjacent variable and / or constant domains in a single polypeptide molecule. Furthermore, antigen-binding fragments of antibodies of the present invention may be non-covalently associated with each other and / or with one or more monomeric V domains. H Or V L It may comprise homodimers or heterodimers (or other multimers) of any of the variable and constant domain configurations listed above in non-covalent association (e.g., via disulfide bonds) between the domains.

[0100] As with intact antibody molecules, antigen-binding fragments may be monospecific or multispecific (e.g., bispecific). Multispecific antigen-binding fragments of antibodies typically contain at least two different variable domains, each capable of specifically binding to a separate antigen or to a different epitope on the same antigen. Any multispecific antibody format, including the exemplary bispecific antibody formats disclosed herein, can be adapted for use in the context of antigen-binding fragments of antibodies of the present invention using routine techniques available in the art.

[0101] The antibodies of the present disclosure may function through complement-dependent cytotoxicity (CDC) or antibody-dependent cell-mediated cytotoxicity (ADCC). "Complement-dependent cytotoxicity" (CDC) refers to the lysis of antigen-expressing cells by the antibodies of the present disclosure in the presence of complement. "Antibody-dependent cell-mediated cytotoxicity" (ADCC) refers to a cell-mediated reaction in which non-specific cytotoxic cells expressing Fc receptors (FcRs) (e.g., natural killer (NK) cells, neutrophils, and macrophages) recognize bound antibodies on target cells, thereby resulting in the lysis of the target cells. CDC and ADCC can be measured using assays that are well known and available in the art. (See, e.g., U.S. Pat. Nos. 5,500,362 and 5,821,337, and Clynes et al. (1998) Proc. Natl. Acad. Sci. (USA) 95:652-656). The constant region of an antibody is important in the ability of the antibody to fix complement and mediate cell-dependent cytotoxicity. Thus, the isotype of the antibody can be selected based on whether it is desirable for the antibody to mediate cytotoxicity. The antibody of the present disclosure can include a human IgG heavy chain. In various embodiments, the heavy chain constant region can be of IgG1, IgG2, IgG3, or IgG4 isotype. In some cases, the heavy chain constant region is of isotype IgG1. In some cases, the heavy chain constant region is of isotype IgG4.

[0102] In certain embodiments, the antibody or bispecific antibody is a human antibody. The term "human antibody" is intended to include antibodies with variable and constant regions derived from human germline immunoglobulin sequences. The human antibody of the present invention may, for example, in the CDRs, particularly CDR3, contain amino acid residues that are not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by in vitro random or site-specific mutagenesis or by in vivo somatic mutation). However, the term "human antibody" is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, are grafted onto human framework sequences.

[0103] The antibody of the present invention may be a recombinant human antibody in some embodiments. The term "recombinant human antibody" is intended to include all human antibodies prepared, expressed, created, or isolated by recombinant means, such as antibodies expressed using a recombinant expression vector transfected into a host cell (described in more detail below), antibodies isolated from a recombinant combinatorial human antibody library (described in more detail below), antibodies isolated from an animal (e.g., a mouse) that has been introduced with human immunoglobulin genes (see, e.g., Taylor et al. (1992) Nucl. Acids Res. 20:6287-6295), or antibodies prepared, expressed, created, or isolated by any other means involving splicing human immunoglobulin gene sequences to other DNA sequences. Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. However, in certain embodiments, such recombinant human antibodies are subjected to in vitro mutagenesis (or in vivo somatic mutagenesis, when animals transgenic for human Ig sequences are used), thereby improving the V H Area and V L The amino acid sequence of the region is H Array and V L While it is a sequence derived from and related to the sequence, it may not naturally occur in the human antibody germline repertoire in vivo.

[0104] Human antibodies can exist in two forms related to hinge heterogeneity. In one form, the immunoglobulin molecule contains a stable four-chain construct of approximately 150-160 kDa in which the dimers are held together by interchain heavy chain disulfide bonds. In the second form, the dimers are not linked via interchain disulfide bonds and the approximately 75-80 kDa molecule is composed of covalently linked light and heavy chains (half antibodies). These forms have been very difficult to separate, even after affinity purification.

[0105] The frequency of occurrence of the second form in various intact IgG isotypes is due to, but not limited to, structural differences associated with the hinge region isotype of the antibody. A single amino acid substitution in the hinge region of a human IgG4 hinge can significantly reduce the occurrence of the second form to the level typically observed using a human IgG1 hinge (Angal et al. (1993) Molecular Immunology 30:105). The present invention provides a method for the identification of a hinge, C H 2nd area or C H Antibodies with one or more mutations in three regions are included, which mutations may be desirable, for example, to improve the yield of the desired antibody form in production.

[0106] An antibody may be an isolated antibody. By "isolated antibody" is meant an antibody that has been identified and separated and / or recovered from at least one component of its natural environment. For example, an antibody that has been separated or removed from at least one component of an organism, or from a tissue or cell in which the antibody naturally occurs or is naturally produced, is an "isolated antibody" for the purposes of the present invention. An isolated antibody also includes an antibody in situ within a recombinant cell. An isolated antibody is an antibody that has been subjected to at least one purification or isolation step. According to certain embodiments, an isolated antibody may be substantially free of other cellular material and / or chemicals.

[0107] The term "epitope" refers to an antigenic determinant that interacts with a specific antigen-binding site in the variable region of an antibody molecule known as the paratope. A single antigen may have more than one epitope. Thus, different antibodies may bind to different regions on an antigen and have different biological effects. Epitopes may be either conformational or linear. Conformational epitopes are generated by spatially juxtaposed amino acids from different segments of a linear polypeptide chain. Linear epitopes are epitopes generated by adjacent amino acid residues in a polypeptide chain. In certain circumstances, epitopes may include sugar, phosphoryl, or sulfonyl moieties on an antigen.

[0108] The term "substantial identity" or "substantially identical," when referring to a nucleic acid or a fragment thereof, indicates that when optimally aligned with appropriate nucleotide insertions or deletions with another nucleic acid (or its complementary strand), there is nucleotide sequence identity in at least about 95%, more preferably at least about 96%, 97%, 98%, or 99% of the nucleotide bases as measured by any well-known algorithm of sequence identity, such as FASTA, BLAST, or Gap, as discussed below. A nucleic acid molecule having substantial identity to a reference nucleic acid molecule may, in certain cases, encode a polypeptide having the same or substantially similar amino acid sequence as the polypeptide encoded by the reference nucleic acid molecule.

[0109] As applied to polypeptides, the term "substantial similarity" or "substantially similar" refers to two peptide sequences that share at least 95% sequence identity, and even more preferably at least 98% or 99% sequence identity, when optimally aligned, such as by the programs GAP or BESTFIT, using predefined gap weights. Preferably, residue positions that are not identical differ by conservative amino acid substitutions. A "conservative amino acid substitution" is one in which an amino acid residue is replaced by another amino acid residue having a side chain (R group) with similar chemical properties (e.g., charge or hydrophobicity). In general, a conservative amino acid substitution will not substantially change the functional properties of a protein. When two or more amino acid sequences differ from each other by conservative substitutions, the percent sequence identity or degree of similarity may be adjusted upwards to correct for the conservative nature of the substitution. Means for making this adjustment are well known to those of skill in the art. See, for example, Pearson (1994) Methods Mol. Biol. 24:307-331, incorporated herein by reference. Examples of groups of amino acids having side chains with similar chemical properties include: (1) aliphatic side chains: glycine, alanine, valine, leucine, and isoleucine, (2) aliphatic-hydroxyl side chains: serine and threonine, (3) amide-containing side chains: asparagine and glutamine, (4) aromatic side chains: phenylalanine, tyrosine, and tryptophan, (5) basic side chains: lysine, arginine, and histidine, (6) acidic side chains: aspartic acid and glutamic acid, and (7) sulfur-containing side chains are cysteine ​​and methionine. Suitable conservative amino acid substitution groups are valine-leucine-isoleucine, phenylalanine-tyrosine, lysine-arginine, alanine-valine, glutamic acid-aspartic acid, and asparagine-glutamine. Alternatively, a conservative substitution is any change that has a positive value in the PAM250 log-likelihood matrix disclosed in Gonnet et al. (1992) Science 256:1443-1445, which is incorporated herein by reference. A "moderately conservative" substitution is any change that has a non-negative value in the PAM250 log-likelihood matrix.

[0110] Sequence similarity for polypeptides, also referred to as sequence identity, is typically measured using sequence analysis software. Protein analysis software uses a measure of similarity assigned to various substitutions, deletions and other modifications, including conservative amino acid substitutions, to match similar sequences. For example, GCG software contains programs such as Gap and Bestfit, which can be used with default parameters to determine sequence homology or sequence identity between closely related polypeptides, such as homologous polypeptides from different species of organisms, or between a wild-type protein and its mutant protein. See, for example, GCG version 6.1. Polypeptide sequences can also be compared using FASTA, a program in GCG version 6.1, with default or recommended parameters. FASTA (e.g., FASTA2 and FASTA3) provides alignment and percent sequence identity of the best overlapping regions between the query sequence and the search sequence (Pearson (2000) supra). Another suitable algorithm for comparing the sequences of the present invention to a database containing a large number of sequences from different organisms is the computer program BLAST, particularly BLASTP or TBLASTN, with default parameters. See, e.g., Altschul et al. (1990) J. Mol. Biol. 215:403-410 and Altschul et al. (1997) Nucleic Acids Res. 25:3389-402, each of which is incorporated herein by reference.

[0111] Dosing regimen Dosing regimens are provided in the present disclosure for reducing the prevalence or severity, or both, of cytokine release syndrome (CRS) or infusion-related reactions (IRR) due to administration of bispecific antibodies to patients to treat B-cell malignancies. According to certain embodiments of the present invention, these dosing regimens include administration of multiple doses of the bispecific antibody over a defined time course. The dosing regimens include sequential administration of multiple defined doses of the bispecific antibody to a subject, as well as administration of premedications (e.g., steroids and antihistamines) to minimize or eliminate the risk of adverse events associated with administration of the T-cell engaging bispecific antibody. By "sequential administration" it is meant that each dose of the bispecific antibody is administered to a subject at different times, e.g., on different days separated by a predetermined interval (e.g., hours, days, weeks, or months). The present invention includes dosing regimens that include sequential administration of split doses of the bispecific antibody followed by a single administration of the bispecific antibody. The present dosing regimen allows for higher doses of the therapeutic protein that are desirable to enhance therapeutic efficacy but without the adverse effects associated with CRS or IRR. Without intending to be bound by any particular theory, the present dosing regimen provides for priming of the immune response to administration of the bispecific antibody to minimize the incidence and severity of CRS and IRR during the initial phase of the treatment regimen, and then allows for higher doses of the bispecific antibody to be administered during subsequent phases of the treatment regimen without significant adverse events associated with CRS or IRR.

[0112] A dosing regimen according to the invention comprises administering an anti-CD3 x anti-CD20 bispecific antibody to a subject to treat a B-cell malignancy, the dosing regimen comprising: (a) administering to the subject an initial dose of 0.7 mg of the bispecific antibody, the initial dose being divided into a first dose fraction comprising 0.2 mg of the bispecific antibody and a second dose fraction comprising 0.5 mg of the bispecific antibody, the first dose fraction being administered to the subject followed by the second dose fraction over two days in the first week of the dosing regimen; and (b) administering to the subject a first intermediate dose of 4 mg of the bispecific antibody, the first intermediate dose being divided into two equal fractions each comprising 2 mg of the bispecific antibody (a first intermediate dose of 4 mg of the bispecific antibody). (c) administering to the subject a second intermediate dose of 20 mg of the bispecific antibody, wherein the second intermediate dose is divided into two equal fractions (a first fraction and a second fraction) each comprising 10 mg of the bispecific antibody, and wherein the two fractions of the second intermediate dose are administered over two days in week 3 of the dosing regimen; (d) administering to the subject a full dose of the bispecific antibody every week between weeks 4 and 12 of the dosing regimen; and (e) administering to the subject a maintenance dose of the bispecific antibody in week 14 of the dosing regimen. In some embodiments, the initial dose (0.7 mg) may be divided into other fractions, such as 0.1 mg and 0.6 mg, 0.15 mg and 0.55 mg, 0.25 mg and 0.45 mg, or 0.3 mg and 0.4 mg.

[0113] If the subject does not experience a grade 3 or higher CRS event when receiving the initial dose, the first intermediate dose, or the second intermediate dose, then the full dose is administered to the subject as a single dose between weeks 4 and 12 of the dosing regimen. On the other hand, if the subject experiences a grade 3 or higher CRS event when receiving the initial dose, the first intermediate dose, or the second intermediate dose, then the full dose of the bispecific antibody administered to the subject in week 4 is divided into two equal fractions, the two fractions of this full dose are administered over two days in week 4 of the dosing regimen, and then the full dose is administered to the subject as a single dose between weeks 5 and 12 of the dosing regimen.

[0114] Since weekly administration of all doses proceeds from week 4 to week 12 of the dosing regimen, the first maintenance dose administered every other week (Q2W) is administered beginning at week 14 of the dosing regimen. The Q2W administration of the maintenance doses may be continued indefinitely or may be changed to administration of the maintenance doses every four weeks (Q4W), for example, if the subject has demonstrated a sustained response for at least nine months after the initial determination of a complete response. Thus, in some embodiments, the maintenance doses are administered to the subject every four weeks beginning at a subsequent week of the dosing regimen, where the subsequent week is at least week 36 of the dosing regimen. In various embodiments, the subsequent weeks may be weeks 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, or 60, or even more, of the dosing regimen. This Q4W administration of the maintenance dose may also be continued indefinitely.

[0115] In certain embodiments, the weekly administration of the full dose proceeds from week 4 to week 6 of the dosing regimen, so that the first maintenance dose administered every other week (Q2W) is administered starting from week 8 of the dosing regimen. The Q2W administration of the maintenance dose may be continued for at least two cycles, and then modified to administration of the maintenance dose every eight weeks (Q8W). Thus, in some embodiments, the maintenance dose is administered to the subject every eight weeks starting from the subsequent week of the dosing regimen, where the subsequent week is at least week 18 of the dosing regimen. In various embodiments, the subsequent weeks may be weeks 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, or even more of the dosing regimen. This Q8W administration of the maintenance dose may also be continued indefinitely.

[0116] In certain embodiments, the dosing regimen may include a combination therapy comprising a bispecific anti-CD20 x anti-CD3 antibody (e.g., odronextamab) and CHOP (a combination of cyclophosphamide, doxorubicin, vincristine, and prednisone). In certain embodiments, the dosing regimen may include a combination therapy comprising a bispecific anti-CD20 x anti-CD3 antibody (e.g., odronextamab) and CVP (a combination of cyclophosphamide, vincristine, and prednisone). In embodiments in which the bispecific antibody is combined with CHOP or CVP, the first CHOP / CVP administration may be administered the week before week 1 of the dosing regimen (week 1 being when the first dose of the bispecific antibody is administered), and the first maintenance dose of the bispecific antibody may be administered at week 13 (rather than week 14) of the dosing regimen. In some embodiments, CHOP / CVP is administered during the week following week 1 (i.e., week 0 of the dosing regimen), as well as during weeks 3, 6, 9, 12, and 15 of the dosing regimen.

[0117] In some embodiments, cyclophosphamide is administered at 750 mg / m 2 and doxorubicin was administered at a dose of 50 mg / m 2 and vincristine was administered at a dose of 1.4 mg / m 2 (but not more than 2 mg at any one administration), prednisone is administered at a dose of 100 mg, cyclophosphamide, doxorubicin, and vincristine are administered once in week 0 of the dosing regimen and once in each of weeks 3, 6, 9, 12, and 15 of the dosing regimen, and prednisone is administered for five consecutive days in week 0 of the dosing regimen and for five consecutive days in each of weeks 3, 6, 9, 12, and 15 of the dosing regimen.

[0118] As described above, the split doses (i.e., the first dose fraction, the first intermediate dose fraction, and the second intermediate dose fraction) are administered over two days during the relevant week of the dosing regimen. In this context, the two days refer to two calendar days (e.g., Monday and Tuesday, or May 10 and May 11). In some cases, the two days are consecutive days. In some cases, the two days are not consecutive days, but are separated by no more than three days. For example, the first dose fraction of the first dose may be administered on Monday, and the second dose fraction of the first dose may be administered on Wednesday or Thursday. In some cases, the second dose fraction of the first dose is administered to the subject 18-96 hours after the first dose fraction of the first dose. In some cases, the second dose fraction of the first dose is administered to the subject 18-72 hours after the first dose fraction of the first dose. In some cases, the second dose fraction of the first dose is administered to the subject 24-48 hours after the first dose fraction of the first dose. In some cases, the two fractions of the first intermediate dose are administered to the subject 18-96 hours apart. In some cases, the two fractions of the first intermediate dose are administered to the subject 18-72 hours apart. In some cases, the two fractions of the first intermediate dose are administered to the subject 24-48 hours apart. In some cases, the two fractions of the second intermediate dose are administered to the subject 18-96 hours apart. In some cases, the two fractions of the second intermediate dose are administered to the subject 18-72 hours apart. In some cases, the two fractions of the second intermediate dose are administered to the subject 24-48 hours apart. If the total dose is divided into two fractions, the two fractions of the total dose are administered to the subject 18-96 hours apart. In some cases, the two fractions of the total dose are administered to the subject 18 to 72 hours apart. In some cases, the two fractions of the total dose are administered to the subject 24 to 48 hours apart. In any of these embodiments, the two fractions are administered on different calendar days, regardless of the amount of time between administration of the two fractions (e.g., 18 hours).

[0119] In any of the various dosing regimens, the B cell malignancy that the subject is being treated for can be B cell non-Hodgkin's lymphoma. In some cases, the B cell malignancy is follicular lymphoma, diffuse large B cell lymphoma, mantle cell lymphoma, or marginal zone lymphoma. In various embodiments, the subject is a human adult (age 18 or older) diagnosed with a particular B cell malignancy.

[0120] In various embodiments of the dosing regimen, the total dose of the bispecific antibody is 40 mg to 320 mg, or 80 mg to 320 mg. In various embodiments of the dosing regimen, the maintenance dose of the bispecific antibody is 80 mg to 320 mg, or 160 mg to 320 mg. The total dose and / or maintenance dose of the bispecific antibody may vary depending on the particular type of B-cell malignancy being treated. For example, when the cancer is follicular lymphoma (e.g., grade 1-3a), the total dose is 80 mg and the maintenance dose is 160 mg. In another example, when the cancer is diffuse large B-cell lymphoma (e.g., DLBCL where the subject has failed a previous CAR-T therapy), the total dose is 160 mg and the maintenance dose is 320 mg, or the total dose is 320 mg and the maintenance dose is 320 mg. In another example, if the cancer is mantle cell lymphoma (e.g., MCL where the subject has failed a previous Bruton's tyrosine kinase (BTK) inhibitor therapy), the total dose is 160 mg and the maintenance dose is 320 mg. In another example, if the cancer is marginal zone lymphoma, the total dose is 80 mg and the maintenance dose is 160 mg. In another example, if the cancer is follicular lymphoma, diffuse large B-cell lymphoma, mantle cell lymphoma, or non-Hodgkin's lymphoma other than marginal zone lymphoma, the total dose is 160 mg and the maintenance dose is 320 mg. In another example, if the cancer is aggressive lymphoma, the total dose is 160 mg and the maintenance dose is 320 mg.

[0121] A subject will receive the doses discussed herein in a dosing regimen in consecutive weeks, i.e., week 2 follows week 1, week 3 follows week 2, etc., although in some cases, there may be a delay in the administration of doses, such that the next week is not immediately following the previous calendar week. For example, week 1 of a dosing regimen may correspond to calendar week 1, and week 2 of a dosing regimen may correspond to calendar week 3 or calendar week 4.

[0122] In various embodiments, the dosing regimen further comprises administering to the subject a dose of a steroid 12-24 hours prior to administration of the first dose fraction of the first dose, 12-24 hours prior to administration of the first fraction of the first intermediate dose, and 12-24 hours prior to administration of the first fraction of the second intermediate dose. If the first dose fraction of the first dose and the second dose fraction of the first dose are not administered to the subject on consecutive days (i.e., consecutive calendar days), then the dosing regimen further comprises administering to the subject a dose of a steroid 12-24 hours prior to administration of the second dose fraction of the first dose of the bispecific antibody. Similarly, if the first fraction of the first intermediate dose and the second fraction of the first intermediate dose are not administered to the subject on consecutive days, and / or if the first fraction of the second intermediate dose and the second fraction of the second intermediate dose are not administered to the subject on consecutive days, the dosing regimen further comprises administering to the subject a dose of a steroid 12-24 hours prior to administration of the second fraction of the first intermediate dose of the bispecific antibody, and / or administering to the subject a dose of a steroid 12-24 hours prior to administration of the second fraction of the first intermediate dose of the bispecific antibody, respectively.

[0123] In some embodiments of the dosing regimen, the subject has relapsed or refractory disease. In some embodiments of the dosing regimen, the subject is refractory to an anti-CD20 antibody in any previous line of therapy.

[0124] In some embodiments of the dosing regimen, the subject is previously untreated, i.e., has not been previously treated with any systemic anti-lymphoma therapy.

[0125] In some embodiments of the dosing regimen, the B cell malignancy is follicular lymphoma. In some embodiments of the dosing regimen, the B cell malignancy is diffuse large B cell lymphoma.

[0126] In some embodiments of the dosing regimen, the subject is a human aged 18 years or older.

[0127] In various embodiments of the above-described dosing regimens, the bispecific antibody is administered intravenously to a subject.

[0128] In another embodiment of the dosing regimen, the bispecific antibody is administered subcutaneously (SC) to the subject.

[0129] Exemplary SC dosing regimens include administering to the subject an initial dose of 1 mg or 2 mg of the bispecific antibody during week 1 of the dosing regimen, administering to the subject a first intermediate dose of 10 mg or 26 mg of the bispecific antibody during week 2 of the dosing regimen, administering to the subject a second intermediate dose of 50 mg or 100 mg of the bispecific antibody during week 3 of the dosing regimen, and administering to the subject a full dose of the bispecific antibody during week 4 and subsequent weeks of the dosing regimen, wherein the bispecific antibody comprises a first antigen-binding region that binds human CD20 and a second antigen-binding region that binds human CD3, One antigen-binding region comprises three heavy chain complementarity determining regions HCDR1, HCDR2, and HCDR3 comprising the amino acid sequences of SEQ ID NOs: 7, 8, and 9, respectively, and three light chain complementarity determining regions LCDR1, LCDR2, and LCDR3 comprising the amino acid sequences of SEQ ID NOs: 13, 14, and 15, respectively, and the second antigen-binding region comprises three heavy chain complementarity determining regions HCDR1, HCDR2, and HCDR3 comprising the amino acid sequences of SEQ ID NOs: 10, 11, and 12, and three light chain complementarity determining regions LCDR1, LCDR2, and LCDR3 comprising the amino acid sequences of SEQ ID NOs: 13, 14, and 15, respectively.

[0130] In some embodiments of the SC dosing regimen, the first dose is 2 mg. In some embodiments of the SC dosing regimen, the first intermediate dose is 26 mg. In some embodiments of the SC dosing regimen, the second intermediate dose is 100 mg. In some embodiments of the SC dosing regimen, the total dose is 200 mg, 400 mg, or 600 mg. In some cases, the total dose is 400 mg. In some cases, the total dose is 600 mg.

[0131] In some embodiments of the SC dosing regimen, the entire dose is administered to the subject once every three weeks. In some embodiments of the SC dosing regimen, the entire dose is administered to the subject every week. In some cases of the SC dosing regimen, the entire dose is administered to the subject every week for three weeks, and then the entire dose is administered to the subject once every three weeks.

[0132] In some embodiments of the SC dosing regimen, the subject has relapsed or refractory disease. In some embodiments of the SC dosing regimen, the subject is refractory to an anti-CD20 antibody in any previous line of therapy.

[0133] In some embodiments of the SC administration regimen, the subject is previously untreated, ie, has not been previously treated with any systemic anti-lymphoma therapy.

[0134] In some embodiments of the SC dosing regimen, the B cell malignancy is follicular lymphoma. In some embodiments of the SC dosing regimen, the B cell malignancy is diffuse large B cell lymphoma.

[0135] In some embodiments of the SC dosing regimen, the subject is a human aged 18 years or older.

[0136] In some embodiments, the dosing regimen is intended for administration of the bispecific antibody to pediatric subjects (e.g., under the age of 18).

[0137] An example of a pediatric dosing regimen includes administering to the subject an initial dose of a bispecific antibody, where the initial dose is split into a first dose fraction of the bispecific antibody and a second dose fraction of the bispecific antibody, where the first dose fraction is administered to the subject followed by the second dose fraction over two days in week one of the dosing regimen, and administering to the subject a first intermediate dose of a bispecific antibody, where the first intermediate dose is split into two equal fractions of the bispecific antibody (a first fraction and a second fraction), where the two fractions of the first intermediate dose are administered to the subject over two days in week two of the dosing regimen. administering a first dose of the bispecific antibody to the subject, the first intermediate dose being divided into two equal fractions (a first fraction and a second fraction) of the bispecific antibody and administering the two fractions of the second intermediate dose over two days in week 3 of the dosing regimen; administering a full dose of the bispecific antibody every week to the subject in weeks 4-12 of the dosing regimen; and administering a maintenance dose of the bispecific antibody to the subject in week 14 of the dosing regimen, wherein the initial dose, the first intermediate dose, the second intermediate dose, the full dose, and the maintenance dose are Depending on the weight of the elephant, (i) if the subject has a body weight of between 40 kg and less than 165 kg, the initial dose is 0.7 mg, the first dose fraction of the initial dose is 0.2 mg, the second dose fraction of the initial dose is 0.5 mg, the first intermediate dose is 4 mg, two equal fractions of the first intermediate dose each contain 2 mg, the second intermediate dose is 20 mg, and two equal fractions of the second intermediate dose each contain 10 mg, the total dose is 160 mg, and the maintenance dose is 320 mg; or (ii) if the subject has a body weight of between 20 kg and less than 40 kg, the initial dose is 0. 4 mg, the first dose fraction of the initial dose is 0.1 mg, the second dose fraction of the initial dose is 0.3 mg, the first intermediate dose is 2 mg, two equal fractions of the first intermediate dose each contain 1 mg, the second intermediate dose is 12 mg, two equal fractions of the second intermediate dose each contain 6 mg, the upper total dose is 90 mg, and the maintenance dose is 150 mg; or (iii) if the subject has a body weight of 10 kg to less than 20 kg, the initial dose is 0.3 mg, the first dose fraction of the initial dose is 0.1 mg, and the second dose fraction of the initial dose is 0.2 mg, the first intermediate dose is 1.6 mg, two equal fractions of the first intermediate dose each contain 0.8 mg, the second intermediate dose is 8 mg, two equal fractions of the second intermediate dose each contain 4 mg, the total dose is 60 mg, and the maintenance dose is 100 mg; or (iv) if the subject has a body weight of 6 kg to less than 10 kg, the initial dose is 0.24 mg, the first dose fraction of the initial dose is 0.07 mg, the second dose fraction of the initial dose is 0.17 mg, the first intermediate dose is 1.2 mg, two equal fractions of the first intermediate dose each contain 0.6 mg, the second intermediate dose is 6 mg, and two equal fractions of the second intermediate dose each contain 3 mg, the total dose is 45 mg, and the maintenance dose is 75 mg. The bispecific antibody comprises a first antigen-binding region that binds to human CD20 and a second antigen-binding region that binds to human CD3, the first antigen-binding region comprising three heavy chain complementarity determining regions HCDR1, HCDR2, HCDR3 comprising the amino acid sequences of SEQ ID NOs: 7, 8, and 9, respectively, and three light chain complementarity determining regions LCDR1, LCDR2, and LCDR3 comprising the amino acid sequences of SEQ ID NOs: 13, 14, and 15, respectively, and the second antigen-binding region comprising three heavy chain complementarity determining regions HCDR1, HCDR2, and HCDR3 comprising the amino acid sequences of SEQ ID NOs: 10, 11, and 12, respectively, and three light chain complementarity determining regions LCDR1, LCDR2, and LCDR3 comprising the amino acid sequences of SEQ ID NOs: 13, 14, and 15, respectively.

[0138] In some embodiments of the pediatric dosing regimen, the entire dose is administered to the subject as a single dose between weeks 4 and 12 of the dosing regimen. In some embodiments of the pediatric dosing regimen, a maintenance dose is administered to the subject every two weeks beginning at week 14 of the dosing regimen.

[0139] In some embodiments of the pediatric dosing regimen, the second dose fraction of the first dose is administered to the subject 18-96 hours after the first dose fraction of the first dose. In some embodiments of the pediatric dosing regimen, the two fractions of the first intermediate dose are administered to the subject 18-96 hours apart. In some embodiments of the pediatric dosing regimen, the two fractions of the second intermediate dose are administered to the subject 18-96 hours apart.

[0140] In some embodiments of the pediatric dosing regimen, the two days are consecutive days. In some embodiments of the pediatric dosing regimen, the two days are no more than three days apart.

[0141] In some embodiments of the pediatric dosing regimen, the B cell malignancy is a B cell non-Hodgkin's lymphoma. In some embodiments of the pediatric dosing regimen, the B cell malignancy is a follicular lymphoma, a diffuse large B cell lymphoma, a mantle cell lymphoma, or a marginal zone lymphoma.

[0142] In any of the various embodiments of the pediatric dosing regimen, the bispecific antibody may be administered intravenously.

[0143] In various embodiments, the dosing regimen includes administering to the subject a dose of a steroid 1 to 3 hours prior to administration of the first dose fraction of the first dose, 1 to 3 hours prior to administration of the second dose fraction of the first dose, and 1 to 3 hours prior to administration of each of the first intermediate dose and the second intermediate dose; administering to the subject a dose of an antihistamine 30 to 60 minutes prior to administration of the first dose fraction of the first dose, 30 to 60 minutes prior to administration of the second dose fraction of the first dose, and 30 to 60 minutes prior to administration of each of the first intermediate dose and the second intermediate dose; and, optionally, administering to the subject a dose of acetaminophen 30 to 60 minutes prior to administration of the first dose fraction of the first dose, 30 to 60 minutes prior to administration of the second dose fraction of the first dose, and 30 to 60 minutes prior to administration of each of the first intermediate dose and the second intermediate dose.

[0144] In various embodiments, the dosing regimen further comprises administering to the subject a dose of steroid 20 to 28 hours after the end of administration of the second dose fraction of the first dose, 20 to 28 hours after the end of administration of the second fraction of the first intermediate dose, and 20 to 28 hours after the end of administration of the second fraction of the second intermediate dose.

[0145] In various embodiments in which the subject receives the initial dose, the first intermediate dose, or the second intermediate dose, and the subject does not experience a grade 3 or higher CRS event when all doses are administered to the subject as a single dose during week 4, the dosing regimen further comprises administering to the subject a dose of a steroid 1-3 hours prior to administration of all doses during week 4 of the dosing regimen, administering to the subject a dose of an antihistamine 30-60 minutes prior to administration of all doses during week 4 of the dosing regimen, and optionally administering to the subject a dose of acetaminophen 30-60 minutes prior to administration of all doses during week 4 of the dosing regimen. Additionally, in some embodiments, the dosing regimen further comprises administering to the subject a dose of a steroid 20-28 hours after completion of administration of all doses during week 4 of the dosing regimen.

[0146] In embodiments of the dosing regimen in which the subject experiences a Grade 3 or higher CRS event when administered the initial dose, the first intermediate dose, or the second intermediate dose, the total dose of the bispecific antibody administered to the subject during week 4 is divided into two equal fractions (a first and a second fraction), and the dosing regimen then further comprises administering to the subject a dose of a steroid 12-24 hours prior to administration of the first fraction of the total dose, administering to the subject a dose of a steroid 1-3 hours prior to administration of the first fraction of the total dose, administering to the subject a dose of an antihistamine 30-60 minutes prior to administration of the first fraction of the total dose, and optionally administering to the subject a dose of acetaminophen 30-60 minutes prior to administration of the first fraction of the total dose.

[0147] In those cases where the first fraction of the full dose and the second fraction of the full dose are not administered to the subject on consecutive days, the dosing regimen further comprises administering to the subject a dose of a steroid 12 to 24 hours prior to administration of the second fraction of the full dose of the bispecific antibody.

[0148] Furthermore, if the subject experiences a grade 3 or higher CRS event when administered the initial dose, the first intermediate dose, or the second intermediate dose, then the dosing regimen further comprises administering to the subject a dose of a steroid 1-3 hours prior to administration of all doses during week 5 of the dosing regimen, administering to the subject a dose of an antihistamine 30-60 minutes prior to administration of all doses during week 5 of the dosing regimen, and optionally administering to the subject a dose of acetaminophen 30-60 minutes prior to administration of all doses during week 5 of the dosing regimen. Furthermore, in some embodiments, the dosing regimen further comprises administering to the subject a dose of a steroid 20-28 hours after completion of administration of all doses during week 5 of the dosing regimen.

[0149] In various embodiments, administering a dose of a steroid, administering a dose of an antihistamine, or administering a dose of acetaminophen includes instructing the subject to take a dose of a steroid, a dose of an antihistamine, or a dose of acetaminophen, respectively. In some cases, the subject may orally self-administer the steroid, antihistamine, or acetaminophen, so that the act of administration is only the instruction to self-administer the drug. In other cases, administering a dose of a steroid or administering a dose of an antihistamine includes intravenously administering a dose of a steroid or a dose of an antihistamine. In some cases, the steroid or antihistamine may be administered by a physician, for example, intravenously or by injection.

[0150] In various embodiments, the steroid is dexamethasone, and in some cases the dose is 20 mg, hi other embodiments, the steroid is another equivalent steroid.

[0151] In various embodiments, the antihistamine is diphenhydramine and the dosage is 25 mg. In other embodiments, the antihistamine is another equivalent antihistamine.

[0152] In various embodiments, the dose of acetaminophen is 650 mg. In some cases, acetaminophen may not be administered as part of the dosing regimen, for example, if the subject has received or ingested acetaminophen within 4 hours prior to administration of a dose of the bispecific antibody, or if the subject is allergic to acetaminophen.

[0153] In various embodiments, the dosing regimen further comprises administering an anti-IL6 therapy (e.g., an anti-IL6 receptor antibody such as sarilumab or tocilizumab).

[0154] If the subject does not experience any grade of IRR or CRS after the first full dose of the bispecific antibody as a single dose (i.e., week 4 or 5 of the dosing regimen), then the dose of steroid (e.g., dexamethasone) may be reduced to 10 mg for all subsequent doses. Similarly, if the subject does not experience any grade of IRR or CRS after administration of the reduced (e.g., 10 mg dexamethasone) full dose of steroid dose, then the subsequent dose of bispecific antibody may be administered without prior medication.

[0155] In any embodiment of the dosing regimen discussed above, the bispecific antibody may be as discussed herein or below.

[0156] bispecific antibody In various embodiments of the disclosure, the bispecific antibody comprises A1-HCDR1, A1-HCDR2, and A1-HCDR3 comprising the amino acid sequences of SEQ ID NOs: 7, 8, and 9, respectively; A2-HCDR1, A2-HCDR2, and A2-HCDR3 comprising the amino acid sequences of SEQ ID NOs: 10, 11, and 12, respectively; and LCDR1, LCDR2, and LCDR3 comprising the amino acid sequences of SEQ ID NOs: 13, 14, and 15, respectively.

[0157] In some embodiments, the first antigen binding domain comprises a HCVR having at least 90% identity to the amino acid sequence of SEQ ID NO: 4 and a LCVR having at least 90% identity to the amino acid sequence of SEQ ID NO: 6, and the second antigen binding domain comprises a HCVR having at least 90% identity to the amino acid sequence of SEQ ID NO: 5 and a LCVR having at least 90% identity to the amino acid sequence of SEQ ID NO: 6. In some embodiments, the first antigen binding domain comprises a HCVR having at least 95% identity to the amino acid sequence of SEQ ID NO: 4 and a LCVR having at least 95% identity to the amino acid sequence of SEQ ID NO: 6, and the second antigen binding domain comprises a HCVR having at least 95% identity to the amino acid sequence of SEQ ID NO: 5 and a LCVR having at least 95% identity to the amino acid sequence of SEQ ID NO: 6. In some embodiments, the first antigen-binding domain comprises an HCVR having at least 99% identity to the amino acid sequence of SEQ ID NO:4 and an LCVR having at least 99% identity to the amino acid sequence of SEQ ID NO:6, and the second antigen-binding domain comprises an HCVR having at least 99% identity to the amino acid sequence of SEQ ID NO:5 and an LCVR having at least 99% identity to the amino acid sequence of SEQ ID NO:6.

[0158] In some embodiments, the first antigen-binding domain comprises an HCVR comprising the amino acid sequence of SEQ ID NO:4 and an LCVR comprising the amino acid sequence of SEQ ID NO:6, and the second antigen-binding domain comprises an HCVR comprising the amino acid sequence of SEQ ID NO:5 and an LCVR comprising the amino acid sequence of SEQ ID NO:6.

[0159] The present invention also relates to a first CH 3 domain and second Ig C H The present invention relates to a bispecific antibody comprising a first and a second IgC domain. H In one embodiment, the first Ig C domain is a IgG1 domain, and the first Ig C domain is a IgG2 domain. The first Ig C domain is a IgG1 ... H The 3 domain binds to protein A and the second Ig C H The third domain contains a mutation that reduces or eliminates Protein A binding ability, for example, the H95R modification (according to the IMGT exon numbering; H435R according to the EU numbering). H 3 may further contain a Y96F modification (Y436F according to IMGT and according to the EU). See, e.g., U.S. Patent No. 8,586,713. H Additional modifications that may be found in 3 include: D16E, L18M, N44S, K52N, V57M, and V82I for IgG1 antibodies (D356E, L358M, N384S, K392N, V397M, and V422I in EU by IMGT), N44S, K52N, and V82I for IgG2 antibodies (N384S, K392N, and V422I in EU by IMGT), and Q15R, N44S, K52N, V57M, R69K, E79Q, and V82I for IgG4 antibodies (Q355R, N384S, K392N, V397M, R409K, E419Q, and V422I in EU by IMGT).

[0160] In some embodiments, the bispecific antibody comprises a human IgG heavy chain constant region attached to the HCVR of each of the first antigen binding domain and the second antigen binding domain. In some cases, the heavy chain constant region is of isotype IgG1. In some cases, the heavy chain constant region is of isotype IgG4. In some embodiments, the heavy chain constant region attached to the HCVR of the first antigen binding domain or the heavy chain constant region attached to the HCVR of the second antigen binding domain, but not both, comprises an amino acid modification that reduces Protein A binding ability relative to a heavy chain of the same isotype without the modification. In some cases, the modification comprises a H435R substitution (EU numbering) in a heavy chain of isotype IgG1 or IgG4. In some cases, the modification comprises a H435R substitution and a Y436F substitution (EU numbering) in a heavy chain of isotype IgG1 or IgG4.

[0161] In certain embodiments, the Fc domain may be a chimera that combines Fc sequences from two or more immunoglobulin isotypes. For example, a chimeric Fc domain may be a chimeric Fc domain that combines Fc sequences from human IgG1, human IgG2, or human IgG4. H C derived from 2 regions H 2 sequences, and C derived from human IgG1, human IgG2, or human IgG4. H The chimeric Fc domain may comprise some or all of the three sequences. The chimeric Fc domain may also contain a chimeric hinge region. For example, the chimeric hinge may comprise an "upper hinge" sequence derived from a human IgG1, human IgG2, or human IgG4 hinge region combined with a "lower hinge" sequence derived from a human IgG1, human IgG2, or human IgG4 hinge region. A specific example of a chimeric Fc domain that may be included in any of the antigen-binding molecules described herein is one that comprises, from the N-terminus to the C-terminus, [IgG4 C H Another example of a chimeric Fc domain that may be included in any of the antigen-binding molecules described herein comprises, from the N-terminus to the C-terminus, [IgG1 C HIgG1 CH3]-[IgG1 upper hinge]-[IgG2 lower hinge]-[IgG4 CH2]-[IgG1 CH3]. These and other examples of chimeric Fc domains that may be included in any of the antigen-binding molecules of the invention are described in U.S. Patent Application Publication No. 2014 / 0243504, published August 28, 2014, which is incorporated herein in its entirety. Chimeric Fc domains having these general structural arrangements, and variants thereof, may have altered Fc receptor binding capabilities and therefore affect Fc effector functions.

[0162] In some embodiments, the bispecific antibody may comprise a chimeric hinge. For example, the chimeric hinge, in one embodiment, comprises a first amino acid sequence or "upper hinge" sequence derived from a human IgG1 hinge region or a human IgG4 hinge region, and a second amino acid sequence or "lower hinge" sequence derived from a human IgG2 hinge region. In certain embodiments, the first or "upper hinge" sequence comprises amino acid residues at positions 216-227 according to the EU numbering. In some embodiments, the second or "lower hinge" sequence comprises amino acid residues at positions 228-236 according to the EU numbering. In some cases where the antibody heavy chain constant region is of isotype IgG4, the chimeric hinge comprises an upper hinge sequence derived from human IgG4 (positions 216-227 according to the EU numbering) and a lower hinge sequence derived from human IgG2 (positions 228-236 according to the EU numbering). In some cases where the antibody heavy chain constant region is of isotype IgG1, the chimeric hinge comprises an upper hinge sequence from human IgG1 (positions 216-227 according to EU numbering) and a lower hinge sequence from human IgG2 (positions 228-236 according to EU numbering). In some embodiments where the heavy chain constant region is of isotype IgG1 and the antibody comprises a chimeric hinge, the CH2 domain of the other IgG1 heavy chain constant region is of isotype IgG4. Unless otherwise indicated, reference to an IgG1 or IgG4 heavy chain constant region includes a heavy chain constant region comprising a chimeric hinge (e.g., an IgG1 or IgG4 upper hinge sequence, respectively, and an IgG2 lower hinge sequence). For example, reference to an IgG1 heavy chain constant region includes an IgG1 heavy chain constant region comprising an IgG2 lower hinge sequence, and reference to an IgG4 heavy chain constant region includes an IgG4 heavy chain constant region comprising an IgG2 lower hinge sequence.

[0163] In some embodiments, the bispecific antibody comprises a heavy chain constant region comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 16, 17, 18, and 19. In some embodiments, the bispecific antibody comprises a heavy chain constant region comprising the amino acid sequence of SEQ ID NO: 16 and a heavy chain constant region comprising the amino acid sequence of SEQ ID NO: 17. In some embodiments, the bispecific antibody comprises a heavy chain constant region comprising the amino acid sequence of SEQ ID NO: 18 and a heavy chain constant region comprising the amino acid sequence of SEQ ID NO: 19.

[0164] In various embodiments, the bispecific antibody comprises a first heavy chain containing the HCVR of the first antigen binding domain and a second heavy chain containing the HCVR of the second antigen binding domain, where the first heavy chain comprises residues 1-452 of the amino acid sequence of SEQ ID NO: 1 and the second heavy chain comprises residues 1-448 of the amino acid sequence of SEQ ID NO: 2. In some embodiments, the antibody comprises a common light chain containing the LCVR of the first and second antigen binding domains, where the common light chain comprises the amino acid sequence of SEQ ID NO: 3.

[0165] In various embodiments of any of the pharmaceutical compositions discussed above or herein, the antibody comprises a first heavy chain containing the HCVR of the first antigen binding domain and a second heavy chain containing the HCVR of the second antigen binding domain, wherein the first heavy chain comprises the amino acid sequence of SEQ ID NO: 1 and the second heavy chain comprises the amino acid sequence of SEQ ID NO: 2. In some embodiments, the antibody comprises a common light chain containing the LCVR of the first and second antigen binding domains, wherein the common light chain comprises the amino acid sequence of SEQ ID NO: 3.

[0166] The first antigen-binding domain and the second antigen-binding domain may be directly or indirectly connected to each other to form the bispecific antibody of the present invention. Alternatively, the first antigen-binding domain and the second antigen-binding domain may each be connected to a separate multimerization domain. The association of one multimerization domain with another multimerization domain promotes the association between the two antigen-binding domains, thereby forming a bispecific antigen-binding molecule. A "multimerization domain" is any macromolecule, protein, polypeptide, peptide, or amino acid that has the ability to associate with a second multimerization domain of the same or similar structure or composition. For example, a multimerization domain may be a multimerization domain that is capable of associating with a second multimerization domain of the same or similar structure or composition. H A non-limiting example of a multimerizing component is the Fc portion of an immunoglobulin (C H 2-C H 3 domains), for example, the Fc domain of IgG selected from the isotypes IgG1, IgG2, IgG3, and IgG4, as well as any allotype within each isotype group.

[0167] A bispecific antibody of the present disclosure typically comprises two multimerization domains, e.g., two Fc domains, each part of a separate antibody heavy chain. The first and second multimerization domains may be of the same IgG isotype, e.g., IgG1 / IgG1, IgG2 / IgG2, IgG4 / IgG4, etc. Alternatively, the first and second multimerization domains may be of different IgG isotypes, e.g., IgG1 / IgG2, IgG1 / IgG4, IgG2 / IgG4, etc.

[0168] In certain embodiments, the multimerization domain is an Fc fragment or an amino acid sequence of 1 to about 200 amino acids in length containing at least one cysteine ​​residue. In other embodiments, the multimerization domain is a cysteine ​​residue or a short cysteine-containing peptide. Other multimerization domains include peptides or polypeptides that include or consist of a leucine zipper, a helix-loop motif, or a coiled-coil motif. Binding properties

[0169] The term "binding" in the context of binding of an antibody (e.g., a bispecific antibody) to either a given antigen, e.g., a cell surface protein or fragment thereof, typically refers to an interaction or association between at least two entities or molecular structures, such as an antibody-antigen interaction.

[0170] For example, binding affinities are typically on the order of about 10 when measured by surface plasmon resonance (SPR) techniques on a BIAcore 3000 instrument, using, for example, an antigen as the ligand and an antibody, Ig, antibody-binding fragment, or Fc-containing protein as the analyte (or anti-ligand agent). -7 M or less, about 10 -8 M or less, about 10 -9 K below M D Cell-based binding strategies such as fluorescence-activated cell sorting (FACS) binding assays are also routinely used, and FACS data correlate well with other methods such as radioligand competitive binding and SPR (Benedict, CA, J Immunol Methods. 1997, 201(2):223-31; Geuijen, CA, et al. J Immunol Methods. 2005, 302(1-2):68-77).

[0171] Thus, an antibody or antigen-binding protein of the invention has a K that is at least 10-fold lower than its affinity for binding to a non-specific antigen (e.g., BSA, casein). DAccording to the present invention, the antibody binds to a given antigen or cell surface molecule (receptor) with an affinity corresponding to a K value that is 10 times lower than that of a non-specific antigen. D Although an antibody affinity corresponding to the value may be considered as undetectable binding, such an antibody may be paired with a second antigen-binding arm to generate a bispecific antibody of the invention.

[0172] The term “K D " (M) refers to the dissociation equilibrium constant of a particular antibody-antigen interaction, or the dissociation equilibrium constant of an antibody or antibody-binding fragment that binds to an antigen. D There is an inverse relationship between binding affinity and K D The smaller the value, the higher or stronger the affinity. Thus, the terms "higher affinity" or "stronger affinity" refer to a greater ability to form an interaction and thus a smaller K D Conversely, the term "lower affinity" or "weaker affinity" refers to a lower ability to form an interaction and thus a larger K D In some situations, the binding affinity (or K) of a particular molecule (e.g., an antibody) to an interaction partner molecule (e.g., antigen X) is D ) relative to the binding affinity of that molecule (e.g., an antibody) for another interaction partner molecule (e.g., antigen Y) indicates a larger K D The smaller the K value (lower, or weaker, affinity), the D This can be expressed as a binding ratio determined by dividing by a value (higher, or stronger, affinity), and can be expressed as, for example, 5-fold or 10-fold higher binding affinity, in some cases.

[0173] The term "k" d " (sec-1 or 1 / s) refers to the dissociation rate constant of a particular antibody-antigen interaction, or the dissociation rate constant of an antibody or antibody-binding fragment. The aforementioned values ​​are k off Also called value.

[0174] The term "k" a" (M-1 x sec-1 or 1 / M) refers to the association rate constant of a particular antibody-antigen interaction, or the association rate constant of an antibody or antibody binding fragment.

[0175] The term “K A " (M-1 or 1 / M) refers to the association equilibrium constant of a particular antibody-antigen interaction, or the association equilibrium constant of an antibody or antibody binding fragment. The association equilibrium constant is k a k d It is obtained by dividing by.

[0176] "EC50" or "EC 50 The term "half maximal effective concentration" refers to the concentration of antibody that induces a response halfway between the baseline and maximum after a specified exposure time. EC 50 Essentially, the EC represents the concentration of an antibody at which 50% of its maximal effect is observed. In certain embodiments, the EC 50 The EC value is equal to the concentration of an antibody of the invention that gives half-maximal binding to cells expressing, for example, CD3 or a tumor-associated antigen (e.g., CD20), as determined, for example, by a FACS binding assay. Thus, the EC 50 Alternatively, decreased or weakened binding is observed with increasing half effective concentration.

[0177] In one embodiment, the reduction in binding is an EC2 that allows binding to half the maximal amount of target cells. 50 It can be defined as an increase in antibody concentration.

[0178] In another embodiment, EC 50 The values ​​represent the concentration of the antibody of the present invention that elicits half-maximal depletion of target cells by T cell cytotoxicity. Thus, an increase in cytotoxicity (e.g., T cell-mediated tumor cell killing) is observed with an EC 50 or a decrease in the median effective concentration is observed.

[0179] Sequence variants The antibodies (e.g., bispecific antibodies) of the present disclosure may contain one or more amino acid substitutions, insertions, and / or deletions in the framework and / or CDR regions of the heavy and light chain variable domains compared to the corresponding germline sequences from which the individual antigen-binding domains were derived. Such mutations can be readily ascertained by comparing the amino acid sequences disclosed herein to germline sequences available, for example, from public antibody sequence databases. The antigen-binding molecules of the present invention may contain antigen-binding domains derived from any of the exemplary amino acid sequences disclosed herein, in which one or more amino acids in one or more framework and / or CDR regions are mutated to the corresponding residues in the germline sequence from which the antibody is derived, or to the corresponding residues in another human germline sequence, or to conservative amino acid substitutions of the corresponding germline residues (such sequence changes are collectively referred to herein as "germline mutations"). Starting from the heavy and light chain variable region sequences disclosed herein, one of skill in the art can readily produce many antibodies and antigen-binding fragments containing one or more individual germline mutations or combinations thereof. In certain embodiments, the V H Domain and / or V LAll of the framework and / or CDR residues in the domain are mutated back to the residues found in the original germline sequence from which the antigen-binding domain was originally derived. In other embodiments, only certain residues are mutated back to the original germline sequence, for example only the mutated residues found within the first 8 amino acids of FR1 or the last 8 amino acids of FR4, or only the mutated residues found within CDR1, CDR2, or CDR3. In other embodiments, one or more framework and / or CDR residues are mutated to the corresponding residues in a different germline sequence (i.e., a germline sequence different from the germline sequence from which the antigen-binding domain was originally derived). Furthermore, the antigen-binding domain may contain any combination of two or more germline mutations in the framework and / or CDR regions, for example, certain individual residues are mutated to the corresponding residues in a particular germline sequence, while certain other residues that differ from the original germline sequence are maintained or mutated to the corresponding residues in a different germline sequence. Once obtained, an antigen-binding domain containing one or more germline mutations can be readily tested for one or more desired properties, such as improved binding specificity, increased binding affinity, improved or enhanced antagonist or agonist biological properties (as the case may be), reduced immunogenicity, etc. Bispecific antigen-binding molecules comprising one or more antigen-binding domains obtained in this general manner are encompassed by the present disclosure.

[0180] The invention also includes antibodies comprising variants of any HCVR, LCVR, and / or CDR amino acid sequence disclosed herein having one or more conservative substitutions. For example, the invention includes antibodies having HCVR, LCVR, and / or CDR amino acid sequences that have, for example, 10 or less, 8 or less, 6 or less, or 4 or less conservative amino acid substitutions relative to any HCVR, LCVR, and / or CDR amino acid sequence described herein.

[0181] pH dependent binding The present invention includes antibodies (e.g., bispecific antibodies) with pH-dependent binding properties. For example, the antibodies of the present invention may exhibit reduced binding to tumor antigens, such as CD20, at acidic pH compared to neutral pH. Alternatively, the antibodies of the present invention may exhibit enhanced binding to tumor antigens, such as CD20, at acidic pH compared to neutral pH. The term "acidic pH" includes pH values ​​less than about 6.2, such as about 6.0, 5.95, 5.9, 5.85, 5.8, 5.75, 5.7, 5.65, 5.6, 5.55, 5.5, 5.45, 5.4, 5.35, 5.3, 5.25, 5.2, 5.15, 5.1, 5.05, 5.0 or less. The term "neutral pH" refers to a pH of about 7.0 to about 7.4. The expression "neutral pH" includes pH values ​​of about 7.0, 7.05, 7.1, 7.15, 7.2, 7.25, 7.3, 7.35, and 7.4.

[0182] In one particular example, "reduced binding to ... at acidic pH compared to neutral pH" refers to the K D value and the K of an antibody that binds to its antigen at neutral pH D For example, an antibody or antigen-binding fragment thereof may be used that has an acidic / neutral K value of about 3.0 or greater. D For purposes of the invention, when an antibody or antigen-binding fragment of the invention exhibits an acidic / neutral K ratio, it may be considered to exhibit "reduced binding to, for example, CD20 at acidic pH compared to neutral pH." In certain exemplary embodiments, an acidic / neutral K ratio for an antibody or antigen-binding fragment of the invention may be used. D The ratio can be about 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0, 10.5, 11.0, 11.5, 12.0, 12.5, 13.0, 13.5, 14.0, 14.5, 15.0, 20.0, 25.0, 30.0, 40.0, 50.0, 60.0, 70.0, 100.0 or more.

[0183] Antibodies with pH-dependent binding properties can be obtained, for example, by screening antibody populations for reduced (or enhanced) binding to a particular antigen at acidic pH compared to neutral pH. In addition, modification of the antigen-binding domain at the amino acid level can produce antibodies with pH-dependent properties. For example, by replacing one or more amino acids in the antigen-binding domain (e.g., in the CDR) with histidine residues, an antibody with reduced antigen-binding properties at acidic pH compared to neutral pH can be obtained. Fc variants

[0184] According to certain embodiments of the present invention, bispecific antigen-binding molecules are provided that include an Fc domain that includes one or more mutations that enhance or decrease antibody binding to the FcRn receptor at, for example, acidic pH as compared to neutral pH. H 2 or C HThese include antibodies containing mutations in the 3 region that increase the affinity of the Fc domain for FcRn in acidic environments (e.g., within endosomes at pHs ranging from about 5.5 to about 6.0), and such mutations can result in increased serum half-life of the antibody when administered to an animal. Non-limiting examples of such Fc modifications include, for example, modifications at positions 250 (e.g., E or Q), 250 and 428 (e.g., L or F), 252 (e.g., L / Y / F / W or T), 254 (e.g., S or T), and 256 (e.g., S / R / Q / E / D or T), or modifications at positions 428 and / or 433 (e.g., H / L / R / S / P / Q or K) and / or 434 (e.g., H / F or Y), or modifications at positions 250 and / or 428, or modifications at positions 307 or 308 (e.g., 308F, V308F), and 434. In one embodiment, the modifications include 428L (e.g., M428L) and 434S (e.g., N434S) modifications, 428L, 259I (e.g., V259I), and 308F (e.g., V308F) modifications, 433K (e.g., H433K) and 434 (e.g., 434Y) modifications, 252, 254, and 256 (e.g., 252Y, 254T, and 256E) modifications, 250Q and 428L modifications (e.g., T250Q and M428L), and 307 and / or 308 modifications (e.g., 308F and / or 308P).

[0185] For example, the present invention includes antibodies and bispecific antigen-binding molecules comprising an Fc domain that comprises one or more pairs or groups of mutations selected from the group consisting of: 250Q and 248L (e.g., T250Q and M248L); 252Y, 254T and 256E (e.g., M252Y, S254T and T256E); 428L and 434S (e.g., M428L and N434S); and 433K and 434F (e.g., H433K and N434F). All possible combinations of the aforementioned Fc domain mutations, and other mutations in the antibody variable domains disclosed herein, are contemplated to be within the scope of the present invention.

[0186] Preparation of antibodies An antigen-binding domain specific for a particular antigen can be prepared by any antibody generation technique known in the art. Once two different antigen-binding domains specific for two different antigens (e.g., CD3 and CD20) are obtained, they can be appropriately positioned relative to each other to produce a bispecific antibody of the present disclosure using routine methods. In certain embodiments, one or more of the individual components (e.g., heavy and light chains) of a bispecific antibody of the present disclosure are derived from a chimeric antibody, a humanized antibody, or a fully human antibody. Methods for making such antibodies are well known in the art. For example, one or more of the heavy and / or light chains of a bispecific antibody of the present disclosure can be prepared using VELOCIMMUNE™ technology. Using VELOCIMMUNE™ technology (or any other human antibody generation technique), a high affinity chimeric antibody against a particular antigen (e.g., CD3 or CD20) with a human variable region and a mouse constant region is first isolated. The antibody is characterized and selected for desirable characteristics including affinity, selectivity, epitope, etc. The mouse constant regions are replaced with the desired human constant regions to generate fully human heavy and / or light chains that can be incorporated into the bispecific antigen-binding molecules of the invention.

[0187] Genetically engineered animals may be used to generate human bispecific antigen-binding molecules. For example, genetically modified mice that cannot rearrange and express endogenous mouse immunoglobulin light chain variable sequences may be used, and the mice express only one or two human light chain variable domains encoded by human immunoglobulin sequences operably linked to mouse kappa constant genes at the endogenous mouse kappa locus. Such genetically modified mice may be used to produce fully human bispecific antibodies that include two different heavy chains associated with the same light chain, the heavy chains including variable domains derived from one of two different human light chain variable region gene segments. (See, for example, US Patent Application Publication No. 2011 / 0195454). Fully human refers to an antibody or antigen-binding fragment thereof or immunoglobulin domain that includes an amino acid sequence encoded by DNA derived from a human sequence over the entire length of each polypeptide of the antibody or antigen-binding fragment thereof or immunoglobulin domain. In some cases, the fully human sequence is derived from an endogenous protein of a human. In other cases, the fully human protein or protein sequence includes a chimeric sequence in which each component sequence is derived from a human sequence. Without being bound to any one theory, chimeric proteins or sequences are generally designed to minimize the generation of immunogenic epitopes at the junctions of the component sequences, e.g., compared to any wild-type human immunoglobulin region or domain.

[0188] biological equivalent The present invention encompasses antigen-binding molecules having amino acid sequences that differ from those of the exemplary molecules disclosed herein but that retain the ability to bind to the same antigen or antigens. Such variant molecules may contain one or more amino acid additions, deletions, or substitutions compared to the parent sequence, but exhibit biological activity that is essentially equivalent to that of the described antibodies (e.g., bispecific antibodies).

[0189] The present invention includes antigen-binding molecules that are biologically equivalent to any of the exemplary antibodies described herein. Two antigen-binding proteins or antibodies are considered to be biologically equivalent if they are, for example, pharmaceutical equivalents or pharmaceutical substitutes and do not show significant differences in the rate and extent of absorption when administered in the same molar dose under similar experimental conditions, either in single or multiple doses. Some antigen-binding proteins are considered equivalents or pharmaceutical substitutes when they are equivalent in degree of absorption but not in absorption rate, and furthermore, such differences in absorption rate are considered to be biologically equivalent because they are intentional, are reflected in the labeling, are not essential for achieving effective body drug concentrations in long-term use, and are not considered medically significant for the particular pharmaceutical product studied.

[0190] In one embodiment, two antigen binding proteins are bioequivalent if there are no clinically significant differences in their safety, purity, or efficacy.

[0191] In one embodiment, two antigen binding proteins are bioequivalent if a patient can make one or more switches between the reference product and the biological product without a predicted increased risk of adverse effects, including clinically significant changes in immunogenicity, or a decrease in efficacy, compared to continuing therapy without such switches.

[0192] In one embodiment, two antigen binding proteins are bioequivalent if they both act by one or more common mechanisms for one or more conditions of use, to the known extent of such mechanisms.

[0193] Bioequivalence may be demonstrated by in vivo and in vitro methods. Bioequivalence measurements include, for example, (a) in vivo tests in humans or other mammals in which the concentration of an antibody or its metabolites is measured as a function of time in blood, plasma, serum, or other biological fluids, (b) in vitro tests that correlate with and reasonably predict human in vivo bioavailability data, (c) in vivo tests in humans or other mammals in which the relevant acute pharmacological effect of the antibody (or its target) is measured as a function of time, and (d) well-controlled clinical trials that demonstrate the safety, efficacy, or bioavailability or bioequivalence of the antigen binding protein.

[0194] Biologically equivalent variants of the exemplary antibodies described herein (e.g., bispecific antibodies) can be constructed, for example, by making various substitutions of residues or sequences, or by deleting terminal or internal residues or sequences that are not required for biological activity. For example, cysteine ​​residues that are not essential for biological activity can be deleted or replaced with other amino acids to prevent the formation of unnecessary or incorrect intramolecular disulfide bridges during renaturation. In other contexts, biologically equivalent antigen-binding proteins can include variants of the exemplary antibodies and bispecific antigen-binding molecules described herein that contain amino acid changes that alter the glycosylation characteristics of the molecule, for example, mutations that eliminate or remove glycosylation.

[0195] Therapeutic Formulation and Delivery The present invention provides pharmaceutical compositions comprising the antibodies (e.g., bispecific antibodies) of the present disclosure. Specific pharmaceutical compositions of exemplary bispecific antibodies of the present disclosure are provided, for example, in WO2021 / 119135.

[0196] A variety of delivery systems are known and can be used to administer the pharmaceutical compositions of the present invention, such as encapsulation in liposomes, microparticles, microcapsules, recombinant cells capable of expressing mutant viruses, receptor-mediated endocytosis, etc. (See, e.g., Wu et al., 1987, J.Biol.Chem.262:4429-4432). Methods of introduction include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and oral routes. The compositions can be administered by any convenient route, such as by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal mucosa, intestinal mucosa, etc.), and can be administered in conjunction with other biologically active agents. Administration can be systemic or local. In some embodiments, the therapeutic proteins of the present invention are administered via intravenous infusion or subcutaneous injection.

[0197] The pharmaceutical composition of the present invention can be delivered subcutaneously or intravenously using a standard needle and syringe. Furthermore, for subcutaneous delivery, a pen delivery device is easily applied in the delivery of the pharmaceutical composition of the present invention. Such a pen delivery device can be reusable or disposable. A reusable pen delivery device generally utilizes a replaceable cartridge containing the pharmaceutical composition. Once all of the pharmaceutical composition in the cartridge has been administered and the cartridge is empty, the empty cartridge can be easily discarded and replaced with a new cartridge containing the pharmaceutical composition. The pen delivery device can then be reused. In a disposable pen delivery device, there is no replaceable cartridge. Rather, the disposable pen delivery device is sold in a pre-filled state, with the pharmaceutical composition held in a reservoir inside the device. Once the reservoir is empty of pharmaceutical composition, the entire device is discarded.

[0198] Numerous reusable pen and autoinjector delivery devices find use in the subcutaneous delivery of the pharmaceutical compositions of the present invention. Examples include, but are not limited to, the AUTOPEN™ (Owen Mumford, Inc., Woodstock, UK), DISETRONIC™ pen (Disetronic Medical Systems, Bergdorf, Switzerland), HUMALOG MIX 75 / 25™ pen, HUMALOG™ pen, HUMALIN 70 / 30™ pen (Eli Lilly and Co., Indianapolis, IN), NOVOPEN™ I, II, and III (Novo Nordisk, Copenhagen, Denmark), NOVOPEN JUNIOR™ (Novo Nordisk, Copenhagen, Denmark), BD™ pen (Becton Dickinson, Franklin Lakes, NJ), OPTIPEN™, OPTIPEN PRO™, OPTIPEN™, to name just a few. Examples of disposable pen delivery devices having application in the subcutaneous delivery of the pharmaceutical compositions of the present invention include, but are not limited to, the SOLOSTAR Pen (Sanofi-Aventis), FLEXPEN (Novo Nordisk), and KWIKPEN (Eli Lilly), SURECLICK Autoinjector (Amgen, Thousand Oaks, CA), PENLET (Haselmeier, Stuttgart, Germany), EPIPEN (Dey, LP), and HUMIRA Pen (Abbott Labs, Abbott Park, IL).

[0199] The injectable preparations may include dosage forms for intravenous injection, subcutaneous injection, intradermal injection, and intramuscular injection, infusion, etc. These injectable preparations may be prepared by known methods.

[0200] The pharmaceutical compositions of the present disclosure may be included in a kit comprising a container containing the bispecific antibody and a label having instructions for administering the bispecific antibody according to any one or more of the dosing regimens discussed herein. In some cases, the label also includes instructions for administering a steroid and / or an antihistamine to reduce the risk of CRS and / or IRR.

[0201] Therapeutic Uses of Antigen-Binding Molecules The present invention includes a method comprising administering to a subject in need thereof a therapeutically effective amount of the bispecific antibody of the present disclosure for the treatment of B-cell malignancies. The bispecific antibody may be contained in a composition comprising a pharma- ceutically acceptable carrier or diluent. The term "subject" or "subject in need thereof" refers to a human or non-human animal that exhibits one or more symptoms or signs of cancer (e.g., a subject that develops a tumor or is afflicted with any of the cancers described herein below).

[0202] In some embodiments, the bispecific anti-CD3 x anti-CD20 antibodies are useful for treating B-cell malignancies including non-Hodgkin's lymphoma, Hodgkin's lymphoma, chronic lymphocytic leukemia, acute lymphoblastic leukemia, small lymphocytic lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, marginal zone lymphoma, Waldenstrom's macroglobulinemia, primary mediastinal B-cell lymphoma, lymphoblastic lymphoma, or Burkitt's lymphoma. In some embodiments, the cancer is follicular lymphoma. In some embodiments, the cancer is diffuse large B-cell lymphoma (DLBCL). In some embodiments, the cancer is mantle cell lymphoma. In some embodiments, the cancer is marginal zone lymphoma.

[0203] Non-Hodgkin's lymphoma (NHL) is the most common hematological malignancy. Among the heterogeneous group of NHLs, 85-90% are of B-cell origin and include follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), and several other B-NHLs. Anti-CD20 antibodies in combination with chemotherapy are the standard of care for the treatment of B-NHL, but despite initial responses, many patients relapse and often have increasingly shorter durations of response in subsequent lines of therapy, resulting in poor outcomes. Thus, in some embodiments, the antigen-binding molecule is a bispecific anti-CD3 x anti-CD20 that binds to CD3+ T cells and CD20+ B cells and targets CD20+ tumor cells via T cell-mediated cytotoxicity. In some cases, the anti-CD3xCD20 bispecific antibody is for the treatment of a B cell cancer (e.g., NHL) in a subject who has failed previous therapy with an anti-CD20 monospecific antibody.

[0204] For patients who do not achieve a complete response to CAR-T therapy, outcomes are generally poor and there are no standard treatment options. Thus, in some cases, the anti-CD3×CD20 bispecific antibodies of the present invention are for the treatment of B-cell cancers (e.g., NHL, such as DLBCL) in subjects who have failed or failed previous CAR-T therapy (e.g., anti-CD19 CAR-T therapy).

[0205] In one embodiment, odronextamab is indicated for the treatment of adult patients with relapsed or refractory follicular lymphoma (FL) after at least two prior systemic therapies.

[0206] In one embodiment, odronextamab is indicated for the treatment of adult patients diagnosed with follicular lymphoma or DLBCL who have not previously been treated with any systemic anti-lymphoma therapy.

[0207] For relapsed or refractory follicular lymphoma (R / R FL), administration may be via intravenous (IV) infusion. Treatment consists of a step-up dose in cycle 1, weekly doses in cycles 2-4, followed by maintenance doses every 2 weeks until disease progression, e.g., as shown in Table 1 below.

[0208] A single treatment cycle (for FL) consisted of 21 days. Cycle 1: Step Up -Odronextamab is administered as a 4-hour infusion. The recommended starting dose of odronextamab is 0.2 mg on day 1. If tolerated, administer 0.5 mg on day 2. If tolerated, administer a 2 mg dose on day 8 and a 2 mg dose on day 9. If tolerated, administer a 10 mg dose on day 15 and a 10 mg dose on day 16. Administer cycle 2 if tolerated. Cycles 2-4: 80m per week g- 80 mg is administered as a 4-hour infusion on day 1 of cycle 2. If tolerated, the infusion time may be reduced to 1 hour for all subsequent doses. Doses of 80 mg are administered on days 1, 8, and 15. Maintenance: 160 mg every 2 weeks After cycle 4, odronextamab will be administered as a 1-hour infusion every 2 weeks at a dose of 160 mg. If the patient has been in complete remission for 9 months, a dose of 160 mg will be administered every 4 weeks, or 320 mg will be administered every 8 weeks.

[0209] [Table 1]

[0210] In one embodiment, odronextamab is indicated for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) after at least two prior systemic therapies.

[0211] For diffuse large B-cell lymphoma (DLBCL), administration may be via intravenous (IV) infusion. Treatment consists of a step-up dose in cycle 1, weekly doses in cycles 2-4, followed by maintenance doses every 2 weeks until disease progression, e.g., as shown in Table 2 below.

[0212] A single treatment cycle (for DLBCL) consists of 21 days. Cycle 1: Step Up -Odronextamab is administered as a 4-hour infusion. The recommended starting dose of odronextamab is 0.2 mg on day 1. If tolerated, administer 0.5 mg on day 2. If tolerated, administer a 2 mg dose on day 8 and a 2 mg dose on day 9. If tolerated, administer a 10 mg dose on day 15 and a 10 mg dose on day 16. Administer cycle 2 if tolerated. Cycles 2-4: 160m per week g- 160 mg is administered as a 4-hour infusion on day 1 of cycle 2. If tolerated, the infusion time may be reduced to 1 hour for all subsequent doses. Doses of 160 mg are administered on days 1, 8, and 15. Maintenance: 320 mg every 2 weeks -After Cycle 4, odronextamab will be administered as a 1-hour infusion every 2 weeks at a dose of 320 mg. If the patient has been in complete remission for 9 months, a dose of 320 mg will be administered every 4 weeks.

[0213] [Table 2]

[0214] In the indications described above or referred to herein, administration of premedication may be desirable to reduce the risk of cytokine release syndrome (CRS) and / or infusion-related reactions (IRR), as detailed below in Table 3A. Table 3B describes specific options for management of CRS.

[0215] [Table 3]

[0216] [Table 4]

[0217] Premedication may be continued beyond day 8 of cycle 2 until the dose is tolerated without experiencing IRR and / or CRS. Early use of anti-IL6 therapy (e.g., tocilizumab) is recommended for patients over 65 years of age or with comorbidities.

[0218] Combination therapy The present invention provides a method comprising administering a pharmaceutical composition comprising any of the exemplary antibodies (e.g., bispecific antibodies) described herein in combination with one or more additional therapeutic agents. Exemplary additional therapeutic agents that may be combined with or administered in combination with the antigen binding molecules of the present invention include, for example, anti-tumor agents (e.g., chemotherapeutic agents disclosed elsewhere herein). In certain embodiments, the additional therapeutic agent is a regimen that includes radiation therapy or hematopoietic stem cell transplantation. In certain embodiments, the additional therapeutic agent may be an immunomodulatory agent. In certain embodiments, the additional therapeutic agent may be a monoclonal antibody, an antibody drug conjugate, a bispecific antibody conjugated to an anti-tumor agent, an immune checkpoint inhibitor (e.g., PD-1 or CTLA-4, or a combination thereof), or a combination thereof.

[0219] The additional therapeutically active ingredient may be administered immediately prior to, simultaneously with, or immediately following administration of the antigen binding molecule of the present invention (for purposes of this disclosure, such an administration regimen is considered to be administration of the antigen binding molecule "in combination" with the additional therapeutically active ingredient).

[0220] The present invention includes pharmaceutical compositions in which the antigen-binding molecules of the present invention are co-formulated with one or more of the additional therapeutically active ingredients described elsewhere herein.

[0221] array An overview of the sequences and corresponding SEQ ID NOs referred to herein are set forth below in Table 4. Anti-CD33 x anti-CD20 antibodies comprising a heavy chain and a common light chain of SEQ ID NOs: 1-3, a HCVR and a LCVR of SEQ ID NOs: 4-6, and CDRs of SEQ ID NOs: 7-15 are also referred to herein as odronextamab. [Table 5] EXAMPLES

[0222] The following examples are provided to provide those skilled in the art with a complete disclosure and description of how to make and use the methods and compositions of the present invention, and are not intended to limit the scope of what the inventor regards as his invention. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperatures, etc.), but some experimental error and deviation should be allowed for. Unless otherwise indicated, parts are parts by weight, molecular weight is average molecular weight, temperature is degrees Celsius, and pressure is at or near atmospheric pressure.

[0223] Example 1: Clinical evaluation of anti-CD3 x anti-CD20 bispecific antibodies in patients with CD20+ B-cell malignancies This is an open-label, multicenter, dose-escalation study of odronextamab (anti-CD3 × anti-CD20) administered as an IV infusion. The study consists of a dose-escalation part in the B-NHL cohort and a CLL cohort, as well as disease-specific expansion in DLBCL, aggressive lymphoma (excluding prior CAR-T therapy), and follicular lymphoma grade 1-3a after CAR-T failure.

[0224] The treatment period will include 12 weekly (QW) doses, followed by once every two weeks (Q2W) doses until disease progression or other protocol-defined reasons for treatment discontinuation. Furthermore, if a patient demonstrates a complete response (CR) and a sustained response for at least 9 months after initial CR determination, then the frequency of study drug administration at the assigned dose will be reduced from Q2W to every four weeks (Q4W).

[0225] Patients will receive odronextamab at an initial dose of 0.7 mg (administered as 0.2 mg / 0.5 mg split doses) in week 1 of treatment, followed by intermediate dose 1 of 4 mg (administered as 2 mg / 2 mg split doses) in week 2 of treatment, intermediate dose 2 of 20 mg (administered as 10 mg / 10 mg split doses) in week 3 of treatment, then all assigned QW doses in weeks 4-12 of treatment, then Q2W administration. The initial dose (0.7 mg) and intermediate dose 1 of 4 mg, as well as intermediate dose 2 of 20 mg, will always be administered as split infusions over 2 days, preferably consecutively, but no more than 3 days apart, even if administration of these doses is delayed beyond week 3 of treatment. Administration of QW doses will proceed only if the full initial dose and the full intermediate doses 1 and 2 have been received and tolerated. If the patient does not experience grade 3 CRS with the initial and intermediate doses, then from week 4 of treatment onwards, the QW dose of odronextamab will be administered as a single infusion. However, if the patient experiences grade 3 CRS with the initial or intermediate doses, the first QW dose of odronextamab will be administered as a split infusion over 2 days.

[0226] Premedication will be required prior to the start of odronextamab infusion for each fractional initial dose, each fractional intermediate dose, each fractional QW dose (if applicable), and the first administration of the QW dose as a single infusion, and premedication will be administered as detailed in Example 3. If no IRR / CRS of any grade is experienced after the first QW dose administered as a single infusion, the investigator may initiate tapering of dexamethasone premedication over subsequent administrations of odronextamab at the week 5 dose, as detailed in Example 3. Implementation of the use of intensive tocilizumab will be dependent on the rate of Grade 3 or higher CRS events observed at any time point.

[0227] Patients will receive odronextamab QW at their assigned dose during a 4-week run-in period, followed by eight additional QW doses, followed by Q2W treatment at their assigned dose until disease progression or other protocol-defined reasons for discontinuation. If patients experience a CR and have a sustained response for at least 9 months after initial CR determination, the frequency of study drug administration at their assigned dose will be reduced from a Q2W interval to a Q4W interval. Patients must have received a full dose of Q2W for at least three prior doses before switching from Q2W to Q4W dosing.

[0228] Selection Criteria

[0229] Patients must meet the following criteria to be eligible for enrollment in the study: 1. Patients with a documented CD20+ B-cell malignancy with active disease unresponsive to previous therapy, for which no standard treatment options exist and for whom treatment with an anti-CD20 antibody may be appropriate. B-NHL confirmed by the NCI Working Group Criteria 2007 CLL as defined by the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) Working Group Criteria 2008 - Patients with small lymphocytic lymphoma (SLL) will be enrolled in the CLL arm and will follow the B-NHL evaluation. NOTE: Patients who have had a CD20 negative lymph node (NHL) biopsy performed as standard of care immediately prior to enrollment are still eligible for the study if they have previously had documented CD20+ disease and have been previously treated with rituximab or other CD20-targeted antibody therapy within approximately 6 months. 2. B-NHL patients must have had prior treatment with an anti-CD20 antibody therapy. CLL patients do not need to have had prior treatment with an anti-CD20 antibody therapy if the patient has failed either a BTK inhibitor or a PI3K inhibitor, as well as if the treating physician deems it appropriate to enroll the patient in a Phase 1 trial. Refractory is defined as failure to respond (SD / PD) or relapse within 6 months of last treatment. To be included in the expansion cohort for FL grades 1-3a, patients must have received at least two prior lines of systemic therapy, including an anti-CD20 antibody and an alkylating agent. Patients must have failed the combination of lenalidomide + rituximab if approved or not suitable to receive this treatment according to the investigator. To be included in disease-specific expansion cohorts enrolling DLBCL patients after CAR-T failure, patients must have recovered from the toxicities of lymphodepleting therapy and CAR-T infusion. The prior CAR-T therapy does not have to be the most recent line of therapy prior to study enrollment. Patients with aggressive lymphoma assigned to the aggressive lymphoma expansion cohort must have received at least one prior line of treatment consisting of an anti-CD20 antibody. Patients who received prior CAR-T therapy will not be included in this cohort. Lymphoma patients eligible for the expanded aggressive lymphoma cohort included the following subtypes based on the WHO classification: -DLBCL Not otherwise specified (NOS) -Germline centered B cell type -Activated B cell type (Note: DLBCL includes both de novo DLBCL and transformed DLBCL arising from indolent lymphoma / CLL.) -Primary mediastinal (thymic) large B-cell lymphoma -T-cell / histiocytic-rich large B-cell lymphoma -Epstein-Barr virus (EBV)+ type DLBCL, NOS - High-grade B-cell lymphoma with MYC and BCL2 and / or BCL6 rearrangements -High-grade B-cell lymphoma, NOS -Unclassifiable B-cell lymphoma with features intermediate between DLBCL and classical Hodgkin lymphoma -Follicular lymphoma, grade 3b 3. All patients (B-cell NHL and CLL) must have at least one bidimensionally measurable lesion ≥ 1.5 cm (longest diameter) documented by CT scan or MRI scan if CT scan is not feasible. 4. CLL patients must have white blood cells (WBC) ≤ 200 x 109 / L. As of revision 16 of the protocol, enrollment of CLL patients is closed. 5. Age ≥ 18 years 6. Eastern Cooperative Oncology Group (EOCG) Performance Status ≦1 7. Life expectancy of at least 6 months 8. Adequate bone marrow function documented as follows: A platelet count ≥ 75 x 10 9 / L B. Hb level ≥ 9 g / dL c. ANC ≥ 1 × 10 9 / L NOTE: Patients with cell counts below the thresholds mentioned above may be considered for enrollment if, in the investigator's opinion, this is attributable to bone marrow infiltration or splenic cell pooling due to the underlying disease. Patients with bone marrow disease or splenic pools must meet the following hematological parameters: Platelet count ≥ 25 × 109 / L. Patients were not required to have received platelet transfusion therapy within 3 days prior to receiving the first dose of odronextamab to meet the platelet eligibility criteria. Hemoglobin ≥ 7.0g / dL Absolute neutrophil count (ANC) ≥ 0.5 × 109 / L. Patients must not have received granulocyte colony-stimulating factor within 2 days prior to the first dose of odronextamab to meet the ANC eligibility criteria. 9. Adequate organ function documented as follows: Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN Total bilirubin ≦1.5×ULN NOTE: Gilbert syndrome patients do not need to meet this requirement if total bilirubin is unchanged from baseline. Creatinine clearance calculated by Cockcroft-Gault ≥ 50 mL / min NOTE: Patients may be considered for enrollment if, in the opinion of the investigator, abnormal laboratory results are attributable to an underlying disease. NOTE: Patients with borderline creatinine clearance by Cockcroft-Gault may be considered for enrollment if their measured creatinine clearance (based on 24-h urine or other reliable methods) is ≥ 50 mL / min. 10. Willing to undergo mandatory tumor biopsy prior to treatment if, in the opinion of the Investigator, the patient has accessible lesions that can be biopsied without significant risk to the patient. 11. Willing and able to comply with clinic and study-related procedures. 12. Provide signed informed consent or a legally acceptable alternative.

[0230] Exclusion criteria

[0231] Patients meeting any of the following criteria will be excluded from the study: 1. Primary central nervous system (CNS) lymphoma or known or suspected CNS disease due to non-primary CNS NHL. 2. History of or current association with CNS pathology, such as: Epilepsy, seizures, paralysis, aphasia, stroke, severe brain injury, cerebellar disease, organic brain syndrome, psychiatric disorder, or Evidence of inflammatory lesions and / or vasculitis on brain MRI 3. Standard antineoplastic chemotherapy (non-biologic) within 5 half-lives or 28 days, whichever is shorter, prior to the first dose of investigational drug. 4. Standard radiotherapy within 14 days of first dose of study drug. NOTE: Symptomatic radiation therapy to symptomatic nodes / lesions is acceptable if the irradiated lesion or lymph node is not included as a target lesion in the tumor evaluation. 5. Allogeneic stem cell transplantation. 6. Treatment with rituximab, alemtuzumab, or other investigational or marketed biologics within 12 weeks prior to the first dose of investigational drug. NOTE: For patients with aggressive lymphoma requiring immediate treatment, the washout period may be shortened to 28 days. 7. Immunosuppressive therapy (other than biologic) within 28 days of first dose of investigational drug. 8. Treatment with a non-biologic investigational agent within 28 days of the first dose of investigational drug. 9. History of allergic reactions due to compounds of similar chemical or biological composition to the investigational drug. 10. History of hypersensitivity to any compound in the tetracycline antibiotic group. 11. Concurrent active malignancy for which the patient is receiving treatment. 12. Known active bacterial, viral, fungal, mycobacterial, or other infection, or any major episode of infection requiring hospitalization or treatment with IV anti-infectives within 4 weeks of the first dose. 13. Evidence of any significant comorbidity or medical condition that may interfere with study performance or place the patient at significant risk, including, but not limited to, significant cardiovascular disease (e.g., New York Heart Association class III or IV heart disease, myocardial infarction within the past 6 months, unstable arrhythmia or unstable angina pectoris) and / or significant pulmonary disease (e.g., history of obstructive pulmonary disease and symptomatic bronchospasm). NOTE: Patients with a history of cardiac disease should be evaluated by ECHO or multi-gated acquisition scan (MUGA) prior to the first dose of odronextamab to ensure adequate cardiac reserve and function. 14. Ongoing systemic corticosteroid treatment, excluding use of corticosteroids for other (non-oncology and non-immunosuppressive) indications, with a maximum of 10 mg / day of prednisone or equivalent. 15. Human immunodeficiency virus (HIV) infection or chronic infection with hepatitis B virus (HBV) or hepatitis C virus (HCV). Patients with controlled hepatitis B (HepBsAg+) infection (undetectable serum hepatitis B DNA and receiving antiviral therapy for hepatitis B) are permitted with consultation with the physician managing their infection. 16. Known hypersensitivity to both allopurinol and rasburicase. 17. Pregnant or lactating women. 18. Females of childbearing potential who are unwilling to practice highly effective contraception prior to their first study drug treatment, throughout the study, and for at least 6 months after the last dose.* Highly effective contraception includes stable use of combined (estrogen- and progesterone-containing) hormonal contraception (oral, intravaginal, transdermal) or progesterone-only hormonal contraception (oral, injectable, implantable) associated with ovulation inhibition, intrauterine device, intrauterine hormone-releasing system, bilateral tubal ligation, partner vasectomy, and sexual abstinence, initiated for at least 2 menstrual cycles prior to screening†,‡. *Postmenopausal women must be amenorrhea for at least 12 months to not be considered fertile. Pregnancy testing and contraception are not required for women with documented hysterectomy or tubal ligation. †Sexual abstinence is considered to be highly effective only if it is defined as abstinence from heterosexual intercourse for the entire period of risk associated with study treatment. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the patient's preferred usual lifestyle. ‡Periodic abstinence (calendar, symptom-temperature, and postovulatory methods), withdrawal (withdrawal), spermicide only, and lactational amenorrhea method (LAM) are not acceptable methods of contraception. Female and male condoms should not be used together. 19. Receipt of live vaccination within 28 days of first dose of investigational product.

[0232] [Table 6]

[0233] Example 2: Clinical evaluation of anti-CD3 x anti-CD20 bispecific antibodies in patients with relapsed or refractory B-cell non-Hodgkin's lymphoma This is a phase 2, open-label, multi-cohort, multicenter study of odronextamab (anti-CD3 × anti-CD20) administered as an IV infusion in patients with B-NHL that has relapsed after or is refractory to prior systemic therapy. The study consists of five disease-specific cohorts, each with independent parallel enrollment. Patients in the DLBCL cohort were randomized 1:1 to either arm 1 or arm 2 in the initial step of this cohort, with two different odronextamab dosing regimens. Cohort assignment was based on the patient's diagnosis and treatment history at the time of study enrollment.

[0234] The treatment period included 12 weekly doses followed by every 2 weeks (Q2W) doses until disease progression or other protocol-defined reasons for treatment discontinuation. In addition, if a patient experienced a CR and a sustained response for at least 9 months after the initial CR determination, the frequency of study drug administration at the assigned dose was then reduced from Q2W to once every 4 weeks (Q4W) intervals based on the local investigator's assessment. Patients were required to have received the full (nominal) dose of the assigned QW dose on the Q2W dosing schedule for at least the three prior doses before switching from Q2W to Q4W dosing.

[0235] Odronextamab was administered intravenously (IV) as a single agent at an initial divided dose of 0.7 mg (0.2 / 0.5 mg), followed by an interim divided dose of 4 mg 1, followed by an interim divided dose of 20 mg 2. Thereafter, dosing in each disease-specific cohort was as follows: FL grade 1–3a cohort: 80 mg QW followed by 160 mg Q2W DLBCL Cohort 1: 160mg QW followed by 320mg Q2W DLBCL cohort 2: 320mg QW followed by 320mg Q2W MCL after BTK inhibitor therapy: 160mg QW followed by 320mg Q2W MZL: 80mg QW followed by 160mg Q2W Other B-NHL: 160mg QW followed by 320mg Q2W

[0236] Patients in the DLBCL cohort were randomized 1:1 to either Arm 1 or Arm 2 in the initial step of this cohort with two different odronextamab dosing regimens. Patients in Arm 1 received a total dose of 160 mg QW followed by 320 mg Q2W. Patients in Arm 2 received a total dose of 320 mg QW followed by 320 mg Q2W.

[0237] The study population for each of the five separate independent registered disease-specific cohorts consisted of: FL grade 1-3a cohort: Patients with FL that has relapsed or is refractory to at least two prior lines of systemic therapy including anti-CD20 antibodies and alkylating agents. Patients had to have failed lenalidomide plus rituximab combination therapy if approved or not considered appropriate to receive this treatment according to the investigator. DLBCL cohort: Patients with DLBCL that are relapsed or refractory to at least two prior lines of systemic therapy, including anti-CD20 antibodies and alkylating agents. Patients with de novo DLBCL, or DLBCL transformed from a lower grade neoplasm (e.g., FL or CLL) may be enrolled. Patients with DLBCL transformed from prior CLL may only be enrolled in the absence of a leukemic CLL component. For patients with transformed DLBCL, prior systemic therapy administered for a lower grade neoplasm among prior lines of therapy shall not be considered for purposes of determining eligibility. · MZL cohort: Patients with MZL that has relapsed or is refractory to at least two prior lines of systemic therapy. Other B-NHL cohort: Patients with other B-NHL subtypes (excluding WM, SLL, CLL, Burkitt lymphoma, and Burkitt-like lymphoma with 11q aberration) who have relapsed or are refractory to at least two prior lines of systemic therapy. Post-BTK Inhibitor MCL Cohort: Patients with MCL who have failed prior Bruton's tyrosine kinase (BTK) inhibitor therapy.

[0238] The initial dose (0.7 mg [0.2 / 0.5 mg]), 4 mg intermediate dose 1, and 20 mg intermediate dose 2 were always administered as split infusions over 2 days, and if these doses were delayed beyond the third week of treatment, they were preferably consecutive but no more than 3 days apart. Administration of the full QW dose (nominal) proceeded only if the full initial dose and the full intermediate doses 1 and 2 had been received and tolerated.

[0239] All QW doses of odronextamab were administered as a single infusion in patients who did not experience grade 3 cytokine release syndrome (CRS) with the initial dose, intermediate dose 1, and intermediate dose 2. Patients received all initial doses before intermediate dose 1, patients received all intermediate doses 1 before intermediate dose 2, and all intermediate doses 2 before receiving any single infusion. Dosing beyond week 4 of treatment, odronextamab was administered as a single infusion.

[0240] When administration of the first full QW dose as a single infusion was tolerated, subsequent doses were administered as single infusions over 1 to 4 hours depending on previous tolerance.

[0241] Treatment duration included 12 QW doses followed by Q2W dosing until disease progression or other protocol-defined reasons for treatment discontinuation. In addition, if a patient experienced a CR and a sustained response for at least 9 months after the initial CR determination, the frequency of study drug administration at the assigned dose was then reduced from a Q2W to a Q4W interval based on the local investigator's assessment. Patients were required to have received the full assigned QW dose on a Q2W dosing schedule for at least three prior doses before switching from Q2W to Q4W dosing. Patients were followed for efficacy until disease progression or initiation of non-protocol antilymphoma therapy.

[0242] Selection Criteria

[0243] Patients must meet the following criteria to be eligible for enrollment in the study: 1. Age 18 or older 2.FL grade 1-3a cohort only: Central histopathological confirmation of a diagnosis of FL grade 1-3a must be obtained prior to study enrollment. Patients with FL grade 3b are ineligible for this cohort but may be included in the "other B-NHL" cohort. Follicular lymphoma subtyping will be based on the World Health Organization (WHO) classification. 3.Disease-specific cohorts: Patients must require systemic therapy for lymphoma at the time of study entry, in the opinion of the investigator, and be deemed unsuitable for other approved therapies with established benefit for that indication. Refractory is defined as failure to respond (SD / PD) or relapse within 6 months of last treatment. FL grade 1-3a cohort: Patients with FL grade 1-3a that have relapsed after or are refractory to at least two prior lines of systemic therapy including anti-CD20 antibodies and alkylating agents. Patients must have failed lenalidomide and rituximab combination therapy if approved to receive this treatment or not considered appropriate according to the investigator. DLBCL cohort: Patients with DLBCL who have relapsed after or are refractory to at least two prior lines of systemic therapy, including anti-CD20 antibodies and alkylating agents. Patients with de novo DLBCL or DLBCL transformed from a lower grade neoplasm (e.g., FL or CLL) may be enrolled. Patients with DLBCL transformed from prior CLL may only be enrolled in the absence of a leukemic CLL component. For patients with transformed DLBCL, prior systemic therapy administered for a lower grade neoplasm among prior lines of therapy shall not be considered for purposes of determining eligibility. The following subtypes based on the WHO classification are eligible: -DLBCL Not otherwise specified (NOS) -Germline centered B cell type -Activated B cell type · MCL after BTK inhibitor therapy cohort: Patients with MCL who have failed prior Bruton's tyrosine kinase (BTK) inhibitor therapy. · MZL cohort: Patients with MZL who have relapsed or are refractory to at least two prior lines of systemic therapy. The following subtypes based on the WHO classification are eligible: -Extranodal MZL of mucosa-associated lymphoid tissue (MALT lymphoma) -Nodal marginal zone lymphoma -Splenic marginal zone lymphoma · Other B-NHL cohort: Patients with B-NHL other than FL grade 1-3a, DLBCL, MCL, or MZL that has relapsed or is refractory to at least two prior lines of systemic therapy. WHO The following subtypes based on classification are eligible: -Primary mediastinal (thymic) large B-cell lymphoma -T-cell / histiocytic-rich large B-cell lymphoma -Epstein-Barr virus (EBV)+ type DLBCL, NOS - High-grade B-cell lymphoma with MYC and BCL2 and / or BCL6 rearrangements -High-grade B-cell lymphoma, NOS -Unclassifiable B-cell lymphoma with features intermediate between DLBCL and classical Hodgkin lymphoma -Follicular lymphoma, grade 3b Patients with Waldenström's macroglobulinemia (WM, lymphoplasmacytic lymphoma), small lymphocytic leukemia (SLL), and chronic lymphocytic leukemia (CLL), Burkitt lymphoma, and Burkitt-like lymphoma with 11q aberration are excluded. 4. Measurable disease on cross-sectional imaging (defined as at least one bidimensionally measurable nodular lesion ≥1.5 cm in maximum transverse diameter (GTD) regardless of short-axis diameter) documented by diagnostic imaging (computed tomography [CT], or magnetic resonance imaging [MRI]). 5. Eastern Cooperative Oncology Group (EOCG) Performance Status: 0 or 1 6. Adequate bone marrow function documented as follows: A platelet count ≥ 50 x 10 9 / L. Patients were not required to have received platelet transfusion therapy within 7 days prior to receiving the first dose of odronextamab to meet the platelet eligibility criteria. B. Hemoglobin ≥ 9.0 g / dL Absolute neutrophil count (ANC) ≥ 1.0 x 10 9 / L. Patients were not required to have received granulocyte-colony stimulating factor within 2 days prior to the first dose of odronextamab to meet ANC eligibility criteria. Patients with bone marrow disease or splenic pools must meet the following hematological parameters: Platelet count ≥ 25 × 10 9 / L. Patients were not required to have received platelet transfusion therapy within 3 days prior to receiving the first dose of odronextamab to meet the platelet eligibility criteria. -Hemoglobin ≥ 7.0g / dL Absolute neutrophil count (ANC) ≥ 0.5 x 10 9 / L. Patients were not required to have received granulocyte-colony stimulating factor within 2 days prior to the first dose of odronextamab to meet ANC eligibility criteria. 7. Proper Liver Function: Total bilirubin ≤ 1.5 x upper limit of normal (ULN) (≤ 3 x ULN if due to lymphoma infiltration of the liver) b. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x ULN (≤ 5 x ULN if due to lymphoma infiltration of the liver) c. Alkaline phosphatase (ALP) ≤ 2.5 x ULN (≤ 5 x ULN if caused by lymphoma infiltration of the liver) Note: Patients with total bilirubin >1.5xULN and simultaneously AST >2.5xULN and / or ALT >2.5xULN, regardless of the presence of lymphomatous infiltration of the liver, will be excluded. Patients with known Gilbert's syndrome will be excluded if their total bilirubin level is >4 × the upper limit of normal (ULN) for the local general population. 8. Serum creatinine ≤ 1.5 × ULN or creatinine clearance ≥ 50 mL / min calculated by the Cockcroft-Gault equation. NOTE: Patients with a calculated creatinine clearance <50 mL / min may be considered for enrollment if their measured creatinine clearance (based on a 24-h urine collection or other reliable method) is ≥50 mL / min. 9. Willingness to undergo a tumor biopsy at baseline. If the Investigator determines that a baseline tumor biopsy cannot be safely obtained, the Sponsor may grant an exception to the biopsy requirement only after consultation with and approval by the Medical Monitor. 10. Ability to understand the purpose and risks of the clinical trial and provide signed and dated informed consent and permission to use protected health information (in accordance with national and local subject privacy regulations). 11. Willing and able to comply with clinic and study-related procedures. 12. Provide informed consent signed by the study patient or legally acceptable representative. 13. Able to understand and complete clinical trial-related questionnaires.

[0244] Exclusion criteria

[0245] Patients who meet any of the following criteria will be excluded from the study. 1. Primary central nervous system (CNS) lymphoma or known complications from non-primary CNS NHL (suspected CNS lymphoma should be evaluated by mandatory head CT or MRI plus lumbar puncture as indicated). 2. Treatment with any systemic anti-lymphoma therapy within 5 half-lives or 28 days prior to the first dose of investigational drug, whichever is shorter. 3. History of allogeneic stem cell transplantation. 4. Previous treatment with any chimeric antigen receptor T cell (CAR-T) therapy. 5. Continuous systemic corticosteroid treatment with >10 mg per day of prednisone or anti-inflammatory equivalent within 72 hours prior to starting study drug. 6. History of neurodegenerative conditions or CNS movement disorders. Patients with a history of seizures within 12 months prior to study enrollment will be excluded. 7. Vaccination with a replication-competent vector within 28 days prior to the first study drug administration. 8. Another malignancy other than B-NHL within the last 5 years, except for non-melanoma skin cancer or non-invasive cervical cancer that has undergone potentially curative therapy, or any other tumor considered to have been effectively treated with curative intent with definitive local control. 9. Evidence of any significant comorbidity or medical condition that may interfere with study performance or place the patient at significant risk, including, but not limited to, significant cardiovascular disease (e.g., New York Heart Association class III or IV heart disease, myocardial infarction within the past 6 months, unstable arrhythmia or unstable angina pectoris) and / or significant pulmonary disease (e.g., history of obstructive pulmonary disease and symptomatic bronchospasm). 10. Cardiac output fraction <40% by echocardiogram or multi-gated acquisition (MUGA) scan. 11. Any infection requiring hospitalization or IV administration of anti-infectives within 2 weeks of first dose of study drug. 12. Uncontrolled infection with human immunodeficiency virus (HIV), hepatitis B, or hepatitis C infection, or other uncontrolled infection. a. HIV patients with controlled infection (either naturally occurring or on a stable antiviral regimen, with an undetectable viral load and a CD4 count greater than 350 cells / microliter) are permitted. b. Patients with hepatitis B whose infection is controlled (HepBsAg+) (serum hepatitis B DNA polymerase chain reaction [PCR] undetectable and receiving antiviral therapy for hepatitis B) are permitted. Patients who are hepatitis C virus antibody positive (HCV Ab+) and have controlled infection (HCV RNA undetectable by PCR, either spontaneously or in response to a previous successful course of anti-HCV therapy) are admitted. 13. History of severe allergic reaction due to compounds with a chemical or biological composition similar to that of the investigational drug or excipients. A severe allergic reaction is defined for this purpose as requiring hospitalization and / or treatment with epinephrine. 14. Known hypersensitivity to both allopurinol and rasburicase. 15. Women of childbearing potential (WOCBP) with a positive serum β-hCG pregnancy test are ineligible for this study. 16. Pregnant or lactating women. 17. Females* or males of childbearing potential who are not willing to use highly effective contraception prior to first dose / initiation of first treatment, throughout the study, and for at least 6 months after the last dose. Sperm donation is prohibited during the study and for 6 months after the last dose of investigational product. Highly effective methods of contraception include: Stable use of a combined (estrogen- and progesterone-containing) hormonal contraceptive method associated with the inhibition of ovulation (oral, intravaginal, transdermal) or a progesterone-only hormonal contraceptive method (oral, injectable, implantable) initiated for at least two menstrual cycles prior to screening, b. Intrauterine devices (IUDs), intrauterine hormone-releasing systems (IUS), C. tubal ligation, d. Vasectomy of a partner (provided that the vasectomized male partner is the study participant's only sexual partner and that this partner has received a medical evaluation of the surgical success of the procedure); e. and / or sexual abstinence † , ‡ . *Women of childbearing potential are defined as women who are fertile after menarche until postmenopause, unless permanently infertile. Permanent methods of contraception include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. Postmenopausal status is defined as the absence of menstruation for 12 months without alternative medical causes. Elevated follicle-stimulating hormone (FSH) levels within the postmenopausal range may be used to establish postmenopausal status in women who do not use hormonal contraception or hormone replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient to determine the occurrence of postmenopausal status. The above definition follows guidance from the Clinical Trial Facilitation Group (CTFG). Pregnancy testing and contraception are not required for women with documented hysterectomy or tubal ligation. † Sexual abstinence is considered to be highly effective only if it is defined as abstinence from heterosexual intercourse for the entire period of risk associated with the investigational drug. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the patient's preferred usual lifestyle. ‡ Periodic abstinence (calendar, symptom-temperature, or postovulatory methods), withdrawal (withdrawal), spermicide only, and lactational amenorrhea method (LAM) are not acceptable methods of contraception. Female and male condoms should not be used together. 18. Previous treatment with anti-CD20 × anti-CD3 bispecific therapy.

[0246] [Table 7]

[0247] Follicular lymphoma outcomes

[0248] As discussed herein, odronextamab is a hinge-stabilized human IgG4-based CD20xCD3 bispecific antibody that binds CD20 on B cells and CD3 on T cells, inducing T cell-mediated cytotoxicity of malignant B cells. In a phase I study (discussed in Example 4), FL grade 1-3a patients who received two or more prior lines of therapy and were treated with odronextamab doses of 5 mg or more had an ORR of 91% and a CR rate of 72%. Responses were durable, with a 4-year progression-free survival (PFS) of 54%. The phase II dose in R / R FL patients was determined as 80 mg per week. Below are the results of a preliminary analysis of the FL grade 1-3a cohort of the phase II study, which incorporated a step-up regimen designed to maintain efficacy while minimizing acute toxicities, including cytokine release syndrome (CRS).

[0249] The phase II study enrolled adult patients with FL grades 1-3a who had relapsed or were refractory to two or more prior lines of therapy, including anti-CD20 antibodies and alkylating agents. Odronextamab was administered IV in 21-day cycles with steroid prophylaxis and weekly step-up dosing during cycle 1 (C1) to reduce the risk of acute toxicity. The initial step-up regimen consisted of 1 mg in divided doses across days 1 (D1) and C1D2 of C1, and 20 mg in divided doses across C1D8 and C1D9, followed by a total dose of 80 mg on C1D15 (1 / 20 regimen). The 1 / 20 regimen was revised during the study to further reduce CRS risk by adding an intermediate step-up dose. The modified regimen consisted of 0.7 mg in divided doses on C1D1 (0.2 mg) and C1D2 (0.5 mg), 4 mg in divided doses on C1D8 and C1D9, and 20 mg in divided doses on C1D15 and C1D16, followed by a total dose of 80 mg on C2D1 (0.7 / 4 / 20 regimen). 80 mg weekly was continued until the end of C4. After C4, maintenance treatment was with odronextamab 160 mg every 2 weeks until disease progression or unacceptable toxicity. The primary endpoint was ORR assessed by independent central review (ICR) according to the Lugano 2014 criteria. CRS was assessed using the 2019 ASTCT criteria.

[0250] As of April 20, 2022, 96 patients were evaluable for safety and 85 for efficacy. Median age was 59 years (range 22-84), 52% were male, 58% had FLIPI 3-5, 15.6% had bulky disease, and median number of prior lines of therapy was 3 (range 2-13). 74% were refractory to last therapy, 79% were refractory to prior anti-CD20 therapy, and 48% had disease progression within 2 years (POD24). Median follow-up: 17.3 months. ORR and CR rates confirmed by ICR were 81% (69 / 85) and 75% (64 / 85), respectively. ORR and CR rates were consistent across high-risk subgroups, including patients aged 65 years or older, POD24, FLIPI 3-5, and those refractory to last line of therapy, and ORR and CR rates were consistent in the subgroup of patients treated with the 0.7 / 4 / 20 step-up regimen. Responses were durable, with both median response and CR durations of 18.2 months. Median PFS was 20.2 months, and median OS was not reached (95% CI 23.0 months to not estimable).

[0251] TEAEs occurred in 95 patients (99%), with 86 (90%) considered treatment-related. In the entire safety-evaluable population, the most common TEAEs (>30% of all grades) were CRS (51%), pyrexia (32%), anemia (31%), and infusion-related reactions (31%). After implementation of the 0.7 / 4 / 20 step-up regimen in C1, grade 1 CRS was observed in 39% of patients, and no grade ≥2 CRS was reported. All CRS events resolved, and only one patient received tocilizumab for CRS management. No ICANS were reported after the revised step-up dosing compared with 3% for the 1 / 20 regimen. Treatment-related grade 5 AEs were reported for 2 patients (2%), and treatment-related AEs led to discontinuation in 6 patients (6%).

[0252] Consistent with the phase I study, in the phase II study, odronextamab exhibited convincing efficacy in patients with FL grade 1–3a who had received two or more prior lines of therapy, with 75% of patients achieving a confirmed CR by ICR. The durability of response and favorable survival outcome are clinically relevant in the setting of heavily pretreated, high R / R FL, where prognosis is typically poor. The overall tolerability profile with the 0.7 / 4 / 20 step-up regimen was favorable, with only grade 1 CRS observed during C1.

[0253] Outcome of diffuse large B-cell lymphoma

[0254] As discussed herein, odronextamab is a hinge-stabilized human IgG4-based CD20xCD3 bispecific antibody that binds CD20 on B cells and CD3 on T cells, inducing T cell-mediated cytotoxicity of malignant B cells. In a Phase I study (discussed in Example 4), odronextamab showed promising activity in DLBCL patients who had received two or more prior lines of therapy. DLBCL patients treated with odronextamab at doses of 80 mg or higher had an ORR of 53% and a CR rate of 53%. Responses were durable, with an 88% probability of ongoing response at 12 months. The Phase II dose for expansion in R / R DLBCL patients was determined to be 160 mg per week. Below are the results of a preliminary analysis of the 160 mg DLBCL cohort of the Phase II study, which incorporated a step-up regimen designed to maintain efficacy while minimizing acute toxicities, including cytokine release syndrome (CRS).

[0255] The phase II study enrolled adult patients with DLBCL who had relapsed or were refractory to two or more prior lines of therapy, including anti-CD20 antibodies and alkylating agents. Odronextamab was administered IV in 21-day cycles with steroid prophylaxis and weekly step-up dosing during cycle 1 (C1) to reduce the risk of acute toxicity. The initial step-up regimen consisted of 1 mg in divided doses across days 1 (D1) and C1D2 of C1, and 20 mg in divided doses across C1D8 and C1D9, followed by a total dose of 160 mg on C1D15 (1 / 20 regimen). The 1 / 20 regimen was revised during the study to further reduce CRS risk by adding an intermediate step-up dose. The modified regimen consisted of 0.7 mg in divided doses on C1D1 (0.2 mg) and C1D2 (0.5 mg), 4 mg in divided doses on C1D8 and C1D9, and 20 mg in divided doses on C1D15 and C1D16, followed by a total dose of 160 mg on C2D1 (0.7 / 4 / 20 regimen). Weekly 160 mg was continued until the end of C4. After C4, maintenance treatment was with odronextamab 320 mg every 2 weeks until disease progression or unacceptable toxicity. The primary endpoint was ORR assessed by independent central review (ICR) according to the Lugano 2014 criteria. CRS was assessed using the 2019 ASTCT criteria.

[0256] As of April 20, 2022, 121 patients with DLBCL were evaluable for safety and 90 for efficacy. Median age 67 years (range 24-88), 60% male, 80% Ann Arbor stage III-IV, 58% IPI score ≥3, median 2 prior lines of therapy (range 2-8). 56% were primary refractory and 65% were double refractory. Median follow-up study duration: 17.1 months. ORR and CR rates confirmed by ICR were 53% (48 / 90) and 37% (33 / 90), respectively. ORR and CR rates were consistent across high-risk subgroups as well as in the subgroup treated with the 0.7 / 4 / 20 step-up regimen. CR was durable, with the median CR duration not reached (95% CI: 10.2 months to not estimable), and the probability of ongoing CR at 9 months was 70%.

[0257] TEAEs occurred in 117 patients (97%), with 102 (84%) considered treatment-related. In the entire safety-evaluable population, the most common TEAEs (all grades >30%) were CRS (53%), pyrexia (41%), and anemia (34%). No grade 3 or higher CRS events were observed after implementation of the 0.7 / 4 / 20 step-up regimen in C1. Only grade 1 and 2 CRS were observed in 35% and 13% of DLBCL patients, respectively. All CRS events resolved with supportive measures, 20% of patients received tocilizumab, and neither vasopressors nor mechanical ventilation were required for CRS management. ICANS were reported in only 2 patients (3%) after revision of the step-up regimen, both of which were low grade, and ICANS occurred in 6% of patients with the 1 / 20 regimen. Treatment-related grade 5 AEs occurred in 2 patients (2%), and treatment-related AEs led to discontinuation of odronextamab in 8 patients (7%).

[0258] In a phase II study, odronextamab demonstrated clinically meaningful efficacy, durable CR, and a favorable safety profile in a difficult-to-treat, aggressive R / R DLBCL patient population. Overall, the results of this phase 2 study confirm the activity observed in phase I, demonstrating that odronextamab has compelling activity both before and after CAR-T therapy and a tolerable safety profile.

[0259] The step-up dosing regimen of 0.7 / 4 / 20 odronextamab for C1 reduces the risk of high-grade CRS, which has been consistently observed with other bispecific and CAR-T therapies. Moreover, only low-grade ICANS has been reported with the 0.7 / 4 / 20 regimen.

[0260] Example 3: Premedication Applied for IV Administration of Odronextamab The following premedication is applied to odronextamab administration from the first dose through the first once weekly (QW) dose administration as a single infusion, as discussed in the Examples herein.

[0261] If a patient experiences any grade infusion-related reaction (IRR) and / or cytokine release syndrome (CRS) with the first QW dose, premedication should be continued until all QW doses are tolerated without IRR or CRS. 1. For each odronextamab dose administered on non-consecutive days, 12 to 24 hours prior to the scheduled start of the first fractional infusion and 12 to 24 hours prior to the scheduled start of the second fractional infusion: Dexamethasone 20 mg PO or equivalent dose of steroids 2. Premedication on each day of odronextamab split infusions and on the day of administration of the full dose QW as a single infusion: a. Dexamethasone 20 mg IV 1-3 hours before the start of the infusion on the day of treatment b. Diphenhydramine 25 mg IV or PO 30 to 60 minutes prior (may be substituted with another equivalent antihistamine) c. Acetaminophen 650 mg PO 30-60 minutes prior to odronextamab infusion, unless the patient has received it within the past 4 hours or is allergic to acetaminophen 3. 24 (± 4) hours from the end of the second split infusion or 24 (± 4) hours from the end of the first QW full dose as a single infusion: Dexamethasone 20 mg PO or equivalent dose of steroids

[0262] First dose administered after full dose administered QW as a single infusion without experiencing any grade IRR and / or CRS with 20 mg dexamethasone IV: a. Dexamethasone 10 mg IV 1-3 hours before the start of the infusion on the day of treatment b. Diphenhydramine 25 mg IV or PO 30 to 60 minutes prior (may be substituted with another equivalent antihistamine) c. Acetaminophen 650 mg PO 30-60 minutes prior to odronextamab infusion, unless the patient has received it within the past 4 hours or is allergic to acetaminophen

[0263] For subsequent doses, no premedication is required if a single infusion of reduced dexamethasone 10 mg IV is tolerated without any grade IRR and / or CRS.

[0264] For anti-IL6 therapy (eg, tocilizumab), 8 mg / kg is infused over 1 hour, with the dose not to exceed 800 mg.

[0265] Example 4: Human CD20xCD3 Bispecific Antibody Odronextamab in Relapsed or Refractory B-Cell Non-Hodgkin's Lymphoma Odronextamab is a hinge-stabilized fully human IgG4-based CD20xCD3 bispecific antibody that binds to CD3+ T cells and malignant B cells. Below are findings from a first-in-human study of odronextamab in patients with relapsed / refractory (R / R) B-cell non-Hodgkin lymphoma (B-NHL):

[0266] This phase 1 study enrolled patients with CD20-positive relapsed / refractory (R / R) B-cell malignancies previously treated with a CD20-targeted antibody therapy. Eligible patients aged 18 years or older and with an ECOG performance status ≤1 received odronextamab intravenously, consisting of a step-up dose in cycle 1, followed by weekly treatment at target dose levels ranging from 0.1 to 320 mg in cycles 2-4. Maintenance treatment was given every 2 weeks until progression. Primary endpoints were safety, pharmacokinetics, and maximum tolerated dose, as well as preliminary antitumor activity.

[0267] A total of 145 patients were enrolled (n=94 for dose escalation and n=51 for dose expansion). Patients had received a median of 3 (range: 1-11) prior lines of therapy, 42 (29.0%) had previously received chimeric antigen receptor (CAR) T-cell therapy, and 119 (82.1%) were refractory to their last line of therapy. Median follow-up was 4.2 months (interquartile range 1.6-11.5). During dose escalation, odronextamab was administered weekly at a maximum dose of 320 mg, and no dose-limiting toxicities were observed. For dose expansion in patients with R / R follicular lymphoma (FL) grade 1-3a, the recommended dose of odronextamab 80 mg was selected, and for expansion in patients with R / R diffuse large B-cell lymphoma (DLBCL), odronextamab 160 mg was selected. The most common adverse events were fever, cytokine release syndrome (CRS), chills, anemia, and fatigue. CRS and neurotoxicity were mostly low grade and did not lead to treatment discontinuation.

[0268] The objective response rate (ORR) for patients with all B-NHL subtypes treated with odronextamab across all doses was 51%, with 37% having a complete response. In patients with FL 1-3a treated with odronextamab doses ≥5 mg (n=32), the ORR was 91%, with 72% having a complete response. In patients with DLBCL without prior CAR T treated with odronextamab doses ≥80 mg (n=15), the ORR was 53%, with all of them having a complete response. In patients with DLBCL with prior CAR T treated with odronextamab doses ≥80 mg (n=30), the ORR was 33%, with 27% having a complete response. Durability of responses was observed in FL1–3a patients, DLBCL patients not treated with CAR T, and DLBCL patients who had previously received CAR T, with 60%, 88%, and 100% ongoing complete responses at 12 months, respectively.

[0269] Study Design and Treatment

[0270] Patients were eligible for enrollment if they were aged 18 years or older with documented B-NHL, had at least one measurable lesion, had been previously treated with an anti-CD20 antibody, had an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1, and had adequate hematologic and organ function. Patients with primary central nervous system (CNS) lymphoma or previous allogeneic stem cell transplant were excluded.

[0271] A conventional 3+3 dose escalation design was implemented during dose escalation. Patients received odronextamab intravenously according to a step-up dosing schedule in cycle 1, and were then treated weekly at target dose levels ranging from 0.1 to 320 mg during cycles 2-4 (each cycle was 21 days). Maintenance treatment was every 2 weeks until disease progression or unacceptable toxicity. During the course of dose escalation, prophylactic measures were implemented to reduce the risk of cytokine release syndrome (CRS), including steroid prophylaxis, split dosing, and step-up dosing.

[0272] On-site availability of tocilizumab was confirmed prior to step-up dosing. Odronextamab was administered intravenously over 4 hours during cycle 1 (days 1, 2, 8, 9, 15, and 16), with the first full dose administered on day 1 of cycle 2. The infusion duration was shortened to 60 minutes for subsequent doses during cycles 2-4 and during maintenance treatment. Patients were monitored in an inpatient setting for approximately 24 hours after the end of each infusion during cycle 1 and on day 1 of cycle 2. Subsequent doses were administered in an outpatient setting. Premedication was administered to further reduce the risk of CRS during cycle 1. Full details are provided in Example 3. Briefly, prophylactic steroids were administered 1 day before, on the day of, and 1 day after the infusion. Additionally, acetaminophen and diphenhydramine were administered 30-60 minutes before the infusion. Steroid premedication was tapered for dosing on day 8 of cycle 2, with all premedication discontinued for subsequent doses. Treatment at target dose levels occurred on days 1, 8, and 15 of cycles 2-4, with maintenance doses every 2 weeks thereafter.

[0273] Patients were permitted to receive supportive care medications as needed to manage CRS (antipyretics, corticosteroids, intravenous fluids, vasopressors, tocilizumab, oxygen, and mechanical ventilation), urate-lowering agents to manage tumor lysis syndrome (TLS), and anti-infective precautions including Pneumocystis jirovecii pneumonia prophylaxis according to local health care guidelines, IVIG supplementation, and appropriate antiviral prophylaxis for patients with previous herpes simplex virus, cytomegalovirus, or hepatitis B virus infection. Transfusions of blood products and the use of granulocyte colony-stimulating factor were permitted according to standard of care.

[0274] Study endpoints and evaluations

[0275] The primary objectives were to assess safety, tolerability, and dose-limiting toxicities (DLTs).Secondary objectives were to assess antitumor activity, pharmacokinetics (PK), and immunogenicity.

[0276] The primary endpoint was safety, assessed by the incidence of adverse events (AEs) and DLTs, to determine the maximum tolerated dose (MTD) and / or phase 2 dose of odronextamab. Key secondary endpoints included pharmacokinetics, immunogenicity, and antitumor activity measured by objective response rate (ORR), duration of response (DoR), and progression-free survival (PFS). Treatment-emergent time was defined as the time from the first dose of study drug to 90 days after the last dose of study drug. Relative dose intensity was defined as the actual dose intensity (dose administered per unit time) divided by the planned dose intensity. AE severity was graded using the National Cancer Institute-Common Terminology Criteria for Adverse Events version 4.03, and CRS was graded according to criteria depending on the date of patient enrollment. AEs were considered related to study drug according to the investigator's assessment.

[0277] The antitumor activity of odronextamab was measured as the objective response rate (ORR), assessed every 12 weeks according to the revised NCI International Working Group on Lymphoma response criteria, using the Lugano classification.

[0278] Blood samples for odronextamab concentration measurements were collected by frequent PK sampling followed by infrequent sampling at weeks 1 through 12. Serum odronextamab concentrations were measured using a validated enzyme-linked immunosorbent assay with a lower limit of quantification of 0.003 mg / L. Descriptive statistics were used to summarize serum odronextamab concentrations over time.

[0279] An exploratory exposure response (ER) analysis by logistic regression was performed using best overall efficacy data from patients with FL or DLBCL who had not received prior chimeric antigen receptor T cell (CAR T) therapy after odronextamab IV regimens ranging from 2 to 320 mg doses during dose escalation. This analysis included the exposure metric (mean concentration [C avg ] or area under the curve [AUC] over time, and predose concentrations at week 12 [C min ]) and its relationship with ORR and complete response rate (CR) were evaluated.

[0280] statistical analysis

[0281] A sample size of 102 patients with B-NHL for dose escalation was determined based on the 3+3 design and the number of dose levels. A total of 130 patients with B-NHL were planned to be included in the expansion cohort to further evaluate the safety and efficacy of the recommended dose. No formal statistical hypothesis testing was performed in this study. All patients with B-NHL from the dose escalation and dose expansion parts of the study were pooled for analysis. For analyses of baseline characteristics and safety, all treated patients were included, and data were also evaluated by dose group. Efficacy endpoints were analyzed by B-NHL subtype and treatment group in patients with response evaluability at week 12. For continuous variables, descriptive statistics were presented, including the number of patients (n), mean, median, standard deviation, minimum, and maximum values ​​reflected in the calculations. For categorical or ordinal variables, frequencies and percentages were presented for each category. For time-to-event variables, medians and 95% confidence intervals (CIs) were provided by Kaplan-Meier methods, where applicable. ORR (proportion of patients with best overall response of CR / PR by Lugano classification) and CR rate (proportion of patients with best overall response of CR by Lugano classification) are summarized with two-sided 95% exact binomial CI using the Clopper-Pearson method. Patients who could not be assessed for best overall response were considered non-responders. Response duration (time from first CR / PR to disease progression or death), CR duration (time from first CR to disease progression or death), and PFS (time from start of treatment to disease progression or death) were analyzed using Kaplan-Meier estimates. Patients without disease progression or death were censored at the last adequate tumor assessment on or before the data cutoff date.

[0282] result

[0283] A total of 145 patients were enrolled, 94 in the dose escalation part and 51 in the dose expansion part of the study.Of the 145 B-NHL patients, 98 (68%) had aggressive B-NHL (DLBCL: n=85, MCL: n=12, FL grade 3b: n=1) and 47 patients (32%) had indolent B-NHL (FL grade 1-3a: n=40, MZL: n=6, Waldenström's macroglobulinemia: n=1).Of the DLBCL patients, 35 were enrolled after failure of a previous CD19-targeted CAR T therapy.

[0284] Patient demographic characteristics are summarized as follows: median age was 67 years (interquartile range 57-73), and the majority of patients (n=101, 70%) were male. At study enrollment, all patients had an ECOG PS of 0 (n=58, 40%) or 1 (n=87, 60%), 85% (n=123) had Ann Arbor stage III-IV disease, and 34% (n=49) had bulky disease. Patients comprised a heavily pretreated, refractory population who had received a median of 3 (interquartile range 2-5) prior lines of systemic therapy, including autologous stem cell transplant (ASCT, n=12, 8%) and CAR T therapy (n=42, 29%). Overall, 119 (82%) patients were refractory to their last line of therapy, 123 (85%) were refractory to anti-CD20 antibodies in any line of therapy, and 100 (69%) were double refractory to alkylating agents and anti-CD20 antibodies in any line of therapy.

[0285] At data cutoff, seven (5%) patients remained on treatment (all in the dose expansion cohort), 33 (23%) had completed treatment, and 105 (72%) patients had discontinued treatment, primarily due to progressive disease (n=63, 43%). Median follow-up was 4.2 months (interquartile range 1.6-11.5). During dose escalation, odronextamab was administered weekly at a maximum dose of 320 mg; no DLTs were observed, the MTD was not reached, and there was no dose-related increase in toxicity. Seven patients (5%) were re-treated with odronextamab, three with FL, three with DLBCL, and one with MCL. Six re-treated patients received doses less than 5 mg, one patient received 160 mg, and all cases of re-treatment occurred in patients enrolled in the dose escalation phase of the study.

[0286] Patients received a median 10 (interquartile range 4-20) dose of odronextamab with a median exposure duration of 13.1 (interquartile range 5.0-32.9) weeks. Median relative dose intensity was 1.0. Clinical activity was observed across all dose groups and was substantially increased in FL patients (n=32) receiving 5 mg or more of odronextamab and in DLBCL patients (n=45) receiving 80 mg or more of odronextamab.

[0287] After IV infusion, peak odronextamab serum concentrations were observed at the end of the infusion or between 4 hours after infusion on day 2 of week 1 and day 2 of week 2 when doses were divided. Median odronextamab serum concentrations generally increased in a dose-dependent manner. Odronextamab demonstrated nonlinear PK characteristics with target-mediated drug disposition. At all doses ranging from 12 mg to 320 mg during weeks 3 to 12, drug accumulation ratios with weekly dosing were up to three-fold for median peak concentrations and approximately two- to six-fold for median trough concentrations.

[0288] A preliminary exposure response (ER) analysis evaluated the relationship between exposure metrics and ORR and CR rates over 12 weeks of treatment using data from 40 FL and 38 DLBCL patients with no prior CAR T therapy who were enrolled during dose escalation. avg and AUC at week 12 compared with C min showed the best correlation with clinical response in patients with FL or DLBCL without prior CAR T. In patients with FL and DLBCL, the probability of ORR or CR at 12 weeks and C min A positive relationship was observed between dose and CR, with the highest CR rates observed at doses of 80 mg or higher.

[0289] Immunogenicity to odronextamab was low: among 137 B-NHL patients with available anti-drug antibody (ADA) data, one patient who received odronextamab 2 mg had treatment-emergent ADA with very low titers only at the last safety follow-up visit (day 30 after the last dose).

[0290] All 145 patients experienced at least one treatment-emergent adverse event (TEAE) of any grade, and 93% of patients (n=135) experienced at least one TEAE related to treatment. The most common TEAEs of any grade were fever (n=107, 74%), CRS (n=89, 61%), chills (n=68, 47%), anemia (n=55, 38%), and fatigue (n=47, 32%). Grade ≥3 TEAEs occurred in 119 patients (82%) and occurred in >10% of patients, including anemia (n=36; 25%; treatment related: n=22; 15%), lymphopenia (n=28; 19%; treatment related: n=24; 17%), hypophosphatemia (n=27; 19%; treatment related: n=18; 12%), neutropenia (n=27; 19%; treatment related: n=21; 14%), and thrombocytopenia (n=20; 14%; treatment related: n=11; 8%). Febrile neutropenia occurred in four patients (3%; treatment related: n=3; 2%). A total of 71 patients (49%) experienced an infection, with 33 (23% of patients) suffering from grade 3 or higher infections (grade 3: n = 28, 19%; grade 4: n = 1, 1%; grade 5: n = 4, 3%), the most frequent of which was pneumonia (n = 12, 8%).

[0291] TEAEs of particular interest occurred, including infusion-related reactions (IRR), CRS, CNS / ICANS-like events, tumor lysis syndrome (TLS), and infections. The majority of CRS events were grade 1 (n=52, 36%) or grade 2 (n=27, 19%). Grade 3 CRS events occurred in nine patients (6%), and one MCL patient (1%) had a grade 4 CRS event associated with grade 5 TLS during dose expansion. CRS was primarily limited to cycle 1 (step-up dosing) and resolved within a median of 2 days with supportive measures. All grade ≥3 CRS events occurred prior to optimization of CRS risk-reduction measures during cycle 1. Tocilizumab was used to manage grade ≥3 CRS in seven patients (5%), and no patients discontinued treatment due to CRS. ICANS-like events were noted in 18 patients (12%), and four patients (2.8%) had grade 3 events (delirium, somnolence, encephalopathy, aphasia, and cognitive impairment, n=1 each). Most neurological TEAEs were transient and resolved within a median of 3 days. None led to treatment discontinuation, and there were no grade 4 or 5 events.

[0292] Serious TEAEs occurred in 89 of 145 patients (61%), most frequently CRS (n=41, 28%), fever (n=11, 8%), pneumonia (n=9, 6%), and IRR (n=6, 4%). Sixty-eight patients (47%) had a serious TEAE during the first 4 weeks of treatment, and in 88 patients (61%), the serious TEAE required prolonged or new hospitalization.

[0293] Of 145 patients, 70 patients (48%) had TEAEs leading to treatment interruption / delay and 14 patients (10%) had TEAEs leading to dose taper. Twelve patients (8%) discontinued odronextamab due to TEAEs, and 10 TEAEs were considered treatment-related (grade 1 cytomegalovirus infection, n=1; grade 1 gait disturbance, n=1; grade 3 pneumonia, n=2; grade 3 hemolysis, n=1; grade 3 toxoplasmosis, n=1; grade 3 fatigue, n=2; grade 4 elevated AST, n=1; grade 5 TLS, n=1). Three were unrelated to treatment (grade 3 neck abscess in a patient with previous spinal surgery, n=1; grade 3 device-related infection, n=1; leukemia, n=1). Seventeen patients died during treatment or within 30 days of the last dose; 12 of these deaths were due to disease progression and four were due to AEs, three of which were considered treatment-related (gastric perforation in a patient with gastric complications from lymphoma [n=1, time between last dose of study drug and onset of event=6 days], pulmonary infection [n=1, 22 days], and TLS [n=1, 3 days]). One fatal event, cardiac arrest, was considered unrelated to study drug by the investigator (occurring 22 days after the last dose of study drug). In one patient, the primary cause of death was recurrence / progression of esophagogastric cancer.

[0294] There were no additional safety signals in patients who underwent odronextamab rechallenge (n=7). The most frequent TEAEs in these patients were nausea (n=4), anemia (n=3), and back pain (n=3). One patient had grade 1 CRS, and four grade ≥3 TEAEs were reported: hyponatremia, hypophosphatemia, lymphopenia, and disc protrusion (all n=1). No serious TEAEs or TEAEs leading to treatment discontinuation were reported in patients undergoing retreatment.

[0295] Overall, no dose-safety relationships were observed across all patients treated and at all dose levels.

[0296] Antitumor activity was observed in all dose groups (0.03-320 mg) and in all lymphoma subtypes. Of 145 treated patients, 142 were evaluable for efficacy using response assessment at week 12. For all patients, the ORR was 51% (n=72, 95% CI: 42-59) and the CR rate was 37% (n=52, 95% CI: 29-45). In patients with FL grade 1-3a (n=40), the ORR and CR rate were 78% (n=31, 95% CI: 62-89%) and 63% (n=25, 95% CI: 46-77), respectively. Responses occurred early, with a median time to CR of 2.6 months (interquartile range 2.5-2.9). The median duration of response (DoR) was 12.7 months (95% CI: 6.1; not estimable [NE]; observed range: 1·2 to 53·0+; interquartile range: 4.4 to 19.9), and the median duration of CR (DoCR) was 14.5 months (95% CI: 8.8; NE; observed range: 0·0+ to 53·0+; interquartile range: 3.9 to 19.9). In patients with R / R FL treated with odronextamab ≥ 5 mg (n = 32), ORR and CR rates were 91% (n = 29, 95% CI: 75–98) and 72% (n = 23, 95% CI: 53–86), respectively, with a median duration of response (DoR) of 15.8 months (95% CI: 6.4, NE, interquartile range 5.2–19.9), with the longest CR still ongoing at 53·0+ months. The estimated probability of sustaining CR was 60% (95% CI: 34–79) at 12 months and 54% (95% CI: 28–74) at 48 months. Median progression-free survival (PFS) was 17·1 months (95% CI: 7·5, NE).

[0297] In all DLBCL patients (n=49) without prior CAR T treated with odronextamab (0.03–320 mg), the ORR and CR rates were 39% (n=19, 95% CI: 25–54) and 24% (n=12, 95% CI 13–39), respectively. The median time to CR was 2·3 months (interquartile range 1·0–2·8), the median DoR was 4·4 months (95% CI: 2·9, NE; observed range: 1·5–41·4+; interquartile range 2·8–21.0), and the median DoCR was not reached (95% CI: 4·0, NE; observed range: 2·9–34·9+; interquartile range 4·2–21.4). In patients (n=15) treated with odronextamab at 80 mg or more, determined to be in the active dose range for advanced lymphoma, the ORR was 53% (n=8, 95% CI: 27-79), all responses were complete, the median DoR was not reached (95% CI: 2·9, NE; interquartile range 4·4-21·2), and the longest CR was ongoing at 32·4+ months. The estimated probability of sustaining CR at 12 and 24 months was 88% (95% CI: 39-98) and 66% (95% CI: 16-91), respectively. Median PFS was 11·5 months (95% CI: 0·5, NE).

[0298] Across all DLBCL patients with prior CAR T (n=33) treated with odronextamab (0.03-320 mg), ORR and CR rates were 33% (n=11, 95% CI: 18-52) and 24% (n=8, 95% CI: 11-42), respectively. Median time to CR was 1·5 months (interquartile range 0·8-2·6), median DoR was not reached (95% CI: 1·6, NE; observed range: 0·0+-20·5+; interquartile range 1.6-12.8), and median DoCR was not reached (95% CI: NE, NE; observed range: 0·0+-20·5+; interquartile range 2.6-15.8). In patients treated with odronextamab ≥80 mg (n=30), ORR and CR rates were 33% (n=10, 95% CI: 17–53) and 27% (n=8, 95% CI: 12–46), respectively, median DoR was not reached (95% CI: 1.6, NE, interquartile range 1.6–12.8), and the longest CR lasted for 20·5+ months. Importantly, in this specific group of DLBCL patients treated with odronextamab ≥80 mg, the estimated probability of sustaining CR at 12 months was 100% (95% CI: NE, NE). Median PFS was 2·0 months (95% CI: 0·9, 2·8).

[0299] None of the patients retreated with odronextamab achieved an additional response.

[0300] Consideration

[0301] In this first-in-human study, odronextamab monotherapy demonstrated promising antitumor activity, robust durability of responses, and an overall manageable safety profile in the setting of heavily pretreated, highly refractory, and difficult-to-treat B-NHL patients. Step-up dosing was effective in reducing the risk of CRS, which occurred primarily during cycle 1 and resolved within a median of 2 days with supportive care measures. The majority of patients achieved full target dose exposure with minimal treatment delays, no patients experienced DLTs, and the MTD was not reached. In R / R FL 1-3a patients, we selected 80 mg as the recommended dose for further expansion, and for R / R DLBCL patients, we selected 160 mg as the recommended dose. This is the first study to report long-term treatment outcomes of a CD20 × CD3 bispecific antibody, including patients treated during the dose escalation and dose expansion portions of the study.

[0302] Early phase trials often enroll a diverse and heterogeneous pool of patients. Overall, the baseline characteristics of patients enrolled in this study were consistent with those represented in current trials of CD20xCD3 bispecific antibodies. The patient population included elderly heavily pretreated patients, the majority of whom were dual refractory to both prior alkylating agent and anti-CD20 therapy. However, one notable difference is that 29% of patients enrolled in this trial had failed prior CAR T therapy at the time of study enrollment, which is considerably higher than the 2% and 9% rates reported in recent studies of glofitamab and epolitamab, respectively. Thus, the population included in this trial may embody a particularly poor prognosis, as these patients are exposed to both potential long-term toxicities inherent to CAR T therapy and their associated conditioning regimens. The proportion of patients who underwent prior ASCT was 8%, which is numerically lower than in some recent studies examining CD20xCD3 bispecifics, but this may be explained in part by the elderly nature and high rate of refractory disease to chemotherapy noted in this patient population.

[0303] Acute immune responses leading to transient cytokine release are frequent side effects of T cell-engaged therapy. Steroid premedication and step-up dosing have been used to reduce the occurrence of CRS after treatment with CD20 × CD3 bispecific antibodies, whether the route of administration is intravenous or subcutaneous. In this study, step-up dosing and additional prophylactic treatments were systematically introduced over the course of the study, effectively reducing the risk of CRS. In most cases, CRS was limited to cycle 1, was low grade (1 or 2), and resolved with supportive care without sequelae. No patients discontinued treatment or experienced significant treatment delays due to CRS. The frequency of grade 3 or higher CRS after intravenous administration of odronextamab was 7%. All grade 3 or higher CRS events occurred before optimizing the step-up dosing schedule to include three steps during cycle 1. The reported incidence of grade 3 or higher CRS is similar to that reported with other intravenously administered CD20 × CD3 bispecific antibodies. In a phase 1 study of intravenously administered glofitamab in patients with R / R B-NHL, 2 Grade ≥3 CRS was observed in 6% of patients treated with IV musnetuzumab, pramotamab, and IGM-2323. The reported incidence of grade ≥3 CRS with intravenous musnetuzumab, pramotamab, and IGM-2323 ranges from 1% to 6%. Epcolitamab has also been investigated in R / R B-NHL, with no grade ≥3 CRS events reported to date in phase 1 / 2 trials employing the subcutaneous route of administration.

[0304] CAR T therapy is a cornerstone treatment in the management of R / R B-NHL, and emerging data suggest that it may be a new approach for some DLBCL patients at first relapse. However, many patients are still poor candidates for CAR T therapy at relapse due to their rapidly progressive phenotype and the need for apheresis, ex vivo genetic engineering, and expansion of T cells, as well as intensive conditioning prior to administration that may lead to prolonged cytopenias. Because both CD20xCD3 bispecific agents and CAR T therapy redirect T cells to initiate malignant B cell killing, early toxicities such as CRS are observed in both therapy classes. In this study, patients who received odronextamab were hospitalized for observation during the step-up administration of cycle 1, when CRS events occurred most frequently. As more data become available from ongoing studies implementing modified step-up regimens (detailed in Examples 1 and 2), the requirement for hospitalization can be reevaluated, and administration of odronextamab entirely within an outpatient setting may be feasible.

[0305] Neurotoxicity has been observed with T-cell-engaged therapy in patients with B-NHL. In a phase 1 trial of glofitamab, ICANS-like events were reported in 5% of patients using a sponsor-derived list of 12 conditions, and the incidence of reported neurological symptoms in a phase 1 / 2 trial of epcolitamab was 6%. After treatment with odronextamab, CNS / ICANS-like events were primarily grade 1 or 2, with only four patients (3%) experiencing grade 3 events. No patients experienced grade 4 or 5 neurological TEAEs or discontinued odronextamab treatment due to neurological TEAEs. The lack of standardized criteria for reporting ICANS-like events somewhat limits the usefulness of comparisons between studies.

[0306] "There remains a significant need for safe, effective, and accessible treatment options for patients with R / R B-NHL. This unmet need is amplified in the setting of patients who progress after CAR T therapy, whose prognosis remains poor with salvage therapy. This study provides evidence that odronextamab can provide durable and clinically meaningful benefit to heavily pretreated patients with R / R B-NHL, including those who have progressed after CAR T therapy."

[0307] In this study, treatment with odronextamab at a therapeutically relevant dose of 80 mg or greater was associated with an ORR of 53% (overall CR) in patients with R / R DLBCL and no prior CAR T therapy, with 88% of CRs estimated to be ongoing at 12 months. Importantly, the ORR and CR rates (33% and 27%, respectively) were lower in DLBCL patients whose disease had progressed after prior CAR T therapy, but 100% complete responses were still estimated to be ongoing at 12 months. These results may mark a clinically important advance in the post-CAR T setting, where few options exist beyond salvage chemotherapy.

[0308] Early observations from a dose escalation study with the CD20×CD3 bispecific have been reported in patients with R / R DLBCL. Recently, IV glofitamab showed an ORR and CR rate of 79% and 71%, respectively, in 14 patients treated at the recommended dose. Results have also been reported with subcutaneous epcolitamab, showing an ORR and CR rate of 91% and 55%, respectively, in 11 patients treated at doses of 48 mg or higher. In a first-in-human study of pramotamab, the overall ORR for patients with non-Hodgkin's lymphoma was 43%, and the ORR for the subgroup of patients with DLBCL was 38%. Preliminary data for IGM-2323 show an ORR of 31% in patients with DLBCL. Long-term follow-up is needed to assess the durability of responses and CRs for these agents.

[0309] CAR T therapy has recently become available as an option for patients with FL whose disease has progressed after at least two prior lines of therapy. The recent approval of axicabtagene ciloleucel in this patient population was supported by the results of the single-arm ZUMA-5 study. In this study, axicabtagene ciloleucel therapy demonstrated an ORR of 91%, with 60% achieving complete responses. Ongoing remission rates at 12 and 18 months were 76% and 74%, respectively. Although CAR T therapy represents an important advance in the management of B-NHL, not all FL patients are eligible to receive this treatment due to the possibility of severe toxicity, complexities in manufacturing, and potential barriers to access in the community. In this study, odronextamab demonstrated an ORR of 91% and a CR rate of 72% at doses of 5 mg or higher in patients with mostly heavily pretreated R / R FL. Importantly, the rate of ongoing complete remission at 48 months was estimated to be 54%. This is the first study of a CD20×CD3 bispecific antibody, showing durability of remission in more than half of the complete responders at 4 years. Administration of odronextamab may provide an important, readily available, and convenient option for R / R FL patients who may be considered candidates for CAR T therapy after progression on two or more lines of therapy. Other studies have reported early experience with CD20×CD3 bispecifics in R / R FL patients. Intravenous musnetuzumab has recently reported ORR and CR rates of 79% and 58%, respectively, and early data from a first-in-human study of subcutaneous epcolitamab reported ORR and CR rates of 90% and 50%, respectively, in 10 evaluable R / R FL patients. Long-term follow-up from these studies is awaited.

[0310] Patients treated in this study received a median of 10 doses of odronextamab therapy, including step-up doses. The treatment regimen was revised during dose expansion to allow treatment until progression, but some patients were able to achieve durable responses with shorter treatment durations. The optimal treatment duration for this class of agents remains to be determined. It is unclear whether clinical outcomes differ between patients who receive the option of retreatment after limited cycles of therapy, or those who continue therapy until disease progression. In this study, a subset of patients received limited cycles of therapy, and seven were retreated at progression, primarily at a lower dose. No patients experienced a response upon retreatment. Recent studies have shown that loss of CD20 may be associated with acquired resistance to odronextamab. Although most patients were retreated at a lower dose, acquired resistance, including loss of CD20, may explain the lack of efficacy observed with retreatment in some cases, thus supporting the treatment paradigm of continuous dosing recommended above. Further studies are needed to delineate the mechanisms of resistance to the CD20xCD3 bispecific class that can inform future clinical trials.

[0311] The development of the CD20xCD3 bispecific antibody drug class heralds great potential to improve the lives of B-NHL patients and is a very strong area of ​​focus in ongoing clinical trials. Odronextamab monotherapy will continue to be explored, as detailed in Examples 1 and 2. Although the results reported to date show very promising monotherapy activity with a manageable tolerability profile, chemotherapy-free regimens combining odronextamab with other immune modulators, such as checkpoint inhibitors or costimulatory antibodies, may present a significant opportunity to improve outcomes for hard-to-treat B-NHL patients. In summary, odronextamab exhibited promising clinical activity, manageable safety, and durable responses in heavily pretreated, highly refractory B-NHL patients. Odronextamab may offer readily available convenience to B-NHL patients, including those with rapidly progressing disease, supporting further exploration of odronextamab as monotherapy and in combination with other modalities.

[0312] Example 5: Clinical evaluation of anti-CD3 x anti-CD20 bispecific antibodies in patients with CD20+ B-cell malignancies previously treated with CD20-targeted antibody therapy This is an open-label, multicenter study of odronextamab administered as a subcutaneous (SC) injection to patients with relapsed / refractory B-cell malignancies. SC studies of odronextamab in B-NHL will include: Dose-finding cohort of patients with follicular lymphoma (FL) grades 1-3a and diffuse large B-cell lymphoma (DLBCL) Expansion cohort to explore dosing frequency in FL grades 1-3a and DLBCL

[0313] The total duration of each patient's study participation will vary based on the occurrence of one or more of the following: disease progression, withdrawal of consent, meeting other study discontinuation criteria, or death.

[0314] The study will consist of three periods, including: Screening Period (maximum 28 days): The screening period begins with the signing of the Informed Consent Form (ICF) and ends when the patient is determined to be eligible for the study and begins treatment, or if the patient is determined to be ineligible and is designated as a screen failure. Duration of Treatment: The treatment period begins with initiation of treatment and continues until disease progression or other protocol-defined reasons for discontinuation. Dosing frequency will vary by cohort. Follow-up period: After treatment discontinuation, patients will be followed for safety and efficacy for the first 90 days after the last dose (safety follow-up period) or until initiation of another anti-lymphoma therapy, whichever occurs first. Patients who discontinue treatment for reasons other than disease progression will continue to be followed after safety follow-up with an extended follow-up period (disease response assessments will be Q12W until the end of year 1, and every 6 months thereafter). After extended follow-up, all study patients will be followed at Q12W intervals for vital status until time of death, loss to follow-up, withdrawal of patient consent for follow-up, or termination of the study by the sponsor, whichever occurs first.

[0315] Up to 102 patients are planned. The actual sample size will depend on the number of patients with DLT observed and whether additional step-up dosing regimens are implemented. Patients with the same disease subtype / regimen enrolled in the dose-finding portion at the recommended Phase II dose (RP2D) will be included in the matched expansion cohort for analysis. The dose-finding portion will enroll approximately 24 patients, assuming up to two dose-finding regimens will be evaluated for FL and DLBCL, respectively. Each dose-finding regimen disease cohort will enroll up to six patients. In the expansion portion, each cohort will enroll a total of 15 patients (including those added from the dose-finding cohort). The oFL expansion will enroll up to 24 patients with FL grades 1-3a into two cohorts (6 patients from the FL dose-finding cohort will be included in FL cohort 1 for analysis). oThe DLBCL expansion will enroll up to 54 patients with DLBCL across four cohorts (6 patients from the DLBCL dose-finding cohort will be included in DLBCL cohort 1 for analysis).

[0316] Patients must have a documented CD20+ B-cell malignancy, with active disease that has relapsed after or is refractory to previous therapy, for which no standard treatment options exist, and for which treatment with an anti-CD20 antibody may be appropriate.

[0317] Patients will receive odronextamab at the assigned dose in 21-day cycles. Cycle 1 will include weekly step-up dosing until the step-up regimen is completed. The step-up regimen will include the initial dose and intermediate doses 1 and 2. Cycle 1 step-up dosing will be followed by treatment cycles at the full dose every 21 days until disease progression or other protocol-defined reasons for treatment discontinuation. During the treatment period, dosing regimens (dosing frequency) will vary by cohort. Cycle length is defined as 3 weeks (21 days) unless otherwise indicated. For cycle 1, cycle length was allowed to extend until the step-up regimen was completed. The step-up regimen will consist of the initial dose and intermediate doses 1 and 2.

[0318] FL: The treatment period will include a 3-week step-up regimen with cycle 1 dosing on days 1, 8, and 15, or through completion of the step-up regimen, followed by Q3W dosing for cycles 2-8 (21-day cycles with dosing on day 1 of each cycle), followed by extended treatment from cycle 9 onwards. The extended treatment cycles will continue until disease progression or other protocol-defined reasons for treatment discontinuation and will have the following dosing frequencies from cycle 9 onwards in the FL dose-finding and expansion cohorts (FL Cohort 1 and FL Cohort 2): FL dose-finding cohort and FL cohort 1: 21-day cycles including 400 mg SC on day 1 of each cycle FL Cohort 2: 400 mg SC on day 1 of each cycle, cycled every 8 weeks

[0319] DLBCL (with and without prior CAR-T): Treatment period consisted of a 3-week step-up regimen during cycle 1 including dosing on days 1, 8, and 15, or until completion of the step-up regimen, followed by full dose dosing on days 1, 8, and 15 of cycle 2, followed by From cycle 3 onwards The study consisted of extended treatment cycles in the following cohorts (DLBCL dose-finding cohort and expansion cohort [DLBCL cohorts 1-4]) until disease progression or other protocol-defined reasons for treatment discontinuation. DLBCL dose-finding cohort and DLBCL cohort 1: 21-day cycles including 400 mg SC on day 1 of each cycle · DLBCL Cohort 2: 21-day cycles including 600mg SC on day 1 of the cycle. DLBCL Cohort 3: 21-day cycles including 400 mg SC on days 1, 8, and 15 of cycle 3, followed by 400 mg SC on day 1 of each cycle from cycle 4 onwards DLBCL cohort 4 (DLBCL after CAR-T failure): RP2D, 21-day cycle (selected from cohorts 1-3). This cohort will be open-label if there are less than 15 patients with DLBCL after CAR-T in the combination of expansion cohorts 1-3.

[0320] Selection Criteria

[0321] Patients must meet the following criteria to be eligible for enrollment in the study: 1. Confirmed diagnosis of B-NHL requiring therapy as defined by the WHO Classification 2017, with documented CD20+ B-cell malignancy, with active disease unresponsive to previous therapy, for which no standard treatment options exist and for which treatment with an anti-CD20 antibody may be appropriate NOTE: Patients who have had a CD20 negative lymph node (NHL) biopsy performed as standard of care immediately prior to enrollment are still eligible for the study if they have previously had documented CD20+ disease and have been previously treated with rituximab or other CD20-targeted antibody therapy within approximately 6 months. 2. B-NHL patients must have received prior treatment with anti-CD20 antibody therapy. Refractory disease is defined as failure to respond (SD / PD) or relapse within 6 months of last treatment. To be included in the expansion cohort for FL grades 1-3a, patients must have received at least two prior lines of systemic therapy, including an anti-CD20 antibody and an alkylating agent. Patients must have failed the combination of lenalidomide + rituximab if approved or not suitable to receive this treatment according to the investigator. For inclusion in disease-specific expansion cohorts enrolling DLBCL patients after CAR-T failure, patients must have recovered from the toxicities of lymphodepleting therapy and CAR-T infusion. The prior CAR-T therapy does not need to be the most recent line of therapy prior to study enrollment. Verbal communication and documentation between the investigator and medical monitor regarding prior toxicities related to CAR-T therapy and their resolution prior to enrollment is required. Patients with aggressive lymphoma assigned to the aggressive lymphoma expansion cohort must have received at least one prior line of treatment consisting of an anti-CD20 antibody. Patients who received prior CAR-T therapy will not be included in this cohort. Patients with FL grades 1-3a and DLBCL must have received at least two prior lines of systemic therapy, including an anti-CD20 antibody and an alkylating agent. 3. All patients must have at least one bidimensionally measurable lesion ≥1.5 cm (longest diameter) documented by CT scan or MRI scan if CT scan is not feasible. 4. Age ≥ 18 years 5. Eastern Cooperative Oncology Group (EOCG) Performance Status ≦1 6. Life expectancy of at least 6 months 7. Adequate bone marrow function documented as follows: A platelet count ≥ 75 x 10 9 / L B. Hb level ≥ 9 g / dL c. ANC ≥ 1 × 10 9 / L NOTE: Patients with cell counts below the above thresholds may be considered for enrollment. Patients with bone marrow disease or splenic pools must meet the following hematological parameters: Platelet count ≥ 25 × 10 9 / L. Patients were not required to have received platelet transfusion therapy within 3 days prior to receiving the first dose of odronextamab to meet the platelet eligibility criteria. -Hemoglobin ≥ 7.0g / dL Absolute neutrophil count (ANC) ≥ 0.5 x 10 9 / L. Patients were not required to have received granulocyte-colony stimulating factor within 2 days prior to the first dose of odronextamab to meet ANC eligibility criteria. 8. Adequate organ function documented as follows: Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN Total bilirubin ≦1.5×ULN NOTE: Gilbert syndrome patients do not need to meet this requirement if total bilirubin is unchanged from baseline. Creatinine clearance calculated by Cockcroft-Gault ≥ 50 mL / min NOTE: Patients may be considered for enrollment if, in the opinion of the investigator, abnormal laboratory results are attributable to an underlying disease. NOTE: Patients with borderline creatinine clearance by Cockcroft-Gault may be considered for enrollment if their measured creatinine clearance (based on 24-h urine or other reliable methods) is ≥ 50 mL / min. 9. Willing to undergo mandatory tumor biopsy prior to treatment if, in the opinion of the Investigator, the patient has accessible lesions that can be biopsied without significant risk to the patient.

[0322] Exclusion criteria

[0323] Patients meeting any of the following criteria will be excluded from the study: 1. Primary central nervous system (CNS) lymphoma or known or suspected CNS disease due to non-primary CNS NHL. 2. History of or current association with CNS pathology, such as: Epilepsy, seizures, paralysis, aphasia, stroke, severe brain injury, cerebellar disease, organic brain syndrome, psychiatric disorder, or Evidence of inflammatory lesions and / or vasculitis on brain MRI 3. Standard antineoplastic chemotherapy (non-biologic) within 5 half-lives or 28 days, whichever is shorter, prior to the first dose of investigational drug. 4. Standard radiotherapy within 14 days of first dose of study drug. NOTE: Symptomatic radiation therapy to symptomatic nodes / lesions is acceptable if the irradiated lesion or lymph node is not included as a target lesion in the tumor evaluation. 5. Allogeneic stem cell transplantation. 6. Treatment with rituximab, alemtuzumab, or other investigational or marketed biologics within 12 weeks prior to the first dose of investigational drug. 7. Immunosuppressive therapy (other than biologic) within 28 days of first dose of investigational drug. 8. Treatment with a non-biologic investigational agent within 28 days of the first dose of investigational drug. 9. History of allergic reactions due to compounds of similar chemical or biological composition to the investigational drug. 10. History of hypersensitivity to any compound in the tetracycline antibiotic group. 11. Concurrent active malignancy for which the patient is receiving treatment. 12. Known active bacterial, viral, fungal, mycobacterial, or other infection, or any major episode of infection requiring hospitalization or treatment with IV anti-infectives within 4 weeks of the first dose. 13. Evidence of any significant comorbidity or medical condition that may interfere with study performance or place the patient at significant risk, including, but not limited to, significant cardiovascular disease (e.g., New York Heart Association class III or IV heart disease, myocardial infarction within the past 6 months, unstable arrhythmia or unstable angina pectoris) and / or significant pulmonary disease (e.g., history of obstructive pulmonary disease and symptomatic bronchospasm). NOTE: Patients with a history of cardiac disease should be evaluated by ECHO or multi-gated acquisition scan (MUGA) prior to the first dose of odronextamab to ensure adequate cardiac reserve and function. 14. Ongoing systemic corticosteroid treatment, excluding use of corticosteroids for other (non-oncology and non-immunosuppressive) indications, with a maximum of 10 mg / day of prednisone or equivalent. 15. Human immunodeficiency virus (HIV) infection, or chronic infection with hepatitis B virus (HBV), hepatitis C virus (HCV), or cytomegalovirus (CMV) infection (as evidenced by detectable levels in a blood PCR assay). a. Patients with controlled hepatitis B (HepBsAg+) infection (serum hepatitis B DNA undetectable and receiving antiviral therapy for hepatitis B) are permitted with consultation with the physician managing their infection. b. Patients who exhibit detectable levels of CMV at screening must be treated with appropriate antiviral therapy and must exhibit at least two undetectable levels of CMV by PCR assay (at least 7 days apart) before being reconsidered for eligibility. 16. Known hypersensitivity to both allopurinol and rasburicase. 17. Pregnant or lactating women. 18.Females of childbearing potential who are not willing to practice highly effective contraception prior to their first study treatment, throughout the study, and for at least 6 months after the last dose* 19. Receipt of live vaccination within 28 days of first dose of investigational product.

[0324] Two extended treatment dosing regimens for FL and three dosing regimens for DLBCL are being investigated in this study to evaluate the frequency of SC dosing. Proposed SC dosing regimens include step-up dosing (2 mg / 26 mg / 100 mg) in cycle 1, 400 mg (total dose) in cycle 2, and 400 mg or 600 mg in subsequent cycles (Tables 7 and 8).

[0325] [Table 8]

[0326] [Table 9]

[0327] If two or more patients in either the SC-1N or SC-2N cohort (combination) experience grade 3 or higher CRS, the step-up regimen will be modified as follows, depending on the dose at which the subsequent CRS event occurs (Tables 9 and 10):

[0328] [Table 10]

[0329] [Table 11]

[0330] In preclinical studies in cynomolgus monkeys, SC administration of odronextamab was associated with reduced serum cytokine levels and induced sustained B cell depletion to levels similar to IV administration. Therefore, it is expected that SC administration of odronextamab in patients may simplify the drug administration process, improve overall patient convenience, and enhance tolerability by further attenuating cytokine release.

[0331] [Table 12]

[0332] Example 6: Premedication Applied for Odronextamab SC Administration The following premedication applies to odronextamab from the first dose through the first full dose. If a patient has CRS of any grade with the first full dose, they will not experience CRS. Without Premedication is continued until the full dose is tolerated. 1. 12 to 24 hours prior to the scheduled start time of SC injection during step-up doses and the first full dose of odronextamab: Dexamethasone 10 mg orally (PO) or equivalent dose of steroids 2. On the day of SC injection between step-up doses of odronextamab and the first full dose: a. Dexamethasone 20 mg IV or PO 1-3 hours prior to SC injection on the day of treatment b. Diphenhydramine 25 mg IV or PO 30 to 60 minutes prior (may be substituted with another equivalent antihistamine) c. Acetaminophen 650 mg PO 30-60 minutes prior to odronextamab injection, unless the patient has received it within the past 4 hours or is allergic to acetaminophen 3. 24 (± 4) hours after odronextamab injection during step-up dosing and the first full dose of odronextamab: Dexamethasone 10 mg PO or equivalent dose of steroids

[0333] Experiencing any grade CRS with 20 mg dexamethasone IV or PO Without Full dose received Later First Dose Administration 4. Premedication on the day of SC injection of odronextamab after administration of the first full dose: a. Dexamethasone 10 mg IV or PO 1-3 hours prior to SC injection on the day of treatment b. Diphenhydramine 25 mg IV or PO 30 to 60 minutes prior (may be substituted with another equivalent antihistamine) c. Acetaminophen 650 mg PO 30-60 minutes prior to SC odronextamab injection, unless the patient has received it within the past 4 hours or is allergic to acetaminophen.

[0334] Subsequent doses were reduced to 10 mg dexamethasone IV or PO if patients experienced CRS of any grade. Without If SC injection is tolerated, no premedication is necessary.

[0335] Example 7: Modeling and Simulation Supporting Subcutaneous Dose Selection of Odronextamab for Adult Patients with Indolent or Aggressive Non-Hodgkin's Lymphoma Odronextamab is a hinge-stabilized human CD20xCD3 IgG4-based bispecific antibody that binds to CD3 on CD20-expressing cells and T cells and induces T cell-mediated cytotoxicity independent of T cell receptor-mediated recognition. Trials of intravenous (IV) odronextamab in patients with previously treated CD20-positive B cell malignancies are ongoing and have shown promising efficacy. The IV regimen includes step-up dosing in cycle 1 of 0.7 / 4 / 20 mg administered over 3 weeks (each dose split over 2 days) to reduce the risk of cytokine release syndrome (CRS). Odronextamab is then administered at 80 mg once weekly (QW) for indolent non-Hodgkin lymphoma (NHL) and 160 mg QW for aggressive NHL during cycles 2-4. To further improve overall tolerability, patient convenience, and reduced hospital resource utilization, subcutaneous (SC) administration of odronextamab is being explored. This analysis, based on modeling and simulation, was performed to determine the SC regimen for clinical trials.

[0336] The analysis included six steps: 1) A population pharmacokinetic (PK) model was developed to estimate PK parameters for IV odronextamab with observed concentration data from B-cell NHL patients participating in the clinical trials described in Examples 1 and 2. 2) A predicted absorption rate constant (based on data from Regeneron's IgG4-based antibody) and predicted SC bioavailability parameters (based on studies of SC odronextamab in cynomolgus monkeys) were added to the model used for the SC PK profile simulation. 3) An exposure response analysis was performed to identify target exposure parameters for clinical efficacy with the IV regimen in patients with indolent and aggressive NHL. 4) The SC PK profile was simulated to determine the maximum concentration (C max) to identify regimens that achieved the target exposure for efficacy without exceeding the IL-6 threshold. 5) A quantitative systems pharmacology (QSP) model was developed to predict interleukin (IL)-6 profiles after SC step-up dosing. 6) Odronextamab SC regimens were simulated to select regimens where IL-6 levels were not predicted to exceed those of the IV regimen.

[0337] Based on the modeling and simulation results, the proposed SC regimen selected for step-up dosing was 2 / 26 / 100 mg in cycle 1 (no split dosing) for both indolent and aggressive NHL. The simulated C during the first week max The median value was lower with 2 mg SC than with 0.7 mg IV in divided doses (0.2 / 0.5 mg). max The predicted time to IV immunization was approximately 4 days for SC, which was much slower than for IV (C max occurs near the end of the injection). max A longer time to chemotherapy may reduce the risk of CRS, which occurs primarily within 1-2 days after IV administration of the divided doses. The proposed SC doses are 400 mg every 3 weeks (Q3W) after cycle 1 for indolent NHL, 400 mg QW in cycle 2 for aggressive NHL, and 400 mg Q3W after cycle 2 for aggressive NHL. Additional SC regimens were proposed for indolent and aggressive NHL for the study based on clinical findings.

[0338] Simulation results show that the proposed SC regimen maintains the necessary and effective odronextamab concentrations over the first four cycles of treatment, where most tumor responses are expected to occur. The simulated IL-6 profile obtained using the SC QSP model showed peak IL-6 values ​​during cycle 1 and that the proposed SC step-up dosing regimen (2 / 26 / 100 mg) did not exceed peak IL-6 values ​​of 0.7 / 4 / 20 mg IV.

[0339] SC administration of odronextamab may be simpler and more convenient than IV administration. PK and IL-6 modeling and simulation analyses will enable the identification of a SC regimen for clinical evaluation that may improve overall tolerability while retaining efficacy for the treatment of patients with B-cell NHL.

[0340] Example 8: Selection of odronextamab pediatric dosing regimens for aggressive non-Hodgkin's lymphoma via modeling and simulation approaches Odronextamab is a hinge-stabilized human CD20xCD3 IgG4-based bispecific antibody that binds to CD3 on CD20-expressing cells and T cells and targets CD20+ cells via T cell-mediated cytotoxicity independent of T cell receptor-mediated recognition. Clinical trials of odronextamab in adult patients with relapsed / refractory CD20+ B cell malignancies are ongoing. Accelerated efficacy has been reported in patients. Approximately 800 new cases of pediatric non-Hodgkin lymphoma (NHL) are diagnosed annually in the United States. Improved treatment options are needed for pediatric patients, especially those with relapsed / refractory disease after chemotherapy with poor outcomes. Trials of odronextamab in pediatric patients with relapsed / refractory B cell NHL (B-NHL) are planned. The objective of this analysis was to determine an intravenous (IV) regimen for testing in pediatric patients that would achieve exposure similar to that achieved in adults.

[0341] The analysis was performed in six steps. 1) A population pharmacokinetic (PK) model was developed using data from adults receiving IV odronextamab to evaluate the effect of body weight (WT) on drug clearance (CL) and volume of distribution (V). 2) A virtual pediatric population was created using demographics obtained from the 2017–2018 National Health and Nutrition Examination Database. 3) Pediatric model parameters were extrapolated from those of adults by applying the effects of WT and age on CL and V accordingly. The effect of maturation on nonspecific elimination was considered in addition to the effect of body weight on infants less than 1 year of age. 4) Using the extrapolated pediatric population model parameters, the PK profile of odronextamab was simulated in virtual pediatric patients aged 6 months to 18 years in four body weight bands (≥40 kg, 20–39 kg, 10–19 kg, and 6–9 kg). 5) The odronextamab drug dose was adjusted for each weight band for each weekly (QW) dosing period and for every 2-week (Q2W) dosing period to match the exposure of adult patients. 6) Pediatric regimens were selected for study based on two criteria. First, for safety, the maximum concentration (C max The median C concentration at steady state (C ) was within 80–125% of the adult value. Second, efficacy was evaluated by comparing the C concentration at steady state (C ) between cycles 2 and onward. min ) is higher than the adult value.

[0342] Odronectamab concentrations in serum after IV doses ranging from 0.03 to 320 mg in patients with relapsed / refractory B-NHL showed biexponential decay, which was adequately described by a two-compartment model with parallel first-order and modified Michaelis-Menten elimination terms. The latter is not only concentration-dependent but also time-dependent. Body weight was found to be a significant covariate on linear CL and V. With PK parameter estimates, simulations were performed for odronectamab IV dosing regimens by body weight band in pediatric patients, as shown in Table 12. Similar to the adult regimen, C maxTo limit doses and reduce the risk of CRS, step-up dosing with divided doses was implemented during cycle 1. Children weighing ≥40 kg received the adult regimen, whereas those weighing <40 kg received tapered doses.

[0343] The proposed regimen was predicted to achieve similar odronextamab exposure to the adult regimen during step-up dosing (weeks 1-3) and during the weekly and every-other-week treatment periods. max No significant difference was predicted in the C of the pediatric WT group compared to adults. max The median ratios were in the range of 0.831 to 1.24. min The median values ​​were less than those observed in adults, with no significant difference in C between weight groups. min No significant difference was observed.

[0344] Additional exploratory simulations were conducted to evaluate uniform weight-based dosing (mg / kg) for the entire pediatric population. This approach was inferior to regimens stratified by WT bands, as it overshot target concentrations among individuals weighing ≥20 kg and undershot target concentrations in individuals weighing 6–9 kg.

[0345] Modeling and simulation approaches enabled the identification of potentially suitable dosing regimens for use in children with B-NHL. Based on predicted PK profiles, pediatric dosing regimens stratified by WT band should maintain the efficacy of odronextamab observed in adults without increasing the risk of acute toxicity.

[0346] [Table 13]

[0347] Example 9: Intravenous odronextamab step-up regimen to reduce the risk of high-grade cytokine release syndrome Odronextamab is a hinge-stabilized human CD20xCD3 IgG4-based bispecific antibody that binds to CD3 on CD20-expressing cells and T cells and targets CD20+ cells via T cell-mediated cytotoxicity independent of T cell receptor-mediated recognition. Transient cytokine release is common with T cell-engaging bispecific antibodies, especially in the early weeks of treatment. This is associated with an increased risk of cytokine release syndrome (CRS), a severe and potentially life-threatening adverse event. Because the intensity of cytokine release is positively associated with drug exposure, especially in the first 3 weeks of treatment, administration of a low dose prior to the full therapeutic dose (i.e., step-up dosing) is an approach to reduce the risk of CRS.

[0348] Intravenous (IV) odronextamab has shown promising efficacy in patients with B-cell non-Hodgkin's lymphoma (B-NHL). Generally, CRS was low grade (Gr), and Gr ≥ 3 occurred in 7% of patients according to B-NHL histology, despite a step-up dosing regimen (1 mg / 20 mg in divided doses over 2 days in weeks 1-2) and steroid prophylaxis. The aim of this work was to determine a step-up regimen to reduce the incidence of Gr ≥ 3 CRS.

[0349] The following step-up dosing conditions were evaluated: 1) the effect of dose on peak odronextamab concentrations during weeks 1-3, including split dosing and the addition of more intermediate doses via pharmacokinetic model-based simulations, 2) predicted time profiles of interleukin (IL)-6 (a surrogate cytokine associated with CRS) using a quantitative systems pharmacology (QSP) model under various dosing scenarios, 3) the effect of premedication type and timing on the occurrence of CRS, and 4) baseline cytokine levels as risk factors for Gr ≥ 3 CRS.

[0350] Based on evaluation of multiple factors mentioned above, the step-up dosing regimen consisted of 0.7 mg (0.2 / 0.5 mg divided over 2 days) in week 1, 4 mg (2 / 2 divided) in week 2, and 20 mg (10 / 10 divided) in week 3. Early administration of premedication (12-24 h before the first divided dose and on the day of each divided dose vs only on the day of each divided dose) significantly reduced baseline (pretreatment) cytokine levels.

[0351] Compared with the previously tested regimen, the new regimen reduced the total initial dose (week 1) by 30% (from 1 mg to 0.7 mg) and showed a more significant reduction of 60% (from 0.5 mg to 0.2 mg) on ​​day 1. This resulted in a mean peak drug concentration reduction of approximately 50% observed on day 1, and a median posttreatment peak IL-6 concentration of 21.1 pg / mL (range 0.6-1163), corresponding to a 17% reduction compared with day 1 with 0.5 mg (median 25.5 pg / mL [range 0.8-3560]).

[0352] According to the QSP simulation, the dose reduction on day 1 in week 1 and the addition of an intermediate dose of 4 mg in week 2 reduced the intensity of cytokine release compared to the previously tested 1 mg (0.5 / 0.5) / 20 mg (10 / 10) dose. This new regimen is being tested in clinical trials in patients with follicular lymphoma and diffuse large B-cell lymphoma. As of April 2022, there are no Gr≥3 CRS in the first 100 patients treated with this regimen.

[0353] Importantly, the odronextamab IV step-up dosing regimen demonstrated lower concentrations of odronextamab compared to the original regimen during weeks 1-3, but the concentrations were similar after the first full dose and had similar trough concentrations at week 4. This indicates that the same therapeutic levels are achieved with both regimens, which is beneficial for treating the disease.

[0354] This odronextamab dosing regimen reduced the risk of CRS and reduced baseline cytokine levels compared with the original regimen. During the first 3 weeks, when the risk of CRS is higher, drug exposure was lower but equivalent to that of the original regimen after receiving a full treatment dose, confirming that the odronextamab dose level required for efficacy was maintained.

[0355] Example 10: Quantitative systems pharmacology modeling framework for the assessment of cytokine release mediated by intravenous odronextamab monotherapy in patients with B-cell non-Hodgkin's lymphoma Odronextamab is a hinge-stabilized human CD20xCD3 IgG4-based bispecific antibody that binds to CD3 on CD20-expressing cells and T cells and targets CD20+ cells via T cell-mediated cytotoxicity independent of T cell receptor-mediated recognition. T cell activation following odronextamab administration can transiently increase levels of circulating cytokines, which is associated with a risk of cytokine release syndrome (CRS). CRS occurs primarily during the first cycle of treatment and is a recognized safety concern associated with all T cell-engaging bispecific antibodies.

[0356] This study was conducted to evaluate cytokine profiles, specifically interleukin (IL)-6 (a surrogate cytokine associated with CRS), in patients with B-cell non-Hodgkin lymphoma (B-NHL) receiving intravenous (IV) odronextamab monotherapy. Quantitative systems pharmacology (QSP) modeling is an emerging mathematical modeling approach that builds on and integrates our understanding of disease biology and the mechanism of action of a drug of interest. Various questions arising from drug research and clinical development may be evaluated and addressed using QSP approaches. The objective of this work was to use the QSP model to determine step-up dosing regimens to achieve an improved safety profile.

[0357] A QSP model was developed using odronextamab pharmacokinetic (PK) data, T and B cell cellular dynamics, and disease characteristics of B-NHL patients. A semi-mechanistic model was fitted and modified to describe the IL-6 profile. A time-varying negative feedback loop was incorporated to account for the observed decay of IL-6 release after repeated dosing. Model parameters were developed using in vivo and in vitro preclinical data and relevant literature information, and calibrated with clinically observed IL-6 data, observed serum odronextamab concentrations, B cell counts, CD8+ T cell counts, and tumor size data from clinical trials from patients treated with odronextamab monotherapy.

[0358] The calibrated model was used to evaluate the time profile of IL-6 release associated with different odronextamab dosing regimens. These evaluations were performed using a hypothetical population of B-NHL patients (n=300 per dosing regimen).

[0359] The calibrated QSP model was used to simulate IL-6 profiles with different proposed step-up dosing scenarios, including testing different dose levels in weeks 1-4, with or without splitting the dose each week, the ratio in which the dose is split over the two days each week, and a step-up dosing period of 2-4 weeks before giving the full dose of treatment. Simulations suggested that splitting the dose in weeks 1, 2, and 3 would reduce the likelihood of IL-6 release in the early weeks of treatment. Since the highest IL-6 peak is expected to occur in week 1, an uneven split ratio of the 0.7 mg dose over two days in week 1 (0.2 / 0.5 mg) would result in the highest IL-6 release on day 1, while maintaining a similar or even lower IL-6 release on day 2. Since IL-6 release in week 2 was likely to be high, a dose as low as 4 mg (2 / 2 split) is predicted to release less IL-6 than doses above 4 mg. After comparison of simulation results for various dosing scenarios, a step-up dosing regimen using 0.7 (0.2 / 0.5) mg in week 1, 4 (2 / 2) mg in week 2, and 20 (10 / 10) mg in week 3 was identified for testing in the clinical trial.

[0360] Furthermore, the QSP model was able to include variability in odronextamab PK parameters and predict the PK profile of odronextamab in a hypothetical B-NHL population, which demonstrated comparable exposure to odronextamab concentrations observed following previously tested step-up dosing regimens of 1 mg (week 1), 20 mg (week 2), and 160 mg (week 3). The model was also able to predict CD8+ T-cell and B-cell profiles over time following an IV odronextamab split-dose regimen.

[0361] This QSP model was developed to address safety concerns related to CRS after odronextamab administration. This study demonstrated that QSP modeling is a powerful tool that allows for decisions on step-up dosing of odronextamab to minimize the risk of higher-grade (i.e., grades 2 and 3) CRS in patients with lymphoma treated with odronextamab.

[0362] Example 11: Evaluation of the kinetics of IL-6 release during step-up dosing of subcutaneous odronextamab via a quantitative systems pharmacological modeling approach Odronextamab is a hinge-stabilized human CD20xCD3 IgG4-based bispecific antibody that binds to CD3 on CD20-expressing cells and T cells and induces T cell-mediated cytotoxicity independent of T cell receptor-mediated recognition. T cell activation following odronextamab administration can result in a transient but clinically meaningful increase in circulating cytokine concentrations. This may lead to cytokine release syndrome (CRS), one of the most important safety concerns regarding T cell-engaged therapies. Because most cytokine release occurs during the early weeks of treatment, a step-up dosing strategy prior to administration of the full therapeutic dose is considered to be a successful strategy to mitigate the level of cytokine release and attenuate the occurrence of CRS.

[0363] This study was conducted to evaluate the interleukin (IL)-6 profile after subcutaneous (SC) injection of odronextamab during cycle 1 step-up dosing (weeks 1-3) in patients with B-cell non-Hodgkin lymphoma (B-NHL). Quantitative systems pharmacology (QSP) models are an emerging mathematical modeling approach that can help improve the understanding of drug-disease interactions and can be used to evaluate hypothetical scenarios in preclinical and clinical settings. A QSP model was developed and applied to identify SC step-up doses of odronextamab suitable for investigation in preclinical studies.

[0364] A QSP model capable of describing the IL-6 profile (a surrogate cytokine associated with CRS) following intravenous (IV) odronextamab was previously developed and calibrated using pharmacodynamic data from clinical trials (Example 10). The IV QSP model was updated by adding relevant components (e.g., drug absorption compartment, lymph node compartment) to enable it to describe the IL-6 profile following SC administration of odronextamab. The model parameters were calibrated using IL-6 concentration data of other CD20xCD3 bispecific antibodies under SC administration reported in the literature.

[0365] Targeted odronextamab SC step-up doses were proposed and the IL-6 profiles of these regimens were simulated with the SC QSP model. For each dosing scenario, the IL-6 profiles were simulated in 300 virtual patients. The cytokine release criterion for regimen selection is that the peak IL-6 concentration of the SC step-up regimen should be lower than the peak IL-6 concentration observed in the previously tested IV regimen.

[0366] Simulation results showed that the predicted IL-6 profile was similar with or without split dosing, and the former was effectively used in the IV regimen for CRS management. The predicted highest peak IL-6 value in week 1 with a 2 mg SC dose was significantly lower than that of 0.7 mg IV (0.2 mg and 0.5 mg split over 2 days in week 1). The predicted highest IL-6 concentration with 2 mg SC was 150 pg / mL and for 0.7 mg IV it was 2,100 pg / mL, indicating a reduction of more than 90%. The predicted IL-6 profile in week 4 was similar to that of 160 mg IV or 400 mg SC. Based on the comparison of the IL-6 profiles of multiple SC dosing scenarios, we selected a SC step-up dose of 2 mg in week 1, 26 mg in week 2, and 100 mg in week 3, followed by a full dose of 400 mg. The proposed SC regimen is being tested in a clinical trial described in Example 5 for evaluation of safety and efficacy.

[0367] QSP modeling supported the selection of the odronextamab SC step-up dosing regimen to be evaluated in clinical trials in patients with B-NHL. The selected step-up regimen of SC odronextamab allows for appropriate step-up to an effective therapeutic dose while simplifying and improving overall convenience. Simulations suggest that SC administration does not require split dosing, which may further reduce overall hospital resource burden and the need for inpatient monitoring.

[0368] Example 12: Odronextamab in patients with relapsed / refractory (R / R) follicular lymphoma (FL) grades 1-3a: Results of a preliminary analysis of a pivotal phase II study Results from a phase 2 study of odronextamab monotherapy in patients with relapsed / refractory (refractory to or relapsed to two or more prior lines of therapy including an anti-CD20 antibody and an alkylating agent) follicular lymphoma (grade 1-3a) with ECOG performance status of 0 or 1 are presented below.

[0369] The study was initiated with a 1 / 20 mg step-up dosing regimen, which was then modified to a 0.7 / 4 / 20 mg step-up dosing regimen to further reduce the risk of cytokine release syndrome (CRS), as shown in Figure 1. In the modified dosing regimen, the initial dose (0.7 mg) was split into two dose fractions of 0.2 mg and 0.5 mg and administered over two days in week 1 of the dosing regimen, followed by a first intermediate dose (4 mg) split into two dose fractions of 2 mg each administered over two days in week 2 of the dosing regimen, followed by a second intermediate dose (20 mg) split into two dose fractions of 10 mg each administered over two days in week 3 of the dosing regimen. The full dose (80 mg) was then administered weekly during weeks 4-12 of the dosing regimen, followed by a maintenance dose of odronextamab (160 mg) every other week.

[0370] Baseline characteristics of treated patients (N=131) included 30.5% had previous autologous stem cell transplant (ASCT), 13.7% had been previously treated with phosphoinositide 3-kinase (PI3K), 13.7% had been previously treated with immunomodulatory agents, 71.0% were refractory to last line of therapy, 74.8% were refractory to anti-CD20 antibody therapy, 43.5% were dual refractory to alkylating agent / anti-CD20 antibody therapy, and 48.1% showed disease progression within 24 months of initiating first-line therapy.

[0371] The breakdown of the 131 patients is shown in Table 13 below.

[0372] [Table 14]

[0373] The objective response rates of the 121 efficacy-evaluable patients are shown in Table 14 below, including a comparison of the 1 / 20 step-up dosing regimen with the 0.7 / 4 / 20 step-up dosing regimen. Regardless of the step-up regimen in cycle 1, consistent efficacy was observed at week 12, with the majority of patients achieving a complete response.

[0374] [Table 15]

[0375] Additional efficacy data for these 121 efficacy-evaluable patients are shown in Figures 2, 3, 4, and 5, which confirm that the majority of patients with relapsed / refractory FL had substantial tumor shrinkage (Figure 2), there was consistent antitumor activity in high-risk subgroups (Figure 3), the observed responses were durable (Figure 4), and treatment positively impacted progression-free and overall survival (Figure 5).

[0376] The safety profile of odronextamab administration in this study, including a comparison of the rate / grade of CRS and other adverse events in patients receiving the 1 / 20 step-up dosing regimen or the 0.7 / 4 / 20 step-up dosing regimen, is shown below in Tables 15, 16, and 17. As described in Table 16, the 0.7 / 4 / 20 step-up dosing regimen reduced the incidence of grade 2 and grade 3 CRS, while approximately half of the patients with relapsed / refractory follicular lymphoma had CRS (mostly grade 1). All CRS events resolved within a median of 2 days (range 1-51), and no patients required mechanical ventilation or ICU admission for CRS management.

[0377] [Table 16]

[0378] [Table 17]

[0379] [Table 18]

[0380] Overall, these results demonstrate that odronextamab monotherapy was effective in heavily pretreated patients with relapsed / refractory follicular lymphoma (ORR 81.8%, CR 75.2%, 92% of responders were complete responders, and durable responses with a median progression-free survival of 20.2 months). Moreover, odronextamab monotherapy showed a manageable safety profile, especially with the modified 0.7 / 4 / 20 step-up dosing regimen.

[0381] As of the data cut of September 18, 2022, of 166 patients treated with the 07 / 4 / 20 mg revised step-up regimen, 86 (51.9%) experienced CRS, with the highest grade of CRS observed being grade 1 in 62 patients (37.3%), grade 2 in 21 patients (12.7%), and grade 3 in 3 patients (1.8%). The revised (0.7 / 4 / 20) step-up dosing regimen was successful in further reducing the incidence and severity of CRS events. The occurrence of CRS events of any grade decreased from 183 / 300 patients (61%) on the 1 / 20 regimen to 86 / 166 patients (51.8%) on the revised regimen, and grade ≥3 CRS events decreased from 8.7% on the 1 / 20 regimen to 1.8% on the revised regimen. Furthermore, the overall incidence of grade ≥2 CRS events decreased from 28.3% with the 1 / 20 regimen to 14.5% with the revised regimen.

[0382] Example 13: Preliminary analysis results of an odronextamab pivotal Phase II study in relapsed / refractory (R / R) diffuse large B-cell lymphoma (DLBCL) The results of a phase 2 study of odronextamab monotherapy in patients with relapsed / refractory (refractory to or relapsed to two or more prior lines of therapy including an anti-CD20 antibody and an alkylating agent) diffuse large B-cell lymphoma (according to the WHO 2016 classification) with ECOG performance status of 0 or 1 are shown below.

[0383] The study was initiated with a 1 / 20 mg step-up dosing regimen, which was then modified to a 0.7 / 4 / 20 mg step-up dosing regimen to further reduce the risk of cytokine release syndrome (CRS), as shown in Figure 6. In the modified dosing regimen, the initial dose (0.7 mg) was split into two dose fractions of 0.2 mg and 0.5 mg administered over two days in week 1 of the dosing regimen, followed by a first intermediate dose (4 mg) split into two dose fractions of 2 mg each administered over two days in week 2 of the dosing regimen, followed by a second intermediate dose (20 mg) split into two dose fractions of 10 mg each administered over two days in week 3 of the dosing regimen. The full dose (160 mg) was then administered weekly during weeks 4-12 of the dosing regimen, followed by a maintenance dose of odronextamab (320 mg) every other week.

[0384] Baseline characteristics of treated patients (N=140) included: 15.7% had prior autologous stem cell transplant (ASCT), 57.1% were primary refractory, 90.7% were refractory to any prior line of therapy, 86.4% were refractory to last line of therapy, 78.6% were refractory to anti-CD20 antibody therapy in any line of therapy, and 65.7% were dually refractory to alkylating agent / anti-CD20 antibody therapy in any line of therapy.

[0385] The breakdown of the 140 patients is shown in Table 18 below.

[0386] [Table 19]

[0387] The objective response rates of the 130 efficacy-evaluable patients are shown below in Table 19, including a comparison of the 1 / 20 step-up dosing regimen with the 0.7 / 4 / 20 step-up dosing regimen. Regardless of the step-up regimen in cycle 1, consistent efficacy was observed at week 12, with 62% of responders achieving a complete response.

[0388] [Table 20]

[0389] The objective response rates for the 31 efficacy-evaluable patients with prior CAR-T therapy are shown in Table 20 below.

[0390] [Table 21]

[0391] Additional efficacy data for these 130 efficacy-evaluable patients are shown in Figures 7, 8, and 9, which confirm that there was consistent antitumor activity in the high-risk subgroup (Figure 7), that the observed responses were durable (Figure 8), and that treatment positively impacted progression-free survival (Figure 9).

[0392] The safety profile of odronextamab administration in this study, including a comparison of the rate / grade of CRS and other adverse events in patients receiving the 1 / 20 step-up dosing regimen or the 0.7 / 4 / 20 step-up dosing regimen, is shown below in Tables 21, 22, and 23. As described in Table 22, the 0.7 / 4 / 20 step-up dosing regimen reduced the incidence of grade 2 and grade 3 CRS, while approximately half of the patients with relapsed / refractory DLBCL had CRS (mostly grade 1). All CRS events resolved within a median of 2 days (range 1-133), and no patients required mechanical ventilation or ICU admission for CRS management.

[0393] [Table 22]

[0394] [Table 23]

[0395] [Table 24]

[0396] Overall, these results indicate that odronextamab monotherapy in heavily pretreated patients with relapsed / refractory diffuse large B-cell lymphoma was effective both pre- and post-CAR-T (ORR 49.2%, CR 30.8%, and durable complete response with a median duration of 17.9 months). Furthermore, odronextamab monotherapy demonstrated a manageable safety profile, especially with the modified 0.7 / 4 / 20 step-up dosing regimen.

[0397] As of September 18, 2022, of 166 patients treated with the revised 0.7 / 4 / 20 mg step-up regimen, 86 participants (51.8%) experienced CRS. The highest grade of CRS observed (cytokine release syndrome) was grade 1 in 62 participants (37.3%), grade 2 in 21 (12.7%), and grade 3 in 3 (1.8%). The revised step-up dosing regimen was successful in reducing the incidence and severity of CRS events. The occurrence of CRS events of any grade decreased from 183 / 300 participants (61%) in the 1 / 20 regimen to 86 / 166 participants (51.8%) in the revised regimen, and grade ≥3 CRS events decreased from 8.7% in the 1 / 20 regimen to 1.8% in the revised regimen. The overall incidence of grade ≥2 CRS events decreased from 28.3% with the 1 / 20 regimen to 14.5% with the revised regimen.

[0398] Example 14: Clinical Evaluation of Anti-CD20 x Anti-CD3 Bispecific Antibody Odronextamab (REGN1979) vs. Investigator's Choice in Previously Untreated Participants with Follicular Lymphoma This is an open-label, multicenter, randomized, phase 3 study comparing the efficacy and safety of odronextamab with investigator's choice of chemotherapy (rituximab-CHOP, rituximab-CVP, or rituximab-bendamustine) for the treatment of participants with previously untreated follicular lymphoma. Part 1 (safety run-in) will test the planned dose of odronextamab monotherapy to proceed to part 2 (randomization phase). The efficacy and safety of the recommended dose of odronextamab will be evaluated in part 2 vs investigator's choice of chemotherapy. All participants will undergo 6 cycles of induction. Participants with a complete response (CR) or partial response (PR) at the end of cycle 6 induction will continue into a maintenance treatment period with either odronextamab or rituximab monotherapy depending on the study arm. Participants who relapse / progress during treatment or have stable disease (SD) at the end of induction will be withdrawn from treatment and continue with safety and survival follow-up.

[0399] Participants with high-risk FL (Follicular Lymphoma International Prognostic Index 1 [FLIPI 1] score 3–5) will be enrolled in the safety run-in part (12–24 patients). Approximately 446 participants will be enrolled and randomly assigned in a 1:1 ratio to receive either (A) odronextamab for induction followed by odronextamab maintenance or (B) investigator's choice of immunotherapy followed by rituximab maintenance. The choice of therapy (CHOP, CVP, or bendamustine) will be at the investigator's clinical discretion. For participants assigned to receive odronextamab, odronextamab will be administered as monotherapy at the selected dose for 6 cycles during part 1 (see Table 24). At the end of cycle 6, participants with a CR or PR based on the week 24 scan assessment will continue treatment with odronextamab monotherapy at a dose of 320 mg Q8W for up to 12 doses or until disease progression, loss to follow-up, or withdrawal of consent, whichever occurs first. For participants assigned to receive rituximab in combination with chemotherapy, treatment will be 6 cycles of induction chemotherapy followed by up to 12 doses of rituximab monotherapy at Q8W intervals (participants with CR and PR only) per standard operating procedure, or until disease progression, loss to follow-up, or withdrawal of consent, whichever occurs first.

[0400] [Table 25]

[0401] The study population was aged 18 years or older, with previously untreated CD20 gliomas based on the World Health Organization (WHO) classification. + It will consist of participants with FL.

[0402] Selection Criteria Participants must meet the following criteria to be eligible for enrollment in the study: 1. CD20 + Those diagnosed with FL grade 1-3a, stage II bulky, or stage III / IV: CD20 +Local histopathological confirmation of FL grade 1-3a must be obtained prior to study enrollment. Biopsy must be obtained within 18 months prior to study enrollment. Matched tumor biopsy specimens should be submitted to a central laboratory. Part 1 (safety induction) only: FLIP1 score 3–5. 2. Treatment is indicated as indicated below. Presence of one or more of the following: B symptoms, large tumor masses (characterized by three or more areas of lymphoma >3 cm in diameter or one area of ​​lymphoma >6 cm in diameter), and / or presence of lymphoma-related complications. 3. Have measurable disease on cross-sectional imaging documented by diagnostic imaging CT or MRI (measurable disease is defined as at least one bidimensionally measurable nodal lesion >1.5 cm or extranodal pathology >1 cm in greatest transverse diameter (GTD), regardless of short-axis diameter). 4. Eastern Cooperative Oncology Group (EOCG) Performance Status: 0-2. 5. Age 3 18 years old 6. Adequate bone marrow function documented as follows: A platelet count 3 50×10 9 / L. Participants were not required to have received platelet transfusion therapy within 7 days prior to receiving the first dose of odronextamab to meet the platelet eligibility criteria. B hemoglobin 3 9.0 g / dL C. Absolute neutrophil count (ANC) 3 1.0×10 9 / L. Participants were not required to have received G-CSF within 2 days prior to the first dose of odronextamab to meet the ANC eligibility criteria. d. Participants with bone marrow disease or splenic pools must meet the following hematological parameters: Platelet count 3 25×10 9 / L. Participants were not required to have received platelet transfusion therapy within 3 days prior to receiving the first dose of odronextamab to meet the platelet eligibility criteria. ·hemoglobin 3 7.0 g / dL ANC≧0.5×10 9 / L. Participants were not required to have received G-CSF within 2 days prior to the first dose of odronextamab to meet the ANC eligibility criteria. 7. Participants with adequate liver function: Total bilirubin ≤ 1.5 × upper limit of normal (ULN) (≤ 3 × ULN if due to hepatic lymphoma infiltration). b. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x ULN (≤ 5 x ULN if due to lymphoma infiltration of the liver) c. Alkaline phosphatase (ALP) ≤ 2.5 x ULN (≤ 5 x ULN if caused by lymphoma infiltration of the liver) Note: *Participants with total bilirubin >1.5xULN and concomitant AST >2.5ULN and / or ALT >2.5xULN will be excluded, regardless of the presence of lymphomatous infiltration of the liver. *Participants with known Gilbert syndrome will be excluded if their total bilirubin levels are >4×ULN for the local general population. 8. Creatinine clearance calculated by the Cockcroft-Gault formula 3 50mL / min NOTE: Patients with a calculated creatinine clearance <50 mL / min may be considered for enrollment if their measured creatinine clearance (based on a 24-h urine collection or other reliable method) is ≥50 mL / min. 9. Ability by the study participant or legally acceptable representative (subject to national and local participant privacy regulations) to understand the purpose and risks of the study and to provide signed and dated informed consent and authorization to use protected health information. 10. Willing and able to comply with visit and study-related procedures 11. Able to understand and complete clinical trial-related questionnaires.

[0403] Exclusion criteria: Participants who meet any of the following criteria will be excluded from the study: 1. Participants with central nervous system (CNS) lymphoma or leptomeningeal lymphoma. Known disease due to primary CNS lymphoma or non-primary CNS lymphoma (even if treated to complete remission). b. Suspicion of CNS disease due to lymphoma must be evaluated by CNS imaging (MRI or CT) and lumbar puncture if necessary. 2. Participants with histologic evidence of transformation to high-grade or diffuse large B-cell lymphoma. 3. Participants with Waldenström's macroglobulinemia (WM, lymphoplasmacytic lymphoma), grade 3b follicular lymphoma, chronic lymphocytic leukemia, or small lymphocytic lymphoma. 4. Treatment with any systemic anti-lymphoma therapy. 5. Recent major surgery (within 4 weeks prior to initiation of assigned study treatment). 6. Standard radiotherapy within 14 days of the first dose of assigned study treatment. 7. History of solid organ transplantation. 8. Continuous systemic corticosteroid treatment with >10 mg per day of prednisone or anti-inflammatory equivalent within 72 hours prior to starting study drug. 9. Malignancies other than NHL, provided that participants have been adequately and definitively treated and have been cancer-free for at least 3 years with the exception of localized prostate cancer treated with hormonal therapy or localized radiation therapy (i.e., pellets), non-invasive cervical cancer, non-invasive breast cancer, or definitively treated non-melanoma skin cancer. 10. Any other significant active disease or medical condition that may interfere with the study or place the participant at significant risk, including, but not limited to, significant cardiovascular disease (e.g., New York Heart Association class III or IV heart disease, myocardial infarction within the past 6 months, unstable arrhythmia, or unstable angina pectoris), significant pulmonary disease (e.g., history of obstructive pulmonary disease and symptomatic bronchospasm), or gastrointestinal, hepatic, renal, endocrine, hematological, autoimmune, psychiatric, or neurological disorders. 11. Has a history of or currently has any relevant CNS pathology, including epilepsy, seizures, paralysis, aphasia, stroke, severe brain injury, cerebellar disease, organic brain syndrome, psychiatric disorder, inflammatory lesions, and / or vasculitis. 12. Vaccination with a replication-competent vector within 28 days prior to the first study drug administration. 13. Cardiac output fraction <50% by echocardiogram or multi-gated acquisition (MUGA) scan. 14. Pregnant or breastfeeding women. 15. Women of childbearing potential (WOCBP)* or men who are not willing to use highly effective contraception prior to first dose / initiation of first treatment, throughout the study, and for at least 6 months after the last dose. Sperm donation is prohibited during the study and for 6 months after the last dose of investigational product. Highly effective methods of contraception include: Stable use of a combined (estrogen- and progesterone-containing) hormonal contraceptive method associated with the inhibition of ovulation (oral, intravaginal, transdermal) or a progesterone-only hormonal contraceptive method (oral, injectable, implantable) initiated for at least two menstrual cycles prior to screening, b. Intrauterine device (IUD), intrauterine hormone releasing system (IUS) c. Bilateral tubal occlusion / ligation, d. Vasectomy of a partner (provided that the vasectomized male partner is the WOCBP study participant's only sexual partner and that the vasectomized partner has received a medical evaluation of the surgical success of the procedure); and / or e. Sexual abstinence. 16. History of any clinically significant cardiovascular, respiratory, hepatic, renal, gastrointestinal, endocrine, hematological, psychiatric, or neurological disease as assessed by the investigator that may confound the results of the study or pose additional risk to the participant from participation in the study. 17. History of active tuberculosis or systemic fungal disease within the past 6 months. 18. Infection: Infection requiring hospitalization or treatment with IV anti-infectives within 2 weeks of the first dose of assigned study treatment. There must be evidence that the infection has resolved or is well controlled by the time study therapy is started. Evidence of any active infection (bacterial, viral, fungal, mycobacterial, parasitic, other) at the time of study entry or within 2 weeks of study entry if requiring ongoing treatment and / or if capable of causing disseminated disease or severe infection when immunosuppressed. Active COVID-19 infection defined as PCR+ · Uncontrolled infection with human immunodeficiency virus (HIV), hepatitis B (HBV), or hepatitis C (HCV). Cytomegalovirus (CMV) infection as demonstrated by detectable levels by peripheral blood PCR assay. Patients who demonstrate detectable levels of CMV at screening must be treated with appropriate antiviral therapy and must demonstrate at least two undetectable levels of CMV by PCR assay (at least 7 days apart) before being reconsidered for eligibility. NOTE: Participants with HIV whose infection is controlled (either spontaneously or on a stable antiviral regimen, with an undetectable viral load and a CD4 count >350 cells / µL) are accepted. NOTE: Participants who are hepatitis B surface antigen positive or hepatitis B core antibody positive must be evaluated by a specialist and considered for antiviral prophylaxis before being allowed into the study. NOTE: Patients who are hepatitis C virus antibody positive (HCV Ab+) and have controlled infection (undetectable HCV RNA by PCR, either spontaneously or in response to a previous successful course of anti-HCV therapy) are accepted. 19. Allergies / hypersensitivities: History of severe allergic reactions caused by compounds with a similar chemical or biological composition to that of the investigational drug or excipients. b. Known hypersensitivity to both allopurinol and rasburicase. 20. Participated in any clinical research trial evaluating another investigational drug, including a biologic, or another therapy, including certain immunotherapies, within 90 days or at least 5 half-lives of an investigational biologic (whichever is longer) prior to the Screening Visit, or within at least 4 weeks for other investigational drugs. 21. Participants who are committed to the facility pursuant to an order issued by either a judicial or administrative authority.

[0404] The study interventions administered in this study are shown in Table 25 below.

[0405] [Table 26]

[0406] The dose of odronextamab administered will be a fixed dose and will not depend on the participant's weight or body surface area. During the induction treatment period, odronextamab will be administered IV in a step-up dosing in cycle 1 to reduce the risk of CRS. Cycle 1 will consist of an initial dose of 0.7 mg (divided as 0.2 mg on day 1 of cycle 1 and 0.5 mg on day 2 of cycle 1), intermediate dose 1 of 4 mg (divided as 2 mg on day 8 of cycle 1 and 2 mg on day 9 of cycle 1), and intermediate dose 2 of 20 mg (divided as 10 mg on day 15 of cycle 1 and 10 mg on day 16 of cycle 1). From cycle 2 to cycle 4, odronextamab will be administered IV at 80 mg on days 1, 8, and 15, and from cycle 5 and cycle 6 onwards, odronextamab will be administered IV at 160 mg on day 8 of cycle 5 and days 1 and 15 of cycle 6 (Table 26). During the monotherapy maintenance treatment period, odronextamab will be administered IV at 320 mg Q8W (Table 26). The first dose of odronextamab (320 mg) during maintenance will be administered 6 weeks after the last dose (160 mg) administered during induction on day 15 of cycle 6.

[0407] [Table 27]

[0408] For the initial dose, intermediate dose 1, and intermediate dose 2, treatment will be split into two separate infusions given on two separate days, preferably consecutive, but no more than 3 days apart. Each split infusion during cycle 1 and the first full dose infusion of the QW (day 1 of cycle 2) should be administered over 4 hours. Subsequent treatments may be administered as a single infusion or as two separate infusions, and may be administered over at least 1 hour, as tolerated.

[0409] Premedication to mitigate the risk and reduce severity of CRS is detailed in Example 3. CRS toxicity assessments are shown, for example, in Table 6.

[0410] The study allows the use of rituximab or a biosimilar. Rituximab must be administered according to institutional guidelines or as directed in the product insert. Rituximab is administered at 375 mg / m on day 1 of each cycle. 2 Rituximab will be administered IV at a dose of 0.01 mg / kg / day. The frequency and duration of rituximab will be Q3W in combination with induction chemotherapy (CHOP / CVP) for 6 cycles of 21 days each, and Q4W in combination with induction benzamustine for 6 cycles of 28 days each (induction treatment phase). Upon completion of the combination treatment period or early termination of chemotherapy, rituximab will be continued as Q8W monotherapy for up to 12 maintenance doses (if the participant has a CR or PR), unless the participant discontinues early due to toxicity, progressive disease, or initiation of subsequent lymphoma therapy, or for any reason (participant or investigator). Rituximab and chemotherapy dosing is listed in Table 27. For more information on CHOP / CVP and benzamustine, including formulation and administration, please refer to the product insert. Eight weeks after the day 1 dose of cycle 6, participants (those who had a CR or PR) will begin the maintenance treatment period of rituximab monotherapy on a Q8W schedule.

[0411] [Table 28]

[0412] Example 15: Clinical Evaluation of Anti-CD20 x Anti-CD3 Bispecific Antibody Odronextamab (REGN1979) in Combination with CHOP (O-CHOP) vs. Rituximab in Combination with CHOP (R-CHOP) in Previously Untreated Participants with Diffuse Large B-Cell Lymphoma This is a phase 3, open-label, randomized, multicenter study of odronextamab in combination with CHOP (O-CHOP) compared with rituximab in combination with CHOP (R-CHOP) in previously untreated participants with DLBCL with an International Prognostic Index (IPI) score of ≥2. The trial consists of two parts. Part 1 of the study is a safety run-in to evaluate the safety and tolerability of O-CHOP and to determine the intended dosing regimen of O-CHOP in part 2. Part 2 is the randomized part of the study, which will evaluate the efficacy and safety of O-CHOP compared with R-CHOP.

[0413] In Part 1, all participants will receive odronextamab only (without rituximab). Up to 48 participants will be enrolled and treated at the lower dose level 1 (DL1) and escalated to DL2 according to Table 28. Dose-limiting toxicities (DLTs) and tolerability of O-CHOP will also be evaluated. Table 28 provides the dosing scheme of odronextamab for combination (with CHOP) in Part 1 (safety run-in). Dose levels will start with 80 mg odronextamab full dose (DL 1). CHOP dose will remain the same across dose levels, and CHOP will be initiated on cycle 1 day 1 (C1D1) for all DLs. CHOP will be given every 21 days for a total of 6 cycles (1 cycle = 21 days). Odronextamab will be initiated on C1D8 for all DLs. [Table 29]

[0414] In part 2, approximately 840 participants will be enrolled and randomly assigned in a 1:1 ratio to receive either O-CHOP or R-CHOP. At least 546 participants will be enrolled with an IPI score ≥3. There will be no maintenance therapy in either arm. Crossover between arms will not be permitted. Randomization will be stratified according to International Prognostic Index (2 vs. 3 vs. 4 vs. 5) and age (<65 vs. ≥65). Study treatment will begin within 5 days of randomization unless otherwise permitted by the medical monitor. For participants assigned to receive O-CHOP, odronextamab will be administered in combination with six cycles of induction CHOP. For participants assigned to receive R-CHOP, treatment will follow standard operating procedure, i.e., six cycles of induction CHOP.

[0415] The study population consisted of participants aged 18 years or older with intermediate- to high-risk previously untreated diffuse large B-cell lymphoma.

[0416] Selection criteria: Participants must meet the following criteria to be eligible for enrollment in the study: 1. Previously untreated participants with lymphoma with documented CD20+ DLBCL, including one of the following diagnoses according to the 2016 WHO Classification of Lymphoid Neoplasms: a.**Not otherwise specified (NOS), including DLBCL, germinal center B-cell type, and activated B-cell type. b. High-grade B-cell neoplasms with MYC, bcl-2, and / or bcl-6 rearrangements Part 1 only: Participants must have at least one of the following high-risk features to be eligible: IPI score 3–5, cellular origin (non-GCB type), double-hit or triple-hit lymphoma (classified as high-grade B-cell neoplasms with MYC, bcl-2 and / or bcl-6 rearrangements according to the 2016 WHO classification of lymphoid neoplasms), TP53 mutations, and CDKN2A loss (Sehn and Salles, 2021). *Local histopathological confirmation of DLBCL must be obtained prior to study enrollment. Biopsy must be obtained within 3 months prior to study enrollment. Study enrollment requires availability of tumor tissue for submission to a central testing laboratory. **Diagnosed as de novo or histologically transformed follicular lymphoma 2. Have measurable disease documented by diagnostic imaging (computed tomography [CT] or magnetic resonance imaging [MRI]) with at least one nodal lesion with an LDi >1.5 cm or at least one extranodal lesion with an LDi >1.0 cm. 3. Age ≥ 18 years 4. Eastern Cooperative Oncology Group (EOCG) Performance Status ≦2 5. Life expectancy ≥ 12 months 6. International Prognostic Index (IPI) ≥ 2 7. Adequate hematologic function as measured by: Platelet count ≥ 75 x 109 / L. Participants must not have received a platelet transfusion within 7 days of receiving the first dose of their assigned study treatment to meet this eligibility requirement. b. Absolute neutrophil count (ANC) ≥ 1.0 x 109 / L. Participants were not required to have received granulocyte colony-stimulating factor (G-CSF) within 2 days of receiving the first dose of their assigned study treatment to meet this eligibility requirement. C. Hemoglobin level ≥ 9 g / dL NOTE: Participants with cell counts below the thresholds mentioned above may be considered for enrollment if, in the investigator's opinion, this is attributable to bone marrow infiltration or splenic cell pooling due to the underlying disease. Participants with bone marrow disease or splenic pools must meet the following hematological parameters: Platelet count ≥ 25 x 109 / L. Participants must not have received platelet transfusion therapy within 3 days prior to the first dose of study treatment to meet the platelet eligibility criteria. b. Absolute neutrophil count (ANC) ≥ 0.5 x 109 / L. Participants must not have received granulocyte colony-stimulating factor within 2 days prior to administration of the first dose of study treatment to meet the ANC eligibility criteria. C. Hemoglobin ≥ 7.0 g / dL 8. Documented organ function as follows: Cardiac output fraction >50% by echocardiogram or multi-gated acquisition (MUGA) scan b. Total bilirubin ≦1.5×upper limit of normal (ULN) (≦3×ULN if caused by hepatic lymphoma infiltration) c. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 x ULN (≤ 5 x ULN if due to lymphoma infiltration of the liver) d. Alkaline phosphatase (ALP) ≦2.5ULN (≦5×ULN if caused by lymphoma infiltration of the liver) e. Serum creatinine ≤ 1.5 ULN or creatinine clearance ≥ 50 mL / min calculated by the Cockcroft-Gault formula. NOTE: Participants with total bilirubin >1.5 × ULN and concomitant AST >3 × ULN and / or ALT >3 × ULN will be excluded, regardless of the presence of lymphomatous infiltration of the liver. NOTE: Participants with known Gilbert syndrome were randomized to receive a total bilirubin Values ​​>4×ULN were excluded. NOTE: Patients with a calculated creatinine clearance <50 mL / min may be considered for enrollment if their measured creatinine clearance (based on a 24-h urine collection or other reliable method) is ≥50 mL / min. 9. Willing and able to comply with clinic and study related procedures. 10. Provide informed consent signed by the study participant or legally acceptable representative. 11. Able to understand and complete study-related questionnaires, with physical assistance as needed.

[0417] Exclusion criteria: Participants who meet any of the following criteria will be excluded from the study: 1. Primary central nervous system (CNS) lymphoma or known disease due to non-primary CNS NHL. 2. History of or current association with CNS pathology, such as: Epilepsy, seizures, paralysis, aphasia, stroke, severe brain injury, cerebellar disease, organic brain syndrome, psychiatric disorder, or b. Evidence of inflammatory lesions and / or vasculitis on brain MRI 3. Peripheral neuropathy grade ≥ 3 4. Another malignancy (other than B-NHL) within the last 5 years, except for non-melanoma skin cancer or non-invasive cervical cancer that has undergone potentially curative therapy, or any other tumor considered to have been effectively treated with curative intent with definitive local control. 5. Any other significant active disease or medical condition that may interfere with the study or place the participant at significant risk, including but not limited to significant cardiovascular disease (e.g., New York Heart Association class III or IV heart disease, myocardial infarction within the past 6 months, unstable arrhythmia, or unstable angina pectoris), or significant pulmonary disease (e.g., history of obstructive pulmonary disease and symptomatic bronchospasm). 6. Treatment with any systemic anti-lymphoma therapy. 7. Any investigational therapy within 28 days or 5 half-lives of the drug, whichever is shorter, prior to starting study treatment 8. Recent major surgery (within 4 weeks prior to initiation of study treatment). 9. Standard radiotherapy within 14 days of the first dose of study treatment. 10. Before organ transplant 11. Allergies / hypersensitivities: Known hypersensitivity to both allopurinol and rasburicase b. History of allergic reaction or hypersensitivity due to compounds of similar chemical or biological components contained in CHOP or rituximab 12. Infection: Evidence of any active infection (bacterial, viral, fungal, mycobacterial, parasitic, other) at or within 2 weeks of study enrollment if requiring ongoing treatment and / or if capable of causing disseminated disease or severe infection when immunosuppressed. There must be evidence that the infection has resolved or is well controlled by the time study therapy is started. b. Active COVID-19 infection c. Uncontrolled infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV) d. Cytomegalovirus (CMV) infection as demonstrated by detectable levels by peripheral blood polymerase chain reaction (PCR) assay. Patients who demonstrate detectable levels of CMV at screening will be required to be treated with appropriate antiviral therapy and will be required to demonstrate at least two undetectable levels of CMV by PCR assay (at least 7 days apart) before being reconsidered for eligibility. NOTE: HIV patients with controlled infection (either spontaneously or on a stable antiviral regimen, with an undetectable viral load and a CD4 count >350 cells / µL) are allowed. NOTE: Patients who are hepatitis B surface antigen positive or hepatitis B core antibody positive should be evaluated by an expert and considered to have their infection controlled (serum hepatitis B virus DNA PCR below the limit of detection and receiving antiviral therapy for hepatitis B) before being admitted to the study. NOTE: Patients who are HCV seropositive and have controlled infection (HCV RNA undetectable by PCR, either spontaneously or in response to a previous successful course of anti-HCV therapy) are accepted. 13. Receipt of live vaccination within 28 days of the first dose of the study (COVID-19 vaccines can be administered more than one week prior to the first dose) 14. Participants committed to the institution by order issued by either a judicial or administrative authority (German institutions only) 15.Being a member of the investigational site study team and / or their immediate family members only prior to approval by the sponsor. 16. Pregnant or breastfeeding women. 17. Women of childbearing potential (WOCBP)* or men who are not willing to use highly effective contraception prior to first dose / initiation of first treatment, throughout the study, and for at least 6 months after the last dose. Sperm donation is prohibited during the study and for 6 months after the last dose of assigned study treatment. Highly effective methods of contraception include: Stable use of a combined (estrogen- and progesterone-containing) hormonal contraceptive method associated with the inhibition of ovulation (oral, intravaginal, transdermal) or a progesterone-only hormonal contraceptive method (oral, injectable, implantable) initiated for at least two menstrual cycles prior to screening, b. Intrauterine device (IUD), intrauterine hormone releasing system (IUS) C. Bilateral tubal ligation / occlusion d. Vasectomy of a partner (provided that the vasectomized male partner is the WOCBP study participant's only sexual partner and that the vasectomized partner has received a medical evaluation of the surgical success of the procedure); e. Sexual abstinence

[0418] The study interventions administered in this study are shown in Table 25 below.

[0419] [Table 30]

[0420] Odronextamab will be administered for 21 days in combination with CHOP (O-CHOP) for 6 cycles. CHOP will be administered on C1D1, and odronextamab will be initiated on C1D8 to reduce the risk of CRS. During the induction period, odronextamab will be administered intravenously in step-up doses in cycles 1 and 2 to reduce the risk of CRS. The step-up doses consist of an initial dose of 0.7 mg (divided as 0.2 mg on C1D8 and 0.5 mg on C1D9), an intermediate dose 1 of 4 mg (divided as 2 mg on C1D15 and 2 mg on C1D16), followed by an intermediate dose 2 of 20 mg (divided as 10 mg on C2D1 and 10 mg on C2D2). From C2D8 to C5D1, odronextamab will be administered intravenously weekly at 80 mg or 160 mg on days 1 (except cycle 2), 8, and 15. Odronextamab will be administered Q2W starting on C5D8 and on C5D8, C6D1, and C6D15. See Table 30.

[0421] [Table 31]

[0422] For the initial dose, intermediate dose 1, and intermediate dos...

Claims

1. 1. A pharmaceutical composition for use in a method of treating a subject, comprising a bispecific antibody comprising a first antigen-binding region that binds to human CD20 and a second antigen-binding region that binds to human CD3, wherein the first antigen-binding region comprises three heavy chain complementarity-determining regions, HCDR1, HCDR2, and HCDR3, comprising the amino acid sequences of SEQ ID NOs: 7, 8, and 9, respectively, and three light chain complementarity-determining regions, LCDR1, LCDR2, and LCDR3, comprising the amino acid sequences of SEQ ID NOs: 13, 14, and 15, respectively; and the second antigen-binding region comprises three heavy chain complementarity-determining regions, HCDR1, HCDR2, and HCDR3, comprising the amino acid sequences of SEQ ID NOs: 10, 11, and 12, respectively, and three light chain complementarity-determining regions, LCDR1, LCDR2, and LCDR3, comprising the amino acid sequences of SEQ ID NOs: 13, 14, and 15, respectively; The method comprises administering the bispecific antibody to the subject in a dosing regimen, wherein the method is for treating: (I) B-cell malignancies, the administration regimen comprising: administering to the subject an initial dose of 0.7 mg of the bispecific antibody, wherein the initial dose is divided into a first dose fraction comprising 0.2 mg of the bispecific antibody and a second dose fraction comprising 0.5 mg of the bispecific antibody, and wherein the first dose fraction is administered to the subject followed by the second dose fraction over two days during week 1 of the dosing regimen; administering to the subject a first intermediate dose of 4 mg of the bispecific antibody, wherein the first intermediate dose is divided into two equal fractions (a first fraction and a second fraction) each containing 2 mg of the bispecific antibody, and the two fractions of the first intermediate dose are administered over two days during week two of the dosing regimen; administering to the subject a second intermediate dose of 20 mg of the bispecific antibody, wherein the second intermediate dose is divided into two equal fractions (a first fraction and a second fraction) each containing 10 mg of the bispecific antibody, and the two fractions of the second intermediate dose are administered over two days during week three of the dosing regimen; administering a full dose of the bispecific antibody to the subject weekly between weeks 4 and 12 of the dosing regimen; and at week 14 of the dosing regimen, administering to the subject a maintenance dose of the bispecific antibody. (II) B-cell malignancies, the administration regimen comprising: administering to the subject an initial dose of 1 mg or 2 mg of the bispecific antibody in week 1 of the dosing regimen; administering to the subject a first intermediate dose of 10 mg or 26 mg of the bispecific antibody during week two of the dosing regimen; administering to the subject a second intermediate dose of 50 mg or 100 mg of the bispecific antibody during week 3 of the dosing regimen; administering a full dose of the bispecific antibody to the subject on week 4 and subsequent weeks of the dosing regimen. (III) follicular lymphoma, the administration regimen comprising: administering to the subject an initial dose of 0.7 mg of the bispecific antibody, wherein the initial dose is divided into a first dose fraction comprising 0.2 mg of the bispecific antibody and a second dose fraction comprising 0.5 mg of the bispecific antibody, and wherein the first dose fraction is administered to the subject followed by the second dose fraction over two days during week 1 of the dosing regimen; administering to the subject a first intermediate dose of 4 mg of the bispecific antibody, wherein the first intermediate dose is divided into two equal fractions (a first fraction and a second fraction) each containing 2 mg of the bispecific antibody, and the two fractions of the first intermediate dose are administered over two days during week two of the dosing regimen; administering to the subject a second intermediate dose of 20 mg of the bispecific antibody, wherein the second intermediate dose is divided into two equal fractions (a first fraction and a second fraction) each containing 10 mg of the bispecific antibody, and the two fractions of the second intermediate dose are administered over two days during week three of the dosing regimen; administering to the subject a total dose of 40 mg or 80 mg of the bispecific antibody weekly between weeks 4 and 12 of the dosing regimen; At week 14 of the dosing regimen, administering to the subject a maintenance dose of 80 mg or 160 mg of the bispecific antibody; or (IV) diffuse large B-cell lymphoma, the administration regimen comprising: administering to the subject an initial dose of 0.7 mg of the bispecific antibody, wherein the initial dose is divided into a first dose fraction comprising 0.2 mg of the bispecific antibody and a second dose fraction comprising 0.5 mg of the bispecific antibody, and wherein the first dose fraction is administered to the subject followed by the second dose fraction over two days during week 1 of the dosing regimen; administering to the subject a first intermediate dose of 4 mg of the bispecific antibody, wherein the first intermediate dose is divided into two equal fractions (a first fraction and a second fraction) each containing 2 mg of the bispecific antibody, and the two fractions of the first intermediate dose are administered over two days during week two of the dosing regimen; administering to the subject a second intermediate dose of 20 mg of the bispecific antibody, wherein the second intermediate dose is divided into two equal fractions (a first fraction and a second fraction) each containing 10 mg of the bispecific antibody, and the two fractions of the second intermediate dose are administered over two days during week three of the dosing regimen; administering to the subject a total dose of 80 mg or 160 mg of the bispecific antibody weekly between weeks 4 and 12 of the dosing regimen; and at week 13 or 14 of the dosing regimen, administering to the subject a maintenance dose of 160 mg or 320 mg of the bispecific antibody. Pharmaceutical compositions.

2. (I) (A) the entire dose is administered to the subject as a single dose between weeks 4 and 12 of the dosing regimen; or (B) if the subject experiences a Grade 3 event of cytokine release syndrome when administered the initial dose, the first intermediate dose, or the second intermediate dose, then the total dose of the bispecific antibody administered to the subject in week 4 is divided into two equal fractions, and the two fractions of the total dose are administered over two days in week 4 of the dosing regimen, and the total dose is administered to the subject as a single dose between weeks 5 and 12 of the dosing regimen, optionally wherein the two fractions of the total dose are administered to the subject 18 to 96 hours apart. (II) the maintenance dose is administered to the subject every two weeks starting on week 14 of the dosing regimen. (III) the maintenance dose is administered to the subject every four weeks or every eight weeks starting on a subsequent week of the dosing regimen, and the subsequent week is at least week 36 of the dosing regimen. (IV) (A) the second dose fraction of the first dose is administered to the subject 18 to 96 hours after the first dose fraction of the first dose, and the two fractions of the first intermediate dose are administered to the subject 18 to 96 hours apart, and / or the two fractions of the second intermediate dose are administered to the subject 18 to 96 hours apart; or (B) the two days are no more than three days apart, and optionally, the two days are consecutive days; (V) the B cell malignancy is a B cell non-Hodgkin's lymphoma, optionally wherein the B cell malignancy is a follicular lymphoma, a diffuse large B cell lymphoma, a mantle cell lymphoma, or a marginal zone lymphoma. (VI) the total dose of the bispecific antibody is between 80 mg and 320 mg. (VII) the maintenance dose of the bispecific antibody is 160 mg to 320 mg. (VIII) (A) the cancer is follicular lymphoma, the total dose is 80 mg, and the maintenance dose is 160 mg, and optionally the follicular lymphoma is grade 1-3a. (B) the cancer is diffuse large B-cell lymphoma, the total dose is 160 mg, and the maintenance dose is 320 mg, and optionally the subject has failed a prior CAR-T therapy. (C) the cancer is diffuse large B-cell lymphoma, the total dose is 320 mg, and the maintenance dose is 320 mg, and optionally the subject has failed a prior CAR-T therapy. (D) the cancer is mantle cell lymphoma, the total dose is 160 mg, and the maintenance dose is 320 mg, and optionally the subject has failed prior Bruton's tyrosine kinase (BTK) inhibitor therapy. (E) the cancer is marginal zone lymphoma, the total dose is 80 mg, and the maintenance dose is 160 mg. (F) the cancer is follicular lymphoma, diffuse large B-cell lymphoma, mantle cell lymphoma, or non-Hodgkin's lymphoma other than marginal zone lymphoma, and the total dose is 160 mg and the maintenance dose is 320 mg; or (G) the cancer is aggressive lymphoma, the total dose is 160 mg, and the maintenance dose is 320 mg. (IX) (A) the subject has a documented CD20+ B-cell malignancy with active disease that has not responded to previous therapy, there are no standard treatment options for the subject, and treatment with an anti-CD20 antibody may be appropriate; or (B) the subject has documented progressive B-NHL and is receiving frontline therapy The cancer has recurred within one year of the procedure, and the patient intends to proceed with autologous stem cell transplantation (ASCT). (X) the subject has relapsed or refractory disease; (XI) the subject has relapsed or is refractory to at least two prior lines of systemic therapy, including an anti-CD20 antibody and an alkylating agent; (XII) the subject is refractory to an anti-CD20 antibody in any previous line of therapy. (XIII) the subject is dual refractory to alkylating agents and anti-CD20 antibodies in any prior line of therapy; (XIV) the subject is a human being 18 years of age or older, and / or (XV) the bispecific antibody is administered intravenously.

10. The dosing regimen according to claim 1(I).

3. (I) the initial dose is 2 mg; (II) the first intermediate dose is 26 mg; (III) the second intermediate dose is 100 mg; (IV) the total dose is 200 mg, 400 mg, or 600 mg, and optionally (V) the total dose is administered to the subject (A) Once every three weeks (B) weekly, or (C) administered weekly for three weeks, and then the entire dose is administered to the subject once every three weeks. (VI) the subject has relapsed or refractory disease; (VII) the subject is refractory to an anti-CD20 antibody in any previous line of therapy. (VIII) The B-cell malignancy (A) follicular lymphoma, or (B) Diffuse large B-cell lymphoma That is, (IX) the subject is a human being 18 years of age or older, and / or (X) the bispecific antibody is administered subcutaneously. A pharmaceutical composition according to claim 1 (II).

4. (I) the entire dose is administered to the subject as a single dose between weeks 4 and 12 of the dosing regimen; (II) the maintenance dose is administered to the subject (A) every two weeks starting at week 13 or 14 of the dosing regimen; or (B) Every four weeks or every eight weeks be administered, (III) the total dose is (A) 40 mg, or (B) 80 mg That is, (IV) The maintenance dose is (A) 80 mg, or (B) 160 mg That is, (V) the second dose fraction of the initial dose is administered to the subject 18 to 96 hours after the first dose fraction of the initial dose. (VI) the two fractions of the first intermediate dose are administered to the subject 18 to 96 hours apart, and / or (VII) the two fractions of the second intermediate dose are administered to the subject at an interval of 18 to 96 hours. A pharmaceutical composition according to claim 1 (III).

5. (I) the entire dose is administered to the subject as a single dose between weeks 4 and 12 of the dosing regimen; (II) the maintenance dose is administered to the subject (A) every two weeks starting at week 13 or 14 of the dosing regimen; or (B) Every four weeks or every eight weeks be administered, (III) the total dose is (A) 80 mg, or (B) 160 mg That is, (IV) The maintenance dose is (A) 160 mg, or (B) 320 mg That is, (V) the second dose fraction of the initial dose is administered to the subject 18 to 96 hours after the first dose fraction of the initial dose. (VI) the two fractions of the first intermediate dose are administered to the subject 18 to 96 hours apart, and / or (VII) the two fractions of the second intermediate dose are administered to the subject at an interval of 18 to 96 hours. A pharmaceutical composition according to claim 1 (IV).

6. (I) the dosing regimen further comprises administering a combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), and optionally, (A) the CHOP is administered the week prior to week 1 of the dosing regimen and again at weeks 3, 6, 9, 12, and 15 of the dosing regimen; and / or (B) The cyclophosphamide is 750 mg / m 2 and the doxorubicin is administered at a dose of 50 mg / m 2 and the vincristine is administered at a dose of 1.4 mg / m 2 wherein the prednisone is administered at a dose of 100 mg, the cyclophosphamide, doxorubicin, and vincristine are administered once during the week prior to week 1 of the dosing regimen and once during each of weeks 3, 6, 9, 12, and 15 of the dosing regimen, and the prednisone is administered for five consecutive days during the week prior to week 1 of the dosing regimen and for five consecutive days during each of weeks 3, 6, 9, 12, and 15 of the dosing regimen. (II) (A) The subject is (a) have relapsed or refractory disease; (b) refractory to anti-CD20 antibodies in any previous line of therapy; (c) double refractory to alkylating agents and anti-CD20 antibodies; and / or (d) have previously undergone an autologous stem cell transplant; or (B) the subject has not been previously treated with systemic anti-lymphoma therapy, and / or (III) the bispecific antibody is administered intravenously to the subject. The pharmaceutical composition of claim 1.

7. (I) the first antigen-binding region of the bispecific antibody comprises a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 4 and a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 6, and the second antigen-binding region of the bispecific antibody comprises an HCVR comprising the amino acid sequence of SEQ ID NO: 5 and an LCVR comprising the amino acid sequence of SEQ ID NO: 6; (II) the bispecific antibody comprises a human IgG heavy chain constant region, and optionally (A) the human IgG heavy chain constant region is of isotype IgG1; or (B) the human IgG heavy chain constant region is of isotype IgG4; (III) the bispecific antibody comprises a first heavy chain constant region comprising the amino acid sequence of SEQ ID NO: 16 and a second heavy chain constant region comprising the amino acid sequence of SEQ ID NO:

17. (IV) the bispecific antibody comprises a first heavy chain constant region comprising the amino acid sequence of SEQ ID NO: 18 and a second heavy chain constant region comprising the amino acid sequence of SEQ ID NO:

19. (V) the bispecific antibody comprises a first heavy chain comprising amino acid residues 1 to 452 of SEQ ID NO: 1 paired with a common light chain comprising the amino acid sequence of SEQ ID NO: 3, and a second heavy chain comprising amino acid residues 1 to 448 of SEQ ID NO: 2 paired with a common light chain comprising the amino acid sequence of SEQ ID NO: 3, or (VI) the bispecific antibody comprises a first heavy chain comprising the amino acid sequence of SEQ ID NO: 1 paired with a common light chain comprising the amino acid sequence of SEQ ID NO: 3, and a second heavy chain comprising the amino acid sequence of SEQ ID NO: 2 paired with a common light chain comprising the amino acid sequence of SEQ ID NO:

3. The pharmaceutical composition according to any one of claims 1 to 6.

8. the dosing regimen further comprises administering to the subject a dose of a steroid 12 to 24 hours prior to administration of the first dose fraction of the initial dose, 12 to 24 hours prior to administration of the first fraction of the first intermediate dose, and 12 to 24 hours prior to administration of the first fraction of the second intermediate dose; and optionally (I) if the first dose fraction of the initial dose and the second dose fraction of the initial dose are not administered to the subject on consecutive days, the dosing regimen further comprises administering to the subject a dose of a steroid 12 to 24 hours prior to administration of the second dose fraction of the initial dose of the bispecific antibody. (II) if the first fraction of the first intermediate dose and the second fraction of the first intermediate dose are not administered to the subject on consecutive days, the dosing regimen further comprises administering to the subject a dose of a steroid 12 to 24 hours prior to administration of the second fraction of the first intermediate dose of the bispecific antibody. (III) if the first fraction of the second intermediate dose and the second fraction of the second intermediate dose are not administered to the subject on consecutive days, the dosing regimen further comprises administering to the subject a dose of a steroid 12 to 24 hours prior to administration of the second fraction of the second intermediate dose of the bispecific antibody. (IV) The dosing regimen comprises: administering to the subject a dose of a steroid 1 to 3 hours prior to administration of the first dose fraction of the initial dose, 1 to 3 hours prior to administration of the second dose fraction of the initial dose, and 1 to 3 hours prior to administration of each fraction of the first intermediate dose and the second intermediate dose; administering to the subject a dose of an antihistamine 30 to 60 minutes prior to administration of the first dose fraction of the initial dose, 30 to 60 minutes prior to administration of the second dose fraction of the initial dose, and 30 to 60 minutes prior to administration of each fraction of the first intermediate dose and the second intermediate dose, optionally wherein the dosing regimen further comprises administering to the subject a dose of acetaminophen 30 to 60 minutes prior to administration of the first dose fraction of the initial dose, 30 to 60 minutes prior to administration of the second dose fraction of the initial dose, and 30 to 60 minutes prior to administration of each fraction of the first intermediate dose and the second intermediate dose; and / or (V) the dosing regimen further comprises administering to the subject a dose of a steroid 20 to 28 hours after the end of administration of the second dose fraction of the initial dose, 20 to 28 hours after the end of administration of the second fraction of the first intermediate dose, and 20 to 28 hours after the end of administration of the second fraction of the second intermediate dose; and / or (VI) the dosing regimen comprises: administering to the subject a dose of a steroid 1 to 3 hours prior to said administration of all of said doses during week 4 of said dosing regimen; administering to the subject a dose of an antihistamine 30 to 60 minutes prior to said administration of all of said doses during week 4 of the dosing regimen, optionally wherein the dosing regimen further comprises administering to the subject a dose of acetaminophen 30 to 60 minutes prior to said administration of all of said doses during week 4 of the dosing regimen, and further optionally wherein the dosing regimen further comprises administering to the subject a dose of a steroid 20 to 28 hours after completion of said administration of all of said doses during week 4 of the dosing regimen. The pharmaceutical composition according to any one of claims 1 to 6.

9. if the subject experiences a Grade 3 event of cytokine release syndrome when administered the initial dose, the first intermediate dose, or the second intermediate dose, then the total dose of the bispecific antibody administered to the subject in week 4 is divided into two equal fractions (a first fraction and a second fraction), and the two fractions of the total dose are administered over two days in week 4 of the dosing regimen, wherein the dosing regimen further comprises administering to the subject a dose of steroid 12-24 hours prior to the administration of the first fraction of the total dose; and optionally (A) if the first fraction of the total dose and the second fraction of the total dose are not administered to the subject on consecutive days, the dosing regimen further comprises administering to the subject a dose of a steroid 12 to 24 hours prior to administration of the second fraction of the total dose of the bispecific antibody. (B) the administration regimen comprises: administering to said subject a dose of a steroid 1 to 3 hours prior to said administration of said first fraction of said total dose; administering to the subject a dose of an antihistamine 30 to 60 minutes prior to said administration of the first fraction of the total dose, and optionally, the dosing regimen further comprises administering to the subject a dose of acetaminophen 30 to 60 minutes prior to said administration of the first fraction of the total dose. (C) the administration regimen comprises: administering to the subject a dose of a steroid 1 to 3 hours prior to said administration of all of said doses during week 5 of said dosing regimen; 9. The pharmaceutical composition of claim 8, further comprising administering to the subject a dose of an antihistamine 30 to 60 minutes prior to said administration of all of said doses during week 5 of said dosing regimen, optionally wherein said dosing regimen further comprises administering to the subject a dose of acetaminophen 30 to 60 minutes prior to said administration of all of said doses during week 5 of said dosing regimen, and further optionally wherein said dosing regimen further comprises administering to the subject a dose of a steroid 20 to 28 hours after completion of said administration of all of said doses during week 5 of said dosing regimen.

10. (I) (A) administering a dose of a steroid, administering a dose of an antihistamine, or administering a dose of acetaminophen comprises instructing the subject to take the dose of a steroid, the dose of an antihistamine, or the dose of acetaminophen, respectively; or (B) administering a dose of a steroid or administering a dose of an antihistamine comprises intravenously administering the dose of a steroid or the dose of an antihistamine. (II) the steroid is dexamethasone, and optionally, the dose of the steroid is 20 mg; (III) the antihistamine is diphenhydramine, and optionally the dose of the antihistamine is 25 mg; and / or (IV) the dose of acetaminophen is 650 mg; The pharmaceutical composition according to claim 8.

11. The pharmaceutical composition according to any one of claims 1 to 6, wherein the administration regimen further comprises administration of an anti-IL-6 receptor antibody, and optionally the anti-IL-6 receptor antibody is tocilizumab or sarilumab.

12. The method is for treating a B-cell cancer in a subject, the method comprising: selecting a subject diagnosed with B-cell cancer; Administering the bispecific antibody to the subject according to the dosing regimen of any one of claims 1 to 6; The pharmaceutical composition according to any one of claims 1 to 6, comprising:

13. (I) The subject is (a) diagnosed with follicular lymphoma; (b) diagnosed with grade 1-3a follicular lymphoma; (c) diagnosed with relapsed or refractory follicular lymphoma after at least two prior lines of systemic therapy; (d) diagnosed with follicular lymphoma and not previously treated with systemic anti-lymphoma therapy; (e) has been diagnosed with follicular lymphoma and the total dose is 80 mg; and / or (f) diagnosed with follicular lymphoma and the maintenance dose is 160 mg or 320 mg; The pharmaceutical composition of claim 12.

14. The object is (A) diagnosed with diffuse large B-cell lymphoma (DLBCL); (B) has been diagnosed with DLBCL, wherein the DLBCL is de novo or has transformed from a lower grade neoplasm; (C) diagnosed with DLBCL that is refractory to at least two prior lines of systemic therapy; (D) diagnosed with relapsed or refractory DLBCL after at least two prior lines of systemic therapy, including CAR-T therapy; (E) diagnosed with DLBCL and not previously treated with systemic anti-lymphoma therapy; (F) diagnosed with DLBCL and the total dose is 160 mg; and / or (G) Diagnosed with DLBCL and the maintenance dose is 320 mg. The pharmaceutical composition of claim 12.

15. (i) a container containing the bispecific antibody of any one of claims 1 to 6; and (ii) a label comprising instructions for administering the bispecific antibody according to the dosing regimen of any one of claims 1 to 6, and optionally further comprising instructions for administering a steroid and an antihistamine and / or an anti-IL-6 receptor antibody. A pharmaceutical kit comprising:

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