Methods for Treating Lymphoma

Abstract

Provided herein, in certain aspects, is a method for treating lymphoma comprising administration of a CD19 antibody, a CD3xCD20 multispecific antibody, and 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione (Compound A).

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 337,941, filed May 3, 2022, and U.S. Provisional Patent Application No. 63 / 340,909, filed May 11, 2022, the contents of each of which are incorporated by reference in their entirety herein.

[0002] Reference to Electronically Submitted Sequence Listings This application contains a computer readable sequence listing submitted herewith in XML file format, the entire contents of which are incorporated herein by reference in their entirety. The sequence listing XML file submitted herewith, entitled "14718-043-228_SEQLISTING.xml", was created on April 5, 2023, and is 54,710 bytes in size.

[0003] 1. Field As used herein, in certain aspects, there are provided CD19 antibodies, CD3xCD20 multispecific antibodies, and compounds having the structure [ka] (i.e., 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione (Compound A)), or, for example, a pharma- ceutically acceptable salt, solvate, or stereoisomer combination thereof of Compound A is provided for treating lymphoma. Summary of the Invention

[0004] 2. Overview of the Invention Provided herein in one aspect is a method of treating lymphoma in a subject in need thereof, comprising administering to the subject (a) an antibody that binds to CD19 (a CD19 antibody), (b) a multispecific antibody that comprises a first binding domain that binds to CD3 and a second binding domain that binds to CD20 (a CD3xCD20 antibody), and (c) a compound having the following structure: [ka] (i.e., 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione (Compound A)), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof. In a specific embodiment, the subject is administered a first dose of a CD19 antibody at least one day prior to administering (i) a first dose of Compound A, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, or (ii) a first dose of a CD3xCD20 antibody to the subject.

[0005] In one embodiment, the CD19 antibody comprises (i) a heavy chain variable (VH) domain comprising a VH complementarity determining region (CDR)1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NO:1, SEQ ID NO:2, and SEQ ID NO:3, respectively, and (ii) a light chain variable (VL) domain comprising a VL CDR1, a VL CDR2, and a VL CDR3 having the amino acid sequences of SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6, respectively. In one embodiment, a first binding domain of a CD3xCD20 antibody that binds to CD3 comprises (i) a VH domain comprising a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NO:7, SEQ ID NO:8, and SEQ ID NO:9, respectively, and (ii) a VL domain comprising a VL CDR1, a VL CDR2, and a VL CDR3 having the amino acid sequences of SEQ ID NO:10, SEQ ID NO:11, and SEQ ID NO:12, respectively. In one embodiment, the second binding domain of a CD3xCD20 antibody that binds to CD20 comprises (i) a VH domain comprising a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NO:13, SEQ ID NO:14, and SEQ ID NO:15, respectively, and (ii) a VL domain comprising a VL CDR1, a VL CDR2, and a VL CDR3 having the amino acid sequences of SEQ ID NO:16, SEQ ID NO:17, and SEQ ID NO:18, respectively.In another embodiment, (a) the CD19 antibody comprises (i) a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NO:1, SEQ ID NO:2, and SEQ ID NO:3, respectively, and (ii) a VL CDR1, a VL CDR2, and a VL CDR3 having the amino acid sequences of SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6, respectively; (b) a first binding domain of the CD3xCD20 antibody that binds to CD3 comprises (i) a VH domain that comprises a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NO:7, SEQ ID NO:8, and SEQ ID NO:9, respectively, and (ii) a VL domain that comprises a VL CDR1, a VL CDR2, and a VL CDR3 having the amino acid sequences of SEQ ID NO:10, SEQ ID NO:11, and SEQ ID NO:12, respectively; and (c) a second binding domain of the CD3xCD20 antibody that binds to CD20 comprises (i) a VH domain that comprises a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NO:13, SEQ ID NO:14, and SEQ ID NO:15, respectively. and (ii) a VH domain comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NO:16, SEQ ID NO:17, and SEQ ID NO:18, respectively.

[0006] In one embodiment, the CD19 antibody comprises a VH domain having an amino acid sequence that is about 90%, 95%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 19. In another embodiment, the CD19 antibody comprises a VL domain having an amino acid sequence that is about 90%, 95%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 20. In one embodiment, a first binding domain of a CD3xCD20 antibody that binds to CD3 comprises a VH domain having an amino acid sequence that is about 90%, 95%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO:21.

[0007] In one embodiment, a first binding domain of a CD3xCD20 antibody that binds CD3 comprises a VL domain having an amino acid sequence that is about 90%, 95%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 22. In one embodiment, a second binding domain of a CD3xCD20 antibody that binds CD20 comprises a VH domain having an amino acid sequence that is about 90%, 95%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 23. In one embodiment, a second binding domain of a CD3xCD20 antibody that binds CD20 comprises a VL domain having an amino acid sequence that is about 90%, 95%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 24.

[0008] In one embodiment, the CD3xCD20 antibody comprises: (a) a first monomer comprising, from N-terminus to C-terminus, an scFv-linker-CH2-CH3 having the amino acid sequence of SEQ ID NO:25; (b) a second monomer comprising, from N-terminus to C-terminus, a VH-CH1-hinge-CH2-CH3 having the amino acid sequence of SEQ ID NO:26; and (c) a third monomer comprising, from N-terminus to C-terminus, a VL-CL having the amino acid sequence of SEQ ID NO:27.

[0009] In one embodiment, the compound is [ka] (i.e., 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione (Compound A)).

[0010] In one embodiment, the lymphoma is a non-Hodgkin's lymphoma. In one embodiment, the non-Hodgkin's lymphoma is a diffuse large cell lymphoma (DLBCL). In one embodiment, the DLBCL is a relapsed DLBCL, a refractory DLBCL, or a relapsed-refractory DLBCL. In one embodiment, the DLBCL is a primary refractory DLBCL. In one embodiment, the DLBCL is a first-line DLBCL. In one embodiment, the lymphoma is a CD20-expressing lymphoma. In one embodiment, the lymphoma is a CD19-expressing lymphoma. In one embodiment, the subject has not undergone a stem cell transplant. In one embodiment, the subject is not eligible for a stem cell transplant. In one embodiment, the stem cell transplant is an autologous stem cell transplant.

[0011] In one embodiment, the method comprises cyclic administration of a CD19 antibody, Compound A, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, and a CD3xCD20 antibody. In one embodiment, each cycle of the cyclic administration is 28 days. In one embodiment, the cyclic administration comprises about 1 cycle, 2 cycles, 3 cycles, 4 cycles, 5 cycles, 6 cycles, 7 cycles, 8 cycles, 9 cycles, 10 cycles, 11 cycles, 12 cycles, or more than 12 cycles.

[0012] In one embodiment, the first administration of the CD19 antibody is administered to the subject prior to day 1 of the first cycle of the cyclical administration. In one embodiment, the first administration of the CD19 antibody is administered to the subject at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more than 10 days prior to day 1 of the first cycle of the cyclical administration. In one embodiment, the first administration of the CD19 antibody is administered to the subject 4 days prior to day 1 of the first cycle of the cyclical administration. In one embodiment, the CD19 antibody is administered to the subject 8 days prior to day 1 of the first cycle of the cyclical administration. In one embodiment, the CD19 antibody is administered to the subject 4 and 8 days prior to day 1 of the first cycle of the cyclical administration. In one embodiment, the CD19 antibody is administered to the subject on day 1, 8, 15, and / or 22 (or more) of the cycle of the cyclical administration. In one embodiment, the CD19 antibody is administered to the subject on days 1, 8, 15, and 22 of a cycle of cyclical administration. In one embodiment, the CD19 antibody is administered to the subject on days 1 and 15 of a cycle of cyclical administration. In one embodiment, the CD19 antibody is administered to the subject on days 1, 8, 15, and 22 of each of cycles 1 to 3 of cyclical administration. In one embodiment, the CD19 antibody is administered to the subject on days 1 and 15 of cycles 4 and thereafter of cyclical administration. In one embodiment, the CD19 antibody is administered to the subject on days 1 and 15 of cycles 4 to 6 of cyclical administration. In one embodiment, the CD19 antibody is administered to the subject every 6 to 8 days in a cycle of cyclical administration.

[0013] In one embodiment, Compound A, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, is administered to a subject for 21 consecutive days in a cyclical administration. In one embodiment, Compound A, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, is administered to a subject on days 1-21 of the cyclical administration. In one embodiment, Compound A, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, is administered to a subject for 21 days in a 28-day cycle of cyclical administration, followed by a 7-day rest period.

[0014] In one embodiment, the CD3xCD20 antibody is administered to the subject on days 1, 8, 15, and / or 22 (may be multiples) of a cycle of cyclical administration. In one embodiment, the CD3xCD20 antibody is administered to the subject on days 1, 8, 15, and 22 of a cycle of cyclical administration. In one embodiment, the CD3xCD20 antibody is administered to the subject on days 1 and 15 of a cycle of cyclical administration. In one embodiment, the CD3xCD20 antibody is administered to the subject on days 1, 8, 15, and 22 of cycle 1 and cycle 2 of cyclical administration. In one embodiment, the CD3xCD20 antibody is administered to the subject on days 1 and 15 of cycle 3 and thereafter of cyclical administration. In one embodiment, the CD3xCD20 antibody is administered to the subject on days 1 and 15 of cycles 3-6 of cyclical administration. In one embodiment, the CD3xCD20 antibody is administered to a subject every 6-8 days in a periodic administration cycle.

[0015] In one embodiment, the CD19 antibody is administered to the subject in an amount of about 1 mg / kg to about 20 mg / kg per day. In one embodiment, the CD19 antibody is administered to the subject in an amount of about 12 mg / kg per day. In one embodiment, the CD19 antibody is administered to the subject in an amount of about 5 mg / kg per day. In one embodiment, the CD19 antibody is administered to the subject in an amount of about 10 mg / kg per day.

[0016] In one embodiment, Compound A, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, is administered to the subject in an amount of about 1 mg to about 30 mg per day. In one embodiment, Compound A, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, is administered to the subject in an amount of about 2.5 mg, 5 mg, 10 mg, 15 mg, 20 mg, or 25 mg per day. In one embodiment, Compound A, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, is administered to the subject in an amount of about 2.5 mg per day. In one embodiment, Compound A, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, is administered to the subject in an amount of about 5 mg per day. In one embodiment, Compound A, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, is administered to the subject in an amount of about 10 mg per day. In one embodiment, Compound A, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, is administered to a subject in an amount of about 15 mg per day. In one embodiment, Compound A, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, is administered to a subject in an amount of about 20 mg per day. In one embodiment, Compound A, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, is administered to a subject in an amount of about 25 mg per day.

[0017] In one embodiment, the CD3xCD20 antibody is administered to the subject in an amount of about 0.8 mg to about 100 mg per day. In one embodiment, the CD3xCD20 antibody is administered to the subject in an amount of about 0.8 mg to about 50 mg per day. In one embodiment, the CD3xCD20 antibody is administered to the subject in an amount of about 0.8 mg to about 20 mg per day. In one embodiment, the CD3xCD20 antibody is administered to the subject in an amount of about 0.8 mg per day. In one embodiment, the CD3xCD20 antibody is administered to the subject in an amount of about 2 mg per day. In one embodiment, the CD3xCD20 antibody is administered to the subject in an amount of about 20 mg per day. In one embodiment, the CD3xCD20 antibody is administered to the subject in an amount of about 35 mg per day. In one embodiment, the CD3xCD20 antibody is administered to the subject in an amount of about 50 mg per day.

[0018] In one embodiment, the initial administration of the CD3xCD20 antibody is performed on day 1 of the first cycle of the cyclical administration. In one embodiment, the CD3xCD20 antibody is administered to the subject in an amount of about 0.8 mg on day 1 of the first cycle, about 2 mg on day 8 of the first cycle, about 20 mg on days 15 and 22 of the first cycle, and about 20 mg per day in any subsequent cycle. In one embodiment, the CD3xCD20 antibody is administered to the subject in an amount of about 0.8 mg on day 1 of the first cycle, about 2 mg on day 8 of the first cycle, about 20 mg on day 15 of the first cycle, about 35 mg on day 22 of the first cycle, and about 50 mg per day in any subsequent cycle.

[0019] In one embodiment, the initial administration of Compound A, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, is performed on day 1 of the first cycle of the cyclical administration.

[0020] In one embodiment, the first administration of the CD3xCD20 antibody and the first administration of Compound A, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, are both administered on day 1 of the first cycle of the cyclical administration.

[0021] In one embodiment, the CD19 antibody is administered to the subject once a week in a cycle of cyclic administration. In one embodiment, the CD19 antibody is administered to the subject once a week in cycles 1 to 3 of the cyclic administration. In one embodiment, the CD19 antibody is administered to the subject every two weeks in a cycle of cyclic administration. In one embodiment, the CD19 antibody is administered to the subject every two weeks in cycles 4 and onward of the cyclic administration. In one embodiment, the CD3xCD20 antibody is administered to the subject once a week in a cycle of cyclic administration. In one embodiment, the CD3xCD20 antibody is administered to the subject once a week in cycles 1 and 2 of the cyclic administration. In one embodiment, the CD3xCD20 antibody is administered to the subject every two weeks in a cycle of cyclic administration. In one embodiment, the CD3xCD20 antibody is administered to the subject every two weeks in cycles 3 and onward of the cyclic administration. In one embodiment, the CD3xCD20 antibody and the CD19 antibody are each administered to the subject for up to four days in a periodic administration cycle.

[0022] In one embodiment, the method comprises cyclically administering a CD3xCD20 antibody to a subject, wherein a first cycle comprises administering to the subject about 0.8 mg of CD3xCD20 antibody on day 1, about 2 mg on about day 8, about 20 mg on about day 15, and about 20 mg on about day 22, wherein about 20 mg of CD3xCD20 antibody is administered to the subject on day 1 and every 6-8 days in a second cycle of the cyclical administration, wherein the CD3xCD20 antibody is administered to the subject four times in each of the first two cycles, and wherein about 20 mg of CD3xCD20 antibody is administered to the subject on day 1 and every 12-16 days in cycle 3 and any subsequent cycles during the treatment period, wherein each cycle of the cyclical administration is 28 days.

[0023] In one embodiment, the method comprises cyclically administering a CD3xCD20 antibody to a subject, wherein a first cycle comprises administering to the subject about 0.8 mg of CD3xCD20 antibody on day 1, about 2 mg on about day 8, about 20 mg on about day 15, and about 35 mg on about day 22, wherein about 50 mg of CD3xCD20 antibody is administered to the subject on day 1 and every 6-8 days in a second cycle of the cyclical administration, wherein the CD3xCD20 antibody is administered to the subject four times in each of the first two cycles, and wherein about 50 mg of CD3xCD20 antibody is administered to the subject on day 1 and every 12-16 days in cycle 3 and any subsequent cycles during the treatment period, wherein each cycle of the cyclical administration is 28 days.

[0024] In one embodiment, the method comprises cyclically administering a CD3xCD20 antibody to a subject, wherein a first cycle comprises administering to the subject about 0.8 mg of CD3xCD20 antibody on day 1, about 2 mg on day 8, about 20 mg on day 15, and about 20 mg on day 22, wherein about 20 mg of CD3xCD20 antibody is administered to the subject on day 1 and every 7 days in the first two cycles of the cyclical administration, wherein the CD3xCD20 antibody is administered to the subject four times in each of the first two cycles, and about 20 mg of CD3xCD20 antibody is administered to the subject on day 1 and every 14 days in cycle 3 and any subsequent cycles during the treatment period, wherein each cycle of the cyclical administration is 28 days.

[0025] In one embodiment, the method comprises cyclically administering a CD3xCD20 antibody to a subject, wherein a first cycle comprises administering to the subject about 0.8 mg of CD3xCD20 antibody on day 1, about 2 mg on day 8, about 20 mg on day 15, and about 35 mg on day 22, wherein about 50 mg of CD3xCD20 antibody is administered to the subject on day 1 and every 7 days in the first two cycles of the cyclical administration, wherein the CD3xCD20 antibody is administered to the subject four times in each of the first two cycles, and about 50 mg of CD3xCD20 antibody is administered to the subject on day 1 and every 14 days in cycle 3 and any subsequent cycles during the treatment period, wherein each cycle of the cyclical administration is 28 days.

[0026] In one embodiment, the method comprises cyclically administering a CD19 antibody to the subject, wherein about 10 mg / kg to about 15 mg / kg of the CD19 antibody is administered to the subject on day 1 and every 6-8 days in the first three cycles of the cyclical administration, wherein the CD19 antibody is administered to the subject four times in each of the first three cycles, wherein about 10 mg / kg to about 15 mg / kg of the CD19 antibody is administered to the subject on day 1 and every 12-16 days in cycle 4 and any subsequent cycles during the treatment period, wherein about 10 mg / kg to about 15 mg / kg of the CD19 antibody is administered to the subject 8 days and 4 days prior to day 1 of the first cycle of the cyclical administration, wherein each cycle of the cyclical administration is 28 days.

[0027] In one embodiment, the method comprises cyclically administering a CD19 antibody to a subject, wherein about 12 mg / kg of the CD19 antibody is administered to the subject on day 1 and every 7 days in the first three cycles of the cyclical administration, wherein the CD19 antibody is administered to the subject four times in each of the first three cycles, wherein about 12 mg / kg of the CD19 antibody is administered to the subject on day 1 and every 14 days in cycle 4 and any subsequent cycles during the treatment period, wherein about 12 mg / kg of the CD19 antibody is administered to the subject 8 days and 4 days prior to day 1 of the first cycle of the cyclical administration, wherein each cycle of the cyclical administration is 28 days.

[0028] In one embodiment, the method includes cyclically administering Compound A, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, to a subject, wherein about 25 mg of Compound A, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, is administered to the subject daily on days 1 and 21 of each cycle of the cyclical administration, followed by a 7-day rest period, such that each cycle of the cyclical administration is 28 days.

[0029] In one embodiment, the method includes cyclically administering to a subject a CD19 antibody, a CD3xCD20 antibody, and Compound A, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, the method comprising: (a) administering to the subject about 0.6 to about 1 mg of CD3xCD20 antibody on day 1, about 1.8 mg to about 2.2 mg on about day 8, and about 18 mg to about 22 mg on about days 15 and 22 in a first cycle of the cyclical administration, and administering to the subject about 20 mg of CD3xCD20 antibody on day 1 and every 6-8 days in a second cycle, wherein the CD3xCD20 antibody is administered to the subject four times in each of the first two cycles, and about 20 mg of CD3xCD20 antibody is administered to the subject on day 1 and every 12-16 days in cycle 3 and any subsequent cycles during the treatment period; and (b) administering to the subject about 0.6 to about 1 mg of CD3xCD20 antibody on day 1, about 1.8 mg to about 2.2 mg on about day 8, and about 18 mg to about 22 mg on about days 15 and 22 in a first cycle of the cyclical administration, and administering to the subject about 20 mg of CD3xCD20 antibody on day 1 and every 6-8 days in a second cycle, wherein the CD3xCD20 antibody is administered to the subject four times in each of the first two cycles, and (c) administering to the subject about 25 mg of Compound A, or a pharmacokinetically acceptable salt, solvate, or stereoisomer thereof, on day 1 and daily for 21 days of each cycle of the cyclical administration, followed by a 7-day rest period, wherein each cycle of the cyclical administration is 28 days.

[0030] In one embodiment, the method includes cyclically administering to a subject a CD19 antibody, a CD3xCD20 antibody, and Compound A, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, the method comprising: (a) administering to the subject about 0.6 to about 1 mg of CD3xCD20 antibody on day 1, about 1.8 mg to about 2.2 mg on about day 8, about 18 mg to about 22 mg on about day 15, and about 33 mg to about 36 mg on about day 22 of a first cycle of the cyclical administration, and administering to the subject about 50 mg of CD3xCD20 antibody on day 1 and every 6-8 days in a second cycle, wherein the CD3xCD20 antibody is administered to the subject four times in each of the first two cycles, and about 50 mg of CD3xCD20 antibody is administered to the subject on day 1 and every 12-16 days in cycle 3 and any subsequent cycles during the treatment period; and (b) administering to the subject about 0.6 to about 1 mg of CD3xCD20 antibody on day 1, about 1.8 mg to about 2.2 mg on about day 8, about 18 mg to about 22 mg on about day 15, and about 33 mg to about 36 mg on about day 22 of a first cycle of the cyclical administration. and (c) administering to the subject about 25 mg of Compound A, or a pharmacologic agent thereof, on day 1 and every 21 days of each of the cyclical administration cycles, wherein each cycle of the cyclical administration is 28 days.

[0031] In one embodiment, the method includes cyclically administering to a subject a CD19 antibody, a CD3xCD20 antibody, and Compound A, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, the method comprising: (a) administering to the subject about 0.8 mg of CD3xCD20 antibody on day 1, about 2 mg on day 8, and about 20 mg on days 15 and 22 of a first cycle of the cyclical administration, and administering to the subject about 20 mg of CD3xCD20 antibody on day 1 and every 7 days in a second cycle, wherein the CD3xCD20 antibody is administered to the subject four times in each of the first two cycles, and about 20 mg of CD3xCD20 antibody is administered to the subject on day 1 and every 14 days in cycle 3 and any subsequent cycles during the treatment period; and (b) administering to the subject about 0.8 mg of CD3xCD20 antibody on day 1, about 2 mg on day 8, and about 20 mg on days 15 and 22 of a first cycle of the cyclical administration, and administering to the subject about 20 mg of CD3xCD20 antibody on day 1 and every 7 days in cycle 3 of the first cycle of the cyclical administration. (c) administering about 25 mg of Compound A, or a pharmacokinetically acceptable salt, solvate, or stereoisomer thereof, to the subject daily on days 1 and every 21 days of each cycle of the cyclical administration, wherein each cycle of the cyclical administration is 28 days, and wherein the CD19 antibody is administered to the subject four times in each of the first three cycles, and about 12 mg / kg of the CD19 antibody is administered to the subject on day 1 and every 14 days in cycle 4 and any subsequent cycles during the treatment period, and about 12 mg / kg of the CD19 antibody is administered to the subject 8 days and 4 days prior to day 1 of the first cycle of the cyclical administration; and (b) administering about 25 mg of Compound A, or a pharmacokinetically acceptable salt, solvate, or stereoisomer thereof, to the subject daily on days 1 and 21 days of each cycle of the cyclical administration, followed by a 7-day rest period, wherein each cycle of the cyclical administration is 28 days.

[0032] In one embodiment, the method includes cyclically administering to a subject a CD19 antibody, a CD3xCD20 antibody, and Compound A, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, the method comprising: (a) administering to the subject about 0.8 mg of CD3xCD20 antibody on day 1, about 2 mg on day 8, about 20 mg on day 15, and about 35 mg on day 22 of a first cycle of the cyclical administration, and administering to the subject about 50 mg of CD3xCD20 antibody on day 1 and every 7 days in a second cycle, wherein the CD3xCD20 antibody is administered to the subject four times in each of the first two cycles, and about 50 mg of CD3xCD20 antibody is administered to the subject on day 1 and every 14 days in cycle 3 and any subsequent cycles during the treatment period; and (b) administering to the subject about 0.8 mg of CD3xCD20 antibody on day 1, about 2 mg on day 8, about 20 mg on day 15, and about 35 mg on day 22 of a first cycle of the cyclical administration, and administering to the subject about 50 mg of CD3xCD20 antibody on day 1 and every 7 days in a second cycle, wherein the CD3xCD20 antibody is administered to the subject four times in each of the first two cycles, and about 50 mg of CD3xCD20 antibody is administered to the subject on day 1 and every 14 days in cycle 3 and any subsequent cycles during the treatment period. (c) administering to the subject about 25 mg of Compound A, or a pharmacokinetically acceptable salt, solvate, or stereoisomer thereof, daily on days 1 and 21 of each cycle of the cyclical administration, wherein each cycle of the cyclical administration is 28 days, and wherein the CD19 antibody is administered to the subject four times in each of the first three cycles, and about 12 mg / kg of the CD19 antibody is administered to the subject on day 1 and every 14 days in cycle 4 and any subsequent cycles during the treatment period, and about 12 mg / kg of the CD19 antibody is administered to the subject 8 days and 4 days prior to day 1 of the first cycle of the cyclical administration; and (d) administering to the subject about 25 mg of Compound A, or a pharmacokinetically acceptable salt, solvate, or stereoisomer thereof, daily on days 1 and 21 of each cycle of the cyclical administration, followed by a 7-day rest period, wherein each cycle of the cyclical administration is 28 days.

[0033] In one embodiment, the method includes cyclically administering to a subject a CD19 antibody, a CD3xCD20 antibody, and Compound A, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, the method comprising: (a) administering to the subject about 0.8 mg of CD3xCD20 antibody on day 1, about 2 mg on day 8, and about 20 mg on days 15 and 22 of a first cycle of the cyclical administration, and administering to the subject about 20 mg of CD3xCD20 antibody on days 1, 8, 15, and 22 of a second cycle, wherein about 20 mg of CD3xCD20 antibody is administered to the subject on days 1 and 15 of cycle 3 and any subsequent cycles during the treatment period; and (b) administering to the subject about 0.8 mg of CD3xCD20 antibody on day 1, about 2 mg on day 8, and about 20 mg on days 15 and 22 of a first cycle of the cyclical administration, (c) administering about 25 mg of Compound A, or a pharmacokinetically acceptable salt, solvate, or stereoisomer thereof, to the subject daily on days 1 and 21 of each cycle of the cyclical administration, during the treatment period, followed by a 7-day washout period, wherein each cycle of the cyclical administration is 28 days.

[0034] In one embodiment, the method includes cyclically administering to a subject a CD19 antibody, a CD3xCD20 antibody, and Compound A, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, the method comprising: (a) administering to the subject about 0.8 mg of CD3xCD20 antibody on day 1, about 2 mg on day 8, about 20 mg on day 15, and about 35 mg on day 22 of a first cycle of the cyclical administration, and administering to the subject about 50 mg of CD3xCD20 antibody on days 1, 8, 15, and 22 of a second cycle, wherein about 50 mg of CD3xCD20 antibody is administered to the subject on days 1 and 15 of cycle 3 and any subsequent cycles during the treatment period; and (b) administering to the subject about 0.8 mg of CD3xCD20 antibody on day 1, about 2 mg on day 8, about 20 mg on day 15, and about 35 mg on day 22 of a first cycle of the cyclical administration, and administering to the subject about 50 mg of CD3xCD20 antibody on days 1, 8, 15, and 22 of a second cycle, wherein about 50 mg of CD3xCD20 antibody is administered to the subject on days 1 and 15 of cycle 3 and any subsequent cycles during the treatment period; (c) administering about 25 mg of Compound A, or a pharmacologic agent thereof, to the subject daily on days 1 and 21 of each cycle of the cyclical administration, during the treatment period, wherein each cycle of the cyclical administration is 28 days, and wherein the subject is administered about 12 mg / kg of the CD19 antibody on days 1, 8, 15, and 22 of the first three cycles, wherein about 12 mg / kg of the CD19 antibody is administered to the subject on days 1 and 15 of cycle 4 and any subsequent cycles during the treatment period, and about 12 mg / kg of the CD19 antibody is administered to the subject 8 days and 4 days prior to day 1 of the first cycle of the cyclical administration; and (d) administering about 25 mg of Compound A, or a pharmacologic agent thereof, daily on days 1 and 21 of each cycle of the cyclical administration, during the treatment period, followed by a 7-day rest period, wherein each cycle of the cyclical administration is 28 days.

[0035] In one embodiment, the anti-CD19 antibody is tafasitamab. In one embodiment, the anti-CD19 antibody is a biosimilar of tafasitamab. In one embodiment, the CD19 antibody is a bioequivalent of tafasitamab. In one embodiment, the CD3xCD20 antibody is pramotamab. In one embodiment, the CD3xCD20 antibody is a biosimilar of pramotamab. In one embodiment, the CD3xCD20 antibody is a bioequivalent of pramotamab. In one embodiment, compound A is lenalidomide. In some embodiments, the compound is a pharmaceutically acceptable salt of lenalidomide. In some embodiments, the compound is a pharmaceutically acceptable solvate of lenalidomide. In some embodiments, the compound is a pharmaceutically acceptable stereoisomer of lenalidomide.

[0036] In one embodiment, Compound A, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, is orally administered to a subject. In one embodiment, Compound A, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, is administered to a subject in a capsule or tablet.

[0037] In one embodiment, the CD19 antibody is administered intravenously.

[0038] In one embodiment, the CD19 antibody is not administered to the subject on day 4 of the first cycle of the cyclic administration.

[0039] In one embodiment, a CD3xCD20 antibody is not administered to the subject on day 4 of the first cycle of the periodic administration.

[0040] In one embodiment, the method further comprises evaluating positron emission tomography-computed tomography (PET-CT) after every two cycles of cyclical administration.

[0041] In one embodiment, the subject has previously undergone CAR-T therapy.

[0042] In one embodiment, the method provides an improved therapeutic effect upon administration of both a CD19 antibody and Compound A, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, to a subject, but not an improved therapeutic effect upon administration of a CD3xCD20 antibody. In one embodiment, the improved therapeutic effect is measured by an increase in overall survival. In one embodiment, the improved therapeutic effect is measured by an increase in progression-free survival. In one embodiment, the improved therapeutic effect is measured by a decrease in the number of cancer cells in a biological sample obtained from the subject, compared to a reference. In one embodiment, the reference is the number of cancer cells in a biological sample obtained from the subject at an earlier time point. In one embodiment, the reference is a pre-determined value. In one embodiment, the reference is the number of cancer cells in a biological sample obtained from another subject with lymphoma. In one embodiment, the reference is the number of cancer cells in a biological sample obtained from a population of subjects with lymphoma. In one embodiment, the biological sample is blood. In one embodiment, the biological sample is serum. In one embodiment, the biological sample is plasma. In one embodiment, improved therapeutic efficacy is measured by improved overall response rate and / or improved quality of life in the subject.

[0043] In one embodiment, the subject has previously been treated for lymphoma. In one embodiment, the previous treatment comprises chemoimmunotherapy. In one embodiment, the previous treatment comprises administration of an anti-CD20 antibody. In one embodiment, the previous treatment comprises chemoimmunotherapy and administration of an anti-CD20 antibody.

[0044] Provided herein in one aspect is a method of treating lymphoma in a subject in need thereof, comprising administering to the subject (a) an antibody that binds to CD19 (a CD19 antibody), (b) a multispecific antibody that comprises a first binding domain that binds to CD3 and a second binding domain that binds to CD20 (a CD3xCD20 antibody), and (c) a compound having the following structure: [ka] (i.e., 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione (Compound A)), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof.

[0045] In one embodiment, (a) the CD19 antibody comprises (i) a heavy chain variable (VH) domain comprising a VH complementarity determining region (CDR)1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NO:1, SEQ ID NO:2, and SEQ ID NO:3, respectively, and (ii) a light chain variable (VL) domain comprising a VL CDR1, a VL CDR2, and a VL CDR3 having the amino acid sequences of SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6, respectively; (b) the multispecific antibody comprises (i) an anti-CD3e heavy chain having the amino acid sequence of SEQ ID NO:30, an anti-CD3e light chain having the amino acid sequence of SEQ ID NO:31, an anti-CD20 heavy chain having the amino acid sequence of SEQ ID NO:32, and an anti-CD20 light chain having the amino acid sequence of SEQ ID NO:33, or (ii) an anti-CD3e heavy chain having the amino acid sequence of SEQ ID NO:34, an anti-CD3e light chain having the amino acid sequence of SEQ ID NO:35, an anti-CD20 heavy chain having the amino acid sequence of SEQ ID NO:36, and an anti-CD20 light chain having the amino acid sequence of SEQ ID NO: 37; or (iii) an anti-CD3 heavy chain having the amino acid sequence of SEQ ID NO: 38, a light chain having the amino acid sequence of SEQ ID NO: 39, and an anti-CD20 heavy chain having the amino acid sequence of SEQ ID NO: 40; or (iv) an anti-CD20 / CD3 heavy chain having the amino acid sequence of SEQ ID NO: 41, an anti-CD3e light chain having the amino acid sequence of SEQ ID NO: 42, an anti-CD20 heavy chain having the amino acid sequence of SEQ ID NO: 43, and an anti-CD20 light chain having the amino acid sequence of SEQ ID NO: 44.

[0046] In one embodiment, (a) the CD19 antibody comprises a VH domain having an amino acid sequence that is about or at least about 90%, 95%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 19, and (b) the CD19 antibody comprises a VL domain having an amino acid sequence that is about or at least about 90%, 95%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 20.

[0047] In one embodiment, the compound is

[0048] [ka] It is.

[0049] In one embodiment, the lymphoma is a non-Hodgkin's lymphoma. In one embodiment, the non-Hodgkin's lymphoma is a diffuse large cell lymphoma (DLBCL). In one embodiment, the DLBCL is a relapsed DLBCL, a refractory DLBCL, or a relapsed-refractory DLBCL. In one embodiment, the DLBCL is a primary refractory DLBCL. In one embodiment, the DLBCL is a first-line DLBCL.

[0050] In one embodiment, the subject achieves a metabolic complete response as determined by positron emission tomography (PET)-computed tomography (CT) scan. In one embodiment, the subject achieves a metabolic complete response after cycle 2, cycle 4, cycle 6, cycle 8, and / or end of treatment. In one embodiment, the subject achieves a metabolic complete response after day 26 of cycle 2, day 26 of cycle 4, day 26 of cycle 6, day 26 of cycle 8, and / or end of treatment. In one embodiment, the subject achieves a metabolic complete response after 61 days, 117 days, 177 days, 233 days, or 299 days or more after the subject is first administered the multispecific antibody. [Brief description of the drawings]

[0051] 3. Brief description of the drawings [Figure 1]1 shows the structure of an anti-CD3 x anti-CD20 multispecific antibody described herein. The multispecific antibody has a "bottle opener" format (also referred to as "triple F" format). An antibody in the bottle opener format comprises a) a first monomer comprising a first Fc domain and an scFv region (wherein the scFv comprises a first variable heavy chain and a first variable light chain (also referred to herein as "scFv-Fc heavy chain"), b) a second monomer comprising VH-CH1-hinge-CH2-CH3 (wherein VH is a second variable heavy chain and CH2 and CH3 are a second Fc domain (also referred to herein as "Fab-Fc heavy chain")), and c) a light chain comprising a second variable light chain. As shown in FIG. 1, the scFv is a CD3 binding domain and the second variable heavy chain and the second variable light chain comprise a CD20 binding domain. [Diagram 2] FIG. 1 is a schematic diagram of a dosing regimen for combination therapy using a CD19 antibody, an anti-CD3×anti-CD20 multispecific antibody, and Compound A. [Diagram 3] Dose and schedule treatment regimes for Part 1 and Part 2 are shown. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0052] 4. MODE FOR CARRYING OUT THEINVENTION 4.1.Definition Various publications, articles, and patents are cited or described throughout this specification as background art. Each of these references is incorporated herein by reference in its entirety. The discussion of documents, acts, materials, devices, articles, and the like which is included in this specification is for the purpose of describing the background of the invention. Such discussion is not an admission that any or all of these items form part of the prior art with respect to any invention(s) disclosed or claimed.

[0053] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Otherwise, certain terms used herein have the meanings described herein.

[0054] Please note that as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0055] Unless otherwise specified, any numerical value, such as a concentration or concentration range described herein, should be understood to be modified in all cases by the term "about". Thus, numerical values ​​typically include ±10% of the stated value. For example, a concentration of 1 mg / mL includes 0.9 mg / mL to 1.1 mg / mL. Similarly, a concentration range of 1% to 10% (w / v) includes 0.9% (w / v) to 11% (w / v). As used herein, the use of numerical ranges explicitly includes all possible subranges, all individual numerical values ​​within that range, including integers within such ranges and fractions of that value, unless the context clearly indicates otherwise. For example, the term "about" with respect to a reference numerical value may also include a range of values ​​of + or -10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% from that value. In some cases, a numerical value disclosed throughout may be "about" that numerical value, even if the term "about" is not specifically recited.

[0056] Unless otherwise indicated, the term "at least" preceding a series of elements is understood to refer to every element in the series.

[0057] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments described herein which equivalents are intended to be encompassed by the present invention.

[0058] As used herein, the terms "comprises," "comprising," "includes," "including," "has," "having," "contains," "containing," or any other variation thereof, are understood to imply the inclusion of a recited integer or group of integers, but not the exclusion of any other integer or group of integers, and are intended to be non-exclusive or open-ended. For example, a composition, mixture, process, method, article, or device that includes a list of elements is not necessarily limited to only those elements and may include other elements not expressly listed or inherent to such composition, mixture, process, method, article, or device. Further, unless expressly stated otherwise, "or" refers to an inclusive "or" and not an exclusive "or." For example, a condition A or B is satisfied by any one of the following: A being true (or existing) and B being false (or not existing), A being false (not existing) and B being true (or existing), and both A and B being true (or existing).

[0059] As used herein, the conjunction "and / or" between multiple listed elements is understood to encompass both individual and combined options. For example, when two elements are connected by "and / or," the first option refers to the applicability of the first element without the second element. The second option refers to the applicability of the second element without the first element. The third option refers to the applicability of the first and second elements together. Any one of these options is understood to be within the meaning and thus meets the requirements of the term "and / or" as used herein. The simultaneous applicability of more than one of the options is also understood to be within the meaning and thus meets the requirements of the term "and / or."

[0060] As used herein, the terms "comprise", "comprises", or "comprising" may be replaced with "consists of", "consisting of", "consisting essentially of", or "consisting essentially of".

[0061] As used herein, the term "consists of," or variations such as "consist of" or "consisting of," as used in the specification and claims, is inclusive of any recited integer or group of integers, but indicates that additional integers or groups of integers cannot be added to the specified method, structure, or composition.

[0062] As used herein, the term "consists essentially of," or variations such as "consist essentially of" or "consisting essentially of," as used in the specification and claims, refers to the inclusion of any recited integer or group of integers, and the optional inclusion of any recited integer or group of integers that do not materially alter the basic or novel characteristics of the specified method, structure, or composition. See MPEP § 2111.03.

[0063] As used herein, "CD3," also known as "cluster of differentiation 3," refers to a T cell coreceptor that aids in the activation of both cytotoxic T cells (e.g., CD8+ naive T cells) and T helper cells (e.g., CD4+ naive T cells) and is composed of four distinct chains: one CD3γ chain (e.g., Genbank Accession Nos. NM_000073 and MP_000064 (human)), one CD3δ chain (e.g., Genbank Accession Nos. NM_000732, NM_001040651, NP_00732, and NP_001035741 (human)), and two CD3ε chains (e.g., Genbank Accession Nos. NM_000733 and NP_00724 (human)). The chains of CD3 are highly related cell surface proteins of the immunoglobulin superfamily that contain a single extracellular immunoglobulin domain. The CD3 molecule binds to the T cell receptor (TCR) and the zeta chain to form the T cell receptor (TCR) complex, which functions to generate an activation signal for T lymphocytes. In a specific embodiment, the CD3 is human CD3.

[0064] As used herein, "CD20", also known as "B-lymphocyte antigen CD20", "CD20 antigen", "CD20 receptor", "transmembrane 4 domain A1", "transmembrane 4 domain, subfamily A, member 1", "leukocyte surface antigen Leu-16", "Bp35", "B-lymphocyte cell surface antigen 1", "LEU-16", "CVID5", "MS4A", "B1", and "S7", refers to an activated glycosylated phosphorylated protein expressed on the surface of B cells and encoded in humans by the MS4A1 gene (e.g., Genbank accession numbers NM_152866, NM_021950, NP_068769, and NP_690605 (human)). CD20 plays a role in B-cell development and differentiation into plasma cells. In a specific embodiment, CD20 is human CD20.

[0065] As used herein, "CD19", also known as "B cell surface antigen B4", "B cell antigen CD19", "CD19 antigen", and "Leu-12" refer to a cell surface protein expressed by B cells and encoded by a gene designated CD19 (e.g., HGNC:1633, NCBI Entrez Gene:930, Ensembl:ENSG00000177455, OMIM®:107265, UniProtKB / Swiss-Prot:P15391). CD19 is involved in B cell activation and signaling pathways. In a specific embodiment, CD19 is human CD19.

[0066] As used herein, "lenalidomide" refers to the thalidomide analog 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione (Compound A), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof. Lenalidomide is an immunomodulatory agent with antiangiogenic and antineoplastic properties.

[0067] As used herein, the term "bispecific antibody" or "multispecific antibody" refers to any non-natural or alternative antibody format that binds to two or more different antigens (e.g., CD3xCD20 multispecific antibody).

[0068] As used herein, the term "antibody" is used in a broad sense and includes antibody molecules, including immunoglobulins or human, humanized, composite and chimeric antibodies, as well as antibody fragments that are monoclonal or polyclonal. In general, an antibody is a protein or peptide chain that exhibits binding specificity to a specific antigen. The structure of an antibody is well known. Immunoglobulins can be assigned to five major classes (i.e., IgA, IgD, IgE, IgG, and IgM) depending on the heavy chain constant domain amino acid sequence. IgA and IgG are further subclassified as isotypes IgA1, IgA2, IgG1, IgG2, IgG3, and IgG4. Thus, the antibodies provided herein can be of any of the five major classes or corresponding subclasses. In specific embodiments, the antibodies provided herein are IgG1, IgG2, IgG3, or IgG4. In specific embodiments, the antibodies provided herein are IgG. In other embodiments, the antibodies provided herein are IgG1. Antibody light chains of vertebrate species can be assigned to one of two clearly distinct types, kappa and lambda, based on the amino acid sequences of their constant domains. Thus, the antibodies provided herein may, in certain embodiments, contain a kappa light chain constant domain. The antibodies provided herein may, in certain embodiments, also contain a lambda light chain constant domain. According to certain embodiments, the antibodies provided herein comprise heavy and / or light chain constant regions derived from a rat or human antibody. In specific embodiments, the constant regions are human constant regions.

[0069] In addition to heavy and light chain constant domains, antibodies contain an antigen-binding region made up of a light chain variable region (VL) and a heavy chain variable region (VH), each of which contains three domains, i.e., complementarity determining region 1 (CDR1), CDR2, and CDR3. "CDR" refers to one of the three hypervariable regions (HCDR1, HCDR2, or HCDR3) in the non-framework region of an immunoglobulin (Ig or antibody) VH β-sheet framework, or one of the three hypervariable regions (LCDR1, LCDR2, or LCDR3) in the non-framework region of an antibody VL β-sheet framework. Thus, CDRs are variable region sequences interspersed within framework region sequences. CDR regions are well known to those skilled in the art and are defined, for example, by Kabat (Kabat et al., 2003) as the most hypervariable regions within an antibody variable (V) domain. al., J. Biol. Chem. 252:6609-6616 (1977); Kabat, Adv. Prot. Chem. 32:1-75 (1978)). CDR region sequences have also been structurally defined by Chothia as residues that are not part of the conserved β-sheet framework and thus can accommodate different conformations (Chothia and Lesk, J. Mol. Biol. 196:901-917 (1987)). Both terms are well recognized in the art. CDR region sequences have also been defined by AbM, Contact, and IMGT. Exemplary CDR region sequences are shown herein, for example, in the tables and / or examples provided below. The locations of CDRs within standard antibody variable regions have been determined by comparing multiple structures (Al-Lazikani et al., J. Mol. Biol. 273:927-948 (1997); Morea et al., Methods 20:267-279 (2000)). Because the number of residues in the hypervariable regions varies among antibodies, the additional residues relative to the canonical positions are conventionally numbered with a, b, c, etc. next to the residue number in the canonical variable region numbering scheme (Al-Lazikani et al., supra (1997)). Such nomenclature is likewise well known to those of skill in the art.

[0070] The light chain variable region CDR1 domain is herein interchangeably referred to as LCDR1 or VL CDR1. The light chain variable region CDR2 domain is herein interchangeably referred to as LCDR2 or VL CDR2. The light chain variable region CDR3 domain is herein interchangeably referred to as LCDR3 or VL CDR3. The heavy chain variable region CDR1 domain is herein interchangeably referred to as HCDR1 or VH CDR1. The heavy chain variable region CDR2 domain is herein interchangeably referred to as HCDR2 or VH CDR2. The heavy chain variable region CDR1 domain is herein interchangeably referred to as HCDR3 or VH CDR3.

[0071] As used herein, the term "hypervariable region", e.g., "VH" or "VL", refers to the region of an antibody variable region that is hypervariable in sequence and / or forms structurally defined loops. Generally, antibodies contain six hypervariable regions, three in the VH (HCDR1, HCDR2, HCDR3) and three in the VL (LCDR1, LCDR2, LCDR3). Several hypervariable region descriptive methods are in use and are encompassed herein. The "Kabat" CDRs are based on sequence variability and are the most commonly used (see, e.g., Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD. (1991)). Meanwhile, Chothia refers to the location of the structural loops (see, e.g., Chothia and Lesk, J. Mol. Biol. 196:901-917 (1987)). When numbered using the Kabat numbering convention, the end of the Chothia CDR-HCDR1 loop varies between H32 and H34 depending on the length of the loop (this is because the Kabat numbering scheme places insertions at H35A and H35B, so that if neither 35A nor 35B are present, the loop ends at 32, if only 35A is present, the loop ends at 33, and if both 35A and 35B are present, the loop ends at 34). The "AbM" hypervariable regions are a compromise between the Kabat CDRs and Chothia structural loops and are used by Oxford Molecular's AbM antibody modeling software (see, for example, Martin, in Antibody Engineering, Vol. 2, Chapter 3, Springer Verlag). The "Contact" hypervariable regions are based on an analysis of available complex crystal structures.

[0072] Recently, a universal numbering system has been developed and widely adopted (ImMunoGeneTics (IMGT) Information System® (Lafranc et al., Dev. Comp. Immunol. 27(1):55-77 (2003))). IMGT is an integrated information system dedicated to immunoglobulins (IG), T cell receptors (TR), and major histocompatibility complexes (MHC) of humans and other vertebrates. Herein, CDRs are referred to both in terms of amino acid sequence and location within the light or heavy chain. The "location" of the CDRs within the structure of an immunoglobulin variable domain is easily identified by using a numbering system that aligns variable domain sequences according to structural features, CDR and framework residues, since they are conserved across species and occur in structures called loops. This information can be used to graft and replace CDR residues from one type of immunoglobulin into an acceptor framework, usually derived from a human antibody. An additional numbering system (AHon) has been developed by Honegger and Pluckthun, J. Mol. Biol. 309:657-670 (2001). Correspondence between numbering systems, including, for example, the Kabat numbering and the IMGT unique numbering system, is well known to those of skill in the art (see, for example, Kabat, supra; Chothia and Lesk, supra; Martin, supra; Lefranc et al., supra). The exemplary system presented herein combines Kabat and Chothia. [Table 1]

[0073] The hypervariable regions may include extended hypervariable regions such as: 24-36 or 24-34 (LCDR1), 46-56 or 50-56 (LCDR2), and 89-97 or 89-96 (LCDR3) in VL, and 26-35 or 26-35A (HCDR1), 50-65 or 49-65 (HCDR2), and 93-102, 94-102, or 95-102 (HCDR3) in VH. CDR sequences reflecting each of the above numbering schemes are provided herein.

[0074] The term "constant region" or "constant domain" refers to the carboxy-terminal portions of the light and heavy chains that are not directly involved in binding the antibody to an antigen, but exhibit various effector functions, such as interaction with Fc receptors. The term refers to the portion of the immunoglobulin molecule that has a more conserved amino acid sequence compared to the other portion of the immunoglobulin, the variable region, which contains the antigen-binding site. The constant region may contain the CH1, CH2, and CH3 regions of the heavy chain and the CL region of the light chain.

[0075] The term "framework" or "FR" residues are those variable region residues which flank the CDRs. FR residues are present, for example, in chimeric, humanized, human, domain, diabodies, linear, and bispecific antibodies. FR residues are variable domain residues other than the hypervariable region or CDR residues.

[0076] The term "antigen binding domain" as used herein refers to a set of six CDRs that specifically binds to a target antigen as discussed herein when present as part of a polypeptide sequence. Thus, a "checkpoint antigen binding domain" binds to a target checkpoint antigen as outlined herein. As known in the art, these CDRs are generally present as a first set of variable heavy chain CDRs (vhCDRs or VHCDRs) and a second set of variable light chain CDRs (vlCDRs or VLCDRs), each of which comprises three CDRs (vhCDR1, vhCDR2, and vhCDR3 for the heavy chain, and vlCDR1, vlCDR2, and vlCDR3 for the light chain). The CDRs are present in the variable heavy chain domain and the variable light chain domain, respectively, and together form an Fv region. Thus, in some cases, the six CDRs of the antigen binding domain are provided by the variable heavy chain domain and the variable light chain domain. In the "Fab" format, the set of six CDRs is provided by two different polypeptide sequences, namely a variable heavy domain (vh or VH; containing VH CDR1, VH CDR2, and VH CDR3) and a variable light domain (vl or VL; containing VL CDR1, VL CDR2, and VL CDR3), with the C-terminus of the VH domain attached to the N-terminus of the CH1 domain of the heavy chain and the C-terminus of the VL domain attached to the N-terminus of the constant light domain (thus forming the light chain). In the scFv format, the VH and VL domains are generally covalently linked by the use of a linker ("scFv linker") as outlined herein into a single polypeptide sequence. This can be either VH-linker-VL or VL-linker-VH (starting from the N-terminus), with the former generally being preferred (including optional domain linkers on either side, depending on the format used).

[0077] Generally, the C-terminus of the scFv domain is attached to the N-terminus of the hinge of a second monomer.

[0078] As used herein, the term "isolated antibody" refers to an antibody that is substantially free of other antibodies having different antigenic specificities (e.g., an isolated antibody that specifically binds to a given target is substantially free of antibodies that do not bind to that same target). Moreover, an isolated antibody is substantially free of other cellular material and / or chemicals.

[0079] As used herein, the term "monoclonal antibody" refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies that make up the population are identical except for the possible presence of minor naturally occurring mutations. The monoclonal antibodies provided herein can be produced by hybridoma methods, phage display techniques, single lymphocyte gene cloning techniques, or by recombinant DNA methods. For example, monoclonal antibodies can be produced by hybridomas that contain B cells obtained from a transgenic non-human animal, such as a transgenic mouse or rat, whose genome contains human heavy chain transgenes and light chain transgenes.

[0080] As used herein, the term "antigen-binding fragment" refers to an antibody fragment, such as a diabody, Fab, Fab', F(ab'), Fv fragment, disulfide-stabilized Fv fragment (dsFv), (dsFv), bispecific dsFv (dsFv-dsFv'), disulfide-stabilized diabody (ds diabody), single-chain antibody molecule (scFv), single domain antibody (sdAb), scFv dimer (bivalent diabody), multispecific antibody formed from a portion of an antibody comprising one or more CDRs, camelized single domain antibody, nanobody, domain antibody, bivalent domain antibody, or any other antibody fragment that binds to an antigen but does not comprise a complete antibody structure. An antigen-binding fragment can bind to the same antigen as that bound by the parent antibody or parent antibody fragment. According to certain embodiments, the antigen-binding fragment comprises a light chain variable region, a light chain constant region, and an Fv segment of a heavy chain. According to other particular embodiments, the antigen-binding fragment comprises a Fab and a F(ab').

[0081] As used herein, the term "single chain antibody" refers to a conventional single chain antibody in the field that contains a heavy chain variable region and a light chain variable region connected by a short peptide of about 15 to about 20 amino acids. As used herein, the term "single domain antibody" refers to a conventional single domain antibody in the field that contains a heavy chain variable region and a heavy chain constant region, or contains only a heavy chain variable region.

[0082] As used herein, "Fab" or "Fab region" generally refers to a polypeptide that comprises the VH, CH1, VL, and CL immunoglobulin domains of two different polypeptide chains (e.g., VH-CH1 in one chain and VL-CL in the other). Fab may refer to this region in isolation or in the context of a bispecific antibody provided herein. In the context of Fab, Fab includes the Fv region in addition to the CH1 and CL domains.

[0083] As used herein, "Fv", "Fv fragment", or "Fv region" refers to a polypeptide comprising the VL and VH domains of the ABD. The Fv region can be formatted as both a Fab (which, as discussed above, are generally two different polypeptides that also contain a constant region as outlined above) and an scFv, where the VL and VH domains are combined (generally by a linker as discussed herein) to form an scFv.

[0084] The term "single-chain Fv" or "scFv" generally refers to a variable heavy domain covalently linked to a variable light domain by the use of an scFv linker as discussed herein to form an scFv or scFv domain. The scFv domain can be present in either orientation (VH-linker-VL or VL-linker-VH) from N-terminus to C-terminus. The order of the VH and VL domains can be indicated in the name. For example, H.X_L.Y means that from N-terminus to C-terminus, it is VH-linker-VL and L.Y_H.X is VL-linker-VH.

[0085] As used herein, the terms "Fc", "Fc region", or "Fc domain" refer to a polypeptide comprising the CH2-CH3 domain of an IgG molecule, optionally including the hinge. In the EU numbering of human IgG1, the CH2-CH3 domain comprises amino acids 231-447, and the hinge is 216-230. Thus, the definition of "Fc domain" includes either amino acids 231-447 (CH2-CH3) or 216-447 (hinge-CH2-CH3), or fragments thereof. An "Fc fragment" in this context may contain fewer amino acids from either or both the N-terminus and C-terminus, but generally still retains the ability to form a dimer with another Fc domain or Fc fragment, as can be detected using standard methods based on size (e.g., non-denaturing chromatography, size exclusion chromatography, etc.). Human IgG Fc domains are particularly useful in the methods provided herein and can be Fc domains from human IgG1, IgG2, or IgG4.

[0086] As used herein, "heavy chain constant region" refers to the CH1-hinge-CH2-CH3 portion of an antibody (or fragment thereof), excluding the variable heavy domain (in EU numbering for human IgG1, this is amino acids 118-447). By "heavy chain constant region fragment" herein is meant a heavy chain constant region that contains fewer amino acids from either or both the N-terminus and C-terminus, but still retains the ability to form a dimer with another heavy chain constant region.

[0087] As used herein, a "variable region" or "variable domain" refers to a region of an immunoglobulin that includes one or more Ig domains substantially encoded by any of the Vκ, Vλ, and / or VH genes that constitute the kappa, lambda, and heavy chain immunoglobulin loci, respectively, and contains the CDRs that confer antigen specificity. Thus, a "variable heavy domain" pairs with a "variable light domain" to form an antigen-binding domain ("ABD"). In addition, each variable domain includes three hypervariable regions ("complementarity determining regions", "CDRs") (vhCDR1, vhCDR2, and vhCDR3 for the variable heavy domain, and vlCDR1, vlCDR2, and vlCDR3 for the variable light domain) and four framework (FR) regions (arranged from amino-terminus to carboxy-terminus in the following order: FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4).

[0088] As used herein, the term "multispecific antibody" refers to an antibody that comprises multiple immunoglobulin variable domain sequences, where a first immunoglobulin variable domain sequence of the multiple has binding specificity for a first epitope and a second immunoglobulin variable domain sequence of the multiple has binding specificity for a second epitope. In certain embodiments, the first and second epitopes do not overlap or do not substantially overlap. In certain embodiments, the first and second epitopes are on different antigens, e.g., different proteins (or different subunits of a multimeric protein).

[0089] As used herein, the term "bispecific antibody" refers to a multispecific antibody that binds no more than two epitopes or no more than two antigens. A bispecific antibody is characterized by a first immunoglobulin variable domain sequence that has binding specificity for a first epitope and a second immunoglobulin variable domain sequence that has binding specificity for a second epitope.

[0090] Provided herein are multiple antibody domains that have sequence identity with human antibody domains. In the context of two or more nucleic acid or polypeptide sequences, the term "identical" or percent "identity" refers to two or more sequences or subsequences that are identical or have a certain percentage of amino acid residues or nucleotides that are identical when compared and aligned for maximum correspondence, as measured by one of the following sequence comparison algorithms or by visual inspection. For sequence comparison, typically, one sequence serves as a reference sequence to which test sequences are compared. When using a sequence comparison algorithm, test and reference sequences are input into a computer, subsequence coordinates are designated as necessary, and sequence algorithm program parameters are designated. The sequence comparison algorithm then calculates the percent sequence identity of the test sequence(s) relative to the reference sequence based on the designated program parameters.

[0091] Sequence identity between two similar sequences (e.g., antibody variable domains) can be determined by the methods of Smith, TF & Waterman, MS (1981) “Comparison of Biosequences,” Adv. Appl. Math. 2:482 [local homology algorithm]; Needleman, SB & Wunsch, CD. (1970) “A General Method Applicable to the Search for Similarities in the Amino Acid Sequence of Two Proteins,” J. Mol. Biol. 48:443 [homology alignment algorithm]; Pearson, WR & Lipman, DJ (1988) “Improved Tools for Biological Sequence Comparison,” Proc. Natl. Acad. Sci. (USA) 85:2444 [similarity search]; or Altschul, SF et al, (1990) “Basic Local Alignment Search Tool,” The sequence identity can be measured by an algorithm such as the algorithm of J. Mol. Biol. 215:403-10 (the "BLAST" algorithm) (see, e.g., blast.ncbi.nlm.nih.gov / Blast.cgi). When using any of the aforementioned algorithms, default parameters (for window length, gap penalties, etc.) are used. In one embodiment, sequence identity is performed using the BLAST algorithm using default parameters.

[0092] Examples of algorithms suitable for determining percent sequence identity and sequence similarity are the BLAST and BLAST 2.0 algorithms, which are described in Altschul et al. (1990) J. Mol. Biol. 215:403-410 and Altschul et al. (1997) Nucleic Acids Res. 25:3389-3402, respectively. Software for performing BLAST analyses is publicly available at the National Center for Biotechnology Information. This algorithm involves identifying high-scoring sequence pairs (HSPs) by first identifying short words W in the query sequence that match or meet some positive threshold score T when aligned with words of the same length in database sequences. T is referred to as the neighborhood word score threshold (Altschul et al., supra). These initial neighborhood word hits act as seeds for initiating searches to find longer HSPs containing them. The word hits are extended in both directions along each sequence for as far as the cumulative alignment score can be increased.

[0093] Cumulative scores are calculated using the parameters M (reward score for a pair of matching residues; always >0) and N (penalty score for mismatching residues; always <0) for nucleotide sequences. For amino acid sequences, a scoring matrix is ​​used to calculate the cumulative score. Extension of the word hits in each direction is halted when the cumulative alignment score falls off its maximum achieved value by an amount X, when the cumulative score falls below zero due to the accumulation of one or more negative scoring residue alignments, or when the end of either sequence is reached. The BLAST algorithm parameters W, T, and X determine the sensitivity and speed of the alignment. The BLASTN program (for nucleotide sequences) uses by default a wordlength (W) of 11, an expectation (E) of 10, M=5, N=-4, and a comparison of both strands. For amino acid sequences, the BLASTP program uses as defaults a wordlength of 3, an expectation (E) of 10, and the BLOSUM62 scoring matrix (see Henikoff & Henikoff, Proc. Natl. Acad. Sci. USA 89:10915 (1989)).

[0094] In addition to calculating percent sequence identity, the BLAST algorithm also performs a statistical analysis of the similarity between two sequences (see, for example, Karlin & Altschul, Proc. Nat'l. Acad. Sci. USA 90:5873-5787 (1993)). One measure of similarity provided by the BLAST algorithm is the minimum sum probability (P(N)), which provides an indication of the probability that a match between two nucleotide or amino acid sequences will occur by chance. For example, a nucleic acid is considered to be similar to a reference sequence if the minimum sum probability when comparing the test nucleic acid with the reference nucleic acid is less than about 0.1, more preferably less than about 0.01, and most preferably less than about 0.001.

[0095] Another indicator that two nucleic acid sequences or polypeptides are substantially identical is that the polypeptide encoded by the first nucleic acid is immunologically cross-reactive with the polypeptide encoded by the second nucleic acid, as described below.Thus, for example, when two peptides differ only in conservative substitution, the polypeptide is typically substantially identical to the second polypeptide.Another indicator that two nucleic acid sequences are substantially identical is that the two molecules hybridize to each other under stringent conditions.

[0096] The antibodies provided herein are generally isolated or recombinant antibodies. When used to describe various polypeptides disclosed herein, "isolated" refers to a polypeptide that is identified, separated and / or recovered from a cell or cell culture in which the polypeptide is expressed. Usually, an isolated polypeptide is prepared by at least one purification step. "Isolated antibody" refers to an antibody that is substantially free of other antibodies having different antigen specificities. "Recombinant" means that the antibodies are produced using recombinant nucleic acid techniques in an exogenous host cell and may be isolated.

[0097] As used herein, the term "polynucleotide" is synonymously referred to as "nucleic acid molecule," "nucleotide," or "nucleic acid" and refers to any polyribonucleotide or polydeoxyribonucleotide, which may be unmodified RNA or DNA or modified RNA or DNA. "Polynucleotide" includes, but is not limited to, single-stranded and double-stranded DNA, DNA that is a mixture of single-stranded and double-stranded regions, single-stranded and double-stranded RNA, and RNA that is a mixture of single-stranded and double-stranded regions, hybrid molecules containing DNA and RNA that may be single-stranded or, more typically, double-stranded, or may be a mixture of single-stranded and double-stranded regions. In addition, "polynucleotide" refers to triple-stranded regions that include RNA or DNA, or both RNA and DNA. The term polynucleotide also includes DNA or RNA that contains one or more modified bases, and DNA or RNA with backbones modified for stability or other reasons. "Modified" bases include, for example, tritylated bases and rare bases such as inosine. Various modifications can be made to DNA and RNA. Thus, "polynucleotide" includes chemically, enzymatically, or metabolically modified forms of polynucleotides typically found in nature, as well as the chemical forms of DNA and RNA characteristic of viruses and cells. "Polynucleotide" also includes relatively short nucleic acid strands often referred to as oligonucleotides.

[0098] As used herein, the terms "peptide", "polypeptide", or "protein" may refer to a molecule composed of amino acids and may be recognized as a protein by those skilled in the art. Conventional one-letter or three-letter codes for amino acid residues are used herein. The terms "polypeptide", "peptide", and "protein" may be used interchangeably herein to refer to a polymer of amino acids of any length. The polymer may be linear or branched, may contain modified amino acids, and may be interrupted by non-amino acids. These terms also encompass amino acid polymers that are modified naturally or by intervention, such as disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation or modification, such as conjugation with a labeling component. For example, polypeptides containing one or more analogs of an amino acid (including, for example, unnatural amino acids, etc.), as well as other modifications known in the art, are also included in this definition.

[0099] The peptide sequences described herein are written according to the usual convention that the N-terminal region of the peptide is on the left and the C-terminal region is on the right. Although isomeric forms of amino acids are known, it is the L-form of the amino acid that is represented unless expressly indicated otherwise.

[0100] As used herein, the terms "treat", "treatment", and "treating" refer to the reduction or amelioration or elimination of the progression, severity, and / or effects associated with a solid malignant tumor described herein, or the improvement of the condition of the solid malignant tumor, or the improvement of a disease associated with a solid malignant tumor, or the increase in the immune system response of a human subject, or the improvement of one or more symptoms (preferably one or more identifiable symptoms) of a solid malignant tumor described herein, resulting from the administration of one or more therapies. In specific embodiments, the terms "treat", "treatment", and "treating" refer to the improvement of at least one measurable physical parameter of a solid malignant tumor described herein, such as tumor size, tumor growth rate, tumor cell count, tumor invasiveness, the presence of metastases, or the extent of metastases. In other embodiments, the terms "treat", "treatment", and "treating" refer to the inhibition of progression of a solid malignant tumor described herein, either physically (e.g., by stabilizing an identifiable symptom), physiologically (e.g., by stabilizing a physical parameter), or both. In other embodiments, the terms "treat", "treatment", and "treating" refer to an increase in the immune system response of a human subject, e.g., increased T cell infiltration, increased T cell activation, upregulation of the IFN pathway, upregulation of the antigen presentation pathway, or increased Ki67+ induction in T cells following treatment with pembrolizumab or nivolumab. In exemplary embodiments, treatment of a solid malignant tumor improves or halts the progression of a disease or tumor condition associated with the tumor and / or improves or halts the progression of symptoms associated with the disease or condition. For example, treatment of a solid malignant tumor refers to one or more of the following: (1) a reduction in solid malignant tumor cell number, (2) an increase in solid malignant tumor cell death, (3) an inhibition of solid malignant tumor cell survival, (5) an inhibition (i.e., a slowing to some extent, and preferably a halt in progression) of solid malignant tumor growth (e.g., stabilization of disease), (6) an inhibition of solid malignant tumor cell metastasis, (7) an increase in progression-free survival, (8) an increase in overall survival, and (9) some alleviation of one or more symptoms associated with the disease or condition.Additional explanations regarding treatment can be found in the RECIST criteria (Eisenhauer et al. (2009) Eur J Cancer. 45:228-47; Chalian et al. (2011) Radiographics 31:2093-105), imRECIST criteria (Hodi et al. (2018) J Clin Oncol. 36:850-858), modified IrRC criteria (Wolchok et al. (2009) Clin Cancer Res. 15:7412-20), and PCWG3 criteria (Scher, et al. (2016) Clin Oncol. 34:1402-18). In some embodiments, treating the solid malignancy involves administering the bispecific antibody for a pre-specified period of time, discontinuing administration for another specific period of time, and resuming administration of the bispecific antibody for yet another specific period of time. In some embodiments, treatment of solid malignancies involves administering the bispecific antibody until one of the therapeutic effects described herein is achieved, withdrawing administration of the bispecific antibody while the therapeutic effect continues to be observed, and resuming administration of the bispecific antibody when the therapeutic effect is no longer observed.

[0101] Treatment of solid malignant tumors can be determined by standardized response criteria specific to tumor-related disease or tumor condition.Response of solid malignant tumors can be evaluated by screening techniques, such as magnetic resonance imaging (MRI) scan, positron emission tomography (PET) scan, X-ray imaging, radionuclide scan, computed tomography (CT) scan, bone scan imaging, endoscopy, tumor sampling including bone marrow aspiration (BMA), and tumor marker levels and / or tumor cell counting in circulation, by changes in tumor morphology (i.e., by the use of neoadjuvants in treatment, such as evaluating pathological response) or tumor metrics (i.e., overall tumor burden, tumor size, etc.).

[0102] Treatment according to the methods provided herein includes use of a "therapeutically effective amount" of an agent. A "therapeutically effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result.

[0103] A therapeutically effective amount may vary depending on factors such as the medical condition, age, sex, and weight of the individual, as well as the ability of the agent to elicit a desired response in the individual. A therapeutically effective amount is also one in which any toxic or detrimental effects of the antibody or antibody portion are outweighed by the therapeutically beneficial effects.

[0104] A "therapeutically effective amount" for tumor therapy may also be measured by its ability to stabilize disease progression. The ability of a compound to inhibit cancer can be evaluated in animal model systems predictive of efficacy in human tumors.

[0105] Alternatively, this property of the composition can be evaluated by examining the ability of the compound to inhibit cell proliferation or induce apoptosis by in vitro assays known to those of skill in the art. A therapeutically effective amount of a therapeutic compound may reduce tumor size or otherwise ameliorate symptoms in a subject. One of skill in the art can determine such an amount based on factors such as the size of the subject, the severity of the subject's symptoms, and the particular composition or route of administration selected.

[0106] The terms "patient," "subject," and "human subject" are used interchangeably herein. As used herein, "subject" means any animal, preferably a mammal, most preferably a human. As used herein, the term "mammal" encompasses any mammal. Examples of mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc. In a specific embodiment, the subject is a human.

[0107] Overview Provided herein, in certain embodiments, are methods for treating lymphoma using a combination of a compound having a CD19 antibody, an anti-CD3x anti-CD20 multispecific antibody, and Compound A. The methods provided herein are particularly useful for treating diffuse large cell lymphoma (DLBCL), including relapsed or refractory DLBCL.

[0108] Pharmaceutical Compositions antibody Provided herein is a method of treating lymphoma using combination therapy. In certain embodiments, the combination therapy comprises a multispecific antibody that comprises a first binding domain that binds to CD3 and a second binding domain that binds to CD20 ("CD3xCD20 antibody"), and a CD19 antibody. In a specific embodiment, the combination therapy further comprises Compound A. In other embodiments, the combination therapy further comprises a pharmaceutically acceptable salt, solvate, or stereoisomer of Compound A. Other compounds useful in the methods provided herein are, for example, racemic, stereoisomerically enriched, or stereoisomerically pure compounds (e.g., Compound A), as well as pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, clathrates, and prodrugs thereof.

[0109] The amino acid sequences of exemplary CD19 antibodies and CD3xCD20 multispecific antibodies useful in the methods and combination therapies provided herein are shown in Table 1 below. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7]

[0110] In some embodiments, the CD3xCD20 antibody has a "bottle opener" format (also called "triple F" format), generally as shown in Figure 1. In this embodiment, the CD3 antigen binding domain is a scFv in the bottle opener format and the CD20 antigen binding domain is a Fab in the bottle opener format.

[0111] In some embodiments, the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 sequences are according to the Kabat numbering system. In some embodiments, the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 sequences are according to the Chothia numbering system. In some embodiments, the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 sequences are according to an exemplary numbering system. In some embodiments, the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 sequences are according to the Contact numbering system. In some embodiments, the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 sequences are according to the IMGT numbering system. In some embodiments, the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 sequences are according to the AbM numbering system. An exemplary set of six CDRs (VH CDR1-3 and VL CDR1-3) of certain antibody embodiments is provided herein. Other sets of CDRs are contemplated and are within the scope of the antibody embodiments provided herein.

[0112] In one embodiment, the CD3xCD20 antibody comprises a first binding domain that binds to CD3, the first binding domain comprising a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of the VH CDR1, VH CDR2, and VH CDR3, respectively, of the VH having the amino acid sequences set out in Table 1.

[0113] In one embodiment, the CD3xCD20 antibody comprises a first binding domain that binds to CD3, the first binding domain comprising a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 having the amino acid sequences of the VL CDR1, VL CDR2, and VL CDR3, respectively, of the VL having the amino acid sequence set out in Table 1.

[0114] In one embodiment, the CD3xCD20 antibody comprises a first binding domain that binds to CD3, the first binding domain comprising a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of the VH CDR1, VH CDR2, and VH CDR3, respectively, of the VH having the amino acid sequences set out in Table 1, and a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of the VL CDR1, VL CDR2, and VL CDR3, respectively, of the VL having the amino acid sequences set out in Table 1.

[0115] In one embodiment, the CD3xCD20 antibody comprises a second binding domain that binds to CD20, the second binding domain comprising a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of the VH CDR1, VH CDR2, and VH CDR3, respectively, of the VH having the amino acid sequences set out in Table 1.

[0116] In one embodiment, the CD3xCD20 antibody comprises a second binding domain that binds to CD20, the second binding domain comprising a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 having the amino acid sequences of the VL CDR1, VL CDR2, and VL CDR3, respectively, of the VL having the amino acid sequences set out in Table 1.

[0117] In one embodiment, the CD3xCD20 antibody comprises a second binding domain that binds to CD20, the second binding domain comprising a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of the VH CDR1, VH CDR2, and VH CDR3, respectively, of the VH having the amino acid sequences set out in Table 1, and a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of the VL CDR1, VL CDR2, and VL CDR3, respectively, of the VL having the amino acid sequences set out in Table 1.

[0118] In one embodiment, the CD3xCD20 antibody comprises a first binding domain that binds to CD3 (the first binding domain comprises a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of the VH CDR1, VH CDR2, and VH CDR3 of the VH, respectively, having the amino acid sequence set out in Table 1, and a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of the VL CDR1, VL CDR2, and VL CDR3 of the VL, respectively, having the amino acid sequence set out in Table 1), and a second binding domain that binds to CD20 (the second binding domain comprises a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of the VH CDR1, VH CDR2, and VH CDR3 of the VH, respectively, having the amino acid sequence set out in Table 1, and a VL CDR1, VL CDR2, and VL CDR3 of the VL, respectively, having the amino acid sequence set out in Table 1). and a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 having the amino acid sequences of VL CDR1, VL CDR2, and VL CDR3.

[0119] In one embodiment, the CD3xCD20 antibody comprises a first binding domain that binds to CD3, the first binding domain comprising a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of VH CDR1, VH CDR2, and VH CDR3, respectively, of VH having the amino acid sequence of SEQ ID NO:21.

[0120] In one embodiment, the CD3xCD20 antibody comprises a first binding domain that binds to CD3, the first binding domain comprising a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 having the amino acid sequences of the VL CDR1, VL CDR2, and VL CDR3, respectively, of the VL having the amino acid sequence of SEQ ID NO:22.

[0121] In one embodiment, the CD3xCD20 antibody comprises a first binding domain that binds to CD3, the first binding domain comprising a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of VH CDR1, VH CDR2, and VH CDR3, respectively, of the VH having the amino acid sequence of SEQ ID NO:21, and a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of VL CDR1, VL CDR2, and VL CDR3, respectively, of the VL having the amino acid sequence of SEQ ID NO:22.

[0122] In one embodiment, the CD3xCD20 antibody comprises a second binding domain that binds to CD20, the second binding domain comprising a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of VH CDR1, VH CDR2, and VH CDR3, respectively, of VH having the amino acid sequence of SEQ ID NO:23.

[0123] In one embodiment, the CD3xCD20 antibody comprises a second binding domain that binds to CD20, and the first binding domain comprises a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 having the amino acid sequences of the VL CDR1, VL CDR2, and VL CDR3, respectively, of the VL having the amino acid sequence of SEQ ID NO:24.

[0124] In one embodiment, the CD3xCD20 antibody comprises a second binding domain that binds to CD20, the second binding domain comprising a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of the VH CDR1, VH CDR2, and VH CDR3, respectively, of the VH having the amino acid sequence of SEQ ID NO:23, and a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of the VL CDR1, VL CDR2, and VL CDR3, respectively, of the VL having the amino acid sequence of SEQ ID NO:24.

[0125] In one embodiment, the CD3xCD20 antibody comprises a first binding domain that binds to CD3 (the first binding domain comprises a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of VH CDR1, VH CDR2, and VH CDR3 of the VH having the amino acid sequence of SEQ ID NO:21, respectively, and a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of VL CDR1, VL CDR2, and VL CDR3 of the VL having the amino acid sequence of SEQ ID NO:22), and a second binding domain that binds to CD20 (the second binding domain comprises a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of VH CDR1, VH CDR2, and VH CDR3 of the VH having the amino acid sequence of SEQ ID NO:23, respectively, and a VL CDR1, VL CDR2, and VL CDR3 of the VL having the amino acid sequence of SEQ ID NO:24, respectively). and a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 having the amino acid sequences of VL CDR1, VL CDR2, and VL CDR3.

[0126] In one embodiment, the CD3xCD20 antibody comprises a first binding domain that binds to CD3, the first binding domain comprising a VH domain comprising a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NO:7, SEQ ID NO:8, and SEQ ID NO:9, respectively.

[0127] In one embodiment, the CD3xCD20 antibody comprises a first binding domain that binds to CD3, the first binding domain comprising a VL domain comprising a VL CDR1, a VL CDR2, and a VL CDR3 having the amino acid sequences of SEQ ID NO:10, SEQ ID NO:11, and SEQ ID NO:12, respectively.

[0128] In one embodiment, the CD3xCD20 antibody comprises a first binding domain that binds to CD3, the first binding domain comprising a VH domain comprising a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NO:7, SEQ ID NO:8, and SEQ ID NO:9, respectively, and a VL domain comprising a VL CDR1, a VL CDR2, and a VL CDR3 having the amino acid sequences of SEQ ID NO:10, SEQ ID NO:11, and SEQ ID NO:12, respectively.

[0129] In one embodiment, the CD3xCD20 antibody comprises a second binding domain that binds to CD20, the second binding domain comprising a VH domain comprising a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NO:13, SEQ ID NO:14, and SEQ ID NO:15, respectively.

[0130] In one embodiment, the CD3xCD20 antibody comprises a second binding domain that binds to CD20, the second binding domain comprising a VL domain comprising a VL CDR1, a VL CDR2, and a VL CDR3 having the amino acid sequences of SEQ ID NO:16, SEQ ID NO:17, and SEQ ID NO:18, respectively.

[0131] In one embodiment, the CD3xCD20 antibody comprises a second binding domain that binds to CD20, the second binding domain comprising a VH domain comprising a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NO:13, SEQ ID NO:14, and SEQ ID NO:15, respectively, and a VL domain comprising a VL CDR1, a VL CDR2, and a VL CDR3 having the amino acid sequences of SEQ ID NO:16, SEQ ID NO:17, and SEQ ID NO:18, respectively.

[0132] In one embodiment, the CD3xCD20 antibody comprises a first binding domain that binds CD3 and a second binding domain that binds CD20, the first binding domain comprising a VH domain comprising a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NO:7, SEQ ID NO:8, and SEQ ID NO:9, respectively, and a VL domain comprising a VL CDR1, a VL CDR2, and a VL CDR3 having the amino acid sequences of SEQ ID NO:10, SEQ ID NO:11, and SEQ ID NO:12, respectively, and the second binding domain comprising a VH domain comprising a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NO:13, SEQ ID NO:14, and SEQ ID NO:15, respectively, and a VL domain comprising a VL CDR1, a VL CDR2, and a VL CDR3 having the amino acid sequences of SEQ ID NO:16, SEQ ID NO:17, and SEQ ID NO:18, respectively.

[0133] In one embodiment, the CD3xCD20 antibody comprises a first binding domain that binds to CD3, the first binding domain comprising a VH domain having an amino acid sequence that is about 90%, 95%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO:21. In one embodiment, the first binding domain comprises a VH domain having an amino acid sequence that is about 90% identical to the amino acid sequence of SEQ ID NO:21. In another embodiment, the first binding domain comprises a VH domain having an amino acid sequence that is about 95% identical to the amino acid sequence of SEQ ID NO:21. In another embodiment, the first binding domain comprises a VH domain having an amino acid sequence that is about 98% identical to the amino acid sequence of SEQ ID NO:21. In another embodiment, the first binding domain comprises a VH domain having an amino acid sequence that is about 99% identical to the amino acid sequence of SEQ ID NO:21. In one embodiment, the first binding domain comprises a VH domain having an amino acid sequence that is about 100% identical to the amino acid sequence of SEQ ID NO:21.

[0134] In one embodiment, the CD3xCD20 antibody comprises a first binding domain that binds to CD3, the first binding domain comprises a VL domain having an amino acid sequence that is about 90%, 95%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO:22. In one embodiment, the first binding domain comprises a VL domain having an amino acid sequence that is about 90% identical to the amino acid sequence of SEQ ID NO:22. In another embodiment, the first binding domain comprises a VL domain having an amino acid sequence that is about 95% identical to the amino acid sequence of SEQ ID NO:22. In another embodiment, the first binding domain comprises a VL domain having an amino acid sequence that is about 98% identical to the amino acid sequence of SEQ ID NO:22. In another embodiment, the first binding domain comprises a VL domain having an amino acid sequence that is about 99% identical to the amino acid sequence of SEQ ID NO:22. In another embodiment, the first binding domain comprises a VL domain having an amino acid sequence that is about 100% identical to the amino acid sequence of SEQ ID NO:22.

[0135] In one embodiment, the CD3xCD20 antibody comprises a first binding domain that binds to CD3, the first binding domain comprising a VH domain having an amino acid sequence that is about 90%, 95%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 21, and a VL domain having an amino acid sequence that is about 90%, 95%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 22. In one embodiment, the first binding domain comprises a VH domain having an amino acid sequence that is about 90% identical to the amino acid sequence of SEQ ID NO: 21, and a VL domain having an amino acid sequence that is about 90% identical to the amino acid sequence of SEQ ID NO: 22. In another embodiment, the first binding domain comprises a VH domain having an amino acid sequence that is about 95% identical to the amino acid sequence of SEQ ID NO: 21, and a VL domain having an amino acid sequence that is about 95% identical to the amino acid sequence of SEQ ID NO: 22. In another embodiment, the first binding domain comprises a VH domain having an amino acid sequence about 98% identical to the amino acid sequence of SEQ ID NO: 21, and a VL domain having an amino acid sequence about 98% identical to the amino acid sequence of SEQ ID NO: 22. In another embodiment, the first binding domain comprises a VH domain having an amino acid sequence about 99% identical to the amino acid sequence of SEQ ID NO: 21, and a VL domain having an amino acid sequence about 99% identical to the amino acid sequence of SEQ ID NO: 22. In another embodiment, the first binding domain comprises a VH domain having an amino acid sequence about 100% identical to the amino acid sequence of SEQ ID NO: 21, and a VL domain having an amino acid sequence about 100% identical to the amino acid sequence of SEQ ID NO: 22.

[0136] In one embodiment, the CD3xCD20 antibody comprises a second binding domain that binds to CD20, the second binding domain comprising a VH domain having an amino acid sequence that is about 90%, 95%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO:23. In one embodiment, the second binding domain comprises a VH domain having an amino acid sequence that is about 90% identical to the amino acid sequence of SEQ ID NO:23. In another embodiment, the second binding domain comprises a VH domain having an amino acid sequence that is about 95% identical to the amino acid sequence of SEQ ID NO:23. In another embodiment, the second binding domain comprises a VH domain having an amino acid sequence that is about 98% identical to the amino acid sequence of SEQ ID NO:23. In another embodiment, the second binding domain comprises a VH domain having an amino acid sequence that is about 99% identical to the amino acid sequence of SEQ ID NO:23. In another embodiment, the second binding domain comprises a VH domain having an amino acid sequence that is about 100% identical to the amino acid sequence of SEQ ID NO:23.

[0137] In one embodiment, the CD3xCD20 antibody comprises a second binding domain that binds to CD20, the second binding domain comprising a VL domain having an amino acid sequence that is about 90%, 95%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO:24. In one embodiment, the second binding domain comprises a VL domain having an amino acid sequence that is about 90% identical to the amino acid sequence of SEQ ID NO:24. In another embodiment, the second binding domain comprises a VL domain having an amino acid sequence that is about 95% identical to the amino acid sequence of SEQ ID NO:24. In another embodiment, the second binding domain comprises a VL domain having an amino acid sequence that is about 98% identical to the amino acid sequence of SEQ ID NO:24. In another embodiment, the second binding domain comprises a VL domain having an amino acid sequence that is about 99% identical to the amino acid sequence of SEQ ID NO:24. In another embodiment, the second binding domain comprises a VL domain having an amino acid sequence that is about 100% identical to the amino acid sequence of SEQ ID NO:24.

[0138] In one embodiment, the CD3xCD20 antibody comprises a second binding domain that binds to CD20, the second binding domain comprising a VH domain having an amino acid sequence that is about 90%, 95%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 23, and a VL domain having an amino acid sequence that is about 90%, 95%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 24. In one embodiment, the second binding domain comprises a VH domain having an amino acid sequence that is about 90% identical to the amino acid sequence of SEQ ID NO: 23, and a VL domain having an amino acid sequence that is about 90% identical to the amino acid sequence of SEQ ID NO: 24. In another embodiment, the second binding domain comprises a VH domain having an amino acid sequence that is about 95% identical to the amino acid sequence of SEQ ID NO: 23, and a VL domain having an amino acid sequence that is about 95% identical to the amino acid sequence of SEQ ID NO: 24. In another embodiment, the second binding domain comprises a VH domain having an amino acid sequence about 98% identical to the amino acid sequence of SEQ ID NO: 23, and a VL domain having an amino acid sequence about 98% identical to the amino acid sequence of SEQ ID NO: 24. In another embodiment, the second binding domain comprises a VH domain having an amino acid sequence about 99% identical to the amino acid sequence of SEQ ID NO: 23, and a VL domain having an amino acid sequence about 99% identical to the amino acid sequence of SEQ ID NO: 24. In another embodiment, the second binding domain comprises a VH domain having an amino acid sequence about 100% identical to the amino acid sequence of SEQ ID NO: 23, and a VL domain having an amino acid sequence about 100% identical to the amino acid sequence of SEQ ID NO: 24.

[0139] In one embodiment, the CD3xCD20 antibody comprises a first binding domain that binds CD3 and a second binding domain that binds CD20, wherein the first binding domain comprises a VH domain having an amino acid sequence that is about 90%, 95%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO:21, and a VL domain having an amino acid sequence that is about 90%, 95%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO:22, and the second binding domain comprises a VH domain having an amino acid sequence that is about 90%, 95%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO:23, and a VL domain having an amino acid sequence that is about 90%, 95%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO:24. In one embodiment, the first binding domain comprises a VH domain having an amino acid sequence about 90% identical to the amino acid sequence of SEQ ID NO:21 and a VL domain having an amino acid sequence about 90% identical to the amino acid sequence of SEQ ID NO:22, and the second binding domain comprises a VH domain having an amino acid sequence about 90% identical to the amino acid sequence of SEQ ID NO:23 and a VL domain having an amino acid sequence about 90% identical to the amino acid sequence of SEQ ID NO:24. In another embodiment, the first binding domain comprises a VH domain having an amino acid sequence about 95% identical to the amino acid sequence of SEQ ID NO:21 and a VL domain having an amino acid sequence about 95% identical to the amino acid sequence of SEQ ID NO:22, and the second binding domain comprises a VH domain having an amino acid sequence about 95% identical to the amino acid sequence of SEQ ID NO:23 and a VL domain having an amino acid sequence about 95% identical to the amino acid sequence of SEQ ID NO:24. In another embodiment, the first binding domain comprises a VH domain having an amino acid sequence that is about 98% identical to the amino acid sequence of SEQ ID NO:21 and a VL domain having an amino acid sequence that is about 98% identical to the amino acid sequence of SEQ ID NO:22, and the second binding domain comprises a VH domain having an amino acid sequence that is about 98% identical to the amino acid sequence of SEQ ID NO:23 and a VL domain having an amino acid sequence that is about 98% identical to the amino acid sequence of SEQ ID NO:24.In another embodiment, the first binding domain comprises a VH domain having an amino acid sequence about 99% identical to the amino acid sequence of SEQ ID NO:21 and a VL domain having an amino acid sequence about 99% identical to the amino acid sequence of SEQ ID NO:22, and the second binding domain comprises a VH domain having an amino acid sequence about 99% identical to the amino acid sequence of SEQ ID NO:23 and a VL domain having an amino acid sequence about 99% identical to the amino acid sequence of SEQ ID NO:24. In another embodiment, the first binding domain comprises a VH domain having an amino acid sequence about 100% identical to the amino acid sequence of SEQ ID NO:21 and a VL domain having an amino acid sequence about 100% identical to the amino acid sequence of SEQ ID NO:22, and the second binding domain comprises a VH domain having an amino acid sequence about 100% identical to the amino acid sequence of SEQ ID NO:23 and a VL domain having an amino acid sequence about 100% identical to the amino acid sequence of SEQ ID NO:24.

[0140] In one embodiment, the CD3xCD20 antibody comprises a first monomer comprising, from N-terminus to C-terminus, a scFv-linker-CH2-CH3 having the amino acid sequence of SEQ ID NO: 25. In another embodiment, the CD3xCD20 antibody comprises a second monomer comprising, from N-terminus to C-terminus, a VH-CH1-hinge-CH2-CH3 having the amino acid sequence of SEQ ID NO: 26. In another embodiment, the CD3xCD20 antibody comprises a third monomer comprising, from N-terminus to C-terminus, a VL-CL having the amino acid sequence of SEQ ID NO: 27. In another embodiment, the CD3xCD20 antibody comprises a first monomer comprising, from N-terminus to C-terminus, a scFv-linker-CH2-CH3 having the amino acid sequence of SEQ ID NO:25, a second monomer comprising, from N-terminus to C-terminus, a VH-CH1-hinge-CH2-CH3 having the amino acid sequence of SEQ ID NO:26, and a third monomer comprising, from N-terminus to C-terminus, a VL-CL having the amino acid sequence of SEQ ID NO:27.

[0141] In a specific embodiment, the CD3xCD20 antibody is pramotamab (XmAb13676). In one embodiment, the CD3xCD20 antibody is a biosimilar of pramotamab. In one embodiment, the CD3xCD20 antibody is a bioequivalent of pramotamab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequences of VH CDR1, VH CDR2, and VH CDR3 of the CD3 binding domain of pramotamab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequences of VL CDR1, VL CDR2, and VL CDR3 of the CD3 binding domain of pramotamab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequences of VH CDR1, VH CDR2, and VH CDR3 of the CD20 binding domain of pramotamab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequences of the VL CDR1, VL CDR2, and VL CDR3 of the CD20 binding domain of pramotamab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequences of the VH CDR1, VH CDR2, and VH CDR3 of the CD3 binding domain of pramotamab and the VL CDR1, VL CDR2, and VL CDR3 of the CD3 binding domain of pramotamab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequences of the VH CDR1, VH CDR2, and VH CDR3 of the CD20 binding domain of pramotamab and the VL CDR1, VL CDR2, and VL CDR3 of the CD20 binding domain of pramotamab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequence of the VH CDR1, VH CDR2, and VH CDR3 of the CD3 binding domain of pramotamab, the VL CDR1, VL CDR2, and VL CDR3 of the CD3 binding domain of pramotamab, the VH CDR1, VH CDR2, and VH CDR3 of the CD20 binding domain of pramotamab, and the VL CDR1, VL CDR2, and VL CDR3 of the CD20 binding domain of pramotamab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequence of the VH of the CD3 binding domain of pramotamab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequence of the VL of the CD3 binding domain of pramotamab.In one embodiment, the CD3xCD20 antibody comprises the amino acid sequence of the VH of the CD20 binding domain of pramotamab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequence of the VL of the CD20 binding domain of pramotamab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequence of the VH of the CD3 binding domain of pramotamab and the VL of the CD3 binding domain of pramotamab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequence of the VH of the CD20 binding domain of pramotamab and the VL of the CD20 binding domain of pramotamab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequence of the VH of the CD3 binding domain of pramotamab, the VL of the CD3 binding domain of pramotamab, the VH of the CD20 binding domain of pramotamab and the VL of the CD20 binding domain of pramotamab.

[0142] In another embodiment, the CD3xCD20 antibody is mosunetuzumab. In one embodiment, the CD3xCD20 antibody is a biosimilar of mosunetuzumab. In one embodiment, the CD3xCD20 antibody is a bioequivalent of mosunetuzumab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequences of VH CDR1, VH CDR2, and VH CDR3 of the CD3 binding domain of mosunetuzumab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequences of VL CDR1, VL CDR2, and VL CDR3 of the CD3 binding domain of mosunetuzumab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequences of VH CDR1, VH CDR2, and VH CDR3 of the CD20 binding domain of mosunetuzumab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequences of the VL CDR1, VL CDR2, and VL CDR3 of the CD20 binding domain of mosunetuzumab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequences of the VH CDR1, VH CDR2, and VH CDR3 of the CD3 binding domain of mosunetuzumab and the VL CDR1, VL CDR2, and VL CDR3 of the CD3 binding domain of mosunetuzumab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequences of the VH CDR1, VH CDR2, and VH CDR3 of the CD20 binding domain of mosunetuzumab and the VL CDR1, VL CDR2, and VL CDR3 of the CD20 binding domain of mosunetuzumab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequence of the VH CDR1, VH CDR2, and VH CDR3 of the CD3 binding domain of mosunetuzumab, the VL CDR1, VL CDR2, and VL CDR3 of the CD3 binding domain of mosunetuzumab, the VH CDR1, VH CDR2, and VH CDR3 of the CD20 binding domain of mosunetuzumab, and the VL CDR1, VL CDR2, and VL CDR3 of the CD20 binding domain of mosunetuzumab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequence of the VH of the CD3 binding domain of mosunetuzumab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequence of the VL of the CD3 binding domain of mosunetuzumab.In one embodiment, the CD3xCD20 antibody comprises the amino acid sequence of the VH of the CD20 binding domain of mosunetuzumab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequence of the VL of the CD20 binding domain of mosunetuzumab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequence of the VH of the CD3 binding domain of mosunetuzumab and the VL of the CD3 binding domain of mosunetuzumab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequence of the VH of the CD20 binding domain of mosunetuzumab and the VL of the CD20 binding domain of mosunetuzumab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequences of the VH of the CD3 binding domain of mosunetuzumab, the VL of the CD3 binding domain of mosunetuzumab, the VH of the CD20 binding domain of mosunetuzumab, and the VL of the CD20 binding domain of mosunetuzumab.

[0143] In another embodiment, the CD3xCD20 antibody is epcolitamab. In one embodiment, the CD3xCD20 antibody is a biosimilar of epcolitamab. In one embodiment, the CD3xCD20 antibody is a biological equivalent of epcolitamab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequences of the VH CDR1, VH CDR2, and VH CDR3 of the CD3 binding domain of epcolitamab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequences of the VL CDR1, VL CDR2, and VL CDR3 of the CD3 binding domain of epcolitamab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequences of the VH CDR1, VH CDR2, and VH CDR3 of the CD20 binding domain of epcolitamab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequences of the VL CDR1, VL CDR2, and VL CDR3 of the CD20 binding domain of epcolitamab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequences of the VH CDR1, VH CDR2, and VH CDR3 of the CD3 binding domain of epcolitamab, and the VL CDR1, VL CDR2, and VL CDR3 of the CD3 binding domain of epcolitamab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequences of the VH CDR1, VH CDR2, and VH CDR3 of the CD20 binding domain of epcolitamab, and the VL CDR1, VL CDR2, and VL CDR3 of the CD20 binding domain of epcolitamab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequence of the VH CDR1, VH CDR2, and VH CDR3 of the CD3 binding domain of epcolitamab, the VL CDR1, VL CDR2, and VL CDR3 of the CD3 binding domain of epcolitamab, the VH CDR1, VH CDR2, and VH CDR3 of the CD20 binding domain of epcolitamab, and the VL CDR1, VL CDR2, and VL CDR3 of the CD20 binding domain of epcolitamab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequence of the VH of the CD3 binding domain of epcolitamab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequence of the VL of the CD3 binding domain of epcolitamab.In one embodiment, the CD3xCD20 antibody comprises the amino acid sequence of the VH of the CD20 binding domain of epcolitamab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequence of the VL of the CD20 binding domain of epcolitamab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequence of the VH of the CD3 binding domain of epcolitamab and the VL of the CD3 binding domain of epcolitamab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequence of the VH of the CD20 binding domain of epcolitamab and the VL of the CD20 binding domain of epcolitamab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequences of the VH of the CD3 binding domain of epcolitamab, the VL of the CD3 binding domain of epcolitamab, the VH of the CD20 binding domain of epcolitamab, and the VL of the CD20 binding domain of epcolitamab.

[0144] In another embodiment, the CD3xCD20 antibody is odronextamab. In one embodiment, the CD3xCD20 antibody is a biosimilar of odronextamab. In one embodiment, the CD3xCD20 antibody is a bioequivalent of odronextamab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequences of VH CDR1, VH CDR2, and VH CDR3 of the CD3 binding domain of odronextamab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequences of VL CDR1, VL CDR2, and VL CDR3 of the CD3 binding domain of odronextamab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequences of VH CDR1, VH CDR2, and VH CDR3 of the CD20 binding domain of odronextamab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequences of the VL CDR1, VL CDR2, and VL CDR3 of the CD20 binding domain of odronextamab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequences of the VH CDR1, VH CDR2, and VH CDR3 of the CD3 binding domain of odronextamab and the VL CDR1, VL CDR2, and VL CDR3 of the CD3 binding domain of odronextamab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequences of the VH CDR1, VH CDR2, and VH CDR3 of the CD20 binding domain of odronextamab and the VL CDR1, VL CDR2, and VL CDR3 of the CD20 binding domain of odronextamab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequence of the VH CDR1, VH CDR2, and VH CDR3 of the CD3 binding domain of odronextamab, the VL CDR1, VL CDR2, and VL CDR3 of the CD3 binding domain of odronextamab, the VH CDR1, VH CDR2, and VH CDR3 of the CD20 binding domain of odronextamab, and the VL CDR1, VL CDR2, and VL CDR3 of the CD20 binding domain of odronextamab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequence of the VH of the CD3 binding domain of odronextamab.In one embodiment, the CD3xCD20 antibody comprises the amino acid sequence of the VL of the CD3 binding domain of odronextamab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequence of the VH of the CD20 binding domain of odronextamab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequence of the VL of the CD20 binding domain of odronextamab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequence of the VH of the CD3 binding domain of odronextamab and the VL of the CD3 binding domain of odronextamab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequence of the VH of the CD20 binding domain of odronextamab and the VL of the CD20 binding domain of odronextamab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequences of the VH of the CD3 binding domain of odronextamab, the VL of the CD3 binding domain of odronextamab, the VH of the CD20 binding domain of odronextamab, and the VL of the CD20 binding domain of odronextamab.

[0145] In another embodiment, the CD3xCD20 antibody is glofitamab. In one embodiment, the CD3xCD20 antibody is a biosimilar of glofitamab. In one embodiment, the CD3xCD20 antibody is a bioequivalent of glofitamab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequences of the VH CDR1, VH CDR2, and VH CDR3 of the CD3 binding domain of glofitamab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequences of the VL CDR1, VL CDR2, and VL CDR3 of the CD3 binding domain of glofitamab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequences of the VH CDR1, VH CDR2, and VH CDR3 of the CD20 binding domain of glofitamab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequences of the VL CDR1, VL CDR2, and VL CDR3 of the CD20 binding domain of glofitamab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequences of the VH CDR1, VH CDR2, and VH CDR3 of the CD3 binding domain of glofitamab and the VL CDR1, VL CDR2, and VL CDR3 of the CD3 binding domain of glofitamab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequences of the VH CDR1, VH CDR2, and VH CDR3 of the CD20 binding domain of glofitamab and the VL CDR1, VL CDR2, and VL CDR3 of the CD20 binding domain of glofitamab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequence of the VH CDR1, VH CDR2, and VH CDR3 of the CD3 binding domain of glofitamab, the VL CDR1, VL CDR2, and VL CDR3 of the CD3 binding domain of glofitamab, the VH CDR1, VH CDR2, and VH CDR3 of the CD20 binding domain of glofitamab, and the VL CDR1, VL CDR2, and VL CDR3 of the CD20 binding domain of glofitamab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequence of the VH of the CD3 binding domain of glofitamab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequence of the VL of the CD3 binding domain of glofitamab.In one embodiment, the CD3xCD20 antibody comprises the amino acid sequence of the VH of the CD20 binding domain of glofitamab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequence of the VL of the CD20 binding domain of glofitamab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequence of the VH of the CD3 binding domain of glofitamab and the VL of the CD3 binding domain of glofitamab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequence of the VH of the CD20 binding domain of glofitamab and the VL of the CD20 binding domain of glofitamab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequence of the VH of the CD3 binding domain of glofitamab, the VL of the CD3 binding domain of glofitamab, the VH of the CD20 binding domain of glofitamab and the VL of the CD20 binding domain of glofitamab.

[0146] In one embodiment, the CD19 antibody comprises a heavy chain variable (VH) domain comprising a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NO:1, SEQ ID NO:2, and SEQ ID NO:3, respectively.

[0147] In one embodiment, the CD19 antibody comprises a light chain variable (VL) domain comprising a VL CDR1, a VL CDR2, and a VL CDR3 having the amino acid sequences of SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6, respectively.

[0148] In one embodiment, the CD19 antibody comprises a heavy chain variable (VH) domain comprising a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NO:1, SEQ ID NO:2, and SEQ ID NO:3, respectively, and a light chain variable (VL) domain comprising a VL CDR1, a VL CDR2, and a VL CDR3 having the amino acid sequences of SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6, respectively.

[0149] In one embodiment, the CD19 antibody comprises a VH domain having an amino acid sequence that is about 90%, 95%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 19. In one embodiment, the CD19 antibody comprises a VH domain having an amino acid sequence that is about 90% identical to the amino acid sequence of SEQ ID NO: 19. In another embodiment, the CD19 antibody comprises a VH domain having an amino acid sequence that is about 95% identical to the amino acid sequence of SEQ ID NO: 19. In another embodiment, the CD19 antibody comprises a VH domain having an amino acid sequence that is about 98% identical to the amino acid sequence of SEQ ID NO: 19. In another embodiment, the CD19 antibody comprises a VH domain having an amino acid sequence that is about 99% identical to the amino acid sequence of SEQ ID NO: 19. In another embodiment, the CD19 antibody comprises a VH domain having an amino acid sequence that is about 100% identical to the amino acid sequence of SEQ ID NO: 19.

[0150] In one embodiment, the CD19 antibody comprises a VL domain having an amino acid sequence that is about 90%, 95%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO:20. In one embodiment, the CD19 antibody comprises a VL domain having an amino acid sequence that is about 90% identical to the amino acid sequence of SEQ ID NO:20. In another embodiment, the CD19 antibody comprises a VL domain having an amino acid sequence that is about 95% identical to the amino acid sequence of SEQ ID NO:20. In another embodiment, the CD19 antibody comprises a VL domain having an amino acid sequence that is about 98% identical to the amino acid sequence of SEQ ID NO:20. In another embodiment, the CD19 antibody comprises a VL domain having an amino acid sequence that is about 99% identical to the amino acid sequence of SEQ ID NO:20. In another embodiment, the CD19 antibody comprises a VL domain having an amino acid sequence that is about 100% identical to the amino acid sequence of SEQ ID NO:20.

[0151] In one embodiment, the CD19 antibody comprises a VH domain having an amino acid sequence that is about 90%, 95%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 19, and a VL domain having an amino acid sequence that is about 90%, 95%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 20. In one embodiment, the CD19 antibody comprises a VH domain having an amino acid sequence that is about 90% identical to the amino acid sequence of SEQ ID NO: 19, and a VL domain having an amino acid sequence that is about 90% identical to the amino acid sequence of SEQ ID NO: 20. In another embodiment, the CD19 antibody comprises a VH domain having an amino acid sequence that is about 90% identical to the amino acid sequence of SEQ ID NO: 19, and a VL domain having an amino acid sequence that is about 90% identical to the amino acid sequence of SEQ ID NO: 20. In another embodiment, the CD19 antibody comprises a VH domain having an amino acid sequence that is about 95% identical to the amino acid sequence of SEQ ID NO: 19, and a VL domain having an amino acid sequence that is about 95% identical to the amino acid sequence of SEQ ID NO: 20. In another embodiment, the CD19 antibody comprises a VH domain having an amino acid sequence about 98% identical to the amino acid sequence of SEQ ID NO: 19, and a VL domain having an amino acid sequence about 98% identical to the amino acid sequence of SEQ ID NO: 20. In another embodiment, the CD19 antibody comprises a VH domain having an amino acid sequence about 99% identical to the amino acid sequence of SEQ ID NO: 19, and a VL domain having an amino acid sequence about 99% identical to the amino acid sequence of SEQ ID NO: 20. In another embodiment, the CD19 antibody comprises a VH domain having an amino acid sequence about 100% identical to the amino acid sequence of SEQ ID NO: 19, and a VL domain having an amino acid sequence about 100% identical to the amino acid sequence of SEQ ID NO:20.

[0152] In a specific embodiment, the anti-CD19 antibody is tafasitamab. In one embodiment, the anti-CD19 antibody is a biosimilar of tafasitamab. In one embodiment, the anti-CD19 antibody is a bioequivalent of tafasitamab. In one embodiment, the CD19 antibody comprises the amino acid sequence of VH CDR1, VH CDR2, and VH CDR3 of tafasitamab. In one embodiment, the CD19 antibody comprises the amino acid sequence of VL CDR1, VL CDR2, and VL CDR3 of tafasitamab. In one embodiment, the CD19 antibody comprises the amino acid sequence of VH CDR1, VH CDR2, and VH CDR3 of tafasitamab, and the amino acid sequence of VL CDR1, VL CDR2, and VL CDR3 of tafasitamab. In one embodiment, the CD19 antibody comprises the amino acid sequence of VH of tafasitamab. In one embodiment, the CD19 antibody comprises the amino acid sequence of the VL of tafasitamab. In one embodiment, the CD19 antibody comprises the amino acid sequence of the VH of tafasitamab, as well as the amino acid sequence of the VL of tafasitamab.

[0153] compound In some embodiments, a compound having the structure: [ka] (i.e., 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione (Compound A)). In some embodiments, the compound is a pharmaceutically acceptable salt of Compound A. In some embodiments, the compound is a solvate of Compound A. In some embodiments, the compound is a stereoisomer of Compound A. Other compounds that are useful in the methods provided herein are racemic, stereomerically enriched, or stereomerically pure compounds (e.g., Compound A), as well as pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, clathrates, and prodrugs thereof.

[0154] Compounds useful for the methods provided herein can be commercially available or prepared according to the methods described in the patents or patent publications disclosed herein. For example, compounds can be obtained through standard synthetic methods (see, for example, U.S. Pat. No. 5,635,517, which is incorporated herein by reference in its entirety). In addition, optically pure compounds can be asymmetrically synthesized or resolved using known resolving agents or chiral columns and other standard organic synthetic chemistry techniques. As used herein, unless otherwise indicated, the term "pharmaceutically acceptable salts" includes non-toxic acid addition salts and base addition salts of the compound to which the term refers. Acceptable non-toxic acid addition salts include those derived from organic and inorganic acids or bases known in the art, including, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, acetic acid, tartaric acid, lactic acid, succinic acid, citric acid, malic acid, maleic acid, sorbic acid, aconitic acid, salicylic acid, phthalic acid, embolic acid, enanthic acid, and the like.

[0155] Compounds that are acidic in nature can form salts with various pharma- ceutically acceptable bases. Bases that can be used to prepare pharma-ceutically acceptable base addition salts of such acidic compounds are those that form non-toxic base addition salts, i.e., salts containing pharmacologically acceptable cations (e.g., alkali metal or alkaline earth metal salts, particularly, but not limited to, calcium, magnesium, sodium, or potassium salts). Suitable organic bases include, but are not limited to, N,N-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), lysine, and procaine.

[0156] As used herein, unless otherwise indicated, the term "prodrug" refers to a derivative of a compound that can be hydrolyzed, oxidized, or otherwise reacted under biological conditions (in vitro or in vivo) to provide the compound. Examples of prodrugs include, but are not limited to, derivatives of Compound A that contain a biohydrolyzable moiety, such as a biohydrolyzable amide, a biohydrolyzable ester, a biohydrolyzable carbamate, a biohydrolyzable carbonate, a biohydrolyzable ureide, and a biohydrolyzable phosphate analog. Other examples of prodrugs include derivatives of Compound A that contain a --NO, --NO2, --ONO, or --ONO2 moiety. Prodrugs can typically be prepared using well-known methods, such as those described in 1 Burger's Medicinal Chemistry and Drug Discovery, 172-178, 949-982 (Manfred E. Wolff ed., 5th ed. 1995), and Design of Prodrugs (H. Bundgaard ed., Elselvier, New York 1985).

[0157] As used herein, unless otherwise indicated, the terms "biohydrolyzable amide," "biohydrolyzable ester," "biohydrolyzable carbamate," "biohydrolyzable carbonate," "biohydrolyzable ureide," and "biohydrolyzable phosphate" mean, respectively, an amide, ester, carbamate, carbonate, ureide, or phosphate of a compound that 1) does not interfere with the biological activity of the compound but can confer advantageous properties to the compound in vivo, such as uptake, duration of action, or onset of action, or 2) is biologically inactive but is converted to a biologically active compound in vivo. Examples of biohydrolyzable esters include, but are not limited to, lower alkyl esters, lower acyloxyalkyl esters (e.g., acetoxylmethyl, acetoxyethyl, aminocarbonyloxymethyl, pivaloyloxymethyl, and pivaloyloxyethyl esters), lactonyl esters (e.g., phthalidyl and thiophthalidyl esters), lower alkoxyacyloxyalkyl esters (e.g., methoxycarbonyl-oxymethyl, ethoxycarbonyloxyethyl, and isopropoxycarbonyloxyethyl esters), alkoxyalkyl esters, choline esters, and acylaminoalkyl esters (such as acetamidomethyl ester). Examples of biohydrolyzable amides include, but are not limited to, lower alkyl amides, alpha-amino acid amides, alkoxyacyl amides, and alkylaminoalkylcarbonyl amides. Examples of biohydrolyzable carbamates include, but are not limited to, lower alkyl amines, substituted ethylenediamines, amino acids, hydroxyalkylamines, heterocyclic and heteroaromatic amines, and polyether amines.

[0158] The compounds provided herein (e.g., Compound A) may contain one or more chiral centers and may exist as racemic mixtures of enantiomers or mixtures of diastereomers. The methods provided herein encompass the use of such compounds in stereoisomerically pure forms, as well as the use of mixtures of these forms. For example, mixtures containing equal or unequal amounts of the enantiomers of a particular compound (e.g., Compound A) may be used in the methods provided herein. These isomers may be asymmetrically synthesized or resolved using standard techniques, such as chiral columns or chiral resolving agents. See, e.g., Jacques, J., et al., Enantiomers, Racemates and Resolutions (Wiley-Interscience, New York, 1981); Wilen, S.H., et al., Tetrahedron 33:2725 (1977); Eliel, E.L., Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, S.H., Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, Ind., 1972).

[0159] As used herein, unless otherwise indicated, the term "stereoisomerically pure" refers to a composition that contains one stereoisomer of a compound (e.g., compound A) and is substantially free of other stereoisomers of that compound. For example, a stereoisomerically pure composition of a compound having one chiral center will be substantially free of the opposite enantiomer of that compound. A stereoisomerically pure composition of a compound having two chiral centers will be substantially free of other diastereomers of that compound. A typical stereoisomerically pure compound contains more than about 80% by weight of one stereoisomer of that compound and less than about 20% by weight of other stereoisomers of that compound, more preferably more than about 90% by weight of one stereoisomer of that compound and less than about 10% by weight of other stereoisomers of that compound, even more preferably more than about 95% by weight of one stereoisomer of that compound and less than about 5% by weight of other stereoisomers of that compound, and most preferably more than about 97% by weight of one stereoisomer of that compound and less than about 3% by weight of other stereoisomers of that compound. As used herein, unless otherwise indicated, the term "stereoisomerically enriched" refers to a composition that contains greater than about 60% by weight of one stereoisomer of a compound, preferably greater than about 70% by weight, and more preferably greater than about 80% by weight of one stereoisomer of a compound. As used herein, unless otherwise indicated, the term "enantiomerically pure" refers to a stereoisomerically pure composition of a compound having one chiral center. Similarly, the term "stereoisomerically enriched" refers to a stereoisomerically enriched composition of a compound having one chiral center.

[0160] It should be noted that in the event of a discrepancy between a depicted structure and a name given to that structure, the depicted structure should prevail. Furthermore, if the stereochemistry of a structure or portion of a structure is not shown, for example, in bold or dashed lines, then that structure or portion of the structure is to be interpreted as encompassing all stereoisomers thereof.

[0161] 4.4. Treatment Method The methods provided herein are useful for the treatment of lymphomas, including, but not limited to, non-Hodgkin's lymphomas, such as diffuse large B-cell lymphoma (DLBCL).

[0162] Non-Hodgkin's lymphoma (NHL) is a diverse group of malignant tumors that are primarily of B-cell origin. NHL can develop in any organ associated with the lymphatic system, such as the spleen, lymph nodes, or tonsils, and can occur at any age. NHL is often characterized by swollen lymph nodes, fever, and weight loss. NHL is classified as either B-cell NHL or T-cell NHL. Lymphomas associated with lymphoproliferative disorders after bone marrow or stem cell transplantation are usually B-cell NHL. NHL is classified into low-grade, intermediate-grade, and high-grade categories according to its natural history (see "The Non-Hodgkin's Lymphoma Pathologic Classification Project," Cancer 49(1982):2112-2135). Low-grade lymphomas are indolent, with a median survival of 5 to 10 years (Horning and Rosenberg (1984) N. Engl. J. Med. 311:1471-1475). Chemotherapy can induce remission in the majority of indolent lymphomas, but cures are rare and most patients eventually relapse and require further treatment. Intermediate- and high-grade lymphomas are more aggressive tumors but are more likely to be cured with chemotherapy. However, the majority of these patients will relapse and require further treatment.

[0163] DLBCL is the most common subtype of NHL. Since the introduction of the anti-CD20 antibody rituximab, approximately 50%-70% of patients can achieve cure with initial standard-of-care immunochemotherapy. However, for patients who are resistant to or relapse after frontline therapy, the prognosis is poor. The implementation of salvage chemotherapy followed by high-dose chemotherapy and autologous stem cell transplantation (ASCT) has some advantages in this setting and is associated with significant toxicity. Furthermore, most patients are ineligible for this approach, leaving few treatment options. Thus, there remains a great need to provide effective treatment options for patients with relapsed or refractory (R / R) DLBCL who are ineligible for ASCT (Coiffier B et al. Hematology Am Soc Hematol Educ Program. 2016;(1):366-78).

[0164] Provided herein in an exemplary embodiment is a method of treating lymphoma in a subject, the method comprising administering to the subject a combination of a CD19 antibody, a CD3xCD20 antibody, and Compound A.

[0165] Provided herein in one aspect is a method of treating lymphoma in a subject, the method comprising administering to the subject (a) an antibody that binds to CD19 (a CD19 antibody), (b) a multispecific antibody that comprises a first binding domain that binds to CD3 and a second binding domain that binds to CD20 (a CD3xCD20 antibody), and (c) a compound having the following structure: [ka] (Compound A). In some embodiments, the compound is Compound A, a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof.

[0166] In a specific embodiment, the subject is first administered a CD19 antibody at least one day prior to the subject's first administration of Compound A, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, In another embodiment, the subject is first administered a CD19 antibody at least one day prior to the subject's first administration of a CD3xCD20 antibody.

[0167] In yet other embodiments, the subject is first administered a CD19 antibody at least one day prior to the subject's first administration of Compound A, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, and the subject is first administered a CD19 antibody at least one day prior to the subject's first administration of a CD3xCD20 antibody.

[0168] In certain embodiments, the subject is a subject in need thereof.

[0169] In one embodiment, the lymphoma is a non-Hodgkin's lymphoma. In another embodiment, the non-Hodgkin's lymphoma is DLBCL. In another embodiment, the DLBCL is relapsed DLBCL, refractory DLBCL, or relapsed-refractory DLBCL. In one embodiment, the DLBCL is relapsed DLBCL. In one embodiment, the DLBCL is refractory DLBCL. In one embodiment, the DLBCL is relapsed-refractory DLBCL. In another embodiment, the DLBCL is primary refractory DLBCL. In another embodiment, the DLBCL is first-line DLBCL.

[0170] In one embodiment, the lymphoma is a CD20-expressing lymphoma. In another embodiment, the lymphoma is a CD19-expressing lymphoma. In another embodiment, the lymphoma is a lymphoma that expresses CD20 and CD19.

[0171] In one embodiment, the subject has previously undergone CAR-T therapy.

[0172] In one embodiment, the subject has not undergone a stem cell transplant. In another embodiment, the subject is not eligible for a stem cell transplant. In another embodiment, the stem cell transplant is an autologous stem cell transplant.

[0173] In one embodiment, the subject has undergone treatment for lymphoma prior to the method, hi some embodiments, the treatment comprises chemoimmunotherapy, anti-CD20 antibody, or a combination thereof.

[0174] In some embodiments, a method of treating lymphoma in a subject is provided, the method comprising administering to the subject (i) a first polypeptide comprising a first means capable of binding to CD3 and a second means capable of binding to CD20, (ii) a second polypeptide comprising a third means capable of binding to CD19, and (iii) a compound. In some embodiments, a method of treating DLBCL in a subject is provided, the method comprising administering to the subject (i) a first polypeptide comprising a first means capable of binding to CD3 and a second means capable of binding to CD20, (ii) a second polypeptide comprising a third means capable of binding to CD19, and (iii) a compound. In some embodiments, a method of inhibiting the growth or proliferation of lymphoma cells in a subject is provided, the method comprising administering to the subject (i) a first polypeptide comprising a first means capable of binding to CD3 and a second means capable of binding to CD20, (ii) a second polypeptide comprising a third means capable of binding to CD19, and (iii) a compound. In some embodiments, a method of inhibiting the growth or proliferation of DLBCL cells in a subject is provided, the method comprising administering to the subject (i) a first polypeptide comprising a first means capable of binding to CD3 and a second means capable of binding to CD20, (ii) a second polypeptide comprising a third means capable of binding to CD19, and (iii) a compound. In a specific embodiment, the compound is Compound A. Other compounds useful in the methods provided herein are racemic, stereoisomerically enriched, or stereoisomerically pure compounds, as well as pharma- ceutically acceptable salts, solvates, hydrates, stereoisomers, clathrates, and prodrugs of Compound A. In some embodiments, the first polypeptide is a multispecific antibody. In some embodiments, the first polypeptide is a bispecific antibody. In one embodiment, the multispecific antibody comprises a bispecific antibody. In one embodiment, the first means is a CD3 binding domain. In one embodiment, the second means is a CD20 binding domain. In one embodiment, the first means is a CD3 antigen-binding fragment.In one embodiment, the second means is a CD20 antigen-binding fragment. In a specific embodiment, the bispecific antibody is a CD3xCD20 antibody. In one embodiment, the third means is a CD19 binding domain. In one embodiment, the third means is a CD19 antigen-binding fragment. In some embodiments, the second polypeptide is a CD19 antibody. In certain embodiments, the subject is a subject in need thereof. In a specific embodiment, the subject is a human subject.

[0175] Medication Regimen In one embodiment, the provided CD19 antibody, CD3xCD20 antibody, and compound A are administered according to the dosing regimen provided herein. However, the CD19 antibody, CD3xCD20 antibody, and compound A can be administered by any method known in the art. Those skilled in the art will understand that the route and / or mode of administration can vary depending on the desired outcome.

[0176] Provided herein, in one embodiment, is a method comprising the dosing regimen provided in Figure 2. Provided herein, in another embodiment, is a method comprising the dosing regimen provided in Figure 3. Provided herein, in yet another embodiment, is a method comprising the dosing regimen provided in Example 1.

[0177] In one embodiment, the method comprises cyclic administration of a CD19 antibody. In one embodiment, the method comprises cyclic administration of Compound A, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof. In one embodiment, the method comprises cyclic administration of a CD3xCD20 antibody. In one embodiment, the method comprises cyclic administration of a CD19 antibody, Compound A, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, and a CD3xCD20 antibody.

[0178] In one embodiment, each cycle of the periodic administration is 28 days. In another embodiment, the periodic administration comprises about 1 cycle, 2 cycles, 3 cycles, 4 cycles, 5 cycles, 6 cycles, 7 cycles, 8 cycles, 9 cycles, 10 cycles, 11 cycles, 12 cycles, or more than 12 cycles. In another embodiment, the periodic administration comprises about 1 cycle. In another embodiment, the periodic administration comprises about 2 cycles. In another embodiment, the periodic administration comprises about 3 cycles. In another embodiment, the periodic administration comprises about 4 cycles. In another embodiment, the periodic administration comprises about 5 cycles. In another embodiment, the periodic administration comprises about 6 cycles. In another embodiment, the periodic administration comprises about 7 cycles. In another embodiment, the periodic administration comprises about 8 cycles. In another embodiment, the periodic administration comprises about 9 cycles. In another embodiment, the periodic administration comprises about 10 cycles. In another embodiment, the periodic administration comprises about 11 cycles. In another embodiment, the periodic administration comprises about 12 cycles. In another embodiment, the cyclic administration comprises more than 12 cycles.

[0179] In one embodiment, the first administration of the CD19 antibody is administered to the subject before day 1 of the first cycle of cyclical administration. In one embodiment, the first administration of the CD19 antibody is administered to the subject at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more than 10 days before day 1 of the first cycle of cyclical administration. In one embodiment, the first administration of the CD19 antibody is administered to the subject at least 1 day before day 1 of the first cycle of cyclical administration. In another embodiment, the first administration of the CD19 antibody is administered to the subject at least 2 days before day 1 of the first cycle of cyclical administration. In another embodiment, the first administration of the CD19 antibody is administered to the subject at least 3 days before day 1 of the first cycle of cyclical administration. In another embodiment, the first administration of the CD19 antibody is administered to the subject at least 4 days before day 1 of the first cycle of cyclical administration. In another embodiment, the first administration of the CD19 antibody is administered to the subject at least 5 days prior to day 1 of the first cycle of the cyclical administration. In another embodiment, the first administration of the CD19 antibody is administered to the subject at least 6 days prior to day 1 of the first cycle of the cyclical administration. In another embodiment, the first administration of the CD19 antibody is administered to the subject at least 7 days prior to day 1 of the first cycle of the cyclical administration. In another embodiment, the first administration of the CD19 antibody is administered to the subject at least 8 days prior to day 1 of the first cycle of the cyclical administration. In another embodiment, the first administration of the CD19 antibody is administered to the subject at least 9 days prior to day 1 of the first cycle of the cyclical administration. In another embodiment, the first administration of the CD19 antibody is administered to the subject at least 10 days prior to day 1 of the first cycle of the cyclical administration. In another embodiment, the first administration of the CD19 antibody is administered to the subject more than 10 days prior to day 1 of the first cycle of the cyclical administration. In another embodiment, the first administration of the CD19 antibody is administered to the subject 4 days prior to day 1 of the first cycle of the cyclical administration. In another embodiment, the first administration of the CD19 antibody is administered to the subject 8 days prior to day 1 of the first cycle of the cyclical administration. In another embodiment, the CD19 antibody is administered to the subject 4 and 8 days prior to day 1 of the first cycle of the cyclical administration.

[0180] In one embodiment, the CD19 antibody is administered to the subject on day(s) 1, 8, 15, and / or 22 of a cycle of cyclical administration. In one embodiment, the CD19 antibody is administered to the subject on day(s) 1, 8, 15, and 22 of a cycle of cyclical administration. In one embodiment, the CD19 antibody is administered to the subject on day(s) 1, 8, 15, or 22 of a cycle of cyclical administration. In another embodiment, the CD19 antibody is administered to the subject on day 1 of a cycle of cyclical administration. In another embodiment, the CD19 antibody is administered to the subject on day 8 of a cycle of cyclical administration. In another embodiment, the CD19 antibody is administered to the subject on day 15 of a cycle of cyclical administration. In another embodiment, the CD19 antibody is administered to the subject on day 22 of a cycle of cyclical administration. In another embodiment, the CD19 antibody is administered to the subject on days 1 and 15 of a cycle of cyclical administration. In another embodiment, the CD19 antibody is administered to the subject on days 1, 8, 15, and 22 of each of cycles 1 to 3 of the cyclical administration. In another embodiment, the CD19 antibody is administered to the subject on days 1 and 15 of cycles 4 and onwards of the cyclical administration. In another embodiment, the CD19 antibody is administered to the subject on days 1 and 15 of cycles 4 to 6 of the cyclical administration. In another embodiment, the CD19 antibody is administered to the subject every 6 to 8 days in a cycle of the cyclical administration.

[0181] In one embodiment, Compound A, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, is administered to a subject for 21 consecutive days in a cyclical dosing regimen. In another embodiment, Compound A, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, is administered to a subject on days 1 through 21 of the cyclical dosing regimen. In another embodiment, Compound A, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, is administered to a subject for 21 days in a 28-day cycle of cyclical dosing, followed by a 7-day rest period.

[0182] In one embodiment, the CD3xCD20 antibody is administered to the subject on day(s) 1, 8, 15, and / or 22 of a cycle of periodic administration. In another embodiment, the CD3xCD20 antibody is administered to the subject on day(s) 1, 8, 15, and 22 of a cycle of periodic administration. In another embodiment, the CD3xCD20 antibody is administered to the subject on day(s) 1, 8, 15, or 22 of a cycle of periodic administration. In another embodiment, the CD3xCD20 antibody is administered to the subject on day 1 of a cycle of periodic administration. In another embodiment, the CD3xCD20 antibody is administered to the subject on day 8 of a cycle of periodic administration. In another embodiment, the CD3xCD20 antibody is administered to the subject on day 15 of a cycle of periodic administration. In another embodiment, the CD3xCD20 antibody is administered to the subject on day 22 of a cycle of periodic administration. In another embodiment, the CD3xCD20 antibody is administered to the subject on days 1 and 15 of a cycle of the cyclical administration. In another embodiment, the CD3xCD20 antibody is administered to the subject on days 1, 8, 15, and 22 of cycle 1 and cycle 2 of the cyclical administration. In another embodiment, the CD3xCD20 antibody is administered to the subject on days 1 and 15 of cycle 3 and beyond of the cyclical administration. In another embodiment, the CD3xCD20 antibody is administered to the subject on days 1 and 15 of cycles 3-6 of the cyclical administration. In another embodiment, the CD3xCD20 antibody is administered to the subject every 6-8 days of a cycle of the cyclical administration.

[0183] In one embodiment, the CD19 antibody is administered to the subject in an amount of about 1 mg / kg to about 20 mg / kg per day. In one embodiment, the CD19 antibody is administered to the subject in an amount of about 1 mg / kg per day. In another embodiment, the CD19 antibody is administered to the subject in an amount of about 2 mg / kg per day. In another embodiment, the CD19 antibody is administered to the subject in an amount of about 3 mg / kg per day. In another embodiment, the CD19 antibody is administered to the subject in an amount of about 4 mg / kg per day. In another embodiment, the CD19 antibody is administered to the subject in an amount of about 5 mg / kg per day. In another embodiment, the CD19 antibody is administered to the subject in an amount of about 6 mg / kg per day. In another embodiment, the CD19 antibody is administered to the subject in an amount of about 7 mg / kg per day. In another embodiment, the CD19 antibody is administered to the subject in an amount of about 8 mg / kg per day. In another embodiment, the CD19 antibody is administered to the subject in an amount of about 9 mg / kg per day. In another embodiment, the CD19 antibody is administered to the subject in an amount of about 10 mg / kg per day. In another embodiment, the CD19 antibody is administered to the subject in an amount of about 11 mg / kg per day. In another embodiment, the CD19 antibody is administered to the subject in an amount of about 12 mg / kg per day. In another embodiment, the CD19 antibody is administered to the subject in an amount of about 13 mg / kg per day. In another embodiment, the CD19 antibody is administered to the subject in an amount of about 14 mg / kg per day. In another embodiment, the CD19 antibody is administered to the subject in an amount of about 15 mg / kg per day. In another embodiment, the CD19 antibody is administered to the subject in an amount of about 16 mg / kg per day. In another embodiment, the CD19 antibody is administered to the subject in an amount of about 17 mg / kg per day. In another embodiment, the CD19 antibody is administered to the subject in an amount of about 18 mg / kg per day. In another embodiment, the CD19 antibody is administered to the subject in an amount of about 19 mg / kg per day. In another embodiment, the CD19 antibody is administered to the subject in an amount of about 20 mg / kg per day.

[0184] In one embodiment, Compound A, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, is administered to the subject in an amount of about 1 mg to about 30 mg per day. In another embodiment, Compound A, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, is administered to the subject in an amount of about 2.5 mg, 5 mg, 10 mg, 15 mg, 20 mg, or 25 mg per day. In another embodiment, Compound A, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, is administered to the subject in an amount of about 2.5 mg per day. In another embodiment, Compound A, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, is administered to the subject in an amount of about 5 mg per day. In another embodiment, Compound A, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, is administered to the subject in an amount of about 10 mg per day. In another embodiment, Compound A, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, is administered to the subject in an amount of about 15 mg per day. In another embodiment, Compound A, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, is administered to the subject in an amount of about 20 mg per day. In another embodiment, Compound A, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, is administered to the subject in an amount of about 25 mg per day.

[0185] In one embodiment, the CD3xCD20 antibody is administered to the subject in an amount of about 0.8 mg to about 100 mg per day. In one embodiment, the CD3xCD20 antibody is administered to the subject in an amount of about 0.8 mg to about 50 mg per day. In one embodiment, the CD3xCD20 antibody is administered to the subject in an amount of about 0.8 mg to about 20 mg per day. In another embodiment, the CD3xCD20 antibody is administered to the subject in an amount of about 0.8 mg per day. In another embodiment, the CD3xCD20 antibody is administered to the subject in an amount of about 1 mg per day. In another embodiment, the CD3xCD20 antibody is administered to the subject in an amount of about 2 mg per day. In another embodiment, the CD3xCD20 antibody is administered to the subject in an amount of about 3 mg per day. In another embodiment, the CD3xCD20 antibody is administered to the subject in an amount of about 4 mg per day. In another embodiment, the CD3xCD20 antibody is administered to the subject in an amount of about 5 mg per day. In another embodiment, the CD3xCD20 antibody is administered to the subject in an amount of about 10 mg per day. In another embodiment, the CD3xCD20 antibody is administered to the subject in an amount of about 15 mg per day. In another embodiment, the CD3xCD20 antibody is administered to the subject in an amount of about 20 mg per day. In another embodiment, the CD3xCD20 antibody is administered to the subject in an amount of about 25 mg per day. In another embodiment, the CD3xCD20 antibody is administered to the subject in an amount of about 30 mg per day. In another embodiment, the CD3xCD20 antibody is administered to the subject in an amount of about 35 mg per day. In another embodiment, the CD3xCD20 antibody is administered to the subject in an amount of about 40 mg per day. In another embodiment, the CD3xCD20 antibody is administered to the subject in an amount of about 5 mg per day. In another embodiment, the CD3xCD20 antibody is administered to the subject in an amount of about 50 mg per day. In another embodiment, the CD3xCD20 antibody is administered to the subject in an amount of about 55 mg per day. In another embodiment, the CD3xCD20 antibody is administered to the subject in an amount of about 60 mg per day. In another embodiment, the CD3xCD20 antibody is administered to the subject in an amount of about 65 mg per day. In another embodiment, the CD3xCD20 antibody is administered to the subject in an amount of about 70 mg per day.In another embodiment, the CD3xCD20 antibody is administered to the subject in an amount of about 75 mg per day. In another embodiment, the CD3xCD20 antibody is administered to the subject in an amount of about 80 mg per day. In another embodiment, the CD3xCD20 antibody is administered to the subject in an amount of about 85 mg per day. In another embodiment, the CD3xCD20 antibody is administered to the subject in an amount of about 90 mg per day. In another embodiment, the CD3xCD20 antibody is administered to the subject in an amount of about 95 mg per day. In another embodiment, the CD3xCD20 antibody is administered to the subject in an amount of about 100 mg per day.

[0186] In one embodiment, the initial administration of the CD3xCD20 antibody is performed on day 1 of the first cycle of the periodic administration.

[0187] In one embodiment, the CD3xCD20 antibody is administered to the subject in an amount of about 0.8 mg on day 1 of the first cycle, about 2 mg on day 8 of the first cycle, about 20 mg on days 15 and 22 of the first cycle, and about 20 mg per day for any subsequent cycles. In another embodiment, the CD3xCD20 antibody is administered to the subject in an amount of about 0.8 mg on day 1 of the first cycle, about 2 mg on day 8 of the first cycle, about 20 mg on day 15 of the first cycle, about 35 mg on day 22 of the first cycle, and about 50 mg per day for any subsequent cycles.

[0188] In one embodiment, the initial administration of Compound A, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, is performed on day 1 of the first cycle of the cyclical administration.

[0189] In one embodiment, the first administration of the CD3xCD20 antibody and the first administration of Compound A, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, are both administered on day 1 of the first cycle of the cyclical administration.

[0190] In one embodiment, the CD19 antibody is administered to the subject once a week in a cycle of cyclic administration. In another embodiment, the CD19 antibody is administered to the subject once a week in cycles 1 to 3 of cyclic administration. In another embodiment, the CD19 antibody is administered to the subject every two weeks in a cycle of cyclic administration. In another embodiment, the CD19 antibody is administered to the subject every two weeks from cycle 4 onwards of cyclic administration.

[0191] In one embodiment, the CD3xCD20 antibody is administered to the subject once a week in a cycle of cyclical administration. In another embodiment, the CD3xCD20 antibody is administered to the subject once a week in cycles 1 and 2 of the cyclical administration. In another embodiment, the CD3xCD20 antibody is administered to the subject every two weeks in a cycle of cyclical administration. In another embodiment, the CD3xCD20 antibody is administered to the subject every two weeks in cycles 3 and beyond of the cyclical administration.

[0192] In one embodiment, the CD3xCD20 antibody and the CD19 antibody are each administered to the subject for up to four days in a cyclical administration cycle. In another embodiment, the CD3xCD20 antibody is administered to the subject for one day in a cyclical administration cycle. In another embodiment, the CD3xCD20 antibody is administered to the subject for two days in a cyclical administration cycle. In another embodiment, the CD3xCD20 antibody is administered to the subject for three days in a cyclical administration cycle. In another embodiment, the CD3xCD20 antibody is administered to the subject for four days in a cyclical administration cycle. In another embodiment, the CD19 antibody is administered to the subject for one day in a cyclical administration cycle. In another embodiment, the CD19 antibody is administered to the subject for two days in a cyclical administration cycle. In another embodiment, the CD19 antibody is administered to the subject for three days in a cyclical administration cycle. In another embodiment, the CD19 antibody is administered to the subject for four days in a cyclical administration cycle. In one embodiment, the CD3xCD20 antibody and the CD19 antibody are each administered to the subject on day 1 of the periodic administration cycle. In one embodiment, the CD3xCD20 antibody and the CD19 antibody are each administered to the subject on day 2 of the periodic administration cycle. In one embodiment, the CD3xCD20 antibody and the CD19 antibody are each administered to the subject on day 3 of the periodic administration cycle. In one embodiment, the CD3xCD20 antibody and the CD19 antibody are each administered to the subject on day 4 of the periodic administration cycle.

[0193] In one embodiment, the method comprises cyclically administering a CD3xCD20 antibody to a subject, wherein a first cycle comprises administering to the subject about 0.8 mg of CD3xCD20 antibody on day 1, about 2 mg on about day 8, about 20 mg on about day 15, and about 20 mg on about day 22, wherein about 20 mg of CD3xCD20 antibody is administered to the subject on day 1 and every 6-8 days in a second cycle of the cyclical administration, wherein the CD3xCD20 antibody is administered to the subject four times in each of the first two cycles, and wherein about 20 mg of CD3xCD20 antibody is administered to the subject on day 1 and every 12-16 days in cycle 3 and any subsequent cycles during the treatment period, wherein each cycle of the cyclical administration is 28 days.

[0194] In one embodiment, the method comprises cyclically administering a CD3xCD20 antibody to a subject, wherein a first cycle comprises administering to the subject about 0.8 mg of CD3xCD20 antibody on day 1, about 2 mg on about day 8, about 20 mg on about day 15, and about 35 mg on about day 22, wherein about 50 mg of CD3xCD20 antibody is administered to the subject on day 1 and every 6-8 days in a second cycle of the cyclical administration, wherein the CD3xCD20 antibody is administered to the subject four times in each of the first two cycles, and wherein about 50 mg of CD3xCD20 antibody is administered to the subject on day 1 and every 12-16 days in cycle 3 and any subsequent cycles during the treatment period, wherein each cycle of the cyclical administration is 28 days.

[0195] In one embodiment, the method comprises cyclically administering a CD3xCD20 antibody to a subject, wherein a first cycle comprises administering to the subject about 0.8 mg of CD3xCD20 antibody on day 1, about 2 mg on day 8, about 20 mg on day 15, and about 20 mg on day 22, wherein about 20 mg of CD3xCD20 antibody is administered to the subject on day 1 and every 7 days in the first two cycles of the cyclical administration, wherein the CD3xCD20 antibody is administered to the subject four times in each of the first two cycles, and about 20 mg of CD3xCD20 antibody is administered to the subject on day 1 and every 14 days in cycle 3 and any subsequent cycles during the treatment period, wherein each cycle of the cyclical administration is 28 days.

[0196] In one embodiment, the method comprises cyclically administering a CD3xCD20 antibody to a subject, wherein a first cycle comprises administering to the subject about 0.8 mg of CD3xCD20 antibody on day 1, about 2 mg on day 8, about 20 mg on day 15, and about 35 mg on day 22, wherein about 50 mg of CD3xCD20 antibody is administered to the subject on day 1 and every 7 days in the first two cycles of the cyclical administration, wherein the CD3xCD20 antibody is administered to the subject four times in each of the first two cycles, and about 50 mg of CD3xCD20 antibody is administered to the subject on day 1 and every 14 days in cycle 3 and any subsequent cycles during the treatment period, wherein each cycle of the cyclical administration is 28 days.

[0197] In one embodiment, the method comprises cyclically administering a CD19 antibody to the subject, wherein about 10 mg / kg to about 15 mg / kg of the CD19 antibody is administered to the subject on day 1 and every 6-8 days in the first three cycles of the cyclical administration, wherein the CD19 antibody is administered to the subject four times in each of the first three cycles, wherein about 10 mg / kg to about 15 mg / kg of the CD19 antibody is administered to the subject on day 1 and every 12-16 days in cycle 4 and any subsequent cycles during the treatment period, wherein about 10 mg / kg to about 15 mg / kg of the CD19 antibody is administered to the subject 8 days and 4 days prior to day 1 of the first cycle of the cyclical administration, wherein each cycle of the cyclical administration is 28 days.

[0198] In one embodiment, the method comprises cyclically administering a CD19 antibody to a subject, wherein about 12 mg / kg of the CD19 antibody is administered to the subject on day 1 and every 7 days in the first three cycles of the cyclical administration, wherein the CD19 antibody is administered to the subject four times in each of the first three cycles, wherein about 12 mg / kg of the CD19 antibody is administered to the subject on day 1 and every 14 days in cycle 4 and any subsequent cycles during the treatment period, wherein about 12 mg / kg of the CD19 antibody is administered to the subject 8 days and 4 days prior to day 1 of the first cycle of the cyclical administration, wherein each cycle of the cyclical administration is 28 days.

[0199] In one embodiment, the method includes cyclically administering Compound A, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, to a subject, wherein about 25 mg of Compound A, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, is administered to the subject daily on days 1 and 21 of each cycle of the cyclical administration, followed by a 7-day rest period, such that each cycle of the cyclical administration is 28 days.

[0200] In one embodiment, the method comprises cyclic administration of a CD19 antibody, a CD3xCD20 antibody, and Compound A, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, to a subject, the method comprising: (a) administering to the subject about 0.6 to about 1 mg of CD3xCD20 antibody on day 1, about 1.8 mg to about 2.2 mg on about day 8, and about 18 mg to about 22 mg on about days 15 and 22 in a first cycle of periodic administration, and administering to the subject about 20 mg of CD3xCD20 antibody on day 1 and every 6-8 days in a second cycle, wherein the CD3xCD20 antibody is administered to the subject four times in each of the first two cycles, and about 20 mg of CD3xCD20 antibody is administered to the subject on day 1 and every 12-16 days in cycle 3 and any subsequent cycles during the treatment period; (b) administering to the subject about 10 mg / kg to about 15 mg / kg of a CD19 antibody on day 1 and every 6-8 days in the first three cycles of cyclical administration, wherein the CD19 antibody is administered to the subject four times in each of the first three cycles, and about 10 mg / kg to about 15 mg / kg of the CD19 antibody is administered to the subject on day 1 and every 12-16 days in cycle 4 and any subsequent cycles during the treatment period, and about 10 mg / kg to about 15 mg / kg of the CD19 antibody is administered to the subject 8 days and 4 days prior to day 1 of the first cycle of cyclical administration; (c) during each cycle of cyclical administration, administering to the subject about 25 mg of Compound A, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, daily for days 1 and 21, followed by a 7-day washout period; Each cycle of cyclic administration is 28 days.

[0201] In one embodiment, the method comprises cyclic administration of a CD19 antibody, a CD3xCD20 antibody, and Compound A, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, to a subject, the method comprising: (a) administering to the subject about 0.6 to about 1 mg of CD3xCD20 antibody on day 1, about 1.8 mg to about 2.2 mg on about day 8, about 18 mg to about 22 mg on about day 15, and about 33 mg to about 36 mg on about day 22 in a first cycle of periodic administration, and administering to the subject about 50 mg of CD3xCD20 antibody on day 1 and every 6-8 days in a second cycle, wherein the CD3xCD20 antibody is administered to the subject four times in each of the first two cycles, and about 50 mg of CD3xCD20 antibody is administered to the subject on day 1 and every 12-16 days in cycle 3 and any subsequent cycles during the treatment period; (b) administering to the subject about 10 mg / kg to about 15 mg / kg of a CD19 antibody on day 1 and every 6-8 days in the first three cycles of cyclical administration, wherein the CD19 antibody is administered to the subject four times in each of the first three cycles, and about 10 mg / kg to about 15 mg / kg of the CD19 antibody is administered to the subject on day 1 and every 12-16 days in cycle 4 and any subsequent cycles during the treatment period, and about 10 mg / kg to about 15 mg / kg of the CD19 antibody is administered to the subject 8 days and 4 days prior to day 1 of the first cycle of cyclical administration; (c) during each cycle of cyclical administration, administering to the subject about 25 mg of Compound A, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, daily for days 1 and 21, followed by a 7-day washout period; Each cycle of cyclic administration is 28 days.

[0202] In one embodiment, the method comprises cyclic administration of a CD19 antibody, a CD3xCD20 antibody, and Compound A, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, to a subject, the method comprising: (a) administering to the subject about 0.8 mg of CD3xCD20 antibody on day 1, about 2 mg on about day 8, and about 20 mg on days 15 and 22 in a first cycle of cyclical administration, and administering about 20 mg of CD3xCD20 antibody on day 1 and every 7 days in a second cycle, wherein the CD3xCD20 antibody is administered to the subject four times in each of the first two cycles, and about 20 mg of CD3xCD20 antibody is administered to the subject on day 1 and every 14 days in cycle 3 and any subsequent cycles during the treatment period; (b) administering about 12 mg / kg of a CD19 antibody to the subject on day 1 and every 7 days during the first three cycles of cyclical administration, wherein the CD19 antibody is administered to the subject four times during each of the first three cycles, and about 12 mg / kg of the CD19 antibody is administered to the subject on day 1 and every 14 days during cycle 4 and any subsequent cycles during the treatment period, and about 12 mg / kg of the CD19 antibody is administered to the subject 8 days and 4 days prior to day 1 of the first cycle of the cyclical administration; (c) during the treatment period, in each cycle of cyclical administration, administering to the subject about 25 mg of Compound A, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, daily for days 1 and 21, followed by a 7-day washout period; Each cycle of cyclic administration is 28 days.

[0203] In one embodiment, the method comprises cyclic administration of a CD19 antibody, a CD3xCD20 antibody, and Compound A, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, to a subject, the method comprising: (a) administering to the subject about 0.8 mg of CD3xCD20 antibody on day 1, about 2 mg on about day 8, about 20 mg on day 15, and about 35 mg on day 22 in a first cycle of cyclical administration, and administering about 50 mg of CD3xCD20 antibody on day 1 and every 7 days in a second cycle, wherein the CD3xCD20 antibody is administered to the subject four times in each of the first two cycles, and about 50 mg of CD3xCD20 antibody is administered to the subject on day 1 and every 14 days in cycle 3 and any subsequent cycles during the treatment period; (b) administering about 12 mg / kg of a CD19 antibody to the subject on day 1 and every 7 days during the first three cycles of cyclical administration, wherein the CD19 antibody is administered to the subject four times during each of the first three cycles, and about 12 mg / kg of the CD19 antibody is administered to the subject on day 1 and every 14 days during cycle 4 and any subsequent cycles during the treatment period, and about 12 mg / kg of the CD19 antibody is administered to the subject 8 days and 4 days prior to day 1 of the first cycle of the cyclical administration; (c) during the treatment period, in each cycle of cyclical administration, administering to the subject about 25 mg of Compound A, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, daily for days 1 and 21, followed by a 7-day washout period; Each cycle of cyclic administration is 28 days.

[0204] In one embodiment, the method comprises cyclic administration of a CD19 antibody, a CD3xCD20 antibody, and Compound A, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, to a subject, the method comprising: (a) administering to the subject about 0.8 mg of a CD3xCD20 antibody on day 1, about 2 mg on day 8, and about 20 mg on days 15 and 22 in a first cycle of cyclical administration, and about 20 mg of a CD3xCD20 antibody on days 1, 8, 15, and 22 in a second cycle, wherein about 20 mg of the CD3xCD20 antibody is administered to the subject on days 1 and 15 in cycle 3 and any subsequent cycles during the treatment period; (b) administering about 12 mg / kg of a CD19 antibody to the subject on days 1, 8, 15, and 22 of the first three cycles of cyclical administration, wherein about 12 mg / kg of a CD19 antibody is administered to the subject on days 1 and 15 of cycle 4 and any subsequent cycles during the treatment period, and about 12 mg / kg of a CD19 antibody is administered to the subject 8 days and 4 days prior to day 1 of the first cycle of the cyclical administration; (c) during the treatment period, in each cycle of cyclical administration, administering to the subject about 25 mg of Compound A, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, daily for days 1 and 21, followed by a 7-day washout period; Each cycle of cyclic administration is 28 days.

[0205] In one embodiment, the method comprises cyclic administration of a CD19 antibody, a CD3xCD20 antibody, and Compound A, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, to a subject, the method comprising: (a) administering to the subject about 0.8 mg of CD3xCD20 antibody on day 1, about 2 mg on day 8, about 20 mg on day 15, and about 35 mg on day 22 in a first cycle of cyclical administration, and about 50 mg of CD3xCD20 antibody on days 1, 8, 15, and 22 in a second cycle, wherein about 50 mg of CD3xCD20 antibody is administered to the subject on days 1 and 15 in cycle 3 and any subsequent cycles during the treatment period; (b) administering about 12 mg / kg of a CD19 antibody to the subject on days 1, 8, 15, and 22 of the first three cycles of cyclical administration, wherein about 12 mg / kg of a CD19 antibody is administered to the subject on days 1 and 15 of cycle 4 and any subsequent cycles during the treatment period, and about 12 mg / kg of a CD19 antibody is administered to the subject 8 days and 4 days prior to day 1 of the first cycle of the cyclical administration; (c) during the treatment period, in each cycle of cyclical administration, administering to the subject about 25 mg of Compound A, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, daily for days 1 and 21, followed by a 7-day washout period; Each cycle of cyclic administration is 28 days.

[0206] In one embodiment, the CD19 antibody is not administered to the subject on day 4 of the first cycle of the cyclical administration. In another embodiment, the CD3xCD20 antibody is not administered to the subject on day 4 of the first cycle of the cyclical administration.

[0207] In one embodiment, the method further comprises assessing a PET-CT scan after every two cycles of cyclical administration.

[0208] In one embodiment, the anti-CD19 antibody is tafasitamab. In one embodiment, the CD3xCD20 antibody is pramotamab. In one embodiment, the anti-CD19 antibody is tafasitamab and the CD3xCD20 antibody is pramotamab.

[0209] Administration The pharmaceutical compositions provided herein may be in a variety of forms. These include, for example, liquid, semi-solid and solid dosage forms, such as liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions. The form is determined by the intended mode of administration and therapeutic application. An exemplary composition is in the form of an injectable or infusible solution, such as a composition similar to those used for passive immunization of humans with other antibodies. In an exemplary embodiment, the mode of administration is intravenous administration. In an exemplary embodiment, the antibodies provided herein are administered by intravenous infusion or injection.

[0210] Pharmaceutical compositions typically must be sterile and stable under the conditions of manufacture and storage. Sterile injectable solutions can be prepared by incorporating the bispecific antibody in the required amount in an appropriate solvent with one or a combination of ingredients listed herein, followed by filter sterilization as required. In general, dispersions are prepared by incorporating the bispecific antibody into a sterile vehicle containing a basic dispersion medium and the required other ingredients from those listed herein.

[0211] The pharmaceutical compositions provided herein can be administered by any method known in the art. As will be appreciated by those of skill in the art, the route and / or mode of administration will vary depending on the desired results.

[0212] In one embodiment, Compound A, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, is administered orally to a subject. In another embodiment, Compound A, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, is administered to a subject in a capsule or tablet.

[0213] In an exemplary embodiment, the route / mode of administration is intravenous injection. In one embodiment, the CD19 antibody is administered intravenously.

[0214] Additional drugs In one aspect, a method of treating lymphoma in a subject is provided, the method comprising administering to the subject a combination of a CD19 antibody, a CD3xCD20 antibody, and Compound A, in combination with at least one other agent.

[0215] As used herein, administered "in combination" means that three (or more) different agents are administered to a subject while the subject is suffering from a disorder, for example, three or more agents are administered after a human subject is diagnosed with a tumor and before the tumor is treated. In some embodiments, the administration of a first agent is still occurring at the beginning of the administration of a second agent, resulting in an overlap in administration. This may be referred to herein as "co-administration" or "concomitant administration." In other embodiments, the administration of one agent ends before the administration of the other agent begins. In some embodiments in either case, the treatment is more effective with the combined administration. In some embodiments, the administration is performed such that the reduction in symptoms, or other parameters associated with the tumor, is greater than that observed when one agent is administered in the absence of the other agent. The effect of the agents on the subject may be partially additive, fully additive, or greater than additive. The administration may be performed such that the effect of the first therapeutic administration can still be detected at the time the second therapeutic administration is performed.

[0216] The combinations described herein and the at least one other agent may be administered simultaneously, in the same or separate compositions, or sequentially. For sequential administration, the at least one other agent may be administered before or after administration of the combinations described herein.

[0217] When administered in combination, the CD19 antibody, the CD3xCD20 antibody, the compound A, and the at least one other agent, or all of them, may be administered in amounts or doses that are higher, lower, or the same as the amounts or doses of each therapeutic agent used individually, e.g., as monotherapy. In some embodiments, the doses or doses of the CD19 antibody, the CD3xCD20 antibody, the compound A, and the at least one other agent, or all of them, are lower (e.g., at least 20%, at least 30%, at least 40%, or at least 50%) than the amounts or doses of each therapeutic agent used individually, e.g., as monotherapy. In other embodiments, the amounts or doses of the CD19 antibody, the CD3xCD20 antibody, the compound A, and the at least one other agent, or all of them, that produce the desired effect (e.g., treatment of a tumor) are lower (e.g., at least 20%, at least 30%, at least 40%, or at least 50%) than the amounts or doses of each therapeutic agent used individually, e.g., as monotherapy, that are required to achieve the same therapeutic effect.

[0218] In one embodiment, the other agent is a premedication, hi another embodiment, the premedication is administered prior to administration of the CD3xCD20 antibody.

[0219] In one embodiment, the premedication is dexamethasone, hi another embodiment, dexamethasone is administered intravenously at a dose of 20 mg about 1 hour prior to administration of the CD3xCD20 antibody.

[0220] In one embodiment, the premedication is diphenhydramine. In another embodiment, diphenhydramine is administered orally or intravenously at a dose of 25 mg about 30-60 minutes prior to administration of the CD3xCD20 antibody. In another embodiment, the premedication is acetaminophen. In another embodiment, acetaminophen is administered orally or intravenously at a dose of 650 mg about 30-60 minutes prior to administration of the CD3xCD20 antibody.

[0221] In one embodiment, the other agent is administered to treat a side effect.

[0222] In one embodiment, the side effect is cytokine release syndrome ("CRS"). CRS symptoms may include hyperthermia, nausea, transient hypotension, hypoxia, etc. CRS may include clinical constitutional signs and symptoms, such as fever, fatigue, anorexia, myalgia, arthralgia, nausea, vomiting, and headache. CRS may include clinical skin signs and symptoms (such as a rash). CRS may include clinical gastrointestinal signs and symptoms, such as nausea, vomiting, and diarrhea. CRS may include clinical respiratory signs and symptoms, such as tachypnea and hypoxemia. CRS may include clinical cardiovascular signs and symptoms, such as tachycardia, widened pulse pressure, hypotension, increased cardiac output (early), and potentially decreased cardiac output. CRS may include clinical coagulation signs and symptoms, such as elevated d-dimers, hypofibrinogenemia with or without bleeding. CRS may include clinical renal signs and symptoms, such as azotemia. CRS can include clinical hepatic signs and symptoms such as hypertransaminasemia and hyperbilirubinemia, etc. CRS can include clinical neurological signs and symptoms such as headache, altered mental status, confusion, delirium, speech-finding difficulties or frank aphasia, hallucinations, tremor, dysmetria, gait changes, and seizures.

[0223] In another embodiment, the side effect is digestive disorders. In another embodiment, the side effect is nausea. In another embodiment, the side effect is vomiting. In another embodiment, the side effect is neurotoxicity. In another embodiment, the side effect is an allergic reaction, hypersensitivity, or infusion-related reaction. In another embodiment, the side effect is hematologic toxicity. In another embodiment, the side effect is tumor lysis syndrome.

[0224] In an exemplary embodiment, the other agent is a steroid. In one embodiment, the steroid is a corticosteroid. In another embodiment, the corticosteroid is a glucocorticoid. In another embodiment, the corticosteroid is selected from the group consisting of betamethasone, dexamethasone, prednisone, prednisolone, methylprednisolone, and triamcinolone. In another embodiment, the corticosteroid is selected from the group consisting of hydrocortisone, cortisone, and ethamethasoneb. In another embodiment, the steroid is fludrocortisone. In another embodiment, the steroid is dexamethasone.

[0225] In an exemplary embodiment, the other agent is an antihistamine. In one embodiment, the antihistamine is an H1 antagonist. In another embodiment, the H1 antagonist is acrivastine, azelastine, bilastine, bromodiphenhydramine, brompheniramine, buclizine, carbinoxamine, cetirizine (Zyrtec®), chlorodiphenhydramine, chlorphenamine, clemastine, cyclizine, cyproheptadine, dexbrompheniramine, dexchlorpheniramine, dimenhydrinate, dimethindene, diphenhydramine, doxylamine, ebastine, embra amine, fexofenadine (Allegra®), hydroxyzine (Vistaril®), loratadine (Claritin®), meclizine, mirtazapine, olopatadine, orphenadrine, phenindamine, pheniramine, phenyltoloxamine, promethazine, quetiapine (Seroquel®), rupatadine (Alergoliber®), tripelennamine, and triprolidine.

[0226] In an exemplary embodiment, the antihistamine is acrivastine. In one embodiment, the antihistamine is cetirizine. In another embodiment, the antihistamine is diphenhydramine. In another embodiment, the antihistamine is Benadryl®.

[0227] In an exemplary embodiment, the antihistamine is an H1 inverse agonist, hi one embodiment, the H1 inverse agonist is selected from the group consisting of acrivastine, cetirizine, levocetirizine, desloratadine, and pyrilamine.

[0228] In an exemplary embodiment, the antihistamine is an H2 antihistamine. In one embodiment, the H2 antihistamine is an H2 antagonist. In another embodiment, the H2 antihistamine is an H2 inverse agonist. In another embodiment, the H2 antihistamine is selected from the group consisting of cimetidine, famotidine, lafutidine, nizatidine, ranitidine, roxatidine, and tiotidine.

[0229] In an exemplary embodiment, the other agent is an anti-allergy agent. In one embodiment, the other agent is selected from the group consisting of antihistamines, glucocorticoids, epinephrine (adrenaline), mast cell stabilizers, anti-leukotrienes, anticholinergics, and decongestants. In another embodiment, the other agent is a decongestant. In another embodiment, the other agent is an adrenergic releasing agent. In another embodiment, the other agent is levomethamphetamine, phenylpropanolamine, propylhexedrine (Benzedrex®), or loratadine. In another embodiment, the other agent is an α-adrenergic receptor agonist. In another embodiment, the other agent is naphazoline, oxymetazoline, phenylephrine, synephrine, tetrizoline, tramazoline, or xylometazoline.

[0230] In an exemplary embodiment, the other agent is an antiemetic agent. In one embodiment, the other agent is an antiemetic agent. In another embodiment, the other agent is a 5-HT3 receptor antagonist. In another embodiment, the other agent is dolasetron (Anzemet®), granisetron (Kytril®, Sancuso®), ondansetron (Zofran®), tropisetron (Setrovel®, Navoban®), palonosetron (Aloxi®), mirtazapine (Remeron®). In another embodiment, the other agent is a dopamine antagonist. In another embodiment, the other agent is a 5-HT3 receptor antagonist. In another embodiment, the other agent is domperidone (Motilium®), olanzapine (Zyprexa®), droperidol, haloperidol, chlorpromazine, prochlorperazine, alizapride, prochlorperazine (Compazine®, Stemzine®, Buccastem®, Stemetil®, Phenotil®), metoclopramide (Reglan®). In another embodiment, the other agent is an NK1 receptor antagonist. In another embodiment, the other agent is aprepitant or fosaprepitant (Emend®), casopitant, rolapitant (Varubi®). In an exemplary embodiment, the other agent is an anticholinergic. In another embodiment, the other agent is scopolamine.

[0231] In an exemplary embodiment, the other agent is an analgesic. In one embodiment, the other agent is an antipyretic. In another embodiment, the other agent is a salicylate, or a derivative thereof. In another embodiment, the salicylate is selected from the group consisting of aspirin, diflunisal, salsalate, and salicylic acid, or a derivative thereof. In another embodiment, the salicylate is selected from the group consisting of choline salicylate, magnesium salicylate, and sodium salicylate. In another embodiment, the other agent is aspirin. In another embodiment, the other agent is acetaminophen, or a derivative thereof. In another embodiment, the other agent is an NSAID, or a derivative thereof. In another embodiment, the NSAID is a propionic acid derivative. In another embodiment, the NSAID is selected from the group consisting of ibuprofen, dexibuprofen, naproxen, fenoprofen, ketoprofen, dexketoprofen, flurbiprofen, oxaprozin, loxoprofen, or a derivative thereof. In another embodiment, the NSAID is ibuprofen. In another embodiment, the NSAID is naproxen. In another embodiment, the NSAID is an acetic acid derivative. In another embodiment, the NSAID is selected from the group consisting of indomethacin, tolmetin, sulindac, etodolac, ketorolac, diclofenac, aceclofenac, nabumetone, or derivatives thereof. In another embodiment, the NSAID is an enolic acid derivative. In another embodiment, the NSAID is selected from the group consisting of piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam, phenylbutazone, or derivatives thereof. In another embodiment, the NSAID is an anthranilic acid derivative. In another embodiment, the NSAID is selected from the group consisting of mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, or derivatives thereof. In another embodiment, the other drug is selected from the group consisting of phenazone, metamizole, and nabumetone, or derivatives thereof. In another embodiment, the other agent is an opiate, hi another embodiment, the other agent is codeine, morphine, thebaine, or fentanyl.In another embodiment, the other agent is dihydrocodeine, oxymorphol, oxycodone, oxymorphone, or metopon.

[0232] In an exemplary embodiment, the other agent is a cytoprotective agent. In one embodiment, the other agent is an aminothiol compound. In another embodiment, the other agent is amifostine. In another embodiment, the other agent is bleomycin, dexrazoxane, or coenzyme M.

[0233] In an exemplary embodiment, the other agent is a vasopressor. In one embodiment, the vasopressor is selected from norepinephrine, phenylephrine, epinephrine, ephedrine, dopamine, vasopressin, or a combination thereof. In another embodiment, the vasopressor is selected from dobutamine, midodrine, amezinium, or a combination thereof.

[0234] In an exemplary embodiment, the other agent is an anticonvulsant. In one embodiment, the anticonvulsant is an aldehyde. In another embodiment, the aldehyde is paraldehyde. In another embodiment, the anticonvulsant is an aromatic aryl alcohol. In another embodiment, the aromatic aryl alcohol is stiripentol. In another embodiment, the anticonvulsant is a barbiturate. In another embodiment, the barbiturate is phenobarbital, primidone, methylphenobarbital, or barbexaclone. In an exemplary embodiment, the anticonvulsant is a benzodiazepine. In another embodiment, the benzodiazepine is clobazam, clonazepam, clorazepate, diazepam, midazolam, lorazepam, nitrazepam, temazepam, and nimetazepam. In another embodiment, the anticonvulsant is a carboxamide. In another embodiment, the carboxamide is carbamazepine, oxcarbazepine, or eslicarbazepine acetate. In an exemplary embodiment, the anticonvulsant is a fatty acid. In another embodiment, the fatty acid is valproate. In another embodiment, the valproate is valproic acid, sodium valproate, or divalproex sodium. In another embodiment, the valproate is vigabatrin, progabide, and tiagabine. In another embodiment, the anticonvulsant is a fructose derivative. In another embodiment, the fructose derivative is topiramate. In another embodiment, the anticonvulsant is a GABA analog. In another embodiment, the GABA analog is gabapentin or pregabalin. In another embodiment, the anticonvulsant is a hydantoin. In another embodiment, the hydantoin is ethotoin, phenytoin, mephenytoin, or fosphenytoin. In another embodiment, the anticonvulsant is an oxazolidinedione. In another embodiment, the oxazolidinedione is paramethadione, trimethadione, and ethadione. In another embodiment, the anticonvulsant is a propionate. In another embodiment, the anticonvulsant is a pyrimidinedione. In another embodiment, the anticonvulsant is a pyrrolidine. In another embodiment, the pyrrolidine is brivaracetam, etiracetam, levetiracetam, or seletracetam. In another embodiment, the anticonvulsant is levetiracetam.In another embodiment, the anticonvulsant is a succinimide. In another embodiment, the succinimide is ethosuximide, phensuximide, or mesuximide. In another embodiment, the anticonvulsant is a sulfonamide. In another embodiment, the succinimide is acetazolamide, sulthiame, methazolamide, or zonisamide. In another embodiment, the anticonvulsant is a triazine. In another embodiment, the triazine is lamotrigine. In another embodiment, the anticonvulsant is a urea. In another embodiment, the urea is pheneturide or phenacemide. In another embodiment, the anticonvulsant is valproylamide. In another embodiment, the anticonvulsant is valproylamide. In another embodiment, the valproylamide is valpromide or valnoctamide. In another embodiment, the anticonvulsant is perampanel, stiripentol, or pyridoxine.

[0235] In an exemplary embodiment, the other agent is an anti-inflammatory agent. In one embodiment, the other agent is a TNF-α inhibitor. In another embodiment, the TNF-α inhibitor is an antibody. Examples of anti-TNFα antibody molecules include infliximab (Remicade®), adalimumab (Humira®), certolizumab pegol (Cimzia®), and golimumab (Simponi®). Another example of a TNFα inhibitor is a fusion protein, such as etanercept (Enbrel®). In another embodiment, the TNF-α inhibitor is a small molecule. Small molecule inhibitors of TNFα include, but are not limited to, xanthine derivatives (e.g., pentoxifylline) and bupropion.

[0236] In an exemplary embodiment, the other agent is an anti-inflammatory agent. In one embodiment, the other agent is an IL-6 inhibitor. Examples of IL-6 inhibitors are anti-IL-6 antibody molecules, such as tocilizumab (toc), sarilumab, elsilimomab, CNTO 328, ALD518 / BMS-945429, CNTO 136, CPSI-2364, CDP6038, VX30, ARGX-109, FE301, and FM101. In one embodiment, the anti-IL-6 antibody molecule is tocilizumab.

[0237] The methods described herein may include administering one or more other agents to manage the elevated levels of soluble factors resulting from treatment with the methods described herein. In one embodiment, the soluble factors elevated in the subject are one or more of IFN-γ, TNFα, IL-2, and IL-6. In an embodiment, the factors elevated in the subject are one or more of IL-1, GM-CSF, IL-10, IL-8, IL-5, and fractalkine. Thus, the agent administered to treat this side effect may be an agent that neutralizes one or more of these soluble factors. In one embodiment, the agent that neutralizes one or more of these soluble forms is an antibody or an antigen-binding fragment thereof. Examples of such agents include, but are not limited to, steroids (e.g., corticosteroids), inhibitors of TNFα, and inhibitors of IL-1R, and inhibitors of IL-6. An example of an IL-1R-based inhibitor is anakinra.

[0238] In an exemplary embodiment, the other agent reduces immune-mediated side effects. Exemplary immune-mediated side effects include, but are not limited to, interstitial pneumonitis, colitis, hepatitis, nephritis and renal dysfunction, hypothyroidism, hyperthyroidism, and endocrine disorders (e.g., hypophysitis, type 1 diabetes, and thyroid disorders, e.g., hypothyroidism and hyperthyroidism). In one embodiment, the other agent reduces embryo-fetal toxicity.

[0239] In one embodiment, the other agent is an IV fluid. In another embodiment, the other agent is a bronchodilator. In another embodiment, the other agent is oxygen. In another embodiment, the other agent is tocilizumab. In another embodiment, the other agent is a proton pump inhibitor. In another embodiment, the other agent is a xanthine oxidase inhibitor. In another embodiment, the other agent is allopurinol. In another embodiment, the other agent is rasburicase.

[0240] Efficacy evaluation The effectiveness of the methods provided herein can be evaluated by any method known in the art. For example, standard assays for effectiveness can be performed, such as evaluation of cancer burden, tumor size, presence or extent of metastasis, and immuno-oncological treatments can also be evaluated based on immune status evaluation. This can be done in several ways, including both in vitro and in vivo assays. For example, changes in immune status, tumor burden, size, invasiveness, LN involvement, metastasis, etc. can be evaluated.

[0241] In an exemplary embodiment, the improved efficacy is measured by a reduction in the number of cancer cells in a biological sample obtained from the subject compared to a reference. In another embodiment, the reference is the number of cancer cells in a biological sample obtained from the subject at an earlier time point. In another embodiment, the reference is a predetermined value. In another embodiment, the reference is the number of cancer cells in a biological sample obtained from another subject with lymphoma. In another embodiment, the reference is the number of cancer cells in a biological sample obtained from a population of subjects with lymphoma. In an embodiment, the biological sample is blood. In another embodiment, the biological sample is serum. In another embodiment, the biological sample is plasma.

[0242] In exemplary embodiments, efficacy is assessed by evaluating absolute numbers and percent change from baseline for cell populations. In one embodiment, the cell population is B cells. In another embodiment, the cell population is T cells. In another embodiment, the cell population is natural killer (NK) cells.

[0243] In an exemplary embodiment, efficacy is assessed by evaluating changes in gene expression or protein levels of diagnostic biomarkers, including but not limited to cell of origin [germinal center B cells (GCB) vs. non-GCB] by Hans algorithm, CD10, CD19, CD20, MUM1, BCL2, and BCL6. In one embodiment, expression of one or more genes is increased following treatment with the methods provided herein. In another embodiment, expression of one or more genes is decreased following treatment with the methods provided herein. In one embodiment, levels of one or more proteins are elevated following treatment with the methods provided herein. In another embodiment, levels of one or more proteins are decreased following treatment with the methods provided herein.

[0244] In one embodiment, efficacy is assessed by evaluating peripheral and intratumoral leukocyte frequency, phenotype, and functional and activation markers at baseline and after treatment.

[0245] In an exemplary embodiment, efficacy is assessed using gene expression profiling of cell of origin subtyping and exploratory transcriptome analysis. In another embodiment, efficacy is assessed by genomic analysis of the tumor, including but not limited to FcR genotyping and MRD ctDNA analysis in blood.

[0246] In some embodiments, the treatment is evaluated by assessing T cell activity as measured by cytokine production measured intracellularly in the culture supernatant using cytokines including, but not limited to, IFNγ, TNFα, GM-CSF, IL2, IL6, IL4, IL5, IL10, IL13 using well-known techniques. The administration provided herein has been observed to advantageously induce only limited, low rate and grade of cytokine release syndrome (CRS) reaction in some subjects. In some embodiments, the administration provided herein induces up to grade 1 or grade 2 CRS reaction. See Lee et al., Blood 124(2):188-195 (2014) and Porter et al., J. Hematol Oncol. 11(1):35 (2018), which are incorporated by reference where relevant regarding the CRS grading system. In some embodiments, the administration provided herein advantageously induces a decrease in the level of CRS-associated cytokines in subsequent administrations. In some embodiments, the administration provided herein advantageously induces a decrease in the level of a CRS-associated cytokine after two administrations. In certain embodiments, the CRS-associated cytokine is IL-6 and / or interferon gamma. Cytokine levels can be measured by any suitable method, including, for example, an ELISA assay.

[0247] In an exemplary embodiment, efficacy is assessed by evaluating progression-free survival. In one embodiment, subjects treated using the methods provided herein have an increase in progression-free survival. In an embodiment, progression-free survival is increased by about 1 month. In another embodiment, progression-free survival is increased by about 2 months. In another embodiment, progression-free survival is increased by about 3 months. In another embodiment, progression-free survival is increased by about 4 months. In another embodiment, progression-free survival is increased by about 5 months. In another embodiment, progression-free survival is increased by about 6 months. In another embodiment, progression-free survival is increased by about 7 months. In another embodiment, progression-free survival is increased by about 8 months. In another embodiment, progression-free survival is increased by about 9 months. In another embodiment, progression-free survival is increased by about 10 months. In another embodiment, progression-free survival is increased by about 11 months. In another embodiment, progression-free survival is increased by about 1 year. In another embodiment, progression-free survival is increased by about 2 years. In another embodiment, progression free survival is increased by about 3 years. In another embodiment, progression free survival is increased by about 4 years. In another embodiment, progression free survival is increased by about 5 years. In another embodiment, progression free survival is increased by more than 5 years.

[0248] In an exemplary embodiment, efficacy is assessed by assessing overall survival. In one embodiment, subjects treated using the methods provided herein experience an increase in overall survival. In an embodiment, overall survival is increased by about 1 month. In another embodiment, overall survival is increased by about 2 months. In another embodiment, overall survival is increased by about 3 months. In another embodiment, overall survival is increased by about 4 months. In another embodiment, overall survival is increased by about 5 months. In another embodiment, overall survival is increased by about 6 months. In another embodiment, overall survival is increased by about 7 months. In another embodiment, overall survival is increased by about 8 months. In another embodiment, overall survival is increased by about 9 months. In another embodiment, overall survival is increased by about 10 months. In another embodiment, overall survival is increased by about 11 months. In another embodiment, overall survival is increased by about 1 year. In another embodiment, overall survival is increased by about 2 years. In another embodiment, overall survival is increased by about 3 years. In another embodiment, overall survival is increased by about 4 years. In another embodiment, overall survival is increased by about 5 years. In another embodiment, overall survival is increased by more than 5 years.

[0249] In an exemplary embodiment, efficacy is assessed by assessing an objective response rate. In one embodiment, the objective response rate is assessed by a blinded independent review committee (BIRC). In one embodiment, subjects treated with the methods provided herein have an objective response rate of about 10% to about 100%. In an embodiment, the objective response rate is about 10%. In another embodiment, the objective response rate is about 20%. In another embodiment, the objective response rate is about 30%. In another embodiment, the objective response rate is about 40%. In another embodiment, the objective response rate is about 50%. In another embodiment, the objective response rate is about 60%. In another embodiment, the objective response rate is about 70%. In another embodiment, the objective response rate is about 80%. In another embodiment, the objective response rate is about 90%. In another embodiment, the objective response rate is about 100%.

[0250] In an exemplary embodiment, efficacy is assessed by assessing the time to treatment failure. In one embodiment, subjects treated using the methods provided herein have an extended time to treatment failure.

[0251] In an exemplary embodiment, efficacy is assessed by assessing duration of response. In one embodiment, subjects treated using the methods provided herein experience an increased duration of response.

[0252] In an exemplary embodiment, efficacy is assessed based on Cheson BD et al (2014) "Recommendations for Initial Evaluation, Staging and Response Assessment of Hodgkin and Non-Hodgkin Lymphoma: The Lugano Classification." J Clin Oncol 32:3059-3067. In one embodiment, efficacy is assessed by evaluating fluorodeoxyglucose (FDG) positron emission tomography (PET)-computed tomography (CT) (e.g., for FDG-avid lymphoma). In one embodiment, efficacy is assessed using PET-CT (e.g., for patients showing radiological (CT) Cru or partial response (PR) in non-Hodgkin lymphoma (e.g., DLBCL)). In another embodiment, PET-CT is used to assess the subject's response to the methods of the present disclosure using a 5-point scale (e.g., for clinical trials, interim evaluations, or end-of-treatment evaluations) (Table 15). In another embodiment, interim PET-CT is used to assess early treatment response and / or to confirm remission status at the end of treatment. In one embodiment, a score of 1 or 2 on the PET-CT indicates metabolic complete response at the intermediate time point and / or at the end of treatment. In another embodiment, a change in PET-CT score from 5 to 1 indicates that the patient has achieved metabolic complete response (see Table 15). In another embodiment, a change in PET-CT score from 4 to 1 indicates that the patient has achieved metabolic complete response (see Table 15). In another embodiment, a change in PET-CT score from 5 to 2 indicates that the patient has achieved metabolic complete response (see Table 15). In another embodiment, a change in PET-CT score from 4 to 2 indicates that the patient has achieved metabolic complete response (see Table 15). In one embodiment, if the PET-CT score is 1, the patient has achieved metabolic complete response. In one embodiment, if the PET-CT score is 2, the patient has achieved metabolic complete response.In another embodiment, patients with uptake above the mediastinum but below the liver (score 3) indicate a good prognosis at the end of treatment for non-Hodgkin's lymphoma (e.g., DLBCL). In another embodiment, the interpretation of a score of 3 depends on the timing of the assessment, the clinical situation, and the treatment (e.g., in response-adaptive trials looking for de-escalation of treatment, a score of 3 may be considered an inadequate response (to avoid undertreatment)). In another embodiment, a score of 4 or 5 at intermediate time points indicates chemotherapy-sensitive disease (e.g., the uptake provided is reduced from baseline) and / or indicates a partial metabolic response. In another embodiment, a score of 4 or 5 for residual metabolic disease at the end of treatment indicates treatment failure, even if the uptake is reduced from baseline. In another embodiment, a score of 4 or 5 with unchanged or even increasing intensity from baseline and / or new lesions compatible with lymphoma indicates treatment failure at intermediate time points and end of treatment evaluation. In another embodiment, a CT-based response is used (e.g., for tissues with low or variable FDG avidity and / or when PET-CT is not available). In another embodiment, a 50% or greater increase in the product of perpendicular diameters (PPD) of a single lymph node is indicative of progressive disease by CT criteria. In another embodiment, follow-up scans are used for indolent lymphomas with residual intraperitoneal or retroperitoneal disease.

[0253] In one embodiment, the patient achieves a metabolic complete response at the end of cycle 2 of the method of the present disclosure (e.g., at and / or after day 26 of cycle 2). In one embodiment, the patient achieves a metabolic complete response at the end of cycle 3 of the method of the present disclosure (e.g., at and / or after day 26 of cycle 3). In one embodiment, the patient achieves a metabolic complete response at the end of cycle 4 of the method of the present disclosure (e.g., at and / or after day 26 of cycle 4). In one embodiment, the patient achieves a metabolic complete response at the end of cycle 5 of the method of the present disclosure (e.g., at and / or after day 26 of cycle 5). In one embodiment, the patient achieves a metabolic complete response at the end of cycle 6 of the method of the present disclosure (e.g., at and / or after day 26 of cycle 6). In one embodiment, the patient achieves a metabolic complete response at the end of cycle 7 of the method of the present disclosure (e.g., at and / or after day 26 of cycle 7). In one embodiment, the patient achieves a metabolic complete response at the end of cycle 8 of the method of the present disclosure (e.g., at and / or after day 26 of cycle 8). In one embodiment, the patient achieves a metabolic complete response at the end of cycle 9 of the method of the present disclosure (e.g., at and / or after day 26 of cycle 9). In one embodiment, the patient achieves a metabolic complete response at the end of cycle 10 of the method of the present disclosure (e.g., at and / or after day 26 of cycle 10). In one embodiment, the patient remains in metabolic complete response until the end of treatment of the method of the present disclosure. In one embodiment, the patient is in complete metabolic response after completion of treatment (e.g., 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 1.5 years, 2 years, 2.5 years, 3 years, 3.5 years, 4 years, 4.5 years, 5 years, or more than 5 years after completion of treatment with the methods of the disclosure).In one embodiment, the patient is administered 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 555, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700, 710, 720, 730, 740, 750, 750, 760, 770, 780, 790, 800, 810, 820, 830, 840, 850, 860, 870, 880, 890, 900, 910, 920, 930, 94 The patient achieves a metabolic complete response after 60, 165, 170, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 280, 285, 290, 295, 300, or more than 300 days. In one embodiment, the patient achieves a metabolic complete response after 61 days or more from the initiation or first day of the method of the disclosure or from the first administration of a multispecific antibody of the disclosure to the subject. In one embodiment, the patient achieves a metabolic complete response after 117 days or more from the initiation or first day of the method of the disclosure or from the first administration of a multispecific antibody of the disclosure to the subject. In one embodiment, the patient achieves a metabolic complete response 177 days or more from the initiation or first day of the method of the disclosure or from the first administration of a multispecific antibody of the disclosure to the subject. In one embodiment, the patient achieves a metabolic complete response 233 days or more from the initiation or first day of the method of the disclosure or from the first administration of a multispecific antibody of the disclosure to the subject. In one embodiment, the patient achieves a metabolic complete response 299 days or more from the initiation or first day of the method of the disclosure or from the first administration of a multispecific antibody of the disclosure to the subject.

[0254] In one embodiment, FDG uptake is reduced during the treatment of chemotherapy-sensitive disease.In another embodiment, in patients who achieve metabolic complete response at the end of treatment, residual FDG uptake higher than normal liver uptake is observed at intermediate time points.In another embodiment, partial response (PR) requires a reduction of more than 50% in the sum of the products of the perpendicular diameters of up to six representative lymph nodes or extranodal lesions. [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] EXAMPLES

[0255] 5. Working Example Examples are provided below to illustrate the present invention, but are not intended to limit the invention to any particular application or theory of operation. Example 1 - Treatment of Lymphoma with a Combination of Pramotamab, Tafasitamab, and Lenalidomide

[0256] A multicenter, randomized, open-label, phase 2 study will be conducted to evaluate the efficacy and safety of pramotamab in combination with tafasitamab and lenalidomide in subjects with relapsed or refractory diffuse large B-cell lymphoma (R / R DLBCL).

[0257] The combination of tafasitamab in combination with lenalidomide has been approved in the United States for accelerated use in patients with R / R DLBCL, NOS. Tafasitamab is an Fc-modified monoclonal antibody that binds to the CD19 antigen expressed on the surface of pre-B and mature B lymphocytes, as well as on several B-cell malignancies, including DLBCL. In a single-arm clinical trial (NCT02399085), tafasitamab in combination with lenalidomide resulted in a 57.5% response rate in R / R DLBCL, with a median DOR of 43.9 months and a median PFS of 11.6 months (Duell Haematologica. 2021;106(9):2417-26). Pramotamab is a humanized bsAb that binds to both CD3 and the tumor antigen CD20 to recruit cytotoxic T cells to kill CD20 tumor cells. In an ongoing phase 1 trial (Study XmAb13676-01, NCT02924402), pramotamab produced durable responses in subjects with R / R DLBCL.

[0258] Without wishing to be bound by theory, it is hypothesized that binding of both CD19 and CD20 antigens improves efficacy outcomes in this population due to non-overlapping resistance mechanisms. Furthermore, the combination activates and expands innate immune system cells and adaptive effector cells, and modulates the tumor microenvironment. These characteristics support and justify the testing of the combination of pramotamab, tafasitamab, and lenalidomide. The study will first determine whether the combination of the three products can be safely administered and determine the dose for part 2. The second part of the study is designed to determine the improvement in efficacy, as assessed by PFS, of the addition of pramotamab to the standard of care for DLBCL, tafasitamab and lenalidomide.

[0259] This is a multicenter, randomized, open-label, phase 2 study comparing the combination of tafasitamab plus lenalidomide and pramotamab with tafasitamab plus lenalidomide in adult subjects with DLBCL who have relapsed after or are refractory to at least one prior line of treatment that must have included combination chemoimmunotherapy including an anti-CD20 monoclonal antibody, or who are not candidates for, refuse ASCT, or have relapsed after ASCT.

[0260] After enrollment, the diagnosis of DLBCL will be confirmed retrospectively using archival or recently obtained tissue by central pathologist review. A central radiology and clinical reviewer will assess objective disease response according to the Lugano 2014 (Cheson, 2014 J Clin Oncol. 2014;32(27):3059-68) guidelines. Details of the central review will be provided in an imaging charter outlining the function and process. In addition, investigator-assessed responses will be recorded in a clinical database and concordant analyses will be performed. All subjects will be treated until progression or discontinuation for other reasons, and then followed for up to 5 years for OS.

[0261] The study consists of two sequential parts: Part 1 will enroll subjects, evaluate safety, and determine dose and schedule prior to the start of Part 2.

[0262] 5.1.Treatment regimen The test consists of two parts.

[0263] Part 1: Single-arm, two-cohort, safety run-in period

[0264] Part 2: Open-label, randomized, two-arm efficacy and safety

[0265] Part 1: Single-arm safety run-in period

[0266] Part 1 was a single-arm, two-cohort, safety run-in phase aimed at establishing the safety of the combination of pramotamab, tafasitamab, and lenalidomide.

[0267] Part 1 will consist of a single-arm evaluation of the safety of the triple combination of tafasitamab + lenalidomide and pramotamab in at least 40 subjects in two cohorts with a minimum of 20 subjects per cohort: In cohort 1A, subjects will be treated with the triple combination at pramotamab dose level -1 (Table 2). After enrollment in cohort 1A is completed, enrollment in cohort 1B will begin. In cohort 1B, subjects will be treated with the triple combination at pramotamab dose level 1. The first safety assessment will be performed after all subjects in cohorts 1A and 1B have been treated until at least C4D28 or have discontinued treatment before C4D28 due to AE or disease progression. After the first safety assessment in both cohorts 1A and 1B, the pharmacologically optimal dose of pramotamab (dose level -1 or dose level 1) with an acceptable safety profile will be advanced to the randomized (part 2) portion of the study.

[0268] Treatment consists of a combination of pramotamab, tafasitamab, and lenalidomide administered in 28-day cycles, with two priming doses of tafasitamab prior to cycle 1. Pramotamab and tafasitamab may be administered until disease progression, unacceptable toxicity, or discontinuation for any other reason, whichever occurs first, but lenalidomide may only be administered for a total of 12 cycles. Tafasitamab and pramotamab should not be administered simultaneously. On days when both tafasitamab and pramotamab are administered, tafasitamab should be administered first, followed by pramotamab. It is recommended that infusions be at least 2 hours apart.

[0269] Part 2: Open-label, randomized

[0270] The open-label, randomized portion of the study (Part 2) will begin after the initial safety evaluation of at least 40 subjects in Part 1. Prior to the initiation of Part 2, the protocol will be amended with the dosing regimen selected from Part 1 to include justification to support the dosing / schedule proposed in Part 2.

[0271] In part 2, subjects will be randomized 1:1 to two treatment arms and stratified by baseline International Prognostic Index (IPI) risk score (3-5 vs. 0-2), number of prior lines of therapy (1 vs. ≥2), and primary refractory disease (yes vs. no). Enrollment of primary refractory disease will be limited to 36 of the 200 subjects. Part 2 will enroll approximately 200 subjects. The sample size for part 2 may be adjusted based on the results of part 1. Increasing enrollment beyond 200 will be done by protocol amendment before the start of the randomized portion. An Independent Data Monitoring Committee (IDMC) will review safety data from part 2 at meetings to be held after 50, 100, and 150 subjects have been randomized. The primary analysis of PFS will occur after 89 disease progression and death events. An interim analysis of OS will be performed at that time.

[0272] Part 2 is an efficacy cohort in which subjects are randomized to receive treatment in Arm A or Arm B as follows:

[0273] Group A:

[0274] Treatment consists of a combination of pramotamab, tafasitamab, and lenalidomide administered in 28-day cycles with two priming doses of tafasitamab prior to cycle 1. Pramotamab and tafasitamab may be administered until disease progression, unacceptable toxicity, or discontinuation for any other reason, whichever occurs first. Lenalidomide may be administered for up to a total of 12 cycles.

[0275] Group B:

[0276] Treatment consists of a combination of tafasitamab and lenalidomide administered in 28-day cycles with two priming doses of tafasitamab prior to cycle 1. Tafasitamab may be administered until disease progression, unacceptable toxicity, or discontinuation for any other reason, whichever occurs first. Lenalidomide may be administered for up to a total of 12 cycles.

[0277] The doses and schedules for Parts 1 and 2 are presented in Figure 3 and described in further detail below.

[0278] Primary endpoint

[0279] The primary endpoints of the study were safety, measured by the incidence of CRS and TEAEs, in part 1, and PFS, defined as the time from randomization to first documented disease progression or death, whichever occurred first, assessed by BIRC using the Lugano 2014 criteria, in part 2.

[0280] 5.2. Number of subjects Part 1 will enroll at least 40 subjects into two cohorts with a minimum of 20 subjects per cohort.

[0281] Approximately 200 subjects will be enrolled in Part 2. The sample size for Part 2 may be adjusted based on the results of Part 1. Any increase in enrollment beyond 200 will be made by protocol amendment prior to the start of the randomized portion. Primary refractory enrollment will be limited to 36 of the 200 subjects in Part 2.

[0282] Overall, the study plans to enroll approximately 240 subjects.

[0283] 5.3. Treatment allocation Treatment allocation in Part 1 and randomization in Part 2 will be performed via a third-party Randomization and Trial Supply Management (RTSM) / Interactive Response Technology (IRT) system.

[0284] Part 1: Single-arm safety run-in period

[0285] During the safety run-in period of Part 1, 40 subjects will be enrolled and treated with pramotamab and tafasitamab plus lenalidomide (i.e., single-arm, uncontrolled). Subjects will be considered enrolled if they sign informed consent, are deemed eligible, and receive a priming dose of tafasitamab on day -8.

[0286] Part 2: Open-label, randomized

[0287] In part 2, a total of 200 subjects will be randomized 1:1 to the pramotamab and tafasitamab plus lenalidomide groups and the tafasitamab plus lenalidomide group, stratified by baseline IPI risk score (3-5 vs. 0-2), number of prior lines of therapy (1 vs. ≥2), and primary refractory status (yes vs. no). Up to 36 primary refractory subjects may be enrolled. Subjects will be randomized only if they sign informed consent and are deemed eligible. Initiation of study treatment will occur within 72 hours of randomization. Study treatment will begin with a priming dose of tafasitamab on study day -8.

[0288] 5.4. Inclusion criteria Subjects selected for this study will be at least 18 years of age and have a histologically confirmed diagnosis of DLBCL not otherwise specified (including DLBCL arising from indolent lymphoma). The lymphoma will be relapsed or refractory and will have CD20 expression based on flow cytometry or immunohistochemical assessment. + and CD19 + was confirmed.

[0289] 5.5. Administration schedule and premedication Pramotamab administration schedule and premedication

[0290] Subjects in Part 1 and subjects randomized to Arm A in Part 2 will receive pramotamab IV at a constant infusion rate over a minimum of 2 hours (-5 minute window). In cycle 1, pramotamab will be administered once every 7 days (± 1 day) for a total of 4 doses, and starting in cycle 2, pramotamab will be administered every 2 weeks.

[0291] Subjects in Cohort 1A and Cohort 1B will receive pramotamab according to the doses and schedules in Table 2. [Table 4]

[0292] The dose and schedule of pramotamab in Part 2 will be determined in Part 1.

[0293] Adjustments to the infusion rate may be made to increase the length of infusion time based on the investigator's judgment of safety. Due to variability in pump accuracy, an infusion that ends within 5 minutes before the required 2 hours will not be considered a deviation.

[0294] On days when both pramotamab and tafasitamab are administered, pramotamab will be administered at least 2 hours after tafasitamab. All Part 1 subjects and subjects randomized to Arm A of Part 2 will be premedicated for pramotamab administration as shown in Table 3. [Table 5]

[0295] For subjects who have received four consecutive infusions at a stable dose and schedule and have been free of CRS or infusion reactions, premedication may be modified at the investigator's discretion.

[0296] If pramotamab is discontinued, if there is no disease progression, and if the subject is still benefiting from the study treatment, the subject may continue on the other study treatment(s).

[0297] Tafasitamab administration schedule and premedication

[0298] All subjects will receive tafasitamab. Priming doses will be given on days -8 and -4 of the 1-week lead-in period. During the first 3 cycles of the study, tafasitamab will be infused on days 1, 8, 15, and 22 of each cycle, after which tafasitamab will be administered every other week (every 14 days) (infused on days 1 and 15 of each 28-day cycle, respectively, until disease progression, unacceptable toxicity, or discontinuation for any other reason, whichever occurs first) (Table 4). The first infusion of tafasitamab will be given at a rate of 70 mL / hour for the first 30 minutes. The rate will then be increased so that the infusion is given within 1.5 to 2.5 hours. All subsequent infusions should be given within 1.5 to 2 hours. On days when both tafasitamab and pramotamab are administered, tafasitamab will be administered before pramotamab. [Table 6]

[0299] Tafasitamab should be administered in accordance with the package insert (see, for example, MONJUVI PI, 2021) and by healthcare professionals who have immediate access to emergency equipment and appropriate medical assistance to manage infusion-related reactions.

[0300] All subjects will be premedicated for tafasitamab administration as shown in Table 5. [Table 7]

[0301] On study days when both tafasitamab and pramotamab are administered, a single dose of dexamethasone will be administered prior to the start of the tafasitamab infusion in cycle 1. If pramotamab is withheld and only tafasitamab is administered, premedication with prednisone or equivalent will only be required for the first 3 doses, thereafter if an infusion-related reaction is observed.

[0302] For subjects who do not experience an infusion-related reaction during the first three infusions, premedication is optional for subsequent infusions. If a subject experiences an infusion-related reaction, premedication will be administered prior to each subsequent infusion.

[0303] If tafasitamab is discontinued, if there is no disease progression, and if the subject is still benefiting from the study treatment, the subject may continue on the other study treatment(s).

[0304] Lenalidomide dosing scheme

[0305] All subjects will receive lenalidomide and will self-administer lenalidomide orally daily on days 1-21 of each cycle, starting at a dose of 25 mg. No more than 21 doses of lenalidomide will be administered per cycle. Investigators will follow the package insert or SmPC (see, e.g., REVLIMID PI, 2021; REVLIMID SmPC, 2022) for recommended medications and dose modifications for the prevention of venous thromboembolic events. Subjects will be encouraged to take lenalidomide at approximately the same time each day in the evening, regardless of whether food is consumed. Subjects will be instructed to swallow lenalidomide capsules whole with water and not to open, split, or chew the capsules. Lenalidomide treatment may be modified or discontinued in a dose-decreasing manner based on clinical and laboratory findings. Detailed dose modification guidelines for managing hematological and / or other toxicities are provided in the relevant sections of the protocol.

[0306] If lenalidomide is discontinued, if there is no disease progression, and if the subject is still benefiting from the study treatment, the subject may continue on the other study treatment(s).

[0307] 5.6. Study Drugs and Storage Pramotamab (XmAb13676)

[0308] Pramotamab (XmAb13676) is a humanized bsAb that binds to both CD3 and the tumor antigen CD20 to recruit cytotoxic T cells to kill CD20-positive tumor cells.

[0309] Pramotamab has been designed to maintain the full-length humanized monospecific antibody properties in a bsAb, allowing for the design of a stable molecule with a favorable in vivo half-life and the use of standard antibody production methods.

[0310] Pramotamab (XmAb13676) is in the format of Fab-scFv-Fc (scFv, single-chain variable fragment), i.e. a heterodimeric Fc-based format that can only bind monovalently to its bispecific antigen, in contrast to the bivalency of standard antibodies. The monovalency of CD3 was an important design constraint, as bivalent binding of CD3 results in T cell activation in the absence of CD20-expressing target cells. Pramotamab's Fc region has also been engineered to suppress its affinity for Fc gamma receptors (FcγR), which is critical for blocking T cell activation via cross-linking of pramotamab by FcγR-expressing cells. Xencor's antibody discovery program has demonstrated that several bsAbs based on this format exhibit high, but selective, activity against target cells in primate models.

[0311] IV solution stabilizer (IVSS) is a concentrated form of pramotamab (XmAb13676) buffer solution that also minimizes protein binding to administration equipment when pramotamab is administered at low concentrations.

[0312] Pramotamab (XmAb13676) drug product (DP) is a sterile liquid supplied in 5 mg vials. Each 2 mL disposable glass vial is filled with 1.0 mL of formulation containing 5.0 mg of pramotamab (XmAb13676) in 10 mM sodium succinate, 5% sucrose (weight to volume, w / v), and 0.01% (w / v) polysorbate-80, pH 5.5. Each product vial is intended to deliver 1.0 mL of drug solution. Dilution instructions for any alternate fill volumes required during testing are provided in the drug manual.

[0313] The IVSS is supplied in disposable glass vials. Each vial is filled with 10.0 mL of a solution containing 250 mM sodium succinate and 0.25% (w / v) polysorbate-80, pH 5.5. Each vial is intended to deliver 10.0 mL of IVSS.

[0314] Vials containing pramotamab and IVSS must be stored refrigerated at 2°C to 8°C in a properly controlled area with access only to the pharmacist, investigator, or duly designated personnel. Because pramotamab does not contain a preservative, opened vials of pramotamab must be used within 24 hours.

[0315] Tafasitamab-cxix (tafasitamab)

[0316] Tafasitamab (tafasitamab-cxix) is a CD19-directed cytolytic antibody, indicated in the United States for use in combination with lenalidomide for the treatment of adult patients with not otherwise specified (NOS) R / R DLBCL (including DLBCL arising from low-grade lymphomas) and adult patients who are not eligible for ASCT. Tafasitamab is also approved in the EU for use in combination with lenalidomide followed by tafasitamab monotherapy for the treatment of adult patients with relapsed or refractory DLBCL who are not eligible for ASCT. Tafasitamab is a humanized CD19-directed cytolytic monoclonal antibody that contains an IgG1 / 2 hybrid Fc domain with two amino acid substitutions to modify the Fc-mediated functions of the antibody. It is produced by recombinant DNA technology in mammalian cells (Chinese Hamster Ovary). The molecular weight of tafasitamab is approximately 150 kDa.

[0317] Tafasitamab-cxix for Injection is supplied as a 200 mg vial containing a preservative-free, white to slightly yellowish, sterile, lyophilized powder in a single-dose vial for IV use after reconstitution. After reconstitution with 5 mL of Sterile Water for Injection (USP), the resulting concentration is 40 mg / mL with a pH of 6.0. Each single-dose vial contains 200 mg of tafasitamab, citric acid monohydrate (3.7 mg), polysorbate 20 (1 mg), sodium citrate dihydrate (31.6 mg), and trehalose dihydrate (378.3 mg).

[0318] Vials containing tafasitamab should be stored in accordance with the package insert or SmPC (MONJUVI PI, 2021; MONJUVI smPC, 2021).

[0319] Lenalidomide

[0320] Lenalidomide, a thalidomide analogue, is an immunomodulatory agent (IMiD®) with antiangiogenic and antineoplastic properties. Lenalidomide is indicated for the treatment of adult patients with multiple myeloma, myelodysplastic syndromes, mantle cell lymphoma, follicular lymphoma, and marginal zone lymphoma (see REVLIMID PI, 2021 or REVLIMID SmPC, 2022).

[0321] Lenalidomide may be provided by the investigator or as an investigational drug / investigational medicinal product (REVLIMID or locally approved generic lenalidomide).

[0322] Lenalidomide is stored according to the REVLIMID or generic lenalidomide package label.

[0323] 5.7. Preparation and handling of study drugs Pramotamab (XmAb13676)

[0324] It should be noted that pramotamab exerts its pharmacodynamic effects in vivo at very low concentrations, and therefore each product vial must be extensively diluted prior to administration.

[0325] Pramotamab solutions are prepared under sterile conditions. Prior to administration, pramotamab is diluted to the required final concentration in one or more infusion bags containing 240 mL of 0.9% Sodium Chloride Injection, USP, and 10.0 mL of IV solution stabilizer. A visual inspection should be performed on the vial containing the parenteral formulation prior to dilution. If particulate matter and / or discoloration is observed, the drug should not be administered and the sponsor should be notified. After dilution, the bag containing pramotamab (XmAb13676) should be gently inverted 2-3 times to mix the solution. The bag should not be shaken.

[0326] Pramotamab has previously been administered to humans in a Phase 1 clinical trial (XmAb13676-01). In the XmAb13676-01 study, CRS was frequently observed, particularly with dosing on Day 1 of Cycle 1. Either the principal investigator or co-investigator (MD) must be readily contactable during and for at least 24 hours after administration of pramotamab.

[0327] All subjects will be premedicated with dexamethasone 20 mg IV approximately 30-60 minutes prior to the start of the tafasitamab infusion in cycle 1. If the tafasitamab infusion is withheld for any reason during cycle 1, dexamethasone will be administered 1 hour prior to the start of pramotamab administration. After cycle 1, dexamethasone premedication is not required and is permitted at the investigator's discretion. (Cetirizine or other antihistamines may be used in place of diphenhydramine).

[0328] Pramotamab administration should be initiated as soon as possible after preparation of the dosing solution. If administration is delayed, pramotamab can be stored at room temperature for up to 4 hours or at 2°C to 8°C for up to 12 hours before injection.

[0329] Pramotamab should not be administered by IV injection or bolus.

[0330] Study medication will be administered as an open-label solution using a dedicated infusion set at a constant rate for a minimum of 2 hours (-5 minute window). During pramotamab administration, caution should be exercised for CRS or infusion reactions / anaphylaxis. Because CRS or allergic / infusion reactions may occur, emergency resuscitation equipment ("emergency cart") and medications including steroids and tocilizumab should be located near where subjects are receiving infusions. Additional support should be available and may include, but is not limited to, acetaminophen, antihistamines, corticosteroids, IV fluids, bronchodilators, epinephrine, vasopressors, and oxygen.

[0331] Tafasitamab

[0332] Tafasitamab should be prepared and administered in accordance with the package insert or SmPC (MONJUVI PI, 2021; MONJUVI smPC, 2021).

[0333] Lenalidomide

[0334] Lenalidomide will be provided as oral capsules that will be distributed to subjects at the study site.

[0335] Lenalidomide will be distributed to subjects to be taken orally in the evening according to the package insert or SmPC (REVLIMID PI, 2021; REVLIMID SmPC, 2022). Subjects will be provided with a diary to record the date and time of each dose of lenalidomide and for product accountability.

[0336] Subjects should be instructed to make up a missed dose of lenalidomide if it is within 12 hours of the usual dosing time and then take the next dose according to their usual schedule.

[0337] 5.8. Pharmacokinetic, Pharmacodynamic, and Biomarker Assessment Pharmacokinetic analysis, anti-drug antibodies, cytokines, and serum assessment of rituximab levels

[0338] Venous blood samples for serum analysis of pramotamab and tafasitamab PK, pramotamab and tafasitamab ADA, cytokines, and rituximab levels will be obtained according to the schedules listed in Tables 6 and 7. The remaining samples will be saved for additional testing of biomarkers related to pharmacodynamic activity, clinical response, or resistance to the study drug. In Table 6, pramotamab PK, cytokines, and ADA, as well as ECG testing will be performed for subjects in Part 1 and subjects randomized to Arm A in Part 2. All times are relative to pramotamab infusion. On days when tafasitamab and pramotamab are administered, pre-dose samples will be taken and ECG testing will be performed prior to the start of tafasitamab infusion. In Table 7, tafasitamab anti-drug antibody and pharmacokinetic testing will be performed in all subjects. All times are relative to tafasitamab infusion. [Table 8-1] [Table 8-2] [Table 9]

[0339] Pharmacodynamics and biomarker evaluation

[0340] Peripheral Blood Evaluation

[0341] Blood samples will be collected to examine the pharmacodynamic effects of pramotamab, tafasitamab, and lenalidomide on leukocyte frequency and markers of T cell and / or leukocyte function, including but not limited to checkpoint molecules, markers of proliferation and T cell activation, and markers of T cell exhaustion. Circulating T cell, B cell, and NK cell frequencies will also be monitored. Additional blood samples will be stored in PAXGENE RNA tubes for potential exploratory testing of leukocyte function and pharmacodynamic effects by RNA sequencing and transcriptome gene and pathway analysis. Baseline and pharmacodynamic markers in the periphery will be evaluated for correlation with incidence of CRS and AEs, along with clinical response and tolerability. Evaluation of CRS 24 hours after each dose will include monitoring of serum cytokines and flow cytometric assessment of changes in the amount and activation state of T cells in the peripheral blood.

[0342] Blood samples will be collected at screening and during treatment for measurement of ctDNA. Treatment-related DNA sequencing will be used to track ctDNA levels and mutations to investigate ctDNA as a measure of MRD and as a marker of clinical response. Blood samples may also be used to assess genome-wide germline DNA mutations to interpret tumor-specific DNA mutations.

[0343] Detailed instructions for processing and shipping of peripheral blood samples are provided in the laboratory manual. See Table 9 (Evaluation Schedule) for sampling schedule. Unscheduled samples may be collected and sent to a designated central laboratory at the investigator's discretion. The remaining peripheral blood mononuclear cells, plasma samples, and serum samples will be stored at the designated central laboratory and may be used for evaluation of additional future exploratory biomarkers related to pharmacodynamic activity, clinical response, or resistance to the study drug.

[0344] Tumor biopsy

[0345] Archival tissue-archived blocks (preferred) or unstained slides are requested from lymph node biopsies to confirm the diagnosis of DLBCL, determine cell of origin status, and perform genomic mutation analysis. Cell of origin assay (COO), germinal center B cell (GCB), or activated B cell type (ABC) origin is determined using transcriptional analysis, NANOSTRING LYMPHC2X, or other gene expression methods. Immunohistochemistry analysis is performed using relevant markers with the Hans algorithm (Yoon, 2017).

[0346] Archival tissue from diagnostic tumor masses or lymph nodes must be confirmed as available at the time of study entry and will be collected and sent to a designated central laboratory within 8 weeks of first dose of study drug or randomization. See Table 9 (Evaluation Schedule) for sampling schedule. If archival tissue is not available, a fresh tumor biopsy specimen at baseline will be requested.

[0347] Tumor biopsies at baseline and during treatment: Baseline biopsy: Fresh tumor biopsy specimens (excision or core needle biopsy specimens) are recommended as they allow for unbiased analysis of tumor status, as opposed to archival biopsy specimens that may not reflect the effects of treatment before the start of the study. Therefore, if the subject consents and has palpable diseased lymph nodes (e.g., superficial lymphadenopathy), a pre-treatment baseline biopsy is required, allowing for a low-risk procedure for tissue sampling. Excision or core needle biopsy are acceptable, but fine needle aspiration is not.

[0348] Tumor Biopsies at Baseline and On-Treatment: On-Treatment Biopsies: On-treatment biopsies are required in subjects with palpable lymphadenopathy. On-treatment biopsy specimens are obtained at week 4 of treatment (after administration of C1D22 but prior to administration of C2D1). In responding subjects, additional biopsies are recommended at the time of progression to define the molecular and cellular basis of progression and to definitively rule out loss of CD19 or CD20 expression as a mechanism of acquired resistance.

[0349] Tumor tissue from archival, pre-treatment, on-treatment, and progression biopsies will be processed to allow for analyses including, but not limited to, (1) DNA sequencing to identify acquired genetic mutations in tumor cells, (2) RNA analysis of the tumor and tumor microenvironment, and (3) immunostaining of tumors for expression of CD19 and CD20, as well as inflammatory cells, including T cells, in the microenvironment.

[0350] Biopsy specimens will be taken at baseline and during treatment and sent to a central laboratory. See Table 8 for sampling schedule. [Table 10-1] [Table 10-2] [Table 10-3] [Table 10-4] [Table 10-5] [Table 10-6] [Table 10-7] [Table 10-8]

[0351] Following study-specified tumor biopsy analyses, remaining archival and fresh biopsy samples will be stored at a designated central laboratory for evaluation of additional future exploratory biomarkers related to pharmacodynamic activity, clinical response, or resistance to the study drug.

[0352] 5.9.Efficacy Assessment Efficacy evaluation

[0353] Response assessment will be determined as shown in Table 9. [Table 11-1] [Table 11-2] [Table 11-3]

[0354] Primary Measured Lesions: Select up to six of the largest primary lymph nodes, nodal masses, or extranodal lesions clearly measurable in two dimensions. Lymph nodes should be selected from different parts of the body and should include the mediastinum and retroperitoneum, if present. Non-lymph node lesions include those in parenchymal organs (liver, spleen, kidneys, lungs), gastrointestinal tract, skin, and those visible on palpation. Recently biopsied lesions should not be used as primary measured lesions.

[0355] Non-measurable lesions: Any lesion not selected as a measurable lesion, major and precisely assessable lesion should be considered a non-measurable lesion. These sites include precisely assessable lesions as well as any lymph nodes, nodal masses, or extranodal lesions that are not selected as major or measurable or that do not meet the definition of measurable but are considered abnormal, including any site of suspicious disease that is difficult to quantitatively track by measurement, including pleural effusions, ascites, bone lesions, meningeal lesions, abdominal masses, and other lesions that cannot be identified or tracked by imaging studies.

[0356] The investigators and BIRC will assess response to study drug at each efficacy time point. The following outcomes will be reported:

[0357] Progression-free survival: defined as the time from randomization to the first documented disease progression or death, whichever occurs first. The investigators and BIRC will adjudicate disease progression events in all randomized subjects. PFS assessed by the BIRC is the primary endpoint of Part 2 of the study. For sample size determination, treatment with the triplet combination resulted in a median PFS of 12 months (with tafasitamab + lenalidomide treatment (Duell et al., 2013) and 12 months with tafasitamab + lenalidomide treatment (Duell et al., 2013). Haematologica.2021;106(9):2417-26) to 23.5 months (under treatment with triple combination (pramotamab + tafasitamab + lenalidomide)), corresponding to a hazard ratio (HR) of 0.51 for all randomized subjects (assuming 90% of subjects have centrally pathologically confirmed DLBCL). The log-rank test has 90% power with a sample size of 200 (93 events) to maintain a type I error of 0.025 (one-sided). Sample size calculations assumed a loss to follow-up rate of 1.5% / month Subjects will be randomized 1:1 and stratified by baseline IPI risk score (3-5 vs. 0-2), number of prior lines of therapy (1 vs. ≥2), and primary refractory status (yes vs. no). Up to 36 primary refractory subjects may be enrolled for a sample size of 200. Enrollment of 200 subjects is estimated to require 27 months (with a minimum follow-up period of 6 months). The primary efficacy analysis will be performed when 93 PFS events are observed per independent review. In addition to the final OS analysis, an interim analysis of OS will be performed using a group sequential design at the time of the final PFS analysis.

[0358] Duration of response: defined as the time from first response (CR or PR) to progression or death from any cause in subjects who achieved CR or PR and in subjects with CR. DOR is derived using disease progression as determined by BIRC in subjects who achieved a response (CR or PR).

[0359] Overall survival: defined as the time from randomization to death from any cause. All randomized subjects will be followed for survival for up to 5 years. Overall survival of the randomized population will be evaluated (Part 2). The one-sided alpha level for studying OS is 0.025. Assume that the median OS of Arm B in Part 2 is 34 months, and Arm A in Part 2 has a 40% improvement from Arm B (i.e., median OS = 56.6 months, HR = 0.60). Furthermore, assuming that enrollment is complete at 27 months, the minimum follow-up period is 24 months, and the OS censoring rate (dropout rate) is approximately 1% per month, the study will result in a statistically significant outcome with 60% power. An interim analysis of OS is planned when 65% of the information (death events) is available. Superiority analyses will be performed during the interim and final analyses.

[0360] Time to Treatment Failure: Defined as the time from randomization to discontinuation of all study treatment for any reason, including disease progression, treatment toxicity, and death. Time to treatment failure will use disease progression as assessed by the investigator and BIRC.

[0361] In addition, adverse events, including the incidence of cytokine release syndrome (CRS), and other safety parameters will be evaluated.

[0362] 5.10. Toxicity Management Toxicities of the triple regimen (pramotamab, tafasitamab, and lenalidomide) may be identified during the study. Management of known toxicities, such as CRS, infusion-related reactions, hematologic toxicity, and tumor lysis syndrome, are outlined below.

[0363] Cytokine release syndrome: ASTCT defines CRS as a hyperphysiological response that occurs after the administration of any immunotherapy, resulting in the activation or binding of endogenous or infused T cells and / or other immune effector cells. Symptoms may be progressive, must include fever at onset, and may include hypotension, capillary leak syndrome (hypoxia), and end-organ dysfunction (Lee DW, Santomasso BD, Locke FL, et al. ASTCT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells. Biol Blood Marrow Transplant. 2019; 25(4)625-38).

[0364] CRS can present with a variety of symptoms ranging from mild flu-like symptoms to severe, life-threatening manifestations of inflammatory reactions. Mild symptoms of CRS include fever, fatigue, headache, rash, joint pain, and muscle pain. More severe cases are characterized by hypotension and hyperthermia and can progress to an uncontrolled systemic inflammatory reaction with circulatory shock requiring vasopressors, vascular leakage, disseminated intravascular coagulation, and multiple organ failure (Shimabukuro-Vornhagen A, Godel P,Subklewe M,et al.Cytokine release syndrome.J Immunother Cancer.2018;6(1):56). CRS is more likely to occur after the first dose of pramotamab than subsequent doses, with a somewhat later onset than hypersensitivity reactions, and is more likely to be associated with hepatic and neurological complications. Pramotamab-associated CRS symptoms observed in phase 1 trials include: Aphasia or word-finding difficulties Joint pain Confusion / altered mental status / delirium Increased serum creatinine ·sweating ·dizziness ·Difficulty breathing Fatigue (asthenia, lethargy, malaise) Fever Gait disturbance / dysmetria ·headache ·Hypotension / Hypertension Hypoxia Muscle pain Nausea / vomiting Stiffness / chills Tachycardia ·Tachypnea Seizures Hypertransaminases / hyperbilirubinemia Tremor

[0365] CRS toxicity is defined using the ASTCT CRS consensus grading classification (Lee DW, Santomasso BD, Locke FL, et al. ASTCT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells. Biol Blood Marrow Transplant. 2019;25(4)625-38). For relevant definitions, see Table 10. [Table 12-1] [Table 12-2]

[0366] Safety Run-in and Part 2, Group A (pramotamab, tafasitamab, and lenalidomide): Pramotamab can cause CRS. CRS has not been observed in clinical trials of tafasitamab and lenalidomide. However, lenalidomide may enhance CRS when combined with pramotamab due to its potential to activate T cells. Furthermore, to avoid overlap between pramotamab-induced CRS and tafasitamab-induced infusion-related reactions, pramotamab should always be administered after tafasitamab when administered on the same day. For dose modifications of lenalidomide and pramotamab in cases of CRS, see Section 5.11.

[0367] Part 2, Arm B (tafasitamab and lenalidomide): If CRS is observed with tafasitamab, treatment guidelines provided for pramotamab should be followed.

[0368] Cytokine release syndrome vs. allergic / hypersensitivity / infusion-related reactions: CRS is mechanistically distinct from allergic / hypersensitivity / infusion-related reactions (Brennan FR, Morton LD, Spindeldreher S, et al. Safety and immunotoxicity assessment of immunomodulatory monoclonal antibodies. MAbs. 2010;2(3):233-55), but some symptoms are common to both AEs, and both have been reported to occur with therapeutic antibodies. It is less clear how cytokine release is triggered, but it is likely that cytokine release is related to immune cell activation. In this case, CD3-expressing lymphocytes may be the primary effectors of CRS.

[0369] Use of Tocilizumab for Cytokine Release Syndrome: Tocilizumab (Acterma®) is a therapeutic antibody that inhibits the binding of interleukin-6 (IL-6) to the IL-6 receptor. Tocilizumab can be used to reduce the severity and possibly mortality of severe CRS, and early administration may be useful in improving outcomes. Tocilizumab (dose 8 mg / kg) should be readily available as needed, and repeat doses of tocilizumab may be required if signs and symptoms persist or recur after initial treatment. In some cases, another treatment (instead of tocilizumab) may be used for CRS.

[0370] Fluid Management: CRS may be associated with myocardial dysfunction, pulmonary edema, or capillary leak syndrome (Shimabukuro-Vornhagen A, Godel P, Subklewe M, et al. Cytokine release syndrome. J Immunother Cancer. 2018;6(1):56). Subjects should be monitored for weight gain and intravenous (IV) fluid administration in acute cases. Guidelines for administering fluids are as follows: If a subject experiences a 10% or greater gain in body weight over the past 2 weeks associated with new or significantly increased bilateral lower extremity edema, dosing should be delayed until this finding has been evaluated and treated as necessary. In cases of acute hypotension, IV fluid boluses should be limited to 500-1000 mL of normal saline or equivalent. If there is no adequate response to fluids, treatment with tocilizumab (and vasopressors if necessary) should be considered rather than additional fluid boluses.

[0371] ASTCT CRS Consensus Cytokine Release Syndrome Treatment Guidelines by Grade: CRS treatment guidelines are listed below by grade.

[0372] Grade 1 Symptomatic management is recommended. For rash, pruritus, or other signs and symptoms of a hypersensitivity (allergic) reaction, administer acetaminophen 650 mg orally as an antipyretic or analgesic and / or diphenhydramine 25-50 mg intravenously or orally as clinically indicated. · Vital signs should be measured no more than every 15 minutes or as clinically indicated. · Unscheduled blood samples will be taken for cytokine analysis during the event and approximately 4 hours later (unless scheduled cytokine monitoring is already in progress on the same visit day). Monitor subjects for deterioration. If the severity of the event increases to a higher grade, stop the infusion and administer steroids.

[0373] Grade 2 Hypotension responsive to fluids without the need for vasopressors, or mild respiratory symptoms treatable with low-flow oxygen, are signs of grade 2 toxicity. Elderly subjects or those with significant comorbidities may be at higher risk of decompensation in this setting. Discontinue the infusion and / or administer an additional dose of dexamethasone in doses of 10 to 20 mg intravenously and / or administer acetaminophen 650 mg orally and / or administer diphenhydramine 25 to 50 mg intravenously or orally to treat signs and symptoms. Once symptoms have resolved, resume the infusion at 50% of the baseline rate. If after 1 hour the subject's symptoms have not recurred and vital signs are stable, the infusion rate may be increased, as tolerated, every 30 minutes to reach the baseline rate. If clinically indicated, vital signs should be measured no more than every 15 minutes. The frequency of vital sign assessments during the infusion may be reduced to every 30 minutes for subjects who are able to tolerate an increase in the infusion rate back to the baseline rate and who are able to maintain normotension for 30 minutes after the rate increase. · Unscheduled blood samples will be taken for cytokine analysis during the event and approximately 4 hours later (unless scheduled cytokine monitoring is already in progress on the same visit day). Monitor subjects for deterioration. If the severity of the event increases to a higher grade, stop the infusion and administer appropriate treatment, following guidelines for Grade 3 and 4 reactions, if necessary. Elderly subjects or those with significant comorbidities may be at higher risk for decompensation in this setting. If a reaction occurs or progresses rapidly in these vulnerable subjects, IV treatment with tocilizumab 8 mg / kg over 1 hour with or without additional IV treatment with dexamethasone 10 to 20 mg (or equivalent) may be considered.

[0374] Grades 3 and 4 Stop the infusion and remove the infusion tubing from the subject. Administer an additional 10 mg of dexamethasone intravenously. · Implement aggressive supportive care immediately, using vasopressors, fluids, oxygen, epinephrine or bronchodilators, ventilatory support, antipyretics, and analgesics as indicated. Tocilizumab 8 mg / kg IV over 1 hour (Hallek M, Cheson BD, Catovsky D, et al. CLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL. Blood. 2018;131(25):2745-60) is recommended in CRS (due to high risk of progression and permanent organ dysfunction). Hospitalization for observation is often indicated in intensive care units, as initial improvement may be followed by rapid decompensation. For subjects with Grade 3 CRS or infusion reactions, rechallenge may be performed upon resolution as described in Section 5.11 and Table 14. Subjects with recurrent Grade 3 or any Grade 4 reaction should not receive further pramotamab treatment but will continue to be followed per protocol (i.e., followed for long-term survival). · Unscheduled blood samples will be taken for cytokine analysis during the event and approximately 4 hours later (unless scheduled cytokine monitoring is already in progress on the same visit day). Unscheduled samples will be collected for Anti-Drug Antibody (ADA) testing as close as possible to the onset of the event, upon resolution of the event, and approximately 28 days after the event (unless cytokine monitoring scheduled for the same visit date is already in progress). · Medical professionals and / or medical surveillance personnel should be contacted.

[0375] Neurotoxicity: In addition to CRS, another toxicity observed after CAR-T cell therapy and CD3 bispecific antibodies is neurotoxicity. Immune effector cell-associated neurotoxicity syndrome (ICANS) may manifest as delirium, encephalopathy, aphasia, lethargy, impaired concentration, agitation, tremors, seizures, and rarely cerebral edema (Lee DW, Santomasso BD, Locke FL, et al. ASTCT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells. Biol Blood Marrow Transplant. 2019; 25(4) 625-38). Neurotoxicity is treated separately from CRS due to its timing and response to treatment.

[0376] Neurological symptoms may occur during or after CRS symptoms, but rarely before CRS symptoms. Early symptoms of ICANS are tremor, dysgraphia, mild speech difficulties (especially naming objects), attention problems, apraxia, and mild lethargy. Headache is a nonspecific symptom that often occurs during fever or after chemotherapy in patients without other neurological dysfunction. Thus, headache alone is not a suitable marker of ICANS. Expressive aphasia, on the other hand, appears to be a very specific symptom of ICANS.

[0377] A consensus grading scheme, a slightly modified version of the CARTOX-10 screening tool (incorporating the immune effector cell-associated encephalopathy (ICE) score, a key component of the Mini-Mental State Examination), is used for ICANS grading. (Table 11). The 10-point ICE screening tool is useful for assessing encephalopathy in subjects. However, ICANS grading requires assessment of the 10-point ICE score as well as evaluation of other neurological domains such as level of consciousness, motor symptoms, seizures, and signs of elevated intracranial pressure / cerebral edema with or without encephalopathy. The ASTCT ICANS toxicity grading system is shown in Table 12. This grading scale is used to assess neurotoxicity rather than the CTCAE version 5.0. [Table 13] [Table 14-1] [Table 14-2]

[0378] High levels of IL-6 may directly mediate neurotoxicity. Tocilizumab, a human anti-IL-6 monoclonal antibody, may reverse this neurotoxicity, but it is not expected to cross the blood-brain barrier and its efficacy in this setting has not been confirmed. Corticosteroids may be the first-line therapy, and tocilizumab may be considered if corticosteroids are ineffective.

[0379] Clinical Management of Neurotoxicity: Subjects are monitored for signs and symptoms of the event (including the use of mental status and neurological examinations). If neurotoxicity becomes evident, an unscheduled blood sample for cytokine analysis will be drawn at that time and repeated 4 hours later (unless scheduled cytokine monitoring is already in progress for the same visit). If neurotoxicity is grade 4, discontinue pramotamab. ·For grade 3 neurotoxicity, withhold drug until toxicity resolves to grade 1 (mild) or less and remains at grade 1 or less for at least 3 days before resuming therapy. Resume therapy at 75% of previous dose. If grade ≥ 2 toxicity does not recur, escalate dose to full dose at next dose. Permanently discontinue drug if grade ≥ 2 toxicity recurs at 75% dose or if less than grade 2 toxicity takes > 7 days to resolve. Permanently discontinue pramotamab if grade 3 neurotoxicity persists > 7 days. For severe neurological symptoms, administer an additional 10 mg of dexamethasone intravenously, repeating every 12 hours if symptoms do not rapidly abate. · In cases of recurrent seizures, anticonvulsant therapy may be necessary.

[0380] Allergic / Hypersensitivity / Infusion-Related Reactions: Infusion-related reactions can occur with tafasitamab and pramotamab. Allergic reactions are often caused by a type 1 hypersensitivity mechanism via immunoglobulin E (IgE)-mediated release of histamine and prostaglandins, but can also occur through direct interactions with mast cells and basophils. However, infusion-related reactions (including severe and fatal reactions) are not uncommon with monoclonal antibody therapeutics and tend to occur most frequently during the first few infusions.

[0381] Signs and symptoms usually develop during or shortly after drug infusion in hypersensitivity reactions, are likely to occur after several doses of the drug, and are primarily related to the release of histamine.Typical signs and symptoms include rash / hives, flushing, itching, fever, dyspnea, cough, and hypotension, but may also include the following: Joint pain Bronchospasm Confusion / altered mental status / delirium ·dizziness Fatigue (asthenia, lethargy, malaise) Hallucinations ·headache High blood pressure Muscle pain Nausea / vomiting Stiffness / chills ·sweating Tachycardia

[0382] Allergic / hypersensitivity / infusion-related reactions will be managed according to institutional practices and guidelines. Allergic / hypersensitivity reactions will be defined according to the NCI-CTCAE, version 5.0 (NCI-CTCAE, 2017) definition of allergic reactions.

[0383] Safety Induction and Part 2, Arm A (pramotamab, tafasitamab, and lenalidomide): Infusion-related reactions may occur with pramotamab and tafasitamab. To mitigate overlapping toxicities with pramotamab, on a given treatment day, tafasitamab should be administered first and the interval between the end of the tafasitamab infusion and the start of the pramotamab infusion should be a minimum of 2 hours. If a Grade 1 infusion reaction occurs with tafasitamab, pramotamab will be delayed until resolution of all symptoms of the reaction. Depending on the timing of resolution of all symptoms, pramotamab administration the next day may be necessary.

[0384] Part 2, Arm B (tafasitamab and lenalidomide): Infusion-related reactions may occur with tafasitamab and lenalidomide. Toxicity Management instructions provided in the tafasitamab prescribing information may be followed. See section 5.11 for dose modifications.

[0385] Hematological toxicity: Hematological toxicity, particularly decreases in absolute neutrophil count (ANC) and platelet counts, have been observed in clinical trials of tafasitamab and lenalidomide. Decreases in platelets and ANC may be observed with pramotamab (see Table 13). [Table 15]

[0386] Concomitant use of products may exacerbate these grade or duration reductions. Blood counts should be closely monitored and institutional guidelines followed for treatment of neutropenia and thrombocytopenia. Treatment may include the use of growth factors and administration of whole blood / blood product transfusions. Management may also include delaying administration of study medication until counts return to at least Grade 2 levels. See Section 5.11 for any dose modifications of study medication.

[0387] Safety Run-in and Part 2, Group A (pramotamab, tafasitamab, and lenalidomide): Hematologic toxicities, specifically decreases in ANC and platelet counts, may occur in clinical trials of tafasitamab and lenalidomide. Decreases in platelets and ANC may also occur with pramotamab. Concomitant use of products may exacerbate these decreases in grade or duration. Monitor blood counts closely and follow institutional guidelines for treatment of neutropenia and thrombocytopenia, which may include transfusion of growth factors and whole blood / blood products. Management may also include delaying administration of study drug until counts return to at least Grade 2 levels. See Section 5.11 for any dose modifications of study drug.

[0388] Part 2, Arm B (tafasitamab and lenalidomide): Hematologic toxicities may occur with tafasitamab and lenalidomide. Toxicity management instructions provided in the tafasitamab prescribing information should be followed. See Section 5.11 for any dose modifications of study drug.

[0389] Tumor lysis syndrome: Tumor lysis syndrome (TLS) is a rare but serious and life-threatening condition caused by the rapid release of tumor cell contents after lysis. The resulting metabolic imbalance may cause acute renal failure and / or other life-threatening conditions. Subjects with high tumor burden, hyperproliferative disease, and / or certain underlying diseases, such as renal disease, are at high risk of TLS.

[0390] Safety Induction and Part 2, Arm A (pramotamab, tafasitamab, and lenalidomide): It is unclear whether treatment with pramotamab, tafasitamab, and lenalidomide can cause TLS in R / R DLBCL. A phase 1 pramotamab monotherapy study in CD20-expressing hematologic malignancies reported that 4 of 96 subjects (4.2%) developed TLS of any grade, of which only 2 of 80 R / R NHL subjects (2.5%) experienced TLS. Importantly, no serious or fatal events of TLS were reported with pramotamab monotherapy in R / R DLBCL. Similarly, no events of TLS were reported in a phase 2 open-label, single-arm tafasitamab + lenalidomide study in R / R DLBCL (L-MIND). However, fatal cases of TLS have been reported with other indications and combinations of lenalidomide. All subjects will be assessed for risk of TLS according to institutional practice, based on laboratory parameters and tumor burden, prior to initiation of study drug.

[0391] Tumor Lysis Syndrome Prophylaxis, Monitoring, and Treatment: Prior to initiation of treatment, prophylaxis should be administered to subjects at high risk for TLS. Hospitalization may be considered for subjects considered at high risk for TLS and / or with creatinine clearance <80 mL / min. Allopurinol (or other xanthine oxidase inhibitors) should be initiated at least 48 hours prior to C1D1 in subjects considered at moderate to high risk for TLS. Rasburicase is indicated for elevated uric acid levels and monitoring for TLS. During study treatment, all subjects will require appropriate laboratory testing, including uric acid, potassium, phosphorus, calcium, and creatinine, prior to study drug administration. Laboratory results should be assessed in real time. IV fluids should be added if the subject is unable to take adequate oral fluids.

[0392] If a subject experiences laboratory changes or symptoms suggestive of TLS, treatment with pramotamab, tafasitamab, and lenalidomide should be interrupted. Study treatment will be held until TLS has resolved. If moderate or high risk of TLS remains after resolution, additional precautions and / or continued or reduced dose interruption of pramotamab, tafasitamab, or lenalidomide may be considered.

[0393] Part 2, Arm B (tafasitamab and lenalidomide): Prophylaxis, monitoring, and treatment of TLS should follow the guidelines disclosed above under "Tumor lysis syndrome prophylaxis, monitoring, and treatment."

[0394] 5.11. Dose modification guidelines Subjects experiencing significant toxicity will be treated with standard medical interventions as necessary (e.g., the use of filgrastim to treat neutropenia and / or acetaminophen for fever). Standard treatment practices can be used for infusion reaction / cytokine release syndrome (CRS) and neurotoxicity management.

[0395] In general, subjects may be required to discontinue pramotamab or tafasitamab treatment if >14 days of missed doses and / or 2 consecutive doses are missed due to Grade 2 or greater toxicity (this applies to weekly and Q2W dosing). Subjects may resume study drug after missing 2 or more consecutive doses of pramotamab or tafasitamab if it is determined that the benefits outweigh the risks and the toxicity (if applicable) is controllable with the concomitant medication or by other means. Delays of >14 days and / or 2 consecutive doses require approval from the medical monitor.

[0396] During weekly dosing of pramotamab and / or tafasitamab, a subject dose withheld for 7 days or more should be considered a missed dose. During Q2W dosing of pramotamab and / or tafasitamab, a subject dose withheld for 14 days or more should be considered a missed dose. Subject doses administered outside of the time window or delayed due to safety concerns, including AEs, are not considered protocol deviations.

[0397] Pramotamab may be resumed after multiple cycles of prolonged dosing delays due to reasons other than toxicity (e.g., comorbidities, pseudoprogression, or delayed response). Resumption of initial treatment may be tolerated on an individual basis if it is deemed to best benefit the subject. As a safety precaution, the dose may be reduced to the priming dose for re-titration. Study assessments (including those from local and / or central laboratories) are collected, for example, according to the schedule of assessments shown in Table 14.

[0398] For potentially overlapping toxicities (e.g., CRS, infusion reactions, hematologic toxicities), detailed dose modifications by grade are provided in Table 14 below. [Table 16-1] [Table 16-2] [Table 16-3] [Table 16-4] [Table 16-5] [Table 16-6] [Table 16-7] [Table 16-8]

[0399] 5.12.Results Subjects treated with the combination of pramotamab, tafasitamab, and lenalidomide are expected to have improved outcomes compared to subjects treated with tafasitamab and lenalidomide alone.

[0400] Baseline DLBCL disease assessment: Prior to study initiation (17 days prior to study initiation), a PET-CT scan (5-point scale test) was performed on the subjects, yielding a grade or score of 5 (Table 16). At 61 days after study initiation, the PET-CT scan showed a reduction in score from 5 to 2 in the same subjects (Table 17). A PET-CT scan grade of 2 was also observed at the measurement 117 days after study initiation (Table 17). From 177 days after study initiation until the end of treatment, the subjects had a reduction in PET-CT scan score to 1 (Table 18). Results showed that the subjects had a metabolic complete response at the end of treatment (and also after cycle 2, after cycle 4, after cycle 6, and / or after cycle 8 of the study). [Table 17] [Table 18-1] [Table 18-2] [Table 19] *****

[0401] Those skilled in the art will appreciate that changes may be made to the above-described embodiments without departing from the broad inventive concept thereof. It is understood, therefore, that the invention is not limited to the particular embodiments disclosed, but it is intended to cover modifications within the spirit and scope of the invention as defined by this description.

[0402] The present invention will be described in detail with reference to specific embodiments thereof, but it will be understood that functionally equivalent variations are within the scope of the present invention. Indeed, various modifications of the present invention in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description and accompanying drawings. Such modifications are intended to be included within the scope of the appended claims. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed within the scope of the following claims.

Claims

1. (a) an antibody that binds to CD19 (CD19 antibody), (b) A multispecific antibody (CD3xCD20 antibody) comprising a first binding domain that binds to CD3 and a second binding domain that binds to CD20, and (c) Compounds having the following structure: 【Chemistry 1】 (Compound A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. A combination of pharmaceuticals for treating lymphoma in patients requiring treatment for lymphoma, including, For the aforementioned object, (i) The first dose of compound A, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, (ii) First administration of the CD3xCD20 antibody At least one day prior to the implementation, the first dose of the CD19 antibody is administered to the subject. The aforementioned combination drug.

2. (a) The CD19 antibody is (i) Heavy chain variable (VH) domains comprising VH complementarity-determining regions (CDRs) 1, VH CDR2, and VH CDR3, each having the amino acid sequences of SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3, respectively, and (ii) Light chain variable (VL) domains comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6, respectively, Includes, (b) The first binding domain of the CD3xCD20 antibody that binds to CD3, (i) VH domains comprising VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NO: 7, SEQ ID NO: 8, and SEQ ID NO: 9, respectively, and (ii) VL domains comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NO: 10, SEQ ID NO: 11, and SEQ ID NO: 12, respectively including and / or (c) The second binding domain of the CD3xCD20 antibody that binds to CD20, (i) VH domains comprising VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NO: 13, SEQ ID NO: 14, and SEQ ID NO: 15, respectively, and (ii) VL domains comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NO: 16, SEQ ID NO: 17, and SEQ ID NO: 18, respectively including, The combination pharmaceutical product according to claim 1.

3. (a) The CD19 antibody contains a VH domain having an amino acid sequence that is approximately 90%, 95%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO:

19. (b) The CD19 antibody comprises a VL domain having an amino acid sequence that is approximately 90%, 95%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO:

20. (c) The first binding domain of the CD3xCD20 antibody that binds to CD3 includes a VH domain having an amino acid sequence that is approximately 90%, 95%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO:

21. (d) The first binding domain of the CD3xCD20 antibody that binds to CD3 includes a VL domain having an amino acid sequence that is approximately 90%, 95%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO:

22. (e) The second binding domain of the CD3xCD20 antibody that binds to CD20 includes a VH domain having an amino acid sequence that is approximately 90%, 95%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 23, and / or (f) The second binding domain of the CD3xCD20 antibody that binds to CD20 includes a VL domain having an amino acid sequence that is approximately 90%, 95%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO:

24. The combination pharmaceutical product according to claim 2.

4. The aforementioned CD3xCD20 antibody (a) A first monomer containing scFv-linker-CH2-CH3 having the amino acid sequence of SEQ ID NO: 25 from the N-terminus to the C-terminus, (b) A second monomer comprising VH-CH1-hinge-CH2-CH3 having the amino acid sequence of SEQ ID NO: 26 from the N-terminus to the C-terminus, and (c) A third monomer containing VL-CL having the amino acid sequence of SEQ ID NO: 27 from the N-terminus to the C-terminus, The combination pharmaceutical according to claim 1, including

5. The aforementioned compound, 【Chemistry 2】 The combination pharmaceutical according to claim 1.

6. The combination drug according to claim 1, wherein the lymphoma is non-Hodgkin lymphoma.

7. The combination drug according to claim 6, wherein the non-Hodgkin lymphoma is diffuse large cell lymphoma (DLBCL).

8. The combination pharmaceutical according to claim 7, wherein the DLBCL is relapsed DLBCL, refractory DLBCL, or relapsed and refractory DLBCL.

9. The combination pharmaceutical according to claim 7, wherein the DLBCL is primary refractory DLBCL.

10. The combination pharmaceutical according to claim 7, wherein the DLBCL is a first-line DLBCL.

11. The combination drug according to claim 1, wherein the lymphoma is a CD20-expressing lymphoma.

12. The combination drug according to claim 1, wherein the lymphoma is a CD19-expressing lymphoma.

13. The combination pharmaceutical according to claim 1, wherein the subject has not undergone stem cell transplantation.

14. The combination pharmaceutical according to claim 1, wherein the subject is not eligible for stem cell transplantation.

15. The combination pharmaceutical according to claim 13, wherein the stem cell transplant is autologous stem cell transplant.

16. The combination pharmaceutical according to claim 1, wherein the CD19 antibody, compound A or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, and the CD3xCD20 antibody are administered to the subject by periodic administration.

17. The combination drug according to claim 16, wherein each cycle of the cyclical administration is 28 days.

18. The combination pharmaceutical according to claim 1, wherein the CD19 antibody is administered to the subject in an amount of approximately 1 mg / kg to approximately 20 mg / kg per day.

19. The combination pharmaceutical according to claim 1, wherein compound A, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is administered to the subject in an amount of approximately 1 mg to approximately 30 mg per day.

20. The combination pharmaceutical according to claim 1, wherein the CD3xCD20 antibody is administered to the subject in an amount of approximately 0.8 mg to approximately 100 mg per day.

21. The combination drug according to claim 1, wherein the CD19 antibody is tafacitamab.

22. The combination pharmaceutical according to any one of claims 1 to 21, wherein the CD3xCD20 antibody is pramotamab.

23. (a) an antibody that binds to CD19 (CD19 antibody), (b) A multispecific antibody (CD3xCD20 antibody) comprising a first binding domain that binds to CD3 and a second binding domain that binds to CD20, and (c) Compounds having the following structure: 【Transformation 3】 (Compound A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. A combination of pharmaceuticals for treating lymphoma in patients requiring treatment for lymphoma, including, The combination pharmaceutical in which the CD19 antibody, the CD3xCD20 antibody, and compound A or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof are administered simultaneously or sequentially in the same or separate compositions.

24. (a) The CD19 antibody is (i) Heavy chain variable (VH) domains comprising VH complementarity-determining regions (CDRs) 1, VH CDR2, and VH CDR3, each having the amino acid sequences of SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3, respectively, and (ii) Light chain variable (VL) domains comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6, respectively, Includes, (b) The multispecific antibody is (i) an anti-CD3e heavy chain having the amino acid sequence of SEQ ID NO: 30, an anti-CD3e light chain having the amino acid sequence of SEQ ID NO: 31, an anti-CD20 heavy chain having the amino acid sequence of SEQ ID NO: 32, and an anti-CD20 light chain having the amino acid sequence of SEQ ID NO: 33, or (ii) an anti-CD3e heavy chain having the amino acid sequence of SEQ ID NO: 34, an anti-CD3e light chain having the amino acid sequence of SEQ ID NO: 35, an anti-CD20 heavy chain having the amino acid sequence of SEQ ID NO: 36, and an anti-CD20 light chain having the amino acid sequence of SEQ ID NO: 37, or (iii) an anti-CD3 heavy chain having the amino acid sequence of SEQ ID NO: 38, a light chain having the amino acid sequence of SEQ ID NO: 39, and an anti-CD20 heavy chain having the amino acid sequence of SEQ ID NO: 40, or (iv) Anti-CD20 / CD3 heavy chain having the amino acid sequence of SEQ ID NO: 41, anti-CD3e light chain having the amino acid sequence of SEQ ID NO: 42, anti-CD20 heavy chain having the amino acid sequence of SEQ ID NO: 43, and anti-CD20 light chain having the amino acid sequence of SEQ ID NO: 44 including, The combination pharmaceutical product according to claim 23.

25. (a) The CD19 antibody contains a VH domain having an amino acid sequence that is approximately or at least approximately 90%, 95%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 19, or (b) The CD19 antibody comprises a VL domain having an amino acid sequence that is approximately or at least approximately 90%, 95%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO:

20. The combination drug according to claim 24.

26. The aforementioned compound has the formula: 【Chemistry 4】 The combination pharmaceutical according to claim 23.

27. The combination drug according to claim 23, wherein the lymphoma is non-Hodgkin lymphoma.

28. The combination drug according to claim 27, wherein the non-Hodgkin lymphoma is diffuse large cell lymphoma (DLBCL).

29. The combination pharmaceutical according to claim 28, wherein the DLBCL is relapsed DLBCL, refractory DLBCL, or relapsed and refractory DLBCL.

30. The combination pharmaceutical according to claim 28, wherein the DLBCL is primary refractory DLBCL.

31. The combination pharmaceutical according to claim 28, wherein the DLBCL is a first-line DLBCL.

32. The combination drug according to claim 1, wherein the subject achieves complete metabolic response as determined by positron emission tomography (PET)-computed tomography (CT) scan.

33. The combination pharmaceutical according to claim 32, wherein the CD19 antibody, compound A or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, and the CD3xCD20 antibody are administered to the subject by periodic administration, and the subject achieves complete metabolic response in cycle 2, cycle 4, cycle 6, cycle 8 and / or after the end of treatment.

34. The combination drug according to claim 33, wherein the subject achieves complete metabolic response on day 26 of cycle 2, day 26 of cycle 4, day 26 of cycle 6, day 26 of cycle 8, and / or after the end of treatment.

35. The combination pharmaceutical according to claim 32 or 33, wherein the subject achieves complete metabolic response 61, 117, 177, 233, or 299 days or later after the initial administration of the multispecific antibody to the subject.

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