Methods of treating lymphoma

Abstract

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

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 337,941, filed on May 3, 2022, and U.S. Provisional Patent Application No. 63 / 340,909, filed on May 11, 2022, the contents of each of which are incorporated herein by reference in their entirety.

[0003] Reference to sequence listings submitted electronically

[0004] This application contains a computer-readable sequence list, which has been submitted with this application in XML file format, and its entire contents are incorporated herein by reference in its entirety. The sequence list XML file submitted with this application is named "14718-043-228_SEQLISTING.xml", created on April 5, 2023, and is 54,710 bytes in size. 1. Technical Field

[0005] Provided herein in certain aspects are methods for treating lymphoma using a combination of a CD19 antibody, a CD3xCD20 multispecific antibody, and a compound or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, such as Compound A, wherein the compound has the structure

[0006]

[0007] (ie, 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione (Compound A)). 2. Summary of the invention

[0008] In one aspect, provided herein is a method of treating lymphoma in a subject in need thereof, comprising administering to the subject: (a) an antibody that binds to CD19 (CD19 antibody); (b) a multispecific antibody, wherein the multispecific antibody comprises a first binding domain that binds to CD3 and a second binding domain that binds to CD20 (CD3xCD20 antibody); and (c) a compound having the following structure:

[0009]

[0010] (i.e., 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione (Compound A)), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In a specific embodiment, the subject is administered a first dose of CD19 antibody at least one day prior to administering to the subject: (i) a first dose of Compound A or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; or (ii) a first dose of CD3xCD20 antibody.

[0011] 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 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 amino acid sequences of SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6, respectively. In one embodiment, the first binding domain of the CD3xCD20 antibody that binds to CD3 comprises: (i) a VH domain 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) a VL domain 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. In one embodiment, the second binding domain of the CD3xCD20 antibody that binds to CD20 comprises: (i) a VH domain 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) a VL 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.In another embodiment, (a) a CD19 antibody comprises: (i) a VH CDR1, a VH CDR2, and a VHCDR3 having amino acid sequences of SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3, respectively; and (ii) a VL CDR1, a VLCDR2, and a VL CDR3 having amino acid sequences of SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6, respectively; (b) 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 VHCDR3 having 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 amino acid sequences of SEQ ID NO: 10, SEQ ID NO: 11, and SEQ ID NO: 12, respectively. CDR3; and (c) a second binding domain of the CD3xCD20 antibody that binds to CD20 comprises: (i) a VH domain comprising VH CDR1, VH CDR2 and VH CDR3 having amino acid sequences of SEQ ID NO: 13, SEQ ID NO: 14 and SEQ ID NO: 15, respectively; and (ii) a VL domain comprising VL CDR1, VL CDR2 and VL CDR3 having amino acid sequences of SEQ ID NO: 16, SEQ ID NO: 17 and SEQ ID NO: 18, respectively.

[0012] 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, the first binding domain of the 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.

[0013] In one embodiment, the first binding domain of the CD3xCD20 antibody that binds to 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, the second binding domain of the CD3xCD20 antibody that binds to 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, the second binding domain of the CD3xCD20 antibody that binds to 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.

[0014] In one embodiment, the CD3xCD20 antibody comprises: (a) 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; (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.

[0015] In one embodiment, the compound is

[0016]

[0017] (ie, 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione (Compound A)).

[0018] In one embodiment, lymphoma is non-Hodgkin lymphoma. In one embodiment, non-Hodgkin lymphoma is diffuse large cell lymphoma (DLBCL). In one embodiment, DLBCL is relapsed, refractory or relapsed and refractory DLBCL. In one embodiment, DLBCL is primary refractory DLBCL. In one embodiment, wherein DLBCL is first-line DLBCL. In one embodiment, lymphoma is a lymphoma expressing CD20. In one embodiment, lymphoma is a lymphoma expressing CD19. In one embodiment, the subject has not received a stem cell transplant. In one embodiment, the subject is not suitable for a stem cell transplant. In one embodiment, the stem cell transplant is an autologous stem cell transplant.

[0019] In one embodiment, the method includes cyclic administration of CD19 antibody, Compound A or its pharmaceutically acceptable salt, solvate or stereoisomer and CD3xCD20 antibody. In one embodiment, each cycle of cyclic administration is 28 days. In one embodiment, cyclic administration includes about one cycle, two cycles, three cycles, four cycles, five cycles, six cycles, seven cycles, eight cycles, nine cycles, ten cycles, eleven cycles, twelve cycles or more than twelve cycles.

[0020] In one embodiment, the CD19 antibody of the first dose is administered to the subject before the first day of the first cycle of the cycle. In one embodiment, the CD19 antibody of the first dose is administered to the subject at least one day, two days, three days, four days, five days, six days, seven days, eight days, nine days, ten days or more than ten days before the first day of the first cycle of the cycle. In one embodiment, the CD19 antibody of the first dose is administered to the subject four days before the first day of the first cycle of the cycle. In one embodiment, the CD19 antibody is administered to the subject eight days before the first day of the first cycle of the cycle. In one embodiment, the CD19 antibody is administered to the subject four days and eight days before the first day of the first cycle of the cycle. In one embodiment, the CD19 antibody is administered to the subject on the 1st day, the 8th day, the 15th day and / or the 22nd day of the cycle of the cycle. In one embodiment, the CD19 antibody is administered to the subject on the 1st day, the 8th day, the 15th day and the 22nd day of the cycle of the cycle. In one embodiment, CD19 antibody is administered to a subject on the 1st and 15th day of a cycle of cycle administration. In one embodiment, CD19 antibody is administered to a subject on the 1st, 8th, 15th and 22nd day of each cycle in the 1st-3 cycles of a cycle of cycle administration. In one embodiment, CD19 antibody is administered to a subject on the 1st and 15th day of the 4th cycle and subsequent cycles of cycle administration. In one embodiment, CD19 antibody is administered to a subject on the 1st and 15th day of the 4th-6th cycle of cycle administration. In one embodiment, CD19 antibody is administered to a subject every 6 to 8 days in a cycle of cycle administration.

[0021] In one embodiment, Compound A or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is administered to the subject for 21 days in a cycle of administration. In one embodiment, Compound A or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is administered to the subject from day 1 to day 21 of the cycle of administration. In one embodiment, Compound A or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is administered to the subject for 21 days in a 28-day cycle of cycle administration, followed by a 7-day rest.

[0022] In one embodiment, the CD3xCD20 antibody is administered to the subject on day 1, day 8, day 15 and / or day 22 of the cycle of cycle administration. In one embodiment, the CD3xCD20 antibody is administered to the subject on day 1, day 8, day 15 and day 22 of the cycle of cycle administration. In one embodiment, the CD3xCD20 antibody is administered to the subject on day 1 and day 15 of the cycle of cycle administration. In one embodiment, the CD3xCD20 antibody is administered to the subject on day 1, day 8, day 15 and day 22 of the 1st cycle and the 2nd cycle of cycle administration. In one embodiment, the CD3xCD20 antibody is administered to the subject on day 1 and day 15 of the 3rd cycle and thereafter of cycle administration. In one embodiment, the CD3xCD20 antibody is administered to the subject on day 1 and day 15 of the 3rd-6th cycle of cycle administration. In one embodiment, the CD3xCD20 antibody is administered to the subject every 6 to 8 days in the cycle of cycle administration.

[0023] In one embodiment, the CD19 antibody is administered to a subject in an amount of about 1 mg / kg / day to about 20 mg / kg / day. In one embodiment, the CD19 antibody is administered to a subject in an amount of about 12 mg / kg / day. In one embodiment, the CD19 antibody is administered to a subject in an amount of about 5 mg / kg / day. In one embodiment, the CD19 antibody is administered to a subject in an amount of about 10 mg / kg / day.

[0024] In one embodiment, Compound A or its pharmaceutically acceptable salt, solvate or stereoisomer is applied to the subject in an amount of about 1 mg / day to about 30 mg / day. In one embodiment, Compound A or its pharmaceutically acceptable salt, solvate or stereoisomer is applied to the subject in an amount of about 2.5 mg / day, 5 mg / day, 10 mg / day, 15 mg / day, 20 mg / day or 25 mg / day. In one embodiment, Compound A or its pharmaceutically acceptable salt, solvate or stereoisomer is applied to the subject in an amount of about 2.5 mg / day. In one embodiment, Compound A or its pharmaceutically acceptable salt, solvate or stereoisomer is applied to the subject in an amount of about 5 mg / day. In one embodiment, Compound A or its pharmaceutically acceptable salt, solvate or stereoisomer is applied to the subject in an amount of about 10 mg / day. In one embodiment, Compound A or its pharmaceutically acceptable salt, solvate or stereoisomer is applied to the subject in an amount of about 15 mg / day. In one embodiment, Compound A or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is administered to a subject in an amount of about 20 mg / day. In one embodiment, Compound A or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is administered to a subject in an amount of about 25 mg / day.

[0025] In one embodiment, the CD3xCD20 antibody is administered to a subject in an amount of about 0.8 mg / day to about 100 mg / day. In one embodiment, the CD3xCD20 antibody is administered to a subject in an amount of about 0.8 mg / day to about 50 mg / day. In one embodiment, the CD3xCD20 antibody is administered to a subject in an amount of about 0.8 mg / day to about 20 mg / day. In one embodiment, the CD3xCD20 antibody is administered to a subject in an amount of about 0.8 mg / day. In one embodiment, the CD3xCD20 antibody is administered to a subject in an amount of about 2 mg / day. In one embodiment, the CD3xCD20 antibody is administered to a subject in an amount of about 20 mg / day. In one embodiment, the CD3xCD20 antibody is administered to a subject in an amount of about 35 mg / day. In one embodiment, wherein the CD3xCD20 antibody is administered to a subject in an amount of about 50 mg / day.

[0026] In one embodiment, the first dose of the CD3xCD20 antibody is on day 1 of the first cycle of cyclic 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 / 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 / day in any subsequent cycle.

[0027] In one embodiment, the first dose of Compound A, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, is on day 1 of the first cycle of cyclic administration.

[0028] In one embodiment, the first dose of the CD3xCD20 antibody and the first dose of Compound A or a pharmaceutically acceptable salt, solvate or stereoisomer thereof are both administered on day 1 of the first cycle of cyclic administration.

[0029] In one embodiment, in the cycle of cycle administration, CD19 antibody is administered to the subject once a week. In one embodiment, in the 1st-3rd cycle of cycle administration, CD19 antibody is administered to the subject once a week. In one embodiment, in the cycle of cycle administration, CD19 antibody is administered to the subject every two weeks. In one embodiment, in the 4th cycle of cycle administration and the subsequent cycle, CD19 antibody is administered to the subject every two weeks. In one embodiment, wherein in the cycle of cycle administration, CD3xCD20 antibody is administered to the subject once a week. In one embodiment, wherein in the 1st cycle and the 2nd cycle of cycle administration, CD3xCD20 antibody is administered to the subject once a week. In one embodiment, wherein in the cycle of cycle administration, CD3xCD20 antibody is administered to the subject every two weeks. In one embodiment, wherein in the 3rd cycle of cycle administration and the subsequent cycle, CD3xCD20 antibody is administered to the subject every two weeks. In one embodiment, wherein in the cycle of cycle administration, CD3xCD20 antibody and CD19 antibody are each administered to the subject within a maximum of 4 days.

[0030] 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 on day 1, about 2 mg on about day 8, about 20 mg on about day 15, and about 20 mg of the CD3xCD20 antibody on about day 22, wherein the subject is administered about 20 mg of the CD3xCD20 antibody on day 1 and every 6 to 8 days of a second cycle of cyclic administration, wherein the subject is administered four doses of the CD3xCD20 antibody in each of the first 2 cycles, wherein the subject is administered about 20 mg of the CD3xCD20 antibody on day 1 and every 12 to 16 days in cycle 3 and any subsequent cycles during treatment, and wherein each cycle of cyclic administration is 28 days.

[0031] 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 on day 1, about 2 mg on about day 8, about 20 mg on about day 15, and about 35 mg of the CD3xCD20 antibody on about day 22, wherein the subject is administered about 50 mg of the CD3xCD20 antibody on day 1 and every 6 to 8 days of a second cycle of cyclic administration, wherein the subject is administered four doses of the CD3xCD20 antibody in each of the first 2 cycles, wherein the subject is administered about 50 mg of the CD3xCD20 antibody on day 1 and every 12 to 16 days in cycle 3 and any subsequent cycles during treatment, and wherein each cycle of cyclic administration is 28 days.

[0032] In one embodiment, the method comprises cyclically administering a CD3xCD20 antibody to a subject, wherein the first cycle comprises administering to the subject about 0.8 mg on day 1, about 2 mg on day 8, about 20 mg on day 15, and about 20 mg of the CD3xCD20 antibody on day 22, wherein the subject is administered about 20 mg of the CD3xCD20 antibody on day 1 and every 7 days for the first 2 cycles of cyclic administration, wherein the subject is administered four doses of the CD3xCD20 antibody in each of the first 2 cycles, wherein the subject is administered about 20 mg of the CD3xCD20 antibody on day 1 and every 14 days in cycle 3 and any subsequent cycles during treatment, and wherein each cycle of cyclic administration is 28 days.

[0033] In one embodiment, the method comprises cyclically administering a CD3xCD20 antibody to a subject, wherein the first cycle comprises administering to the subject about 0.8 mg on day 1, about 2 mg on day 8, about 20 mg on day 15, and about 35 mg of the CD3xCD20 antibody on day 22, wherein the subject is administered about 50 mg of the CD3xCD20 antibody on day 1 and every 7 days for the first 2 cycles of cyclic administration, wherein the subject is administered four doses of the CD3xCD20 antibody in each of the first 2 cycles, wherein the subject is administered about 50 mg of the CD3xCD20 antibody on day 1 and every 14 days in cycle 3 and any subsequent cycles during treatment, and wherein each cycle of cyclic administration is 28 days.

[0034] In one embodiment, the method comprises cyclically administering a CD19 antibody to a 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 to 8 days for the first 3 cycles of cyclic administration, wherein in each of the first 3 cycles, four doses of the CD19 antibody are administered 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 12 to 16 days for Cycle 4 and any subsequent cycles during treatment, wherein about 10 mg / kg to about 15 mg / kg of the CD19 antibody is administered to the subject on the 8 days and 4 days prior to Day 1 of the first cycle of cyclic administration, and wherein each cycle of cyclic administration is 28 days.

[0035] In one embodiment, the method comprises cyclically administering a CD19 antibody to the subject, wherein about 12 mg / kg of the CD19 antibody is administered to the subject on Day 1 and every 7 days for the first 3 cycles of cyclic administration, wherein in each of the first 3 cycles, four doses of the CD19 antibody are administered to the subject, 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 treatment, wherein about 12 mg / kg of the CD19 antibody is administered to the subject on the 8 days and 4 days prior to Day 1 of the first cycle of cyclic administration, and wherein each cycle of cyclic administration is 28 days.

[0036] In one embodiment, the method comprises cyclically administering Compound A, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, to a subject, wherein about 25 mg of Compound A, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is administered to the subject daily on day 1 of each cycle of cyclic administration and for 21 days, followed by a 7-day rest, and wherein each cycle of cyclic administration is 28 days.

[0037] In one embodiment, the method comprises cyclically administering a CD19 antibody, a CD3xCD20 antibody, and Compound A, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, to a subject, and wherein the method comprises: (a) administering to the subject about 0.6 to about 1 mg on day 1 of the first cycle, about 1.8 mg to about 2.2 mg on about day 8, and about 18 mg to about 22 mg of the CD3xCD20 antibody on about day 1 of the first cycle; administering to the subject about 20 mg of the CD3xCD20 antibody on day 1 of the second cycle of cyclic administration and every 6 to 8 days, wherein four doses of the CD3xCD20 antibody are administered to the subject in each of the first 2 cycles, wherein the subject is administered about 20 mg of the CD3xCD20 antibody on day 1 of the third cycle and any subsequent cycles during treatment and every 12 to 16 days. 0 antibody; (b) administering to the subject about 10 mg / kg to about 15 mg / kg of CD19 antibody on day 1 and every 6 days for the first 3 cycles of cycle administration, wherein four doses of CD19 antibody are administered to the subject in each of the first 3 cycles, wherein on day 1 and every 12 to 16 days in cycle 4 and any subsequent cycles during treatment, about 10 mg / kg to about 15 mg / kg of CD19 antibody is administered to the subject, wherein about 10 mg / kg to about 15 mg / kg of CD19 antibody is administered to the subject 8 days and 4 days prior to day 1 of the first cycle of cycle administration; and (c) administering to the subject about 25 mg of Compound A or a pharmaceutically acceptable salt, solvate or stereoisomer thereof daily on day 1 of each cycle of cycle administration and for 21 consecutive days, followed by a rest day of 7 days; and wherein each cycle of cycle administration is 28 days.

[0038] In one embodiment, the method comprises cyclically administering a CD19 antibody, a CD3xCD20 antibody, and Compound A, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, to a subject, and wherein the method comprises: (a) administering to the subject about 0.6 mg to about 1 mg of the CD3xCD20 antibody on day 1 of the first cycle, 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; administering to the subject about 50 mg of the CD3xCD20 antibody on day 1 of the second cycle of cyclic administration and every 6 to 8 days, wherein four doses of the CD3xCD20 antibody are administered to the subject in each of the first 2 cycles, wherein about 50 mg is administered to the subject on day 1 and every 12 to 16 days in cycle 3 and any subsequent cycles during treatment (b) administering to the subject about 10 mg / kg to about 15 mg / kg of a CD19 antibody on Day 1 and every 6 days for the first 3 cycles of cyclic administration, wherein four doses of the CD19 antibody are administered to the subject in each of the first 3 cycles, wherein on Day 1 and every 12 to 16 days in Cycle 4 and any subsequent cycles during treatment, about 10 mg / kg to about 15 mg / kg of a CD19 antibody is administered to the subject, wherein about 10 mg / kg to about 15 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 cyclic administration; and (c) administering to the subject about 25 mg of Compound A or a pharmaceutically acceptable salt, solvate or stereoisomer thereof daily on Day 1 of each cycle of cyclic administration and for 21 days, followed by a 7-day rest; and wherein each cycle of cyclic administration is 28 days.

[0039] In one embodiment, the method comprises cyclically administering a CD19 antibody, a CD3xCD20 antibody, and Compound A, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, to a subject, and wherein the method comprises: (a) administering to the subject about 0.8 mg on day 1 of the first cycle, about 2 mg on about day 8, and about 20 mg on days 15 and 22 of the CD3xCD20 antibody; administering to the subject about 20 mg of the CD3xCD20 antibody on day 1 of the second cycle of cyclic administration and every 7 days, wherein four doses of the CD3xCD20 antibody are administered to the subject in each of the first 2 cycles, wherein about 20 mg of the CD3xCD20 antibody is administered to the subject on day 1 of the third cycle and any subsequent cycles during treatment and every 14 days. antibody; (b) administering to the subject about 12 mg / kg of CD19 antibody on day 1 of the first 3 cycles of cycle administration and every 7 days, wherein four doses of CD19 antibody are administered to the subject in each of the first 3 cycles, wherein on day 1 of cycle 4 and any subsequent cycles during the treatment and every 14 days, the subject is administered about 12 mg / kg of CD19 antibody, wherein the subject is administered about 12 mg / kg of CD19 antibody on the 8 days and 4 days prior to day 1 of the first cycle of cycle administration; and (c) administering to the subject about 25 mg of Compound A or a pharmaceutically acceptable salt, solvate or stereoisomer thereof daily on day 1 of each cycle of cycle administration during the treatment and for 21 days, followed by a rest day of 7 days; and wherein each cycle of cycle administration is 28 days.

[0040] In one embodiment, the method comprises cyclically administering a CD19 antibody, a CD3xCD20 antibody, and Compound A or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof to a subject, and wherein the method comprises: (a) administering to the subject about 0.8 mg on day 1 of the first cycle, about 2 mg on about day 8, about 20 mg on day 15, and about 35 mg on day 22 of the CD3xCD20 antibody; administering to the subject about 50 mg of the CD3xCD20 antibody on day 1 of the second cycle of cyclic administration and every 7 days, wherein the subject is administered four doses of the CD3xCD20 antibody in each of the first 2 cycles, wherein the subject is administered about 50 mg of the CD3xCD20 antibody on day 1 of the third cycle and any subsequent cycles during treatment and every 14 days. CD20 antibody; (b) administering about 12 mg / kg of CD19 antibody to the subject on day 1 of the first 3 cycles of cycle administration and every 7 days, wherein four doses of CD19 antibody are administered to the subject in each of the first 3 cycles, wherein about 12 mg / kg of CD19 antibody is administered to the subject on day 1 of cycle 4 and any subsequent cycles during the treatment and every 14 days, wherein about 12 mg / kg of CD19 antibody is administered to the subject on the 8 days and 4 days prior to day 1 of the first cycle of cycle administration; and (c) administering about 25 mg of Compound A or a pharmaceutically acceptable salt, solvate or stereoisomer thereof to the subject daily on day 1 of each cycle of cycle administration during the treatment and for 21 days, followed by a 7-day rest; and wherein each cycle of cycle administration is 28 days.

[0041] In one embodiment, the method comprises cyclically administering a CD19 antibody, a CD3xCD20 antibody, and Compound A, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, to a subject, and wherein the method comprises: (a) administering to the subject about 0.8 mg on day 1 of a first cycle, about 2 mg on day 8, and about 20 mg on days 15 and 22 of the CD3xCD20 antibody; administering to the subject about 20 mg of the CD3xCD20 antibody on days 1, 8, 15, and 22 of a second cycle of cyclic administration, wherein the subject is administered about 20 mg of the CD3xCD20 antibody on days 1 and 15 of the third cycle and any subsequent cycles during treatment. (b) administering about 12 mg / kg of CD19 antibody to the subject on Day 1, Day 8, Day 15 and Day 22 of the first 3 cycles of cycle administration, wherein about 12 mg / kg of CD19 antibody is administered to the subject on Day 1 and Day 15 of the 4th cycle and any subsequent cycles during the treatment, wherein about 12 mg / kg of CD19 antibody is administered to the subject on the 8 days and 4 days prior to Day 1 of the first cycle of cycle administration; and (c) administering about 25 mg of Compound A or a pharmaceutically acceptable salt, solvate or stereoisomer thereof to the subject daily on Day 1 of each cycle of cycle administration during the treatment and for 21 consecutive days, followed by a 7-day rest; and wherein each cycle of cycle administration is 28 days.

[0042] In one embodiment, the method comprises cyclically administering a CD19 antibody, a CD3xCD20 antibody, and Compound A, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, to a subject, and wherein the method comprises: (a) administering to the subject about 0.8 mg on day 1 of a first cycle, about 2 mg on day 8, about 20 mg on day 15, and about 35 mg on day 22 of the CD3xCD20 antibody; administering to the subject about 50 mg of the CD3xCD20 antibody on days 1, 8, 15, and 22 of a second cycle of cyclic administration, wherein the subject is administered about 50 mg of the CD3xCD20 antibody on days 1 and 15 of a third cycle and any subsequent cycles during treatment. 20 antibody; (b) administering about 12 mg / kg of CD19 antibody to the subject on day 1, day 8, day 15 and day 22 of the first 3 cycles of cycle administration, wherein about 12 mg / kg of CD19 antibody is administered to the subject on day 1 and day 15 of the 4th cycle and any subsequent cycles during the treatment, wherein about 12 mg / kg of CD19 antibody is administered to the subject on the 8 days and 4 days prior to day 1 of the first cycle of cycle administration; and (c) administering about 25 mg of Compound A or a pharmaceutically acceptable salt, solvate or stereoisomer thereof to the subject daily on day 1 of each cycle of cycle administration during the treatment and for 21 consecutive days, followed by a 7-day rest; and wherein each cycle of cycle administration is 28 days.

[0043] 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 plamotamab. In one embodiment, the CD3xCD20 antibody is a biosimilar of plamotamab. In one embodiment, the CD3xCD20 antibody is a bioequivalent of plamotamab. 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.

[0044] In one embodiment, Compound A or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is orally administered to a subject. In one embodiment, Compound A or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is administered to a subject in the form of a capsule or tablet.

[0045] In one embodiment, the CD19 antibody is administered intravenously.

[0046] In one embodiment, the CD 19 antibody is not administered to the subject on day 4 of the first cycle of cyclic administration.

[0047] In one embodiment, the CD3xCD20 antibody is not administered to the subject on day 4 of the first cycle of cyclic administration.

[0048] In one embodiment, the method further comprises determining a positron emission tomography-computed tomography (PET-CT) scan after every two cycles of cycle administration.

[0049] In one embodiment, the subject has received prior CAR-T therapy.

[0050] In one embodiment, relative to administering CD19 antibody and compound A or its pharmaceutically acceptable salt, solvate or stereoisomer to the subject but not administering CD3xCD20 antibody, the method results in enhanced therapeutic efficacy. In one embodiment, the enhanced therapeutic efficacy is measured by the overall survival time increased. In one embodiment, the enhanced therapeutic efficacy is measured by the progression-free survival period increased. In one embodiment, the enhanced therapeutic efficacy is measured by the reduction of the number of cancer cells in the biological sample obtained from the subject compared with the reference. In one embodiment, the reference is the number of cancer cells in the biological sample obtained from the subject at an earlier time point. In one embodiment, the reference is a predetermined value. In one embodiment, the reference is the number of cancer cells in the biological sample obtained from another subject with lymphoma. In one embodiment, the reference is the number of cancer cells in the biological sample obtained from a subject population 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, the enhanced therapeutic efficacy is measured by the overall response rate and / or increased quality of life of the subject's improvement.

[0051] In one embodiment, the subject has received prior treatment for lymphoma. In one embodiment, the prior treatment includes chemoimmunotherapy. In one embodiment, the prior treatment includes administration of an anti-CD20 antibody. In one embodiment, the prior treatment includes chemoimmunotherapy and administration of an anti-CD20 antibody.

[0052] In one aspect, provided herein is a method of treating lymphoma in a subject in need thereof, comprising administering to the subject: (a) an antibody that binds to CD19 (CD19 antibody); (b) a multispecific antibody, wherein the multispecific antibody comprises a first binding domain that binds to CD3 and a second binding domain that binds to CD20 (CD3xCD20 antibody); and (c) a compound having the following structure:

[0053]

[0054] (ie, 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione (Compound A)), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0055] In one embodiment, (a) a 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 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 amino acid sequences of SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6, respectively; (b) a multispecific antibody comprises: (i) an anti-CD3 epsilon heavy chain having an amino acid sequence of SEQ ID NO: 30, an anti-CD3 epsilon light chain having an amino acid sequence of SEQ ID NO: 31, an anti-CD20 heavy chain having an amino acid sequence of SEQ ID NO: 32, and an anti-CD20 light chain having an amino acid sequence of SEQ ID NO: 33, or (ii) an anti-CD3 epsilon heavy chain having an amino acid sequence of SEQ ID NO: 34, an anti-CD3 epsilon light chain having an amino acid sequence of SEQ ID NO: 35, an anti-CD3 epsilon light chain having an amino acid sequence of SEQ ID NO: 36. NO:35, an anti-CD3 epsilon light 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-CD3 epsilon 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.

[0056] In one embodiment, (a) the CD19 antibody comprises a VH domain having an amino acid sequence that is approximately or at least about 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 or at least about 90%, 95%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 20.

[0057] In one embodiment, the compound is

[0058]

[0059] In one embodiment, the lymphoma is non-Hodgkin's lymphoma. In one embodiment, the non-Hodgkin's lymphoma is diffuse large cell lymphoma (DLBCL). In one embodiment, the DLBCL is relapsed, refractory, or relapsed and refractory DLBCL. In one embodiment, the DLBCL is primary refractory DLBCL. In one embodiment, the DLBCL is first-line DLBCL.

[0060] In one embodiment, the subject achieves a complete metabolic response as determined by a positron emission tomography (PET)-computed tomography (CT) scan. In one embodiment, the subject achieves a complete metabolic response at or after cycle 2, cycle 4, cycle 6, cycle 8, and / or at the end of treatment. In one embodiment, the subject achieves a complete metabolic response at or after day 26 of cycle 2, day 26 of cycle 4, day 26 of cycle 6, day 26 of cycle 8, and / or at the end of treatment. In one embodiment, the subject achieves a complete metabolic response at or after 61 days, 117 days, 177 days, 233 days, or 299 days from the first administration of the multispecific antibody to the subject. 3. Description of the drawings

[0061] Figure 1 The structure of the anti-CD3 x anti-CD20 multispecific antibody described herein is depicted. The multispecific antibody has a "bottle opener" format (also referred to as a "triple F" format). The bottle opener format antibody 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 a "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 a "Fab-Fc heavy chain"; and c) a light chain comprising a second variable light chain. As Figure 1As shown, the scFv is a CD3 binding domain, and the second variable heavy chain and the second variable light chain comprise a CD20 binding domain.

[0062] Figure 2 Schematic diagram of the dosing regimen for combination therapy using CD19 antibody, anti-CD3 x anti-CD20 multispecific antibody and Compound A.

[0063] Figure 3 Dosing and scheduling treatment regimens for Parts 1 and 2 are depicted. 4. Specific implementation methods

[0064] 4.1 Definitions

[0065] Various publications, articles, and patents are cited or described in the background and throughout the patent specification; each of these references is incorporated herein by reference in its entirety. The discussion of documents, acts, materials, devices, articles, etc. included in this patent specification is intended to provide a context for the present invention. Such discussion does not admit that any or all of these matters constitute part of the prior art for any invention disclosed or claimed.

[0066] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by ordinary technicians in the field to which the invention belongs. Otherwise, certain terms used herein have the meanings set forth in the patent specification.

[0067] It must be noted that as used herein and in the appended claims, the singular forms "a, an, and the" include plural referents unless the context clearly dictates otherwise.

[0068] Unless otherwise indicated, any numerical value described herein, such as concentration or concentration range, should be understood to be modified by the term "about" in all cases. Therefore, numerical values ​​generally include ± 10% of the value. For example, the concentration of 1mg / mL includes 0.9mg / mL to 1.1mg / mL. Similarly, the concentration range of 1% to 10% (w / v) includes 0.9% (w / v) to 11% (w / v). Unless the context clearly indicates otherwise, the use of numerical ranges as used herein clearly includes all possible sub-ranges, all single numerical values ​​within the range, including integers within such ranges and fractions of the value. For example, the term "about" associated with a reference value can also include the value plus or minus 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2% or 1% of the value range. In some cases, even if the term "about" is not specifically mentioned, the numerical value disclosed throughout the text can also be "about" the numerical value.

[0069] Unless otherwise indicated, the term "at least" preceding a series of elements is to be understood to refer to every element in the series.

[0070] 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. Such equivalents are intended to be encompassed by the present invention.

[0071] As used herein, the terms "comprises / comprising", "includes / including", "has / having", "contains / containing" or any other variation thereof, shall be understood to imply inclusion of the stated whole or group of wholes but not exclusion of any other whole or group of wholes, and are intended to be non-exclusive or open-ended. For example, a composition, mixture, process, method, article, or apparatus that comprises / includes a list of elements is not necessarily limited to those elements but may also include other elements not expressly listed or inherent to such composition, mixture, process, method, article, or apparatus. In addition, unless expressly stated to the contrary, "or" refers to an inclusive or rather than an exclusive or. For example, condition A or condition B is satisfied by any of the following: A is true (or present) and B is false (or absent), A is false (or absent) and B is true (or present), and both A and B are true (or present).

[0072] As used herein, the connection term "and / or" between multiple described elements should be understood to cover individual and combined options. For example, when two elements are connected with "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 combination of the first and second elements. Any of these options are understood to be within the scope of this meaning and therefore meet the requirements of the term "and / or" used herein. The simultaneous applicability of more than one option is also understood to be within the scope of this meaning and therefore meets the requirements of the term "and / or".

[0073] As used herein, the terms “comprise / comprises / comprising” may be replaced with “consists of / consisting of”, “consists essentially of / consisting essentially of”.

[0074] As used herein, the term "consists of" or variations such as "consist of / consisting of" as used throughout the patent specification and claims, indicates inclusion of any recited integer or group of integers, but does not include the addition of any additional integer or group of integers to the specified method, structure or composition.

[0075] As used herein, the term "consists essentially of" or variations such as "consist essentially of / consisting essentially of" as used throughout the patent specification and claims indicates inclusion of any recited integer or group of integers, and the optional inclusion of any recited integer or group of integers, which integer or group of integers does not materially alter the basic or novel properties of the specified method, structure, or composition. See MPEP §2111.03.

[0076] As used herein, "CD3", also known as "differentiation cluster 3", refers to a T cell co-receptor that helps activate cytotoxic T cells (e.g., CD8+ naive T cells) and T helper cells (e.g., CD4+ naive T cells), and is composed of four different chains: one CD3γ chain (e.g., Genbank accession numbers NM_000073 and MP_000064 (human)), one CD3δ chain (e.g., Genbank accession numbers NM_000732, NM_001040651, NP_00732, and NP_001035741 (human)), and two CD3ε chains (e.g., Genbank accession numbers NM_000733 and NP_00724 (human)). The CD3 chains are highly related cell surface proteins in the immunoglobulin superfamily that contain a single extracellular immunoglobulin domain. The CD3 molecule associates with the T cell receptor (TCR) and the ζ chain to form a T cell receptor (TCR) complex, which functions to generate activation signals in T lymphocytes. In certain embodiments, the CD3 is human CD3.

[0077] As used herein, "CD20" is also referred to 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", "Bl" and "S7", and refers to an activated glycosylated phosphoprotein expressed on the surface of B cells and encoded by the human MS4A1 gene (e.g., Genbank accession numbers NM_152866, NM_021950, NP_068769 and NP_690605 (human)). CD20 plays a role in the development and differentiation of B cells into plasma cells. In a specific embodiment, CD20 is human CD20.

[0078] As used herein, "CD19", also referred to as "B cell surface antigen B4", "B cell antigen CD19", "CD19 antigen" and "Leu-12", refers to a cell surface protein expressed by B cells and encoded by the gene designated CD19 (e.g., HGNC:1633; NCBI Entrez Gene:930; Ensembl:ENSG00000177455; 107265; UniProtKB / Swiss-Prot:P15391). CD19 is involved in B cell activation and signal transduction pathways. In a specific embodiment, CD19 is human CD19.

[0079] 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 pharmaceutically acceptable salt, solvate or stereoisomer thereof. Lenalidomide is an immunomodulator with anti-angiogenic and anti-tumor properties.

[0080] The term "bispecific antibody" or "multispecific antibody" as used herein refers to any non-natural or alternative antibody format that binds to two or more different antigens (eg, a CD3xCD20 multispecific antibody).

[0081] The term "antibody" as used herein is broad and includes immunoglobulins or antibody molecules, including human antibodies, humanized antibodies, composite antibodies and chimeric antibodies and monoclonal or polyclonal antibody fragments. In general, antibodies are proteins or peptide chains that exhibit specific binding to specific antigens. Antibody structure is well known. According to the heavy chain constant region amino acid sequence, immunoglobulins can be divided into five major categories (i.e., IgA, IgD, IgE, IgG and IgM). IgA and IgG are further subdivided into isotypes IgA1, IgA2, IgG1, IgG2, IgG3 and IgG4. Therefore, antibodies provided herein may belong to any one of the five major categories or corresponding subclasses. In specific embodiments, antibodies provided herein are IgG1, IgG2, IgG3 or IgG4. In specific embodiments, antibodies provided herein are IgG. In other embodiments, antibodies provided herein are or IgG1. The antibody light chain of a vertebrate species can be designated as one of two distinctly different types (called κ and λ) based on the amino acid sequence of its constant domain. Therefore, in certain embodiments, the antibodies provided herein may contain a kappa light chain constant domain. In certain embodiments, the antibodies provided herein may also contain a lambda light chain constant domain. According to specific embodiments, the antibodies provided herein include heavy and / or light chain constant regions from rat or human antibodies. In specific embodiments, the constant region is a human constant region.

[0082] In addition to the heavy and light chain constant domains, antibodies also contain an antigen binding region, which is composed 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) within the non-framework region of the immunoglobulin (Ig or antibody) VH β-sheet framework, or one of the three hypervariable regions (LCDR1, LCDR2, or LCDR3) within the non-framework region of the antibody VL β-sheet framework. Therefore, CDRs are variable region sequences interspersed within the framework region sequences. CDR regions are well known to those skilled in the art and have been defined, for example, by Kabat as the region of highest variability within the variable (V) domain of an antibody (Kabat et al., J. Biol. Chem. 252: 6609-6616 (1977); Kabat, Adv. Prot. Chem. 32: 1-75 (1978)). Chothia has also structurally defined CDR region sequences as residues that are not part of the conserved β-sheet framework and are therefore able to adapt to different conformations (Chothia and Lesk, J. Mol. Biol. 196: 901-917 (1987)). Both terms are well-known in the art. AbM, Contact and IMGT have also defined CDR region sequences. Exemplary CDR region sequences are described herein, for example, in the tables and / or examples provided below. The positions of the CDRs within the variable regions of typical antibodies have been determined by comparison of a large number of structures (Al-Lazikani et al., J. Mol. Biol. 273:927-948 (1997); Morea et al., Methods 20:267-279 (2000)). Since the number of residues within the hypervariable region varies among different antibodies, the additional residues relative to the typical positions are conventionally numbered with a, b, c, etc. next to the residue number in the typical variable region numbering scheme (Al-Lazikani et al., supra (1997)). This nomenclature is also well known to those skilled in the art.

[0083] The light chain variable region CDR1 domain is interchangeably referred to herein as LCDR1 or VL CDR1. The light chain variable region CDR2 domain is interchangeably referred to herein as LCDR2 or VL CDR2. The light chain variable region CDR3 domain is interchangeably referred to herein as LCDR3 or VL CDR3. The heavy chain variable region CDR1 domain is interchangeably referred to herein as HCDR1 or VH CDR1. The heavy chain variable region CDR2 domain is interchangeably referred to herein as HCDR2 or VH CDR2. The heavy chain variable region CDR1 domain is interchangeably referred to herein as HCDR3 or VH CDR3.

[0084] The term "hypervariable region," such as VH or VL, when used herein refers to the regions of the variable region of an antibody that are hypervariable in sequence and / or form structurally defined loops. In general, antibodies contain six hypervariable regions; three in VH (HCDR1, HCDR2, HCDR3) and three in VL (LCDR 1, LCDR2, LCDR3). A variety of hypervariable region divisions are in use and are contemplated herein. The "Kabat" CDR is based on sequence variability and is the most commonly used (e.g., see Kabat et al., Sequences of Proteins of Imm unologicalInterest , 5th ed., Publ ic Health Service, National Institutes of Health, Bethesda, MD. (1991)). "Chothia" instead refers to the location of the structural loops (see, e.g., Chothia and Lesk, J. Mol. Biol. 196:901-917 (1987)). When numbering using the Kabat numbering convention, the ends of the Chothia CDR-HCDR1 loop vary between H32 and H34, depending on the length of the loop (this is because the Kabat numbering scheme places the insertion at H35A and H35B; if neither 35A nor 35B is present, the loop ends at 32; if only 35A is present, the loop ends at 33; if both 35A and 35B are present, the loop ends at 34). The "AbM" hypervariable regions represent a compromise between the Kabat CDRs and the Chothia structural loops and are used by Oxford Molecular's AbM antibody modeling software (see, e.g., Martin's Antibody Engineering , Volume 2, Chapter 3, Springer Verlag). The “Contact” hypervariable regions are based on analysis of available complex crystal structures.

[0085] Recently, a universal numbering system has been developed and widely adopted, the ImMunoGe neTics (IMGT) Information (Lafranc et al., Dev. Comp. Immunol. 27(1):55-77 (2003)). IMGT is a comprehensive information system focused on immunoglobulins (IG), T cell receptors (TR) and major histocompatibility complex (MHC) of humans and other vertebrates. In this article, CDR refers to the amino acid sequence and position within the light chain or heavy chain. Since the "position" of CDR within the structure of the immunoglobulin variable domain is conserved between species and exists in structures called loops, CDR and framework residues are easily identified by using a numbering system that aligns the variable domain sequences according to structural features. This information can be used to transplant and replace CDR residues from an immunoglobulin of a certain species into an acceptor framework (usually that of a human antibody). An additional numbering system (AHon) was developed by Honegger and Plückthun, J. Mol. Biol. 309:657-670 (2001). The correspondence between numbering systems (including, for example, Kabat numbering and the IMGT unique numbering system) is well known to those skilled in the art (see, for example, Kabat, supra; Chothia and Lesk, supra; Martin, supra; Lefranc et al., supra). The exemplary system shown herein combines Kabat and Chothia.

[0086]

[0087] The hypervariable region may comprise the following "extended hypervariable region": 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.

[0088] The term "constant region" or "constant domain" refers to the carboxyl terminal portion of the light chain and the heavy chain, which is not directly involved in the binding of the antibody to the antigen, but exhibits 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 relative to the rest of the immunoglobulin (i.e., the variable region containing 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.

[0089] The term "framework" or "FR" residues are variable region residues located on both sides of the CDR. For example, FR residues are present in chimeric antibodies, humanized antibodies, human antibodies, domain antibodies, diabodies, linear antibodies and bispecific antibodies. FR residues are those variable domain residues other than hypervariable region residues or CDR residues.

[0090] As used herein, the term "antigen binding domain" refers to a set of six CDRs that, when present as part of a polypeptide sequence, specifically bind to a target antigen discussed herein. Thus, a "checkpoint antigen binding domain" binds to a target checkpoint antigen as described herein. As known in the art, these CDRs are generally present in the form of a first set of variable heavy chain CDRs (vhCDR or VHCDR) and a second set of variable light chain CDRs (vlCDR or VLCDR), each group comprising three CDRs: vhCDR1, vhCDR2, vhCDR3 of the heavy chain and vlCDR1, vlCDR2 and vlCDR3 of the light chain. CDRs are present in the variable heavy chain and variable light chain domains, respectively, and together form an Fv region. Thus, in some cases, the six CDRs of the antigen binding domain are contributed by the variable heavy chain domain and the variable light chain domain. In the "Fab" format, the set of 6 CDRs is contributed by two different polypeptide sequences, namely a variable heavy chain domain (vh or VH; containing VH CDR1, VH CDR2 and VH CDR3) and a variable light chain domain (vl or VL; containing VL CDR1, VL CDR2 and VL CDR3), wherein the C-terminus of the VH domain is connected to the N-terminus of the heavy chain CH1 domain, and the C-terminus of the VL domain is connected to the N-terminus of the constant light chain domain (thereby forming a light chain). In the scFv format, the VH and VL domains are usually covalently linked into a single polypeptide sequence by using a linker ("scFv linker") as outlined herein, which can be (starting from the N-terminus) VH-linker-VL or VL-linker-VH, with the former generally preferred (including optional domain linkers on each side, depending on the format used).

[0091] Typically, the C-terminus of the scFv domain is linked to the N-terminus of the hinge in the second monomer.

[0092] As used herein, the term "isolated antibody" refers to an antibody that is substantially free of other antibodies with 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 the same target). In addition, an isolated antibody is substantially free of other cellular material and / or chemicals.

[0093] The term "monoclonal antibody" as used herein refers to an antibody obtained from a population of substantially homogeneous antibodies, that is, the individual antibodies comprising the population are identical, except for possible naturally occurring mutations that may be present in trace amounts. The monoclonal antibodies provided by the present invention can be prepared by hybridoma methods, phage display technology, single lymphocyte gene cloning technology, or recombinant DNA methods. For example, a monoclonal antibody can be produced by a hybridoma comprising a B cell obtained from a transgenic non-human animal (e.g., a transgenic mouse or rat), the transgenic non-human animal having a genome comprising a human heavy chain transgene and a light chain transgene.

[0094] As used herein, the term "antigen binding fragment" refers to an antibody fragment, such as a diabody, Fab, Fab', F(ab')2, an Fv fragment, a disulfide-stabilized Fv fragment (dsFv), (dsFv)2, a bispecific dsFv (dsFv-dsFv'), a disulfide-stabilized diabody (dsdiabody), a single-chain antibody molecule (scFv), a single domain antibody (sdAb), a scFv dimer (bivalent diabody), a multispecific antibody formed by an antibody portion comprising one or more CDRs, a camelized single domain antibody, a nanobody, a domain antibody, a bivalent domain antibody, or any other antibody fragment that binds to an antigen but does not contain a complete antibody structure. An antigen binding fragment is capable of binding to the same antigen as the antigen bound by the parent antibody or parent antibody fragment. According to specific 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 specific embodiments, the antigen binding fragment comprises Fab and F(ab').

[0095] The term "single-chain antibody" as used herein refers to a conventional single-chain antibody in the art, which comprises a heavy chain variable region and a light chain variable region connected by a short peptide of about 15 to about 20 amino acids. The term "single domain antibody" as used herein refers to a conventional single domain antibody in the art, which comprises a heavy chain variable region and a heavy chain variable region or it comprises only a heavy chain variable region.

[0096] As used herein, "Fab" or "Fab region" refers to a polypeptide comprising VH, CH1, VL and CL immunoglobulin domains, which are typically located on two different polypeptide chains (e.g., VH-CH1 is located on one chain and VL-CL is located on another chain). Fab can refer to this region alone, or to this region in the context of bispecific antibodies provided herein. In the context of Fab, Fab includes an Fv region in addition to the CH1 and CL domains.

[0097] As used herein, "Fv", "Fv fragment" or "Fv region" refers to a polypeptide comprising the VL and VH domains of an ABD. Fv regions can be formatted as Fab (usually two different polypeptides, as described above, also including constant regions as outlined above) and scFv, in which the VL and VH domains are combined (usually with a linker as described herein) to form an scFv.

[0098] The term "single-chain Fv" or "scFv" refers to a variable heavy chain domain and a variable light chain domain covalently linked, typically using an scFv linker as discussed herein, to form an scFv or scFv domain. The scFv domain can be oriented in any direction from the N-terminus to the C-terminus (VH-linker-VL or VL-linker-VH). The order of the VH and VL domains can be indicated in the name, for example, H.X_L.Y means VH-linker-VL from the N-terminus to the C-terminus, and L.Y_H.X means VL-linker-VH.

[0099] As used herein, the term "Fc", "Fc region" or "Fc domain" refers to a polypeptide comprising the CH2-CH3 domain of an IgG molecule, and in some cases includes a hinge. In the EU numbering of human IgG1, the CH2-CH3 domain includes amino acids 231 to 447, and the hinge is 216 to 230. Therefore, the definition of "Fc domain" includes amino acids 231-447 (CH2-CH3) or 216-447 (hinge-CH2-CH3), or a fragment thereof. In this context, an "Fc fragment" may contain fewer amino acids from either or both of the N-terminus and the C-terminus, but still retains the ability to form a dimer with another Fc domain or Fc fragment, which can be detected using standard methods, which are generally 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 may be Fc domains from human IgG1, IgG2, or IgG4.

[0100] As used herein, "heavy chain constant region" refers to the CH1-hinge-CH2-CH3 portion of an antibody (or a fragment thereof), excluding the variable heavy chain domain; in EU numbering of human IgG1, this is amino acids 118-447. "Heavy chain constant region fragment" herein means a heavy chain constant region that contains fewer amino acids from either or both of the N-terminus or C-terminus, but still retains the ability to form a dimer with another heavy chain constant region.

[0101] As used herein, "variable region" or "variable domain" refers to a region of an immunoglobulin comprising one or more Ig domains, which are substantially encoded by any one of the Vκ, Vλ and / or VH genes constituting κ, λ and heavy chain immunoglobulin loci, respectively, and contain CDRs that confer antigen specificity. Thus, a "variable heavy chain domain" is paired with a "variable light chain domain" to form an antigen binding domain ("ABD"). In addition, each variable domain comprises three hypervariable regions ("complementarity determining regions", "CDRs") (vhCDR1, vhCDR2 and vhCDR3 for the variable heavy chain domain, vlCDR1, vlCDR2 and vlCDR3 for the variable light chain domain) and four framework (FR) regions, arranged in the following order from amino terminus to carboxyl terminus: FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4.

[0102] As used herein, the term "multispecific antibody" refers to an antibody comprising multiple immunoglobulin variable domain sequences, wherein a first immunoglobulin variable domain sequence in the multiple immunoglobulin variable domain sequences has binding specificity to a first epitope, and a second immunoglobulin variable domain sequence in the multiple immunoglobulin variable domain sequences has binding specificity to a second epitope. In one embodiment, the first and second epitopes do not overlap or do not substantially overlap. In one embodiment, the first and second epitopes are located on different antigens, e.g., different proteins (or different subunits of a multimeric protein).

[0103] As used herein, the term "bispecific antibody" refers to a multispecific antibody that binds no more than two epitopes or two antigens. A bispecific antibody is characterized in that a first immunoglobulin variable domain sequence has binding specificity for a first epitope and a second immunoglobulin variable domain sequence has binding specificity for a second epitope.

[0104] Many antibody domains with sequence identity to human antibody domains are provided herein.In the context of two or more nucleic acids or polypeptide sequences, the term "identity" or "identity" percentage refers to two or more sequences or subsequences that are identical or have a specified percentage of identical amino acid residues or nucleotides when comparing and comparing maximum correspondence, as measured using one of the following sequence comparison algorithms or by visual inspection.For sequence comparison, usually a sequence serves as a reference sequence, and a test sequence is compared thereto.When using a sequence comparison algorithm, a test sequence and a reference sequence are input into a computer, subsequence coordinates are specified if necessary, and sequence algorithm program parameters are specified. The sequence comparison algorithm then calculates the sequence identity percentage of a test sequence relative to a reference sequence based on specified program parameters.

[0105] Sequence identity between two similar sequences (e.g., antibody variable domains) can be measured by algorithms such as Smith, TF and Waterman, MS (1981) "Comparison of Biosequences," Adv. Appl. Math. 2:482 [Local Homology Algorithm]; Needleman, SB and 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 and Lipman, DJ (1988) "Improved Tools for Biological Sequence Comparison," Proc. Natl. Acad. Sci. (USA) 85:2444 [Similarity Search Method]; or Altschul, SF et al., (1990) "Basic Local Alignment Search Method" Tool," J. Mol. Biol. 215:403-10, "BLAST" algorithm, see, e.g., blast.ncbi.nlm.nih.gov / Blast.cgi. When using any of the above algorithms, default parameters (window length, gap penalty, etc.) are used. In one embodiment, sequence identity is determined using the BLAST algorithm using default parameters.

[0106] The example of the algorithm suitable for determining sequence identity and sequence similarity percentage is BLAST and BLAST 2.0 algorithm, which are respectively described in Altschul et al. (1990) J.Mol.Biol.215:403-410 and Altschul et al. (1997) Nucleic Acids Res.25:3389-3402. The software for performing BLAST analysis can be publicly obtained by the National Center for Biotechnology Information. The algorithm first identifies high-scoring sequence pairs (HSPs) by identifying short characters of length W in the query sequence, and when it is compared with the character of the same length in the database sequence, it matches or satisfies a certain positive threshold score T. T is referred to as the adjacent character score threshold (Altschul et al., see above). These initial adjacent characters hit and serve as the seed for initiating the search, to find the longer HSP containing them. Then, the characters are extended in both directions along each sequence to hit, until the cumulative comparison score can be increased.

[0107] For nucleotide sequences, the cumulative score is calculated using the parameters M (reward score for a pair of matching residues; always > 0) and N (penalty score for mismatched residues; always < 0). For amino acid sequences, the cumulative score is calculated using a scoring matrix. The expansion of character hits in each direction stops when the following occurs: the cumulative alignment score drops by the number X from its maximum reached value; the cumulative score becomes zero or below zero due to the accumulation of one or more negative scoring residue alignments; or 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 a word length (W) of 11, an expectation value (E) of 10, M = 5, N = -4, and a comparison of two chains by default. For amino acid sequences, the BLASTP program uses a word length (W) of 3, an expectation value (E) of 10, and a BLOSUM62 scoring matrix by default (see Henikoff and Henikoff, Proc. Natl. Acad. Sci. USA 89: 10915 (1989)).

[0108] In addition to calculating percent sequence identity, the BLAST algorithm also performs a statistical analysis of the similarity between two sequences (see, e.g., Karlin and Altschul, Proc. Nat'l. Acad. Sci. USA 90:5873-5787 (1993)). One similarity metric provided by the BLAST algorithm is the smallest sum probability (P(N)), which indicates the probability of an accidental match between two nucleotide or amino acid sequences. For example, a nucleic acid is considered similar to a reference sequence if the smallest sum probability in a comparison of a test nucleic acid to a reference nucleic acid is less than about 0.1, more preferably less than about 0.01, and most preferably less than about 0.001.

[0109] Another indication 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, a polypeptide is typically substantially identical to a second polypeptide, for example, when the two peptides differ only in conservative substitutions. Another indication that two nucleic acid sequences are substantially identical is that the two molecules hybridize to each other under stringent conditions.

[0110] The antibodies provided herein are generally isolated or recombinant. "Isolated" when used to describe the various polypeptides disclosed herein means that the polypeptide has been identified and separated and / or recovered from a cell or cell culture expressing the polypeptide. Typically, an isolated polypeptide is prepared by at least one purification step. An "isolated antibody" refers to an antibody that is substantially free of other antibodies having different antigenic specificities. "Recombinant" refers to an antibody that is produced in an exogenous host cell using recombinant nucleic acid technology, and it may also be isolated.

[0111] 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 mixed with single-stranded and double-stranded regions, single-stranded and double-stranded RNA, and RNA mixed with single-stranded and double-stranded regions, hybrid molecules containing DNA and RNA that may be single-stranded or more typically double-stranded or a mixture of single-stranded and double-stranded regions. In addition, "polynucleotide" refers to a triple-stranded region containing RNA or DNA or both RNA and DNA. The term polynucleotide also includes DNA or RNA containing one or more modified bases and DNA or RNA with a modified backbone for stability or other reasons. "Modified" bases include, for example, tritylated bases and uncommon bases, such as inosine. DNA and RNA can be modified in a variety of ways; therefore, "polynucleotide" encompasses polynucleotides in chemical, enzymatic or metabolically modified forms common in nature, as well as chemical forms of DNA and RNA that are unique to viruses and cells. "Polynucleotide" also encompasses relatively shorter nucleic acid chains, often referred to as oligonucleotides.

[0112] As used herein, the terms "peptide", "polypeptide" or "protein" may refer to molecules composed of amino acids and may be considered proteins by those skilled in the art. Conventional single-letter or three-letter codes for amino acid residues are used herein. The terms "peptide", "polypeptide" and "protein" are used interchangeably herein to refer to amino acid polymers of any length. The polymer may be linear or branched, it may contain modified amino acids, and it may be interspersed with non-amino acids. The term also encompasses amino acid polymers that have been modified naturally or by intervention; for example, disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation or modification (e.g., conjugation with a labeling component). Also included in the definition are, for example, one or more analogs containing amino acids (including, for example, non-natural amino acids, etc.) and other modified polypeptides known in the art.

[0113] The peptide sequences described herein are written according to the usual convention, with the N-terminal region on the left and the C-terminal region on the right. Although isomeric forms of amino acids are known, the L form of the amino acid is represented unless otherwise specifically indicated.

[0114] As used herein, the terms "treat / treatment / treating" refer to the following conditions caused by the administration of one or more therapies: reducing or improving or eliminating the progression, severity and / or effects associated with the solid malignancies described herein, or improving the condition of the solid malignancies, or improving diseases associated with the solid malignancies, or increasing the immune system response of the human subject, or improving one or more symptoms (preferably, one or more discernible symptoms) of the solid malignancies described herein. In specific embodiments, the terms "treat / treatmentm ent / treating" refer to improving at least one measurable physical parameter of the solid malignancies described herein, such as tumor size, tumor growth rate, number of tumor cells, tumor invasiveness, presence of metastasis, or extent of metastasis. In other embodiments, the terms "treat / treatment / treating" refer to inhibiting the progression of the solid malignancies described herein, either physically, such as by stabilizing discernible symptoms, physiologically, such as by stabilizing physical parameters, or both. In other embodiments, the term "treat / treatment / treating" refers to an increase in the immune system response of a human subject after treatment with pembrolizumab or nivolumab, such as 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. In exemplary embodiments, treatment of solid malignancies provides improvement or lack of progression of a disease associated with a tumor or neoplastic disorder, and / or improvement or lack of progression of symptoms associated with the disease or disorder. For example, treatment of solid malignancies refers to one or more of the following: (1) a decrease in the number of solid malignant tumor cells; (2) an increase in solid malignant tumor cell death; (3) inhibition of solid malignant tumor cell survival; (5) inhibition of solid malignant tumor growth (i.e., slowing to some extent, preferably without progression), such as disease stabilization; (6) inhibition of metastasis of solid malignant tumor cells; (7) an increase in progression-free survival; (8) an increase in overall survival; and (9) a certain degree of relief of one or more symptoms associated with a disease or disorder.Further description of treatment can be found in the following: RECIST criteria (Eisenh auer 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 solid malignancies involves administering a bispecific antibody for a predetermined period of time, stopping administration for another specific period of time, and resuming administration of the bispecific antibody for another specific period of time. In some embodiments, treating a solid malignancy involves administering the bispecific antibody until one of the therapeutic effects described herein is achieved, suspending administration of the bispecific antibody while such therapeutic effect continues to be observed, and resuming administration of the bispecific antibody if such therapeutic effect is no longer observed.

[0115] Treatment of solid malignancies can be determined by standardized response criteria specific to the tumor or disease associated with the neoplastic condition. Changes in tumor morphology (i.e., using neoadjuvant therapy, such as evaluating pathological response) or tumor indices (i.e., overall tumor burden, tumor size, etc.) for solid malignancies response can be assessed using screening techniques such as magnetic resonance imaging (MRI) scans, positron emission tomography (PET) scans, x-ray imaging, radionuclide scanning, computed tomography (CT) scans, bone scan imaging, endoscopy, tumor sampling including bone marrow aspiration (BMA), and circulating tumor marker levels and / or counts of tumor cells.

[0116] Treatment according to the methods provided herein includes the use of a "therapeutically effective amount" of the drug. A "therapeutically effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result.

[0117] A therapeutically effective amount may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the drug to elicit a desired response in the individual. A therapeutically effective amount also refers to an amount in which any toxic or detrimental effects of the antibody or antibody portion are outweighed by the therapeutically beneficial effects.

[0118] A "therapeutically effective amount" for tumor therapy can also be measured by its ability to stabilize disease progression. The ability of a compound to inhibit cancer can be evaluated in an animal model system predictive of efficacy against human tumors.

[0119] Alternatively, the ability of the compound to inhibit cell growth or induce apoptosis can be examined by in vitro assays known to those skilled in the art to evaluate such properties of the composition. A therapeutically effective amount of a therapeutic compound can reduce tumor size or otherwise improve the subject's symptoms. One of ordinary skill in the art will be able to determine such amounts based on factors such as the size of the subject, the severity of the subject's symptoms, and the specific composition or route of administration selected.

[0120] The terms "patient," "subject," and "human subject" are used interchangeably herein. "Subject" as used herein means any animal, preferably a mammal, most preferably a human. The term "mammal" as used herein encompasses any mammal. Examples of mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, guinea pigs, monkeys, humans, etc. In certain embodiments, the subject is a human.

[0121] 4.2 Overview

[0122] In certain aspects, provided herein are methods of treating lymphoma using a combination of CD19 antibodies, anti-CD3 x anti-CD20 multispecific antibodies, and compounds with Compound A. The methods provided herein are particularly useful for treating diffuse large cell lymphoma (DLBCL), including relapsed or refractory DLBCL.

[0123] 4.3 Pharmaceutical Compositions

[0124] Antibody

[0125] Provided herein is a method for treating lymphoma using combination therapy. In certain embodiments, the combination therapy comprises a multispecific antibody, wherein the multispecific antibody comprises a first binding domain bound to CD3 and a second binding domain bound 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 that can be used in the methods provided herein are racemic, stereoisomer-enriched or stereoisomer-pure compounds (e.g., compound A), and pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, clathrates and prodrugs thereof.

[0126] Table 1 below shows the amino acid sequences of exemplary CD19 antibodies and CD3xCD20 multispecific antibodies that can be used in the methods and combination therapies provided herein.

[0127] Table 1. Amino acid sequences of exemplary CD19 and CD3xCD20 antibodies

[0128]

[0129]

[0130]

[0131]

[0132]

[0133]

[0134]

[0135] In some embodiments, the CD3xCD20 antibody has a "bottle opener" format (also known as a "triple F" format), such as Figure 1 In this embodiment, the CD3 antigen binding domain is a scFv in a bottle opener format and the CD20 antigen binding domain is a Fab in a bottle opener format.

[0136] In some embodiments, VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and VL CDR3 sequences are according to the Kabat numbering system. In some embodiments, VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and VL CDR3 sequences are according to the Chothia numbering system. In some embodiments, VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and VL CDR3 sequences are according to the exemplary numbering system. In some embodiments, VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and VL CDR3 sequences are according to the Contact numbering system. In some embodiments, VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and VL CDR3 sequences are according to the IMGT numbering system. In some embodiments, VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and VL CDR3 sequences are according to the AbM numbering system. Exemplary groups of 6 CDRs (VH CDR1-3 and VL CDR1-3) of certain antibody embodiments are provided herein. Other CDR groups are also contemplated and are within the scope of the antibody embodiments provided herein.

[0137] In one embodiment, the CD3xCD20 antibody comprises a first binding domain that binds to CD3, wherein the first binding domain comprises a VH comprising VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of VH CDR1, VH CDR2, and VH CDR3, respectively, of a VH having the amino acid sequences provided in Table 1.

[0138] In one embodiment, the CD3xCD20 antibody comprises a first binding domain that binds to CD3, wherein the first binding domain comprises a VL comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of VL CDR1, VL CDR2, and VL CDR3, respectively, of a VL having the amino acid sequences provided in Table 1.

[0139] In one embodiment, the CD3xCD20 antibody comprises a first binding domain that binds to CD3, wherein the first binding domain comprises VH and VL, wherein the VH comprises VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of VH CDR1, VH CDR2, and VH CDR3, respectively, of VH having the amino acid sequences provided in Table 1, and the VL comprises VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of VL CDR1, VL CDR2, and VL CDR3, respectively, of VL having the amino acid sequences of

[0140] In one embodiment, the CD3xCD20 antibody comprises a second binding domain that binds to CD20, wherein the second binding domain comprises a VH comprising VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of VH CDR1, VH CDR2, and VH CDR3, respectively, of a VH having the amino acid sequences provided in Table 1.

[0141] In one embodiment, the CD3xCD20 antibody comprises a second binding domain that binds to CD20, wherein the second binding domain comprises a VL comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of VL CDR1, VL CDR2, and VL CDR3, respectively, of a VL having the amino acid sequences provided in Table 1.

[0142] In one embodiment, the CD3xCD20 antibody comprises a second binding domain that binds to CD20, wherein the second binding domain comprises VH and VL, wherein the VH comprises VH CDR1, VH CDR2 and VH CDR3 having the amino acid sequences of VH CDR1, VH CDR2 and VH CDR3, respectively, of VH having the amino acid sequences provided in Table 1, and the VL comprises VL CDR1, VL CDR2 and VL CDR3 having the amino acid sequences of VL CDR1, VL CDR2 and VL CDR3, respectively, of VL having the amino acid sequences of

[0143] In one embodiment, the CD3xCD20 antibody comprises a first binding domain that binds to CD3, wherein the first binding domain comprises VH and VL, wherein the VH comprises VH CDR1, VH CDR2, and VH CDR3 having amino acid sequences of VH CDR1, VH CDR2, and VH CDR3, respectively, of VH having the amino acid sequences provided in Table 1, and the VL comprises VL CDR1, VL CDR2, and VL CDR3 having amino acid sequences of VL CDR1, VL CDR2, and VL CDR3, respectively, of VL having the amino acid sequences provided in Table 1; and a second binding domain that binds to CD20, wherein the second binding domain comprises VH and VL, wherein the VH comprises VH CDR1, VH CDR2, and VH CDR3 having amino acid sequences of VH CDR1, VH CDR2, and VH CDR3, respectively, of VH having the amino acid sequences provided in Table 1, and the VL comprises VL CDR1, VL CDR2, and VL CDR3 having amino acid sequences of VL CDR1, VL CDR2, and VL CDR3, respectively, of VL having the amino acid sequences provided in Table 1. The amino acid sequences of VL CDR1, VL CDR2 and VL CDR3.

[0144] In one embodiment, the CD3xCD20 antibody comprises a first binding domain that binds to CD3, wherein the first binding domain comprises a VH comprising VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of VH CDR1, VH CDR2, and VH CDR3, respectively, of a VH having the amino acid sequence of SEQ ID NO: 21.

[0145] In one embodiment, the CD3xCD20 antibody comprises a first binding domain that binds to CD3, wherein the first binding domain comprises a VL comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of VL CDR1, VL CDR2, and VL CDR3, respectively, of a VL having the amino acid sequence of SEQ ID NO: 22.

[0146] In one embodiment, the CD3xCD20 antibody comprises a first binding domain that binds to CD3, wherein the first binding domain comprises VH and VL, wherein the VH comprises VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of VH CDR1, VH CDR2, and VH CDR3, respectively, of a VH having the amino acid sequence of SEQ ID NO: 21, and the VL comprises VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of VL CDR1, VL CDR2, and VL CDR3, respectively, of a VL having the amino acid sequence of SEQ ID NO: 22.

[0147] In one embodiment, the CD3xCD20 antibody comprises a second binding domain that binds to CD20, wherein the second binding domain comprises a VH comprising VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of VH CDR1, VH CDR2, and VH CDR3, respectively, of a VH having the amino acid sequence of SEQ ID NO: 23.

[0148] In one embodiment, the CD3xCD20 antibody comprises a second binding domain that binds to CD20, wherein the first binding domain comprises a VL comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of VL CDR1, VL CDR2, and VL CDR3, respectively, of a VL having the amino acid sequence of SEQ ID NO: 24.

[0149] In one embodiment, the CD3xCD20 antibody comprises a second binding domain that binds to CD20, wherein the second binding domain comprises VH and VL, wherein the VH comprises 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: 23, and the VL comprises 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: 24.

[0150] In one embodiment, the CD3xCD20 antibody comprises a first binding domain that binds to CD3, wherein the first binding domain comprises a VH and a VL, wherein the VH comprises 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 a VH having the amino acid sequence of SEQ ID NO: 21, and the VL comprises a VL CDR1, a VL CDR2, and a VL CDR3 having the amino acid sequences of VL CDR1, VL CDR2, and VL CDR3, respectively, of a VL having the amino acid sequence of SEQ ID NO: 22; and a second binding domain that binds to CD20, wherein the second binding domain comprises a VH and a VL, wherein the VH comprises a VH and a VL, wherein the VH comprises 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 a VH having the amino acid sequence of SEQ ID NO: 23, and the VL comprises a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NO: 24, and the VL comprises a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of VL CDR1, VL CDR2 and VL CDR3 of the amino acid sequence of VL CDR1, VL CDR2 and VL CDR3 of VL of NO:24.

[0151] In one embodiment, the CD3xCD20 antibody comprises a first binding domain that binds to CD3, wherein the first binding domain comprises a VH domain 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.

[0152] In one embodiment, the CD3xCD20 antibody comprises a first binding domain that binds to CD3, wherein the first binding domain comprises a VL domain comprising VL CDR1, VL CDR2 and VL CDR3 having amino acid sequences of SEQ ID NO: 10, SEQ ID NO: 11 and SEQ ID NO: 12, respectively.

[0153] In one embodiment, the CD3xCD20 antibody comprises a first binding domain that binds to CD3, wherein the first binding domain comprises a VH domain and a VL domain, the VH domain comprising VH CDR1, VH CDR2 and VH CDR3 having amino acid sequences of SEQ ID NO: 7, SEQ ID NO: 8 and SEQ ID NO: 9, respectively, and the VL domain comprising VL CDR1, VL CDR2 and VL CDR3 having amino acid sequences of SEQ ID NO: 10, SEQ ID NO: 11 and SEQ ID NO: 12, respectively.

[0154] In one embodiment, the CD3xCD20 antibody comprises a second binding domain that binds to CD20, wherein the second binding domain comprises a VH domain 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.

[0155] In one embodiment, the CD3xCD20 antibody comprises a second binding domain that binds to CD20, wherein the second binding domain comprises a VL 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.

[0156] In one embodiment, the CD3xCD20 antibody comprises a second binding domain that binds to CD20, wherein the second binding domain comprises a VH domain and a VL domain, the VH domain comprising VH CDR1, VH CDR2 and VH CDR3 having amino acid sequences of SEQ ID NO: 13, SEQ ID NO: 14 and SEQ ID NO: 15, respectively, and the VL domain comprising VL CDR1, VL CDR2 and VL CDR3 having amino acid sequences of SEQ ID NO: 16, SEQ ID NO: 17 and SEQ ID NO: 18, respectively.

[0157] In one embodiment, the CD3xCD20 antibody comprises a first binding domain that binds to CD3 and a second binding domain that binds to CD20, wherein the first binding domain comprises a VH domain and a VL domain, the VH domain comprising a VH CDR1, a VH CDR2, and a VH CDR3 having amino acid sequences of SEQ ID NO: 7, SEQ ID NO: 8, and SEQ ID NO: 9, respectively, the VL domain comprising a VL CDR1, a VL CDR2, and a VL CDR3 having amino acid sequences of SEQ ID NO: 10, SEQ ID NO: 11, and SEQ ID NO: 12, respectively, and the second binding domain comprises a VH domain and a VL domain, the VH domain comprising a VH CDR1, a VH CDR2, and a VH CDR3 having amino acid sequences of SEQ ID NO: 13, SEQ ID NO: 14, and SEQ ID NO: 15, respectively, the VL domain comprising a VL CDR1, a VL CDR2, and a VL CDR3 having amino acid sequences of SEQ ID NO: 16, SEQ ID NO: 17, and SEQ ID NO: 18, respectively. CDR2 and VL CDR3.

[0158] In one embodiment, the CD3xCD20 antibody comprises a first binding domain that binds to CD3, 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. 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.

[0159] In one embodiment, the CD3xCD20 antibody comprises a first binding domain that binds to CD3, wherein 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.

[0160] In one embodiment, the CD3xCD20 antibody comprises a first binding domain that binds to CD3, 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. 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 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. 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 and 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 VH domain having an amino acid sequence that is about 100% identical to the amino acid sequence of SEQ ID NO: 21 and a VL domain having an amino acid sequence that is about 100% identical to the amino acid sequence of SEQ ID NO: 22.

[0161] In one embodiment, the CD3xCD20 antibody comprises a second binding domain that binds to CD20, wherein 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. 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.

[0162] In one embodiment, the CD3xCD20 antibody comprises a second binding domain that binds to CD20, wherein the second 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: 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.

[0163] In one embodiment, the CD3xCD20 antibody comprises a second binding domain that binds to CD20, wherein 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 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 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 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 and 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 VH domain having an amino acid sequence that is about 100% identical to the amino acid sequence of SEQ ID NO: 23 and a VL domain having an amino acid sequence that is about 100% identical to the amino acid sequence of SEQ ID NO: 24.

[0164] In one embodiment, the CD3xCD20 antibody comprises a first binding domain that binds to CD3 and a second binding domain that binds to 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 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, and 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 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, and 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 first binding domain comprises a VH domain having an amino acid sequence approximately 98% identical to the amino acid sequence of SEQ ID NO:21 and a VL domain having an amino acid sequence approximately 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 approximately 98% identical to the amino acid sequence of SEQ ID NO:23 and a VL domain having an amino acid sequence approximately 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 that is about 99% identical to the amino acid sequence of SEQ ID NO: 21 and a VL domain having an amino acid sequence that is 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 that is about 99% identical to the amino acid sequence of SEQ ID NO: 23 and 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 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 and a VL domain having an amino acid sequence that is 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 that is about 100% identical to the amino acid sequence of SEQ ID NO: 23 and a VL domain having an amino acid sequence that is about 100% identical to the amino acid sequence of SEQ ID NO: 24.

[0165] 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.

[0166] In a specific embodiment, the CD3xCD20 antibody is paramotozumab (XmAb13676). In one embodiment, the CD3xCD20 antibody is a biosimilar of paramotozumab. In one embodiment, the CD3xCD20 antibody is a bioequivalent of paramotozumab. 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 paramotozumab. 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 paramotozumab. 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 paramotozumab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequence of VL CDR1, VL CDR2 and VL CDR3 of the CD20 binding domain of paramitomab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequence of VH CDR1, VH CDR2 and VH CDR3 of the CD3 binding domain of paramitomab, and VL CDR1, VL CDR2 and VL CDR3 of the CD3 binding domain of paramitomab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequence of VH CDR1, VH CDR2 and VH CDR3 of the CD20 binding domain of paramitomab, and VL CDR1, VL CDR2 and VL CDR3 of the CD20 binding domain of paramitomab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequence of VH CDR1, VH CDR2, and VH CDR3 of the CD3 binding domain of paramatuzumab, VL CDR1, VL CDR2, and VL CDR3 of the CD3 binding domain of paramatuzumab, VHCDR1, VH CDR2, and VH CDR3 of the CD20 binding domain of paramatuzumab, and VL CDR1, VL CDR2, and VLCDR3 of the CD20 binding domain of paramatuzumab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequence of VH of the CD3 binding domain of paramatuzumab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequence of VL of the CD3 binding domain of paramatuzumab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequence of VH of the CD20 binding domain of paramatuzumab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequence of the VL of the CD20 binding domain of paramatuzumab.In one embodiment, the CD3xCD20 antibody comprises the amino acid sequence of the VH of the CD3 binding domain of paramitomab and the VL of the CD3 binding domain of paramitomab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequence of the VH of the CD20 binding domain of paramitomab and the VL of the CD20 binding domain of paramitomab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequence of the VH of the CD3 binding domain of paramitomab, the VL of the CD3 binding domain of paramitomab, the VH of the CD20 binding domain of paramitomab, and the VL of the CD20 binding domain of paramitomab.

[0167] In another embodiment, the CD3xCD20 antibody is motuzumab. In one embodiment, the CD3xCD20 antibody is a biosimilar of motuzumab. In one embodiment, the CD3xCD20 antibody is a bioequivalent of motuzumab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequences of VH CDR1, VHCDR2, and VH CDR3 of the CD3 binding domain of motuzumab. 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 motuzumab. 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 motuzumab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequences of VL CDR1, VL CDR2, and VL CDR3 of the CD20 binding domain of motuzumab. 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 motuzumab and VL CDR1, VL CDR2 and VL CDR3 of the CD3 binding domain of motuzumab. 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 motuzumab and VL CDR1, VL CDR2 and VL CDR3 of the CD20 binding domain of motuzumab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequence of VH CDR1, VH CDR2 and VH CDR3 of the CD3 binding domain of motuzumab, VL CDR1, VL CDR2 and VL CDR3 of the CD3 binding domain of motuzumab, VH CDR1, VH CDR2 and VH CDR3 of the CD20 binding domain of motuzumab, and VL CDR1, VL CDR2 and VL CDR3 of the CD20 binding domain of motuzumab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequence of VH of the CD3 binding domain of motuzumab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequence of VL of the CD3 binding domain of motuzumab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequence of VH of the CD20 binding domain of motuzumab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequence of the VL of the CD20 binding domain of motuzumab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequence of the VH of the CD3 binding domain of motuzumab and the VL of the CD3 binding domain of motuzumab.In one embodiment, the CD3xCD20 antibody comprises the amino acid sequence of the VH of the CD20 binding domain of motuzumab and the VL of the CD20 binding domain of motuzumab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequence of the VH of the CD3 binding domain of motuzumab, the VL of the CD3 binding domain of motuzumab, the VH of the CD20 binding domain of motuzumab, and the VL of the CD20 binding domain of motuzumab.

[0168] In another embodiment, the CD3xCD20 antibody is icoretuzumab. In one embodiment, the CD3xCD20 antibody is a biosimilar of icoretuzumab. In one embodiment, the CD3xCD20 antibody is a bioequivalent of icoretuzumab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequences of VHCDR1, VH CDR2, and VH CDR3 of the CD3 binding domain of icoretuzumab. 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 icoretuzumab. 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 icoretuzumab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequences of VLCDR1, VL CDR2, and VL CDR3 of the CD20 binding domain of icoretuzumab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequence of VH CDR1, VH CDR2 and VH CDR3 of the CD3 binding domain of icoretuzumab and VLCDR1, VL CDR2 and VL CDR3 of the CD3 binding domain of icoretuzumab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequence of VH CDR1, VH CDR2 and VH CDR3 of the CD20 binding domain of icoretuzumab and VL CDR1, VL CDR2 and VL CDR3 of the CD20 binding domain of icoretuzumab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequence of VH CDR1, VH CDR2 and VH CDR3 of the CD3 binding domain of icoretuzumab, VL CDR1, VL CDR2 and VL CDR3 of the CD3 binding domain of icoretuzumab, VH CDR1, VH CDR2 and VHCDR3 of the CD20 binding domain of icoretuzumab, and VL CDR1, VL CDR2 and VL CDR3 of the CD20 binding domain of icoretuzumab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequence of VH of the CD3 binding domain of icoretuzumab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequence of VL of the CD3 binding domain of icoretuzumab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequence of VH of the CD20 binding domain of icoretuzumab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequence of the VL of the CD20 binding domain of icoretuzumab.In one embodiment, the CD3xCD20 antibody comprises the amino acid sequence of the VH of the CD3 binding domain of icoretumomab and the VL of the CD3 binding domain of icoretumomab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequence of the VH of the CD20 binding domain of icoretumomab and the VL of the CD20 binding domain of icoretumomab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequence of the VH of the CD3 binding domain of icoretumomab, the VL of the CD3 binding domain of icoretumomab, the VH of the CD20 binding domain of icoretumomab, and the VL of the CD20 binding domain of icoretumomab.

[0169] In another embodiment, the CD3xCD20 antibody is Oninumab. In one embodiment, the CD3xCD20 antibody is a biosimilar of Oninumab. In one embodiment, the CD3xCD20 antibody is a bioequivalent of Oninumab. 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 Oninumab. 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 Oninumab. 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 Oninumab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequences of VL CDR1, VL CDR2 and VL CDR3 of the CD20 binding domain of Oninumab. 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 onituzumab and VL CDR1, VL CDR2 and VL CDR3 of the CD3 binding domain of onituzumab. 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 onituzumab and VL CDR1, VL CDR2 and VL CDR3 of the CD20 binding domain of onituzumab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequence of VHCDR1, VH CDR2 and VH CDR3 of the CD3 binding domain of onitumab, VL CDR1, VL CDR2 and VL CDR3 of the CD3 binding domain of onitumab, VH CDR1, VH CDR2 and VH CDR3 of the CD20 binding domain of onitumab, and VL CDR1, VL CDR2 and VL CDR3 of the CD20 binding domain of onitumab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequence of VH of the CD3 binding domain of onitumab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequence of VL of the CD3 binding domain of onitumab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequence of VH of the CD20 binding domain of onitumab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequence of the VL of the CD20 binding domain of onitumab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequence of the VH of the CD3 binding domain of onitumab and the VL of the CD3 binding domain of onitumab.In one embodiment, the CD3xCD20 antibody comprises the amino acid sequence of the VH of the CD20 binding domain of onitumab and the VL of the CD20 binding domain of onitumab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequence of the VH of the CD3 binding domain of onitumab, the VL of the CD3 binding domain of onitumab, the VH of the CD20 binding domain of onitumab, and the VL of the CD20 binding domain of onitumab.

[0170] In another embodiment, the CD3xCD20 antibody is Gefituzumab. In one embodiment, the CD3xCD20 antibody is a biosimilar of Gefituzumab. In one embodiment, the CD3xCD20 antibody is a bioequivalent of Gefituzumab. 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 Gefituzumab. 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 Gefituzumab. 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 Gefituzumab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequences of VL CDR1, VL CDR2, and VL CDR3 of the CD20 binding domain of Gefituzumab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequences of VHCDR1, VH CDR2 and VH CDR3 of the CD3 binding domain of Gefituzumab and VL CDR1, VL CDR2 and VL CDR3 of the CD3 binding domain of Gefituzumab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequences of VHCDR1, VH CDR2 and VH CDR3 of the CD20 binding domain of Gefituzumab and VL CDR1, VL CDR2 and VL CDR3 of the CD20 binding domain of Gefituzumab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequence of VHCDR1, VH CDR2 and VH CDR3 of the CD3 binding domain of Gefituzumab, VL CDR1, VL CDR2 and VL CDR3 of the CD3 binding domain of Gefituzumab, VH CDR1, VH CDR2 and VH CDR3 of the CD20 binding domain of Gefituzumab, and VL CDR1, VL CDR2 and VL CDR3 of the CD20 binding domain of Gefituzumab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequence of VH of the CD3 binding domain of Gefituzumab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequence of VL of the CD3 binding domain of Gefituzumab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequence of VH of the CD20 binding domain of Gefituzumab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequence of the VL of the CD20 binding domain of gefuzumab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequence of the VH of the CD3 binding domain of gefuzumab and the VL of the CD3 binding domain of gefuzumab.In one embodiment, the CD3xCD20 antibody comprises the amino acid sequence of the VH of the CD20 binding domain of gefuzumab and the VL of the CD20 binding domain of gefuzumab. In one embodiment, the CD3xCD20 antibody comprises the amino acid sequence of the VH of the CD3 binding domain of gefuzumab, the VL of the CD3 binding domain of gefuzumab, the VH of the CD20 binding domain of gefuzumab, and the VL of the CD20 binding domain of gefuzumab.

[0171] In one embodiment, the CD 19 antibody comprises a heavy chain variable (VH) domain comprising VH CDR 1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3, respectively.

[0172] In one embodiment, the CD 19 antibody comprises a light chain variable (VL) domain 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.

[0173] In one embodiment, the CD19 antibody comprises a heavy chain variable (VH) domain comprising VH CDR 1, VH CDR2, and 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 VLCDR1, 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.

[0174] 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.

[0175] 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.

[0176] 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 that is about 98% identical to the amino acid sequence of SEQ ID NO: 19 and 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 VH domain having an amino acid sequence that is about 99% identical to the amino acid sequence of SEQ ID NO: 19 and 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 VH domain having an amino acid sequence that is about 100% identical to the amino acid sequence of SEQ ID NO: 19 and a VL domain having an amino acid sequence that is about 100% identical to the amino acid sequence of SEQ ID NO: 20.

[0177] In a specific embodiment, the anti-CD19 antibody is tafacitumomab. In one embodiment, the anti-CD19 antibody is a biosimilar of tafacitumomab. In one embodiment, the anti-CD19 antibody is a biological equivalent of tafacitumomab. In one embodiment, the CD19 antibody comprises the amino acid sequence of VH CDR1, VH CDR2 and VH CDR3 of tafacitumomab. In one embodiment, the CD19 antibody comprises the amino acid sequence of VL CDR1, VL CDR2 and VLCDR3 of tafacitumomab. In one embodiment, the CD19 antibody comprises the amino acid sequence of VH CDR1, VH CDR2 and VH CDR3 of tafacitumomab, and the amino acid sequence of VL CDR1, VL CDR2 and VL CDR3 of tafacitumomab. In one embodiment, the CD19 antibody comprises the amino acid sequence of VH of tafacitumomab. In one embodiment, the CD19 antibody comprises the amino acid sequence of VL of tafacitumomab. In one embodiment, the CD19 antibody comprises the amino acid sequence of VH of tafacitumab and the amino acid sequence of VL of tafacitumab.

[0178] Compound

[0179] In some aspects, methods are provided for treating lymphoma using a combination therapy comprising a compound having the structure

[0180]

[0181] (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 can be used in the methods provided herein are racemic compounds, stereoisomerically enriched compounds, or stereoisomerically pure compounds (e.g., Compound A) and pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, clathrates, and prodrugs thereof.

[0182] The compound that can be used in the method provided herein can be purchased commercially, or it can be prepared according to the method described in the patent or patent publication disclosed herein. For example, the compound can be obtained by standard synthesis methods (see, for example, U.S. Patent No. 5,635,517, which is incorporated herein by reference as a whole). In addition, known resolving agents or chiral columns and other standard synthetic organic chemistry techniques can be used to asymmetrically synthesize or split optically pure compounds. As used herein and unless otherwise indicated, the term "pharmaceutically acceptable salt" covers non-toxic acid addition salts and base addition salts of the compound referred to by the term. Acceptable non-toxic acid addition salts include organic and inorganic acid or base derived salts 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, heptanoic acid, etc.

[0183] Compounds that are acidic in nature are capable of forming base salts with various pharmacologically acceptable bases. Bases that can be used to prepare pharmaceutically acceptable base addition salts of such acidic compounds are those that form non-toxic base addition salts, i.e., salts containing pharmacologically acceptable cations, such as, but not limited to, alkali metal or alkaline earth metal salts, especially 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.

[0184] As used herein and unless otherwise indicated, the term "prodrug" refers to a derivative of the compound that can be hydrolyzed, oxidized or otherwise reacted under biological conditions (in vitro or in vivo) to provide a compound. Examples of prodrugs include, but are not limited to, derivatives of compound A, which include bio-hydrolyzable parts, such as bio-hydrolyzable amides, bio-hydrolyzable esters, bio-hydrolyzable carbamates, bio-hydrolyzable carbonates, bio-hydrolyzable ureas, and bio-hydrolyzable phosphate analogs. Other examples of prodrugs include derivatives of compound A including --NO, --NO2, --ONO or -ONO2 parts. Prodrugs can generally be prepared using well-known methods, such as in 1Burger'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) described in methods.

[0185] As used herein and unless otherwise indicated, the terms "biohydrolyzable amide," "biohydrolyzable ester," "biohydrolyzable carbamate," "biohydrolyzable carbonate," "biohydrolyzable urea," "biohydrolyzable phosphate" mean an amide, ester, carbamate, carbonate, urea, or phosphate ester, respectively, of a compound that: 1) does not interfere with the biological activity of the compound but may impart beneficial properties to the compound in vivo, such as uptake, duration of action, or onset of action; or 2) is biologically inactive but is converted in vivo to a biologically active compound. Examples of biohydrolyzable esters include, but are not limited to, lower alkyl esters, lower acyloxyalkyl esters (e.g., acetoxymethyl, acetoxyethyl, aminocarbonyloxymethyl, pivaloyloxymethyl, and pivaloyloxyethyl), lactones (e.g., phthalates and thiophthalates), lower alkoxyacyloxyalkyl esters (e.g., methoxycarbonyloxymethyl, ethoxycarbonyloxyethyl, and isopropoxycarbonyloxyethyl), alkoxyalkyl esters, choline esters, and amidoalkyl esters (e.g., acetamidomethyl). Examples of biohydrolyzable amides include, but are not limited to, lower alkyl amides, α-amino acid amides, alkoxyacyl amides, and alkylaminoalkylcarbonyl amides. Examples of biohydrolyzable carbamates include, but are not limited to, lower alkylamines, substituted ethylenediamines, amino acids, hydroxyalkylamines, heterocyclic and heteroaromatic amines, and polyetheramines.

[0186] Compounds provided herein (e.g., Compound A) may contain one or more chiral centers and may exist as a racemic mixture of enantiomers or a mixture of diastereomers. The methods provided herein encompass the use of stereoisomer-pure forms of such compounds, as well as mixtures using these forms. For example, a mixture of enantiomers comprising equal or unequal amounts of a specific compound (e.g., Compound A) may be used in the methods provided herein. These isomers may be asymmetrically synthesized or split using standard techniques (e.g., chiral columns or chiral resolving agents). See, e.g., Jacques, J. et al., Enantiomers, Racemates and Resolutions (Wiley-Interscience, New York, 1981); Wilen, SH et al., Tetrahedron 33:2725 (1977); Eliel, EL, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, SH, Tables of Resolving Agents and Optical Resolutions, p. 268 (EL Eliel, ed., Univ. of Notre Dame Press, Notre Dame, Ind., 1972).

[0187] As used herein and unless otherwise indicated, the term "stereoisomerically pure" means a composition comprising one stereoisomer of a compound (e.g., Compound A) and substantially free of other stereoisomers of the compound. For example, a stereoisomerically pure composition of a compound having one chiral center will be substantially free of the opposite enantiomer of the compound. A stereoisomerically pure composition of a compound having two chiral centers will be substantially free of other diastereomers of the compound. A typical stereoisomerically pure compound contains one stereoisomer of the compound at greater than about 80% by weight and less than about 20% by weight of other stereoisomers of the compound, more preferably one stereoisomer of the compound at greater than about 90% by weight and less than about 10% by weight of other stereoisomers of the compound, even more preferably one stereoisomer of the compound at greater than about 95% by weight and less than about 5% by weight of other stereoisomers of the compound, and most preferably one stereoisomer of the compound at greater than about 97% by weight and less than about 3% by weight of other stereoisomers of the compound. As used herein and unless otherwise indicated, the term "stereoisomerically enriched" means a composition comprising greater than about 60% by weight of one stereoisomer of a compound, preferably greater than about 70% by weight, more preferably greater than about 80% by weight of one stereoisomer of a compound. As used herein and unless otherwise indicated, the term "enantiomerically pure" means a stereoisomerically pure composition of a compound having one chiral center. Similarly, the term "stereoisomerically enriched" means a stereoisomerically enriched composition of a compound having one chiral center.

[0188] It is important to note that if there is a discrepancy between the structure depicted and the name given to that structure, the depicted structure should be given greater weight. In addition, if the stereochemistry of a structure or portion of a structure is not indicated, for example, by bold or dashed lines, that structure or portion of a structure should be interpreted as encompassing all stereoisomers thereof.

[0189] 4.4 Treatment methods

[0190] The methods provided herein can be used to treat lymphomas, including but not limited to non-Hodgkin lymphomas, such as diffuse large B-cell lymphoma (DLBCL).

[0191] Non-Hodgkin's lymphoma (NHL) is a group of diversified malignancies mainly derived from B cells. NHL can occur in any organ related to the lymphatic system, such as the spleen, lymph nodes or tonsils, and can occur at any age. The common characteristics of NHL are lymphadenopathy, fever and weight loss. NHL is divided into B cell or T cell NHL. Lymphomas associated with lymphoproliferative disorders after bone marrow or stem cell transplantation are usually B cell NHL. According to the natural history of NHL, it is divided into low-grade, intermediate and high-grade categories (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). Although chemotherapy can induce remission in most indolent lymphomas, cure rates are low and most patients will eventually relapse and require further treatment. Intermediate and high-grade lymphomas are more aggressive tumors but have a greater chance of being cured with chemotherapy. However, a large proportion of these patients will relapse and require further treatment.

[0192] DLBCL is the most common NHL subtype. Since the introduction of the anti-CD20 antibody rituximab, approximately 50% to 70% of patients can be cured with initial standard-of-care immunochemotherapy. However, for patients who are refractory or relapse after first-line therapy, the prognosis is poor. Salvage chemotherapy followed by high-dose chemotherapy and autologous stem cell transplantation (ASCT) has some benefit in this setting but is associated with significant toxicity. Furthermore, most patients are not suitable for this approach and have limited treatment options. Therefore, there remains a need to provide effective treatment options for patients with relapsed or refractory (R / R) DLBCL who are not suitable for ASCT (Coiffier B et al. Hematology Am Soc Hematol Educ Program. 2016;(1):366–78).

[0193] In exemplary embodiments, provided herein are methods of treating lymphoma in a subject comprising administering a combination of a CD19 antibody, a CD3xCD20 antibody, and Compound A to the subject.

[0194] In one aspect, provided herein is a method of treating lymphoma in a subject, comprising administering to the subject: (a) an antibody that binds to CD19 (CD19 antibody); (b) a multispecific antibody, wherein the multispecific antibody comprises a first binding domain that binds to CD3 and a second binding domain that binds to CD20 (CD3xCD20 antibody); and (c) a compound having the structure:

[0195]

[0196] (Compound A). In some embodiments, the compound is a pharmaceutically acceptable salt, solvate or stereoisomer thereof of Compound A.

[0197] In certain embodiments, the first dose of CD19 antibody is administered to the subject at least one day before the first dose of Compound A or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is administered to the subject. In other embodiments, the first dose of CD19 antibody is administered to the subject at least one day before the first dose of CD3xCD20 antibody is administered to the subject.

[0198] In other embodiments, the first dose of CD19 antibody is administered to the subject at least one day before the first dose of Compound A, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, is administered to the subject, and the first dose of CD19 antibody is administered to the subject at least one day before the first dose of CD3xCD20 antibody is administered to the subject.

[0199] In some embodiments, the subject is a subject in need thereof.

[0200] In one embodiment, the lymphoma is non-Hodgkin's lymphoma. In another embodiment, the non-Hodgkin's lymphoma is DLBCL. In another embodiment, the DLBCL is relapsed, refractory, or relapsed and 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 and refractory DLBCL. In another embodiment, the DLBCL is primary refractory DLBCL. In another embodiment, the DLBCL is first-line DLBCL.

[0201] In one embodiment, the lymphoma is a lymphoma that expresses CD20. In another embodiment, the lymphoma is a lymphoma that expresses CD19. In another embodiment, the lymphoma is a lymphoma that expresses CD20 and expresses CD19.

[0202] In one embodiment, the subject has received prior CAR-T therapy.

[0203] In one embodiment, the subject has not received a stem cell transplant. In another embodiment, the subject is not suitable for a stem cell transplant. In another embodiment, the stem cell transplant is an autologous stem cell transplant.

[0204] In one embodiment, the subject has been treated for lymphoma prior to the method.In embodiments, the treatment comprises chemoimmunotherapy, anti-CD20 antibodies, or a combination thereof.

[0205] In some embodiments, a method for treating lymphoma in a subject is provided, comprising administering to the subject (i) a first polypeptide comprising a first component capable of binding to CD3 and a second component capable of binding to CD20, (ii) a second polypeptide comprising a third component capable of binding to CD19, and (iii) a compound. In some embodiments, a method for treating DLBCL in a subject is provided, comprising administering to the subject (i) a first polypeptide comprising a first component capable of binding to CD3 and a second component capable of binding to CD20, (ii) a second polypeptide comprising a third component capable of binding to CD19, and (iii) a compound. In some embodiments, a method for inhibiting the growth or proliferation of lymphoma cells in a subject is provided, comprising administering to the subject (i) a first polypeptide comprising a first component capable of binding to CD3 and a second component capable of binding to CD20, (ii) a second polypeptide comprising a third component capable of binding to CD19, and (iii) a compound. In some embodiments, a method for inhibiting the growth or proliferation of DLBCL cells in a subject is provided, comprising administering to the subject (i) a first polypeptide comprising a first component capable of binding to CD3 and a second component capable of binding to CD20, (ii) a second polypeptide comprising a third component capable of binding to CD19, and (iii) a compound. In a specific embodiment, the compound is compound A. Other compounds that can be used in the methods provided herein are racemic compounds, stereoisomerically enriched compounds or stereoisomerically pure compounds, and pharmaceutically 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 component is a CD3 binding domain. In one embodiment, the second component is a CD20 binding domain. In one embodiment, the first component is a CD3 antigen binding fragment. In one embodiment, the second component is a CD20 antigen binding fragment. In a specific embodiment, the bispecific antibody is a CD3xCD20 antibody. In one embodiment, the third component is a CD19 binding domain. In one embodiment, the third component is a CD19 antigen binding fragment. In some embodiments, the second polypeptide is a CD19 antibody. In some embodiments, the subject is a subject in need. In a specific embodiment, the subject is a human subject.

[0206] Dosage regimen

[0207] In one aspect, the CD19 antibody, CD3xCD20 antibody and Compound A provided are administered according to the dosage regimen provided herein. However, the CD19 antibody, CD3xCD20 antibody and Compound A can be administered by any method known in the art. It will be appreciated by those skilled in the art that the route of administration and / or mode may vary depending on the desired result.

[0208] In one embodiment, a method is provided herein, comprising Figure 2 In another embodiment, a method is provided herein, comprising Figure 3 In yet another embodiment, a method is provided herein comprising the dosing regimen provided in Example 1.

[0209] 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 pharmaceutically 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 pharmaceutically acceptable salt, solvate or stereoisomer thereof, and a CD3xCD20 antibody.

[0210] In one embodiment, each cycle of cyclic administration is 28 days. In another embodiment, cyclic administration includes about one cycle, two cycles, three cycles, four cycles, five cycles, six cycles, seven cycles, eight cycles, nine cycles, ten cycles, eleven cycles, twelve cycles or more than twelve cycles. In another embodiment, cyclic administration includes about one cycle. In another embodiment, cyclic administration includes about two cycles. In another embodiment, cyclic administration includes about three cycles. In another embodiment, cyclic administration includes about four cycles. In another embodiment, cyclic administration includes about five cycles. In another embodiment, cyclic administration includes about six cycles. In another embodiment, cyclic administration includes about seven cycles. In another embodiment, cyclic administration includes about eight cycles. In another embodiment, cyclic administration includes about nine cycles. In another embodiment, cyclic administration includes about ten cycles. In another embodiment, cyclic administration includes about eleven cycles. In another embodiment, cyclic administration includes about twelve cycles. In another embodiment, cyclic administration includes more than twelve cycles.

[0211] In one embodiment, the first dose of CD19 antibody is administered to the subject before the first day of the first cycle of the cycle. In one embodiment, the first dose of CD19 antibody is administered to the subject at least one day, two days, three days, four days, five days, six days, seven days, eight days, nine days, ten days or more than ten days before the first day of the first cycle of the cycle. In one embodiment, the first dose of CD19 antibody is administered to the subject at least one day before the first day of the first cycle of the cycle. In another embodiment, the first dose of CD19 antibody is administered to the subject at least two days before the first day of the first cycle of the cycle. In another embodiment, the first dose of CD19 antibody is administered to the subject at least three days before the first day of the first cycle of the cycle. In another embodiment, the first dose of CD19 antibody is administered to the subject at least four days before the first day of the first cycle of the cycle. In another embodiment, the first dose of CD19 antibody is administered to the subject at least five days before the first day of the first cycle of the cycle. In another embodiment, the first dose of CD19 antibody is administered to the subject at least six days before the first day of the first cycle of the cycle. In another embodiment, the first dose of CD19 antibody is administered to the subject at least seven days before the first day of the first cycle of the cycle administration. In another embodiment, the first dose of CD19 antibody is administered to the subject at least eight days before the first day of the first cycle of the cycle administration. In another embodiment, the first dose of CD19 antibody is administered to the subject at least nine days before the first day of the first cycle of the cycle administration. In another embodiment, the first dose of CD19 antibody is administered to the subject at least ten days before the first day of the first cycle of the cycle administration. In another embodiment, the first dose of CD19 antibody is administered to the subject more than ten days before the first day of the first cycle of the cycle administration. In another embodiment, the first dose of CD19 antibody is administered to the subject four days before the first day of the first cycle of the cycle administration. In another embodiment, the first dose of CD19 antibody is administered to the subject eight days before the first day of the first cycle of the cycle administration. In another embodiment, the CD19 antibody is administered to the subject four and eight days before the first day of the first cycle of the cycle administration.

[0212] In one embodiment, CD19 antibody is administered to a subject on the 1st day, the 8th day, the 15th day and / or the 22nd day of the cycle of cycle administration. In one embodiment, CD19 antibody is administered to a subject on the 1st day, the 8th day, the 15th day and the 22nd day of the cycle of cycle administration. In one embodiment, CD19 antibody is administered to a subject on the 1st day, the 8th day, the 15th day or the 22nd day of the cycle of cycle administration. In another embodiment, CD19 antibody is administered to a subject on the 1st day of the cycle of cycle administration. In another embodiment, CD19 antibody is administered to a subject on the 8th day of the cycle of cycle administration. In another embodiment, CD19 antibody is administered to a subject on the 15th day of the cycle of cycle administration. In another embodiment, CD19 antibody is administered to a subject on the 22nd day of the cycle of cycle administration. In another embodiment, CD19 antibody is administered to a subject on the 1st and 15th day of the cycle of cycle administration. In another embodiment, the CD19 antibody is administered to the subject on day 1, day 8, day 15, and day 22 of each cycle of cycles 1-3 of cyclic administration. In another embodiment, the CD19 antibody is administered to the subject on day 1 and day 15 of the 4th and subsequent cycles of cyclic administration. In another embodiment, the CD19 antibody is administered to the subject on day 1 and day 15 of cycles 4-6 of cyclic administration. In another embodiment, the CD19 antibody is administered to the subject every 6 to 8 days in the cycle of cyclic administration.

[0213] In one embodiment, Compound A or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is administered to the subject for 21 days in a cycle of administration. In another embodiment, Compound A or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is administered to the subject from day 1 to day 21 of the cycle of administration. In another embodiment, Compound A or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is administered to the subject for 21 days in a 28-day cycle of cycle administration, followed by a 7-day rest.

[0214] In one embodiment, the CD3xCD20 antibody is administered to the subject on day 1, day 8, day 15 and / or day 22 of the cycle of cycle administration. In another embodiment, the CD3xCD20 antibody is administered to the subject on day 1, day 8, day 15 and day 22 of the cycle of cycle administration. In another embodiment, the CD3xCD20 antibody is administered to the subject on day 1, day 8, day 15 or day 22 of the cycle of cycle administration. In another embodiment, the CD3xCD20 antibody is administered to the subject on day 1 of the cycle of cycle administration. In another embodiment, the CD3xCD20 antibody is administered to the subject on day 8 of the cycle of cycle administration. In another embodiment, the CD3xCD20 antibody is administered to the subject on day 15 of the cycle of cycle administration. In another embodiment, the CD3xCD20 antibody is administered to the subject on day 22 of the cycle of cycle administration. In another embodiment, the CD3xCD20 antibody is administered to the subject on day 1 and day 15 of the cycle of cycle administration. In another embodiment, the CD3xCD20 antibody is administered to the subject on Day 1, Day 8, Day 15, and Day 22 of Cycle 1 and Cycle 2 of cyclic administration. In another embodiment, the CD3xCD20 antibody is administered to the subject on Day 1 and Day 15 of Cycle 3 and subsequent cycles of cyclic administration. In another embodiment, the CD3xCD20 antibody is administered to the subject on Day 1 and Day 15 of Cycles 3-6 of cyclic administration. In another embodiment, the CD3xCD20 antibody is administered to the subject every 6 to 8 days of the cycle of cyclic administration.

[0215] In one embodiment, the CD19 antibody is administered to a subject in an amount of about 1 mg / kg / day to about 20 mg / kg / day. In one embodiment, the CD19 antibody is administered to a subject in an amount of about 1 mg / kg / day. In another embodiment, the CD19 antibody is administered to a subject in an amount of about 2 mg / kg / day. In another embodiment, the CD19 antibody is administered to a subject in an amount of about 3 mg / kg / day. In another embodiment, the CD19 antibody is administered to a subject in an amount of about 4 mg / kg / day. In another embodiment, the CD19 antibody is administered to a subject in an amount of about 5 mg / kg / day. In another embodiment, the CD19 antibody is administered to a subject in an amount of about 6 mg / kg / day. In another embodiment, the CD19 antibody is administered to a subject in an amount of about 7 mg / kg / day. In another embodiment, the CD19 antibody is administered to a subject in an amount of about 8 mg / kg / day. In another embodiment, the CD19 antibody is administered to a subject in an amount of about 9 mg / kg / day. In another embodiment, the CD19 antibody is administered to the subject in an amount of about 10 mg / kg / day. In another embodiment, the CD19 antibody is administered to the subject in an amount of about 11 mg / kg / day. In another embodiment, the CD19 antibody is administered to the subject in an amount of about 12 mg / kg / day. In another embodiment, the CD19 antibody is administered to the subject in an amount of about 13 mg / kg / day. In another embodiment, the CD19 antibody is administered to the subject in an amount of about 14 mg / kg / day. In another embodiment, the CD19 antibody is administered to the subject in an amount of about 15 mg / kg / day. In another embodiment, the CD19 antibody is administered to the subject in an amount of about 16 mg / kg / day. In another embodiment, the CD19 antibody is administered to the subject in an amount of about 17 mg / kg / day. In another embodiment, the CD19 antibody is administered to the subject in an amount of about 18 mg / kg / day. In another embodiment, the CD19 antibody is administered to the subject in an amount of about 19 mg / kg / day. In another embodiment, the CD19 antibody is administered to the subject in an amount of about 20 mg / kg / day.

[0216] In one embodiment, Compound A or its pharmaceutically acceptable salt, solvate or stereoisomer is applied to the subject in an amount of about 1 mg to about 30 mg per day. In another embodiment, Compound A or its pharmaceutically acceptable salt, solvate or stereoisomer is applied 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 its pharmaceutically acceptable salt, solvate or stereoisomer is applied to the subject in an amount of about 2.5 mg per day. In another embodiment, Compound A or its pharmaceutically acceptable salt, solvate or stereoisomer is applied to the subject in an amount of about 5 mg per day. In another embodiment, Compound A or its pharmaceutically acceptable salt, solvate or stereoisomer is applied to the subject in an amount of about 10 mg per day. In another embodiment, Compound A or its pharmaceutically acceptable salt, solvate or stereoisomer is applied to the subject in an amount of about 15 mg per day. In another embodiment, Compound A or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is administered to a subject in an amount of about 20 mg per day. In another embodiment, Compound A or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is administered to a subject in an amount of about 25 mg per day.

[0217] In one embodiment, the CD3xCD20 antibody is administered to a subject in an amount of about 0.8 mg to about 100 mg per day. In one embodiment, the CD3xCD20 antibody is administered to a subject in an amount of about 0.8 mg to about 50 mg per day. In one embodiment, the CD3xCD20 antibody is administered to a subject in an amount of about 0.8 mg to about 20 mg per day. In another embodiment, the CD3xCD20 antibody is administered to a subject in an amount of about 0.8 mg per day. In another embodiment, the CD3xCD20 antibody is administered to a subject in an amount of about 1 mg per day. In another embodiment, the CD3xCD20 antibody is administered to a subject in an amount of about 2 mg per day. In another embodiment, the CD3xCD20 antibody is administered to a subject in an amount of about 3 mg per day. In another embodiment, the CD3xCD20 antibody is administered to a subject in an amount of about 4 mg per day. In another embodiment, the CD3xCD20 antibody is administered to a subject in an amount of about 5 mg per day. In another embodiment, the CD3xCD20 antibody is administered to a subject in an amount of about 10 mg per day. In another embodiment, the CD3xCD20 antibody is administered to a subject in an amount of about 15 mg per day. In another embodiment, the CD3xCD20 antibody is administered to a subject in an amount of about 20 mg per day. In another embodiment, the CD3xCD20 antibody is administered to a subject in an amount of about 25 mg per day. In another embodiment, the CD3xCD20 antibody is administered to a subject in an amount of about 30 mg per day. In another embodiment, the CD3xCD20 antibody is administered to a subject in an amount of about 35 mg per day. In another embodiment, the CD3xCD20 antibody is administered to a subject in an amount of about 40 mg per day. In another embodiment, the CD3xCD20 antibody is administered to a subject in an amount of about 5 mg per day. In another embodiment, the CD3xCD20 antibody is administered to a subject in an amount of about 50 mg per day. In another embodiment, the CD3xCD20 antibody is administered to a subject in an amount of about 55 mg per day. In another embodiment, the CD3xCD20 antibody is administered to a subject in an amount of about 60 mg per day. In another embodiment, the CD3xCD20 antibody is administered to a subject in an amount of about 65 mg per day. In another embodiment, the CD3xCD20 antibody is administered to a subject in an amount of about 70 mg per day. In another embodiment, the CD3xCD20 antibody is administered to a subject in an amount of about 75 mg per day. In another embodiment, the CD3xCD20 antibody is administered to a subject in an amount of about 80 mg per day. In another embodiment, the CD3xCD20 antibody is administered to a subject in an amount of about 85 mg per day. In another embodiment, the CD3xCD20 antibody is administered to a 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.

[0218] In one embodiment, the first dose of the CD3xCD20 antibody is on day 1 of the first cycle of cyclic administration.

[0219] 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 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 in any subsequent cycle.

[0220] In one embodiment, the first dose of Compound A, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, is on day 1 of the first cycle of cyclic administration.

[0221] In one embodiment, the first dose of the CD3xCD20 antibody and the first dose of Compound A or a pharmaceutically acceptable salt, solvate or stereoisomer thereof are both on day 1 of the first cycle of cyclic administration.

[0222] In one embodiment, the CD19 antibody is administered to the subject once a week in the cycle of cycle administration. In another embodiment, the CD19 antibody is administered to the subject once a week in the 1st to 3rd cycle of cycle administration. In another embodiment, the CD19 antibody is administered to the subject every two weeks in the cycle of cycle administration. In another embodiment, the CD19 antibody is administered to the subject every two weeks in the 4th week and subsequent cycles of cycle administration.

[0223] In one embodiment, the CD3xCD20 antibody is administered to the subject once a week during the cycle of cyclic administration. In another embodiment, the CD3xCD20 antibody is administered to the subject once a week during the 1st and 2nd weeks of cyclic administration. In another embodiment, the CD3xCD20 antibody is administered to the subject every two weeks during the cycle of cyclic administration. In another embodiment, the CD3xCD20 antibody is administered to the subject every two weeks during the 3rd week of cyclic administration and subsequent cycles.

[0224] In one embodiment, CD3xCD20 antibody and CD19 antibody are each administered to a subject within a maximum of 4 days in the cycle of cycle administration. In another embodiment, CD3xCD20 antibody is administered to a subject on one day in the cycle of cycle administration. In another embodiment, CD3xCD20 antibody is administered to a subject on two days in the cycle of cycle administration. In another embodiment, CD3xCD20 antibody is administered to a subject on three days in the cycle of cycle administration. In another embodiment, CD3xCD20 antibody is administered to a subject on four days in the cycle of cycle administration. In another embodiment, CD19 antibody is administered to a subject on one day in the cycle of cycle administration. In another embodiment, CD19 antibody is administered to a subject on two days in the cycle of cycle administration. In another embodiment, CD19 antibody is administered to a subject on three days in the cycle of cycle administration. In another embodiment, CD19 antibody is administered to a subject on four days in the cycle of cycle administration. In one embodiment, CD3xCD20 antibody and CD19 antibody are each administered to a subject on one day in the cycle of cycle administration. In one embodiment, CD3xCD20 antibody and CD19 antibody are each administered to a subject on two days of the cycle of cyclic administration. In one embodiment, CD3xCD20 antibody and CD19 antibody are each administered to a subject on three days of the cycle of cyclic administration. In one embodiment, CD3xCD20 antibody and CD19 antibody are each administered to a subject on four days of the cycle of cyclic administration.

[0225] 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 on day 1, about 2 mg on about day 8, about 20 mg on about day 15, and about 20 mg of the CD3xCD20 antibody on about day 22, wherein the subject is administered about 20 mg of the CD3xCD20 antibody on day 1 and every 6 to 8 days of a second cycle of cyclic administration, wherein the subject is administered four doses of the CD3xCD20 antibody in each of the first 2 cycles, wherein the subject is administered about 20 mg of the CD3xCD20 antibody on day 1 and every 12 to 16 days in cycle 3 and any subsequent cycles during treatment, and wherein each cycle of cyclic administration is 28 days.

[0226] 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 on day 1, about 2 mg on about day 8, about 20 mg on about day 15, and about 35 mg of the CD3xCD20 antibody on about day 22, wherein the subject is administered about 50 mg of the CD3xCD20 antibody on day 1 and every 6 to 8 days of a second cycle of cyclic administration, wherein the subject is administered four doses of the CD3xCD20 antibody in each of the first 2 cycles, wherein the subject is administered about 50 mg of the CD3xCD20 antibody on day 1 and every 12 to 16 days in cycle 3 and any subsequent cycles during treatment, and wherein each cycle of cyclic administration is 28 days.

[0227] In one embodiment, the method comprises cyclically administering a CD3xCD20 antibody to a subject, wherein the first cycle comprises administering to the subject about 0.8 mg on day 1, about 2 mg on day 8, about 20 mg on day 15, and about 20 mg of the CD3xCD20 antibody on day 22, wherein the subject is administered about 20 mg of the CD3xCD20 antibody on day 1 and every 7 days for the first 2 cycles of cyclic administration, wherein the subject is administered four doses of the CD3xCD20 antibody in each of the first 2 cycles, wherein the subject is administered about 20 mg of the CD3xCD20 antibody on day 1 and every 14 days in cycle 3 and any subsequent cycles during treatment, and wherein each cycle of cyclic administration is 28 days.

[0228] In one embodiment, the method comprises cyclically administering a CD3xCD20 antibody to a subject, wherein the first cycle comprises administering to the subject about 0.8 mg on day 1, about 2 mg on day 8, about 20 mg on day 15, and about 35 mg of the CD3xCD20 antibody on day 22, wherein the subject is administered about 50 mg of the CD3xCD20 antibody on day 1 and every 7 days for the first 2 cycles of cyclic administration, wherein the subject is administered four doses of the CD3xCD20 antibody in each of the first 2 cycles, wherein the subject is administered about 50 mg of the CD3xCD20 antibody on day 1 and every 14 days in cycle 3 and any subsequent cycles during treatment, and wherein each cycle of cyclic administration is 28 days.

[0229] In one embodiment, the method comprises cyclically administering a CD19 antibody to a 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 to 8 days for the first 3 cycles of cyclic administration, wherein in each of the first 3 cycles, four doses of the CD19 antibody are administered 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 12 to 16 days for Cycle 4 and any subsequent cycles during treatment, wherein about 10 mg / kg to about 15 mg / kg of the CD19 antibody is administered to the subject on the 8 days and 4 days prior to Day 1 of the first cycle of cyclic administration, and wherein each cycle of cyclic administration is 28 days.

[0230] In one embodiment, the method comprises cyclically administering a CD19 antibody to the subject, wherein about 12 mg / kg of the CD19 antibody is administered to the subject on Day 1 and every 7 days for the first 3 cycles of cyclic administration, wherein in each of the first 3 cycles, four doses of the CD19 antibody are administered to the subject, 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 treatment, wherein about 12 mg / kg of the CD19 antibody is administered to the subject on the 8 days and 4 days prior to Day 1 of the first cycle of cyclic administration, and wherein each cycle of cyclic administration is 28 days.

[0231] In one embodiment, the method comprises cyclically administering Compound A, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, to a subject, wherein about 25 mg of Compound A, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is administered to the subject daily on day 1 of each cycle of cyclic administration and for 21 days, followed by a 7-day rest, and wherein each cycle of cyclic administration is 28 days.

[0232] In one embodiment, the method comprises cyclically administering to a subject a CD19 antibody, a CD3xCD20 antibody, and Compound A or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, and wherein the method comprises:

[0233] (a) administering to the subject about 0.6 to about 1 mg on Day 1 of the first cycle, about 1.8 to about 2.2 mg on about Day 8, and about 18 to about 22 mg of the CD3xCD20 antibody on about Day 15 and Day 22; administering to the subject about 20 mg of the CD3xCD20 antibody on Day 1 of the second cycle of cyclic administration and every 6 to 8 days, wherein the subject is administered four doses of the CD3xCD20 antibody in each of the first 2 cycles, wherein the subject is administered about 20 mg of the CD3xCD20 antibody on Day 1 and every 12 to 16 days in Cycle 3 and any subsequent cycles during treatment;

[0234] (b) administering to the subject about 10 mg / kg to about 15 mg / kg of the CD19 antibody on Day 1 and every 6 to 8 days for the first 3 cycles of cycle administration, wherein in each of the first 3 cycles, the subject is administered four doses of the CD19 antibody, wherein on Cycle 4 and any subsequent cycles during the course of treatment, the subject is administered about 10 mg / kg to about 15 mg / kg of the CD19 antibody on Day 1 and every 12 to 16 days, wherein the subject is administered about 10 mg / kg to about 15 mg / kg of the CD19 antibody on the 8 days and 4 days prior to Day 1 of the first cycle of cycle administration, and

[0235] (c) administering to the subject about 25 mg of Compound A or a pharmaceutically acceptable salt, solvate or stereoisomer thereof daily on day 1 of each cycle of cyclic administration and for 21 consecutive days, followed by a 7-day rest period; and

[0236] Each cycle in which the cycles are administered is 28 days.

[0237] In one embodiment, the method comprises cyclically administering to a subject a CD19 antibody, a CD3xCD20 antibody, and Compound A or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, and wherein the method comprises:

[0238] (a) administering to the subject about 0.6 to about 1 mg on Day 1 of the first cycle, about 1.8 to about 2.2 mg on about Day 8, about 18 to about 22 mg on about Days 15 and 22, and about 33 to about 36 mg on Day 22 of the CD3xCD20 antibody; administering to the subject about 50 mg of the CD3xCD20 antibody on Day 1 of the second cycle of cyclic administration and every 6 to 8 days, wherein the subject is administered four doses of the CD3xCD20 antibody in each of the first 2 cycles, wherein the subject is administered about 50 mg of the CD3xCD20 antibody on Day 1 and every 12 to 16 days in Cycle 3 and any subsequent cycles during treatment;

[0239] (b) administering to the subject about 10 mg / kg to about 15 mg / kg of the CD19 antibody on Day 1 and every 6 to 8 days for the first 3 cycles of cycle administration, wherein in each of the first 3 cycles, the subject is administered four doses of the CD19 antibody, wherein on Cycle 4 and any subsequent cycles during the course of treatment, the subject is administered about 10 mg / kg to about 15 mg / kg of the CD19 antibody on Day 1 and every 12 to 16 days, wherein the subject is administered about 10 mg / kg to about 15 mg / kg of the CD19 antibody on the 8 days and 4 days prior to Day 1 of the first cycle of cycle administration, and

[0240] (c) administering to the subject about 25 mg of Compound A or a pharmaceutically acceptable salt, solvate or stereoisomer thereof daily on day 1 of each cycle of cyclic administration and for 21 consecutive days, followed by a 7-day rest period; and

[0241] Each cycle in which the cycles are administered is 28 days.

[0242] In one embodiment, the method comprises cyclically administering to a subject a CD19 antibody, a CD3xCD20 antibody, and Compound A or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, and wherein the method comprises:

[0243] (a) administering to the subject about 0.8 mg on Day 1 of the first cycle, about 2 mg on about Day 8, and about 20 mg on Days 15 and 22 of the CD3xCD20 antibody; administering to the subject about 20 mg of the CD3xCD20 antibody on Day 1 of the second cycle of cyclic administration and every 7 days, wherein the subject is administered four doses of the CD3xCD20 antibody in each of the first 2 cycles, wherein the subject is administered about 20 mg of the CD3xCD20 antibody on Day 1 and every 14 days in the third cycle and any subsequent cycles during treatment;

[0244] (b) administering to the subject about 12 mg / kg of the CD19 antibody on Day 1 and every 7 days for the first 3 cycles of cycle administration, wherein the subject is administered four doses of the CD19 antibody in each of the first 3 cycles, wherein the subject is administered about 12 mg / kg of the CD19 antibody on Day 1 and every 14 days for the 4th cycle and any subsequent cycles during the course of treatment, wherein the subject is administered about 12 mg / kg of the CD19 antibody on the 8 days and 4 days prior to Day 1 of the first cycle of cycle administration; and

[0245] (c) administering to the subject approximately 25 mg of Compound A or a pharmaceutically acceptable salt, solvate or stereoisomer thereof daily on day 1 of each cycle of cyclic administration during the course of treatment and for 21 consecutive days, followed by a 7-day rest period; and

[0246] Each cycle in which the cycles are administered is 28 days.

[0247] In one embodiment, the method comprises cyclically administering to a subject a CD19 antibody, a CD3xCD20 antibody, and Compound A or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, and wherein the method comprises:

[0248] (a) administering to the subject about 0.8 mg on Day 1 of the first cycle, about 2 mg on about Day 8, about 20 mg on Day 15, and about 35 mg on Day 22 of the CD3xCD20 antibody; administering to the subject about 50 mg of the CD3xCD20 antibody on Day 1 of the second cycle of cyclic administration and every 7 days, wherein the subject is administered four doses of the CD3xCD20 antibody in each of the first 2 cycles, wherein the subject is administered about 50 mg of the CD3xCD20 antibody on Day 1 and every 14 days in Cycle 3 and any subsequent cycles during treatment;

[0249] (b) administering to the subject about 12 mg / kg of the CD19 antibody on Day 1 and every 7 days for the first 3 cycles of cycle administration, wherein the subject is administered four doses of the CD19 antibody in each of the first 3 cycles, wherein the subject is administered about 12 mg / kg of the CD19 antibody on Day 1 and every 14 days for the 4th cycle and any subsequent cycles during the course of treatment, wherein the subject is administered about 12 mg / kg of the CD19 antibody on the 8 days and 4 days prior to Day 1 of the first cycle of cycle administration; and

[0250] (c) administering to the subject approximately 25 mg of Compound A or a pharmaceutically acceptable salt, solvate or stereoisomer thereof daily on day 1 of each cycle of cyclic administration during the course of treatment and for 21 consecutive days, followed by a 7-day rest period; and

[0251] Each cycle in which the cycles are administered is 28 days.

[0252] In one embodiment, the method comprises cyclically administering to a subject a CD19 antibody, a CD3xCD20 antibody, and Compound A or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, and wherein the method comprises:

[0253] (a) administering to the subject about 0.8 mg on day 1, about 2 mg on day 8, and about 20 mg on days 15 and 22 of a first cycle of CD3xCD20 antibody; administering to the subject about 20 mg of CD3xCD20 antibody on days 1, 8, 15, and 22 of a second cycle of cyclic administration, wherein the subject is administered about 20 mg of CD3xCD20 antibody on days 1 and 15 of cycle 3 and any subsequent cycles during treatment;

[0254] (b) administering to the subject about 12 mg / kg of the CD19 antibody on Day 1, Day 8, Day 15, and Day 22 of the first 3 cycles of cycle administration, wherein the subject is administered about 12 mg / kg of the CD19 antibody on Day 1 and Day 15 of the 4th cycle and any subsequent cycles during treatment, wherein the subject is administered about 12 mg / kg of the CD19 antibody on the 8 days and 4 days prior to Day 1 of the first cycle of cycle administration; and

[0255] (c) administering to the subject approximately 25 mg of Compound A or a pharmaceutically acceptable salt, solvate or stereoisomer thereof daily on day 1 of each cycle of cyclic administration during the course of treatment and for 21 consecutive days, followed by a 7-day rest period; and

[0256] Each cycle in which the cycles are administered is 28 days.

[0257] In one embodiment, the method comprises cyclically administering to a subject a CD19 antibody, a CD3xCD20 antibody, and Compound A or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, and wherein the method comprises:

[0258] (a) administering to the subject about 0.8 mg 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 CD3xCD20 antibody; administering to the subject about 50 mg of CD3xCD20 antibody on days 1, 8, 15, and 22 of a second cycle of cyclic administration, wherein the subject is administered about 50 mg of CD3xCD20 antibody on days 1 and 15 of cycle 3 and any subsequent cycles during treatment;

[0259] (b) administering to the subject about 12 mg / kg of the CD19 antibody on Day 1, Day 8, Day 15, and Day 22 of the first 3 cycles of cycle administration, wherein the subject is administered about 12 mg / kg of the CD19 antibody on Day 1 and Day 15 of the 4th cycle and any subsequent cycles during treatment, wherein the subject is administered about 12 mg / kg of the CD19 antibody on the 8 days and 4 days prior to Day 1 of the first cycle of cycle administration; and

[0260] (c) administering to the subject approximately 25 mg of Compound A or a pharmaceutically acceptable salt, solvate or stereoisomer thereof daily on day 1 of each cycle of cyclic administration during the course of treatment and for 21 consecutive days, followed by a 7-day rest period; and

[0261] Each cycle in which the cycles are administered is 28 days.

[0262] In one embodiment, the CD19 antibody is not administered to the subject on day 4 of the first cycle of cyclic administration. In another embodiment, the CD3xCD20 antibody is not administered to the subject on day 4 of the first cycle of cyclic administration.

[0263] In one embodiment, the method further comprises determining a PET-CT after every two cycles of cycle administration.

[0264] In one embodiment, the anti-CD19 antibody is tafacitumomab. In one embodiment, the CD3xCD20 antibody is paramatuzumab. In one embodiment, the CD19 antibody is tafacitumomab and the CD3xCD20 antibody is paramatuzumab.

[0265] Application

[0266] The pharmaceutical compositions provided herein can be in various forms. These forms include, for example, liquid, semisolid and solid dosage forms, such as liquid solutions (e.g., injectable solutions and infusible solutions), dispersions or suspensions. The form depends on the intended mode of administration and therapeutic application. Exemplary compositions are in the form of injectable or infusible solutions, such as compositions similar to compositions for passive immunization of humans using other antibodies. In an exemplary embodiment, the mode of administration is intravenous. In an exemplary embodiment, the antibodies provided herein are administered by intravenous infusion or injection.

[0267] Pharmaceutical compositions must generally be sterile and stable under the conditions of manufacture and storage. Sterile injectable solutions can be prepared by incorporating the desired amount of the bispecific antibody with one of the ingredients listed above or a combination thereof in an appropriate solvent as required, followed by filtration sterilization. In general, dispersions are prepared by incorporating the bispecific antibody into a sterile vehicle containing a basic dispersion medium and other ingredients required from those listed above.

[0268] The pharmaceutical compositions provided herein can be administered by any method known in the art. As will be appreciated by those skilled in the art, the route and / or mode of administration will vary depending on the desired results.

[0269] In one embodiment, Compound A or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is orally administered to a subject. In another embodiment, Compound A or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is administered to a subject in the form of a capsule or tablet.

[0270] In exemplary embodiments, the route / mode of administration is intravenous injection. In one embodiment, the CD19 antibody is administered intravenously.

[0271] Additional dose

[0272] In one aspect, a method of treating lymphoma in a subject is provided, 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.

[0273] As used herein, "combination" administration means administering three (or more) different agents to a subject during the course of a subject suffering from a disease, for example, administering three or more agents after a human subject is diagnosed with a tumor and before the tumor is treated. In some embodiments, when the administration of the second agent begins, the administration of one agent is still in progress, so there is overlap in administration. This is sometimes referred to as "simultaneous (simultaneous / concurrent) administration" in this article. In other embodiments, the administration of one agent ends before the administration of other agents begins. In some embodiments of either case, treatment is more effective due to combined administration. In some embodiments, administration causes a reduction in symptoms or other parameters associated with a tumor to be greater than the reduction observed when administering one agent without other agents. The effect of the agent on the subject may be partially additive, completely additive, or greater than additive. Administration may allow the effect of the first treatment administration to still be detected when the second treatment is administered.

[0274] The combination described herein and at least one other agent can be administered simultaneously, in the same or separate compositions, or sequentially. For sequential administration, at least one other agent can be administered before or after administration of the combination described herein.

[0275] When administered in combination, CD19 antibody, CD3xCD20 antibody, compound A and at least one other agent or all can be higher, lower or equal to the amount or dosage of each therapeutic agent used individually as a monotherapy, for example. In some embodiments, the amount or dosage of CD19 antibody, CD3xCD20 antibody, compound A and at least one other agent or all is lower than (e.g., at least 20%, at least 30%, at least 40% or at least 50%), for example, the amount or dosage of each therapeutic agent used individually as a monotherapy. In other embodiments, the amount or dosage of CD19 antibody, CD3xCD20 antibody, compound A and at least one other agent or all that cause a desired effect (e.g., treating a tumor) is lower than (e.g., at least 20%, at least 30%, at least 40% or at least 50%), for example, the amount or dosage required for each agent used individually as a monotherapy to achieve the same therapeutic effect.

[0276] In one embodiment, the additional agent is a premedication. In another embodiment, the premedication is administered prior to administration of the CD3xCD20 antibody.

[0277] In one embodiment, the premedication is dexamethasone. In another embodiment, dexamethasone is administered intravenously at a dose of 20 mg about one hour prior to administration of the CD3xCD20 antibody.

[0278] In one embodiment, the pre-medication is diphenhydramine. In another embodiment, a 25 mg dose of diphenhydramine is administered orally or intravenously approximately thirty to sixty minutes prior to administration of the CD3xCD20 antibody. In another embodiment, the pre-medication is acetaminophen. In another embodiment, a 650 mg dose of acetaminophen is administered orally or intravenously approximately thirty to sixty minutes prior to administration of the CD3xCD20 antibody.

[0279] In one aspect, the additional agent is administered to treat the side effect.

[0280] In one embodiment, the side effect is cytokine release syndrome ("CRS"). Symptoms of CRS may include high fever, nausea, transient hypotension, hypoxia, etc. CRS may include clinical signs and symptoms, such as fever, fatigue, anorexia, myalgia, arthralgia, nausea, vomiting and headache. CRS may include clinical skin signs and symptoms such as 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 shortness of breath and hypoxemia. CRS may include clinical cardiovascular signs and symptoms, such as tachycardia, widened pulse pressure, hypotension, increased cardiac output (early) and potential 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 may include clinical liver signs and symptoms, such as elevated transaminases and hyperbilirubinemia. CRS may include clinical neurologic signs and symptoms such as headache, altered mental status, confusion, delirium, word-finding difficulties or frank aphasia, hallucinations, tremors, dysmetria, gait changes, and seizures.

[0281] In another embodiment, the side effect is dyspepsia. 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 anaphylaxis, hypersensitivity, or infusion-related reaction. In another embodiment, the side effect is hematologic toxicity. In another embodiment, the side effect is tumor lysis syndrome.

[0282] In exemplary embodiments, other agents are steroids. 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.

[0283] In exemplary embodiments, the other agent is an antihistamine. In one embodiment, the antihistamine is an H1 antagonist. In another embodiment, the H1 antagonist is selected from the group consisting of acrivastine, azelastine, bilastine, brompheniramine, brompheniramine, buclizine, carbinoxamine, cetirizine Chlorpheniramine, chlorpheniramine, clemastine, cyclizine, cyproheptadine, dexbrompheniramine, dexchlorpheniramine, dimenhydrinate, dimethinidine, diphenhydramine, doxylamine, ebastine, enbramine, fexofenadine Hydroxyzine Loratadine Meclizine, mirtazapine, olopatadine, orphenadrine, phenindamine, pheniramine, phenyltoloxamine, promethazine, quetiapine Rupatadine Tripirunamine and triprolidine.

[0284] In exemplary embodiments, the antihistamine is acrivastine. In one embodiment, the antihistamine is cetirizine. In another embodiment, the antihistamine is diphenhydramine. In another embodiment, the antihistamine is

[0285] In exemplary embodiments, the antihistamine is H1 Inverse agonists. In one embodiment, the H1 inverse agonist is selected from the group consisting of acrivastine, cetirizine, levocetirizine, desloratadine, and pyrilamine.

[0286] In exemplary embodiments, the antihistamine is H2 In one embodiment, the H2 antihistamine is an H2 antagonist. In another embodiment, H2 Antihistamines are H2 Inverse agonists. In another embodiment, H2 The antihistamine is selected from the group consisting of cimetidine, famotidine, lafutidine, nizatidine, ranitidine, roxatidine and thiotidine.

[0287] In an exemplary embodiment, the other agent is an antiallergic agent. In one embodiment, the other agent is selected from the group consisting of: antihistamines, glucocorticoids, epinephrine (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 adrenaline releaser. In another embodiment, the other agent is levomethamphetamine, phenylpropanolamine, propylhexedrine, phenoxyethanol ... or loratadine. In another embodiment, the other agent is an alpha-adrenergic receptor agonist. In another embodiment, the other agent is naphazoline, oxymetazoline, phenylephrine, synephrine, tetrahydrozoline, tramazoline, or xylometazoline.

[0288] In exemplary embodiments, the other agent is an anti-nausea agent. In one embodiment, the other agent is an antiemetic. In another embodiment, the other agent is a 5-HT3 receptor antagonist. In another embodiment, the other agent is dolasetron. Granisetron Ondansetron Tropisetron Palonosetron Mirtazapine 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 Olanzapine Droperidol, haloperidol, chlorpromazine, prochlorperazine, alizapride, prochlorperazine Metoclopramide In another embodiment, the other agent is a NK1 receptor antagonist. In another embodiment, the other agent is aprepitant or fosaprepitant Cassopitant, Rolapitant In an exemplary embodiment, the other agent is an anticholinergic drug. In another embodiment, the other agent is scopolamine.

[0289] 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, disalicylate 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 a derivative 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 a derivative 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 a derivative thereof. In another embodiment, the other agent is selected from the group consisting of: phenazone, metamizole and nabumetone or a derivative thereof. In another embodiment, the other agent is an opiate. In another embodiment, the other agent is codeine, morphine, thebaine or fentanyl. In another embodiment, the additional agent is dihydrocodeine, oxymorphol, oxycodone, oxymorphone, or metopone.

[0290] In an exemplary embodiment, the other agent is a cell protectant. 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.

[0291] In an exemplary embodiment, the other agent is a vasopressor. In one embodiment, the vasopressor is selected from the group consisting of norepinephrine, phenylephrine, epinephrine, ephedrine, dopamine, vasopressin, or a combination thereof. In another embodiment, the vasopressor is selected from dobutamine, midodrine, amezinum, or a combination thereof.

[0292] In exemplary embodiments, 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 allyl alcohol. In another embodiment, the aromatic allyl alcohol is stiripentol. In another embodiment, the anticonvulsant is a barbiturate. In another embodiment, the barbiturate is phenobarbital, primidone, methylphenobarbital, or barbexalon. In exemplary embodiments, the anticonvulsant is a benzodiazepine. In another embodiment, a benzodiazepine 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, valproate is valproic acid, sodium valproate or divalproex sodium. In another embodiment, valproate is vigabatrin, progab 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 methylethyldione, trimethyldione 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, ethyltiracetam, 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, methosuximide. In another embodiment, the anticonvulsant is a sulfonamide. In another embodiment, the succinimide is acetazolamide, sulthiame, methazolamide and 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 phenylbutyryl urea or phenylacetyl urea. In another embodiment, the anticonvulsant is valproyl amide. In another embodiment, the anticonvulsant is valproyl amide. In another embodiment, the valproyl amide is valproamide or valeronamide. In another embodiment, the anticonvulsant is perampanel, stiripentol, or pyridoxine.

[0293] In exemplary embodiments, 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, such as infliximab Adalimumab Certolizumab Golimumab Another example of a TNFα inhibitor is a fusion protein, such as enacept In another embodiment, the TNF-α inhibitor is a small molecule. Small molecule inhibitors of TNFα include, but are not limited to, xanthine derivatives (eg, pentoxifylline) and bupropion.

[0294] 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), saliru monoclonal antibody, icimumab, 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.

[0295] The methods described herein may include administering one or more other agents to control the level of soluble factors caused by the treatment using the methods described herein. In one embodiment, the soluble factors increased in the subject are one or more of IFN-γ, TNFα, IL-2 and IL-6. In embodiments, the factors increased in the subject are one or more of IL-1, GM-CSF, IL-10, IL-8, IL-5 and fraktalkine. Therefore, 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 its antigen-binding fragment. Examples of such agents include, but are not limited to, steroids (e.g., corticosteroids), TNFα inhibitors, IL-1R inhibitors and IL-6 inhibitors. An example of an inhibitor based on IL-1R is anakinra.

[0296] In exemplary embodiments, other agents are agents that reduce immune-mediated side effects. Exemplary immune-mediated side effects include, but are not limited to, pneumonia, colitis, hepatitis, nephritis and renal dysfunction, hypothyroidism, hyperthyroidism and endocrinopathy (e.g., hypophysitis, type 1 diabetes and thyroid disorders, such as hypothyroidism and hyperthyroidism). In one embodiment, other agents can reduce embryo-fetal toxicity.

[0297] In one embodiment, the other agent is an IV infusion. 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.

[0298] Efficacy evaluation

[0299] The efficacy of the methods provided herein can be evaluated by any method known in the art. For example, standard efficacy assays can be performed, such as evaluation of the presence or extent of cancer burden, tumor size, metastasis, etc., or immuno-oncology treatments can be evaluated based on immune status evaluation. This can be done in a variety of ways, including in vitro and in vivo assays. For example, changes in immune status, tumor burden, size, invasiveness, LN involvement, metastasis, etc. can be evaluated.

[0300] In an exemplary embodiment, the enhanced efficacy is measured by a reduction in the number of cancer cells in a biological sample obtained from a subject compared to a reference. In another embodiment, the reference is the number of cancer cells in a biological sample obtained from a 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.

[0301] In exemplary embodiments, efficacy is assessed by evaluating the absolute counts of the cell population and the percentage change relative to baseline. In one embodiment, the cell population is a B cell. In another embodiment, the cell population is a T cell. In another embodiment, the cell population is a natural killer (NK) cell.

[0302] In exemplary embodiments, efficacy is assessed by evaluating changes in gene expression or protein levels of diagnostic biomarkers, including but not limited to cells of origin [germinal center B cells (GCB) vs. non-GCB], CD10, CD19, CD20, MUM1, BCL2, and BCL6 as determined by the Hans algorithm. In one embodiment, after treatment with the methods provided herein, the expression of one or more genes increases. In another embodiment, after treatment with the methods provided herein, the expression of one or more genes decreases. In one embodiment, after treatment with the methods provided herein, the level of one or more proteins increases. In another embodiment, after treatment with the methods provided herein, the level of one or more proteins decreases.

[0303] In one embodiment, efficacy is assessed by evaluating peripheral and intratumoral leukocyte frequency, phenotype, and functional and activation markers at baseline and after treatment.

[0304] In an exemplary embodiment, efficacy is assessed using gene expression profiling for cell of origin subtypes and exploratory transcriptome analysis. In another embodiment, efficacy is assessed by genomic analysis in the tumor, including but not limited to FcR genotyping and MRD ctDNA analysis of the blood.

[0305] In some embodiments, treatment is assessed by assessing T cell activity measured by cytokine production, using well-known techniques to measure intracellularly using cytokines in culture supernatants, including but not limited to IFNγ, TNFα, GM-CSF, IL2, IL6, IL4, IL5, IL10, IL13. It was observed that the doses provided herein only advantageously induce limited low-rate and low-grade cytokine release syndrome (CRS) reactions in some subjects. In some embodiments, the doses provided herein induce a maximum of grade 1 or grade 2 CRS reactions. 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 in their sections related to the CRS grading system. In some embodiments, the doses provided herein advantageously induce a reduction in CRS-related cytokine levels in subsequent doses. In some embodiments, the doses provided herein advantageously induce a reduction in CRS-related cytokine levels after two doses. 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, ELISA assays.

[0306] In exemplary embodiments, efficacy is assessed by evaluating progression-free survival. In one embodiment, the progression-free survival of a subject treated using the methods provided herein increases. In embodiments, the progression-free survival increases by about one month. In another embodiment, the progression-free survival increases by about two months. In another embodiment, the progression-free survival increases by about three months. In another embodiment, the progression-free survival increases by about four months. In another embodiment, the progression-free survival increases by about five months. In another embodiment, the progression-free survival increases by about six months. In another embodiment, the progression-free survival increases by about seven months. In another embodiment, the progression-free survival increases by about eight months. In another embodiment, the progression-free survival increases by about nine months. In another embodiment, the progression-free survival increases by about ten months. In another embodiment, the progression-free survival increases by about eleven months. In another embodiment, the progression-free survival increases by about one year. In another embodiment, the progression-free survival increases by about two years. In another embodiment, the progression-free survival increases by about three years. In another embodiment, the progression-free survival increases by about four years. In another embodiment, the progression-free survival increases by about five years. In another embodiment, the progression-free survival increases by more than five years.

[0307] In exemplary embodiments, efficacy is assessed by evaluating overall survival. In one embodiment, the overall survival of a subject treated using the methods provided herein is increased. In embodiments, the overall survival is increased by about one month. In another embodiment, the overall survival is increased by about two months. In another embodiment, the overall survival is increased by about three months. In another embodiment, the overall survival is increased by about four months. In another embodiment, the overall survival is increased by about five months. In another embodiment, the overall survival is increased by about six months. In another embodiment, the overall survival is increased by about seven months. In another embodiment, the overall survival is increased by about eight months. In another embodiment, the overall survival is increased by about nine months. In another embodiment, the overall survival is increased by about ten months. In another embodiment, the overall survival is increased by about eleven months. In another embodiment, the overall survival is increased by about one year. In another embodiment, the overall survival is increased by about two years. In another embodiment, the overall survival is increased by about three years. In another embodiment, the overall survival is increased by about four years. In another embodiment, the overall survival is increased by about five years. In another embodiment, the overall survival is increased by more than five years.

[0308] In exemplary embodiments, efficacy is assessed by evaluating the objective response rate. In one embodiment, the objective response rate is assessed by a blind independent review committee (BIRC). In one embodiment, the subject treated with the method provided herein has an objective response rate of about 10% to about 100%. In one 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%.

[0309] In exemplary embodiments, efficacy is assessed by evaluating the time to treatment failure. In one embodiment, the time to treatment failure is increased in subjects treated using the methods provided herein.

[0310] In exemplary embodiments, efficacy is assessed by evaluating the duration of response.In one embodiment, subjects treated using the methods provided herein have an increased duration of response.

[0311] In an exemplary embodiment, the evaluation of efficacy is 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 evaluated by evaluating fluorodeoxyglucose (FDG) positron emission tomography (PET)-computed tomography (CT) (e.g., for FDG-affinity lymphoma). In one embodiment, PET-CT is used to evaluate efficacy (e.g., for patients with radiological (CT) Cru or partial response (PR) in non-Hodgkin lymphoma (e.g., DLBCL). In another embodiment, PET-CT is used to evaluate the response of the subject to the disclosed method, wherein a 5-point scale is used (e.g., for clinical trials, mid-term evaluations, or evaluations at the end of treatment) (Table 15). In another embodiment, mid-term PET-CT is used to evaluate early treatment response and / or to determine remission status at the end of treatment. In one embodiment, a score of 1 or 2 in PET-CT indicates a complete metabolic response at the end of treatment and / or treatment. In another embodiment, a PET-CT score changes from 5 to 1 indicating that the patient has achieved a complete metabolic response (see Table 15). In another embodiment, a PET-CT score changes from 4 to 1 indicating that the patient has achieved a complete metabolic response (see Table 15). In another embodiment, a PET-CT score changes from 5 to 2 indicating that the patient has achieved a complete metabolic response (see Table 15). In another embodiment, a PET-CT score changes from 4 to 2 indicating that the patient has achieved a complete metabolic response (see Table 15). In one embodiment, when the PET-CT result score is 1, the patient has achieved a complete metabolic response. In one embodiment, when the PET-CT result score is 2, the patient has achieved a complete metabolic response. In another embodiment, patients with an uptake higher than the mediastinum but lower than or equal to the liver (score of 3) have a good prognosis at the end of treatment of non-Hodgkin's lymphoma (e.g., DLBCL) therapy. In another embodiment, the interpretation of a score of 3 depends on the time of the assessment, the clinical context, and the treatment (e.g., in a response adaptation trial exploring treatment de-escalation, a score of 3 may be considered insufficient response, thereby avoiding insufficient treatment). In another embodiment, an interim score of 4 or 5 indicates chemosensitive disease (e.g., provided that uptake has decreased 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 uptake has decreased from baseline.In another embodiment, a score of 4 or 5, and no change or even increase in intensity relative to baseline and / or the appearance of new lesions consistent with lymphoma, indicates treatment failure in the mid-term and end-of-treatment evaluations. In another embodiment, a CT-based response is used (e.g., for histology with low or variable FDG affinity and / or if PET-CT is unavailable). In another embodiment, an increase of greater than or equal to 50% in the product of the perpendicular diameter (PPD) of a single nodule indicates the presence of progressive disease according to CT criteria. In another embodiment, a follow-up scan is performed for indolent lymphomas with residual intra-abdominal or retroperitoneal disease.

[0312] In one embodiment, the patient reaches a complete metabolic reaction at the end of the 2nd cycle of the disclosed methods (e.g., after the 26th day and / or the 26th day of the 2nd cycle). In one embodiment, the patient reaches a complete metabolic reaction at the end of the 3rd cycle of the disclosed methods (e.g., after the 26th day and / or the 26th day of the 3rd cycle). In one embodiment, the patient reaches a complete metabolic reaction at the end of the 4th cycle of the disclosed methods (e.g., after the 26th day and / or the 26th day of the 4th cycle). In one embodiment, the patient reaches a complete metabolic reaction at the end of the 5th cycle of the disclosed methods (e.g., after the 26th day and / or the 26th day of the 5th cycle). In one embodiment, the patient reaches a complete metabolic reaction at the end of the 6th cycle of the disclosed methods (e.g., after the 26th day and / or the 26th day of the 6th cycle). In one embodiment, the patient reaches a complete metabolic reaction at the end of the 7th cycle of the disclosed methods (e.g., after the 26th day and / or the 26th day of the 7th cycle). In one embodiment, the patient reaches a complete metabolic reaction at the end of the 8th cycle of the disclosed methods (e.g., after the 26th day and / or the 26th day of the 8th cycle). In one embodiment, the patient reaches a complete metabolic response at the end of the 9th cycle of the disclosed methods (e.g., day 26 and / or after day 26 of the 9th cycle). In one embodiment, the patient reaches a complete metabolic response at the end of the 10th cycle of the disclosed methods (e.g., day 26 and / or after day 26 of the 10th cycle). In one embodiment, the patient is in a complete metabolic response until the end of treatment of the disclosed methods. In one embodiment, the patient is in a complete metabolic response after the end of treatment (e.g., one month, two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, twelve 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 the end of treatment of the disclosed methods). In one embodiment, the patient achieves a complete metabolic response on or after 50 days, 55 days, 60 days, 65 days, 70 days, 75 days, 80 days, 85 days, 90 days, 95 days, 100 days, 105 days, 110 days, 115 days, 120 days, 125 days, 130 days, 135 days, 140 days, 150 days, 151 days, 152 days, 153 days, 154 days, 155 days, 156 days, 157 days, 158 days, 159 days, 160 days, 161 days, 162 days, 163 days, 164 days, 165 days, 166 days, 167 days, 168 days, 169 days, 170 days, 171 days, 172 days, 173 days, 174 days, 175 days, 176 days, 177 days, 178 days, 179 days, 180 days, 181 days 145 days, 150 days, 155 days, 160 days, 165 days, 170 days, 180 days, 185 days, 190 days, 195 days, 200 days, 205 days, 210 days, 215 days, 220 days, 225 days, 230 days, 235 days, 240 days, 245 days, 250 days, 255 days, 260 days, 265 days, 270 days, 280 days, 285 days, 290 days, 295 days, 300 days or more than 300 days.In one embodiment, the patient reaches a complete metabolic response at or after 61 days from the start of the disclosed methods or from the first day of the disclosed methods or from the first administration of the multispecific antibody of the present disclosure to a subject. In one embodiment, the patient reaches a complete metabolic response at or after 117 days from the start of the disclosed methods or from the first day of the disclosed methods or from the first administration of the multispecific antibody of the present disclosure to a subject. In one embodiment, the patient reaches a complete metabolic response at or after 177 days from the start of the disclosed methods or from the first day of the disclosed methods or from the first administration of the multispecific antibody of the present disclosure to a subject. In one embodiment, the patient reaches a complete metabolic response at or after 233 days from the start of the disclosed methods or from the first day of the disclosed methods or from the first administration of the multispecific antibody of the present disclosure to a subject. In one embodiment, the patient reaches a complete metabolic response at or after 299 days from the start of the disclosed methods or from the first day of the disclosed methods or from the first administration of the multispecific antibody of the present disclosure to a subject.

[0313] In one embodiment, FDG uptake decreases during treatment of chemotherapy-sensitive disease. In another embodiment, residual FDG uptake above normal liver uptake is observed in the interim in patients who achieve a complete metabolic response at the end of treatment. In another embodiment, a 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 nodal or extranodal lesions.

[0314] Table 15. Response evaluation criteria

[0315]

[0316]

[0317]

[0318] Abbreviations: 5PS, 5-point scale; CT, computed tomography; FDG, fluorodeoxyglucose; IHC, immunohistochemistry; LDi, longest transverse diameter of lesion; MRI, magnetic resonance imaging; PET, positron emission tomography; PPD, cross product of LDi and perpendicular diameter; SDi, shortest axis perpendicular to LDi; SPD, sum of the products of perpendicular diameters of multiple lesions. For many patients, a score of 3 indicates a good prognosis with standard treatment, especially at interim scans. However, in trials involving PET investigating de-escalation, it may be preferable to consider a score of 3 as an inadequate response (to avoid undertreatment). Major Lesions Measured: Select up to the six largest major nodules, nodal masses, and extranodal lesions that can be clearly measured in two diameters. Nodules should preferably be from different areas of the body and should include the mediastinum and retroperitoneum, if applicable. Non-nodal lesions include lesions of solid organs (e.g., liver, spleen, kidneys, lungs), GI involvement, skin lesions, or lesions found on palpation. Unmeasured Lesions: Any disease not selected for measurement, primary disease, and truly evaluable disease should be considered unmeasured. These sites include any nodules, nodular masses, and extranodal sites that were not selected as primary or measurable or that did not meet the requirements for measurability but were still considered abnormal, as well as truly evaluable disease, which is any suspected site of disease that is difficult to track quantitatively by measurement, including pleural effusions, ascites, bone lesions, leptomeningeal disease, abdominal masses, and other lesions that cannot be confirmed and tracked by imaging. In the Waldeyer's ring or extranodal sites (e.g., GI tract, liver, bone marrow), FDG uptake may be higher than the mediastinum in a full metabolic response but should not be higher than normal physiologic uptake in the surrounding area (e.g., bone marrow activation due to chemotherapy or myeloid growth factor).

[0319] 5PS: 1, no uptake above background; 2, uptake less than or equal to the mediastinum; 3, uptake greater than the mediastinum but less than or equal to the liver; 4, uptake moderately greater than the liver; 5, uptake significantly greater than the liver and / or new lesions; X, new areas of uptake are unlikely to be related to lymphoma.

[0320] 5. Examples

[0321] The following examples are provided to illustrate the present invention. These examples are not meant to limit the present invention to any particular application or theory of operation.

[0322] Example 1 - Treatment of lymphoma using a combination of palamuximab, tafacitinib and lenalidomide

[0323] A phase 2 randomized, open-label, multicenter study was conducted to evaluate the efficacy and safety of palamuximab in combination with tadalafil and lenalidomide in subjects with relapsed or refractory diffuse large B-cell lymphoma (R / R DLBCL).

[0324] The combination of tafaciclib and lenalidomide has been granted accelerated approval in the United States for patients with R / R DLBCL, NOS. Tafaciclib is an Fc-modified monoclonal antibody that binds to the CD19 antigen expressed on the surface of pre-B and mature B lymphocytes and on several B-cell malignancies, including DLBCL. In a single-arm clinical trial (NCT02399085), tafaciclib combined with lenalidomide resulted in a response rate of 57.5%, a median DOR of 43.9 months, and a median PFS of 11.6 months in R / R DLBCL (Duell Haematologica. 2021; 106(9): 2417-26). Parametuzumab is a humanized bsAb that binds CD3 to the tumor antigen CD20 to recruit cytotoxic T cells to kill CD20 tumor cells. In an ongoing phase 1 study (Study XmAb13676-01, NCT02924402), palamuxomab produced durable responses in subjects with R / R DLBCL.

[0325] Without being bound by theory, we hypothesize that the combination of CD19 antigen and CD20 antigen will enhance the efficacy results in this population due to non-overlapping resistance mechanisms. In addition, this combination can activate and expand the innate immune system and adaptive effector cells, as well as modulate the tumor microenvironment. These characteristics support and warrant the study of the combination of palamuxetumab, tafacitinib, and lenalidomide. The trial first determines whether the combination of these 3 products can be safely administered and determines the dose for Part 2. The second part of the trial aims to determine the efficacy improvement (measured by PFS) over the DLBCL standard of care tafacitinib and lenalidomide (with the addition of palamuxetumab to tafacitinib and lenalidomide).

[0326] This is a randomized, multicenter, open-label, phase 2 study of parafitumab in combination with tafamidis plus lenalidomide versus tafamidis plus lenalidomide in adult subjects with DLBCL who had relapsed after or were refractory to at least one prior line of therapy that had included multiple doses of chemoimmunotherapy containing an anti-CD20 monoclonal antibody and who were not candidates for, refused, or had relapsed after ASCT.

[0327] Central pathologist interpretation will retrospectively confirm the diagnosis of DLBCL after enrollment using archival or recently obtained tissue. Central radiology and clinical reviewers 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 the imaging charter outlining the functions and processes. In addition, investigator-assessed responses will be recorded in the clinical database and will be analyzed for consistency. All subjects will be treated until progression or withdrawal for other reasons and then followed up for up to 5 years for OS.

[0328] This study will consist of 2 parts which will be conducted sequentially, with Part 1 enrolling and evaluating the safety of the subjects and determining the dose and schedule before the start of Part 2.

[0329] 5.1 Treatment options

[0330] The study will consist of 2 parts:

[0331] Part 1: Single-arm, dual-queue, safe trial run

[0332] Part 2: Open-label, randomized, two-arm efficacy and safety

[0333] Part 1: Single-arm, safety test run

[0334] Part 1 was a single-arm, two-cohort safety trial designed to determine the safety of the combination of palamuxolizumab, tafamidis, and lenalidomide.

[0335] Part 1 consists of a single-arm evaluation of the safety of the triple combination of palamuxetumab plus tafacitinib plus lenalidomide in 2 cohorts of at least 40 subjects, with at least 20 subjects in each cohort: Cohort 1A treats subjects with the triple combination at palamuxetumab dose level -1 (Table 2). Cohort 1B begins enrollment after cohort 1A completes enrollment. Cohort 1B treats subjects with the triple combination at palamuxetumab dose level 1. An initial safety evaluation is performed after all subjects in cohorts 1A and 1B have received treatment for at least C4D28 or discontinued due to an AE or progressive disease before C4D28. Following the initial safety evaluation of cohorts 1A and 1B, the pharmacologically optimal dose of palamuxetumab (dose level -1 or dose level 1) with an acceptable safety profile will advance to the randomized portion of the study (Part 2).

[0336] Treatment will consist of a combination of palamuxetumab, tafacitinib, and lenalidomide administered in 28-day cycles with 2 initial doses of tafacitinib administered prior to cycle 1. Palamuxetumab and tafacitinib may be administered until disease progression, unacceptable toxicity, or discontinuation for any other reason, whichever occurs first; however, lenalidomide may only be given for a maximum of 12 cycles total. Tafacitinib and palamuxetumab must not be used at the same time. On days when tafacitinib and palamuxetumab are administered, tafacitinib should be administered first, followed by palamuxetumab. It is recommended that each infusion be separated by at least 2 hours.

[0337] Part 2: Open-label, randomized

[0338] The open-label, randomized portion of the study (Part 2) will begin after initial safety evaluation of at least 40 subjects in Part 1. Prior to the start of Part 2, the protocol will be modified using the dosing regimen selected from Part 1 and will include adequate justification to support the dose / schedule proposed in Part 2.

[0339] During Part 2, subjects will be randomized to two treatment groups in a 1:1 ratio, stratified by baseline International Prognostic Index (IPI) risk score (3 to 5 vs. 0 to 2), number of lines of prior therapy (1 vs. ≥2), and primary refractory (yes vs. no). Primary refractory enrollment is limited to 36 of 200 subjects. Part 2 will enroll approximately 200 subjects. The sample size of Part 2 may be adjusted based on the results of Part 1. Enrollment will be increased to more than 200 by protocol amendment before the start of the randomized part. The Independent Data Monitoring Committee (IDMC) will review safety data in Part 2 and schedule meetings after 50, 100, and 150 subjects are randomized. The primary analysis of PFS will be performed after 89 disease progression and death events. An interim analysis of OS will be performed at that time.

[0340] Part 2 is the efficacy cohort, in which subjects are randomized to receive either Arm A or Arm B as follows:

[0341] A-arm:

[0342] Treatment will consist of a combination of palamuximab, tafacizumab, and lenalidomide administered in 28-day cycles with 2 initial doses of tafacizumab given prior to cycle 1. Palamuximab and tafacizumab may be administered until disease progression, unacceptable toxicity, or discontinuation for any other reason, whichever occurs first. Lenalidomide may be given for up to a total of 12 cycles.

[0343] Arm B:

[0344] Treatment consisted of a combination of tafacitinib and lenalidomide administered in 28-day cycles with 2 initial doses of tafacitinib given prior to cycle 1. Tafacitinib was administered until disease progression, unacceptable toxicity, or discontinuation for any other reason, whichever occurred first. Lenalidomide could be given for a maximum of 12 cycles total.

[0345] Dosage and schedule for Part 1 and Part 2 are as follows Figure 3 , and will be provided in further detail below.

[0346] Primary endpoint.

[0347] The primary endpoints of the study were, for part 1, safety, measured by the incidence of CRS and TEAEs, and for part 2, PFS, defined as the time from randomization to the first documented progressive disease or death, whichever occurred first, as assessed by BIRC using the Lugano 2014 criteria.

[0348] 5.2 Number of subjects

[0349] Part 1 will enroll at least 40 subjects, divided into 2 cohorts, with at least 20 subjects in each cohort.

[0350] Part 2 will enroll approximately 200 subjects. The sample size for Part 2 may be adjusted based on the results of Part 1. Enrollment will be increased to more than 200 via protocol amendment before the randomized portion begins. Enrollment in the primary refractory arm of Part 2 will be limited to 36 of the 200 subjects.

[0351] Overall, the study plans to enroll approximately 240 subjects.

[0352] 5.3 Treatment Allocation

[0353] Treatment assignment for Part 1 and randomization for Part 2 will be performed via a third-party randomization and trial supply management (RTSM) / interactive response technology (IRT) system.

[0354] Part 1: Single-arm safety test run

[0355] During the Part 1 safety run-in, 40 subjects will be enrolled and treated with palamuximab and tafacizumab plus lenalidomide (i.e., single-arm, non-controlled). Subjects will be considered enrolled if they sign the informed consent, are determined eligible, and receive the first dose of tafacizumab on Day -8.

[0356] Part 2: Open-label randomization

[0357] During Part 2, a total of 200 subjects will be randomized to: a 1:1 ratio of paramedicum and tafamizumab plus lenalidomide versus tafamizumab plus lenalidomide, stratified by baseline IPI risk score (3–5 vs. 0–2); number of prior lines of therapy (1 vs. ≥2); and primary refractory (yes vs. no). A maximum of 36 primary refractory subjects will be enrolled. Randomization will occur only if subjects have signed informed consent and are determined to be eligible. Study treatment will begin within 72 hours of randomization. Study treatment will begin on Study Day -8 with the first dose of tafamizumab.

[0358] 5.4 Subject inclusion criteria

[0359] Participants were eligible for the study if they were at least 18 years old and had a histologically confirmed diagnosis of DLBCL (not otherwise specified), including DLBCL arising from low-grade lymphoma. + and CD19 + .

[0360] 5.5 Dosing schedule and premedication

[0361] Paclitaxel dosing schedule and premedication

[0362] Subjects in Part 1 and subjects randomized to Arm A in Part 2 will receive palamuximab IV at a constant infusion rate over a minimum of 2 hours (-5 minute window). In Cycle 1, palamuximab will be administered every 7 days (±1 day) for 4 doses; beginning in Cycle 2, palamuximab will be administered every 2 weeks.

[0363] Subjects in Cohort 1A and Cohort 1B received palamuxomab according to the dose and schedule in Table 2.

[0364] Table 2. Paclitaxel dosing schedule for cohorts 1A and 1B

[0365]

[0366] Q2W = every 2 weeks

[0367] The dose and schedule of palamuxomab for part 2 will be determined in part 1.

[0368] The infusion rate may be adjusted to increase the duration of the infusion based on the investigator's judgment of safety. Due to variations in pump accuracy, infusions ending within the first 5 minutes of the required 2-hour period will not be considered a deviation.

[0369] On days when both products are given, palamuximab will be administered at least 2 hours after tafamidis. All subjects in Part 1 and all subjects randomized to Arm A in Part 2 will pre-dosed with the palamuximab dose shown in Table 3.

[0370] Table 3. Prior medications for palamuxomab

[0371]

[0372] IV = intravenous; PO = oral.

[0373] Subjects who have received 4 consecutive infusions at a stable dose and schedule without experiencing CRS or infusion reactions may have their premedication modified at the investigator's discretion.

[0374] If palamuxomab was discontinued, in the absence of disease progression and if the subject was still benefiting from study treatment, the subject could continue to receive other study treatment.

[0375] Tafacitinib dosing schedule and premedication

[0376] All subjects will receive tafacizumab. The initial dose will be administered on Days -8 and -4 of the 1-week run-in period. During the first 3 cycles of the study, tafacizumab will be infused on Days 1, 8, 15, and 22 of each cycle. Thereafter, tafacizumab will be administered every two weeks (every 14 days) on Days 1 and 15 of each 28-day cycle until disease progression, unacceptable toxicity, or discontinuation for any other reason, whichever occurs first (Table 4). The initial infusion rate of tafacizumab will be 70 mL / h for the first 30 minutes; then, the rate will be increased so that the infusion is completed in 1.5 to 2.5 hours. All subsequent infusions should be infused over 1.5 to 2 hours. On days when both products are administered, administer before paramedica.

[0377] Table 4. Dosing schedule of tafacitinib

[0378] Tafacitinib dosing regimen

[0379]

[0380] Q2W = every 2 weeks

[0381] Tafacitinib should be administered according to the package insert (e.g., see MONJUVIPI, 2021) and by a healthcare professional immediately using emergency equipment and appropriate medical support to manage infusion-related reactions.

[0382] All subjects will be pre-treated with the tafacitinib dose shown in Table 5.

[0383] Table 5. Pre-medication with tafacitinib

[0384]

[0385] IV = intravenous; PO = oral.

[0386] On study days when tafacizumab with paramatuzumab was administered, a single dose of dexamethasone was administered prior to the start of the tafacizumab infusion in Cycle 1. If paramatuzumab was withheld and tafacizumab was administered alone, premedication with prednisone or equivalent was required only for the first 3 doses and subsequently if an infusion-related reaction was observed.

[0387] For subjects who did not experience an infusion-related reaction during the first 3 infusions, premedication for subsequent infusions was optional. If a subject experienced an infusion-related reaction, premedication was administered prior to each subsequent infusion.

[0388] If tafacitinib was discontinued, in the absence of disease progression and if the subject was still benefiting from study treatment, the subject could continue to receive other study treatment.

[0389] Lenalidomide dosing regimen

[0390] All subjects will receive lenalidomide and self-administer a starting dose of 25 mg orally daily on days 1 to 21 of each cycle. No more than 21 doses of lenalidomide will be assigned per cycle. Investigators will follow the package insert or SmPC (e.g., REVLIMID PI, 2021; REVLIMID SmPC, 2022) for recommended medications and dose adjustments for the prevention of venous thromboembolic events. Subjects are advised to take lenalidomide with or without food at approximately the same time each evening. Subjects are advised to swallow the lenalidomide capsule whole with water and not to open, break or chew it. Treatment with lenalidomide may be adjusted or discontinued in a stepwise manner based on clinical and laboratory test results. Detailed dose adjustment guidelines for the management of hematologic and / or other toxicities are provided in the relevant sections of the protocol.

[0391] If lenalidomide was discontinued, subjects could continue to receive other study treatments in the absence of disease progression and if the subject was still benefiting from study treatment.

[0392] 5.6 Study Drugs and Storage

[0393] Paramatuzumab (XmAb13676)

[0394] Paramatuzumab (XmAb13676) is a humanized bsAb that binds to CD3 and the tumor antigen CD20 to recruit cytotoxic T cells to kill CD20-positive tumor cells.

[0395] Paramatuzumab has been designed to maintain the properties of full-length humanized monospecific antibodies in bsAbs, enabling the design of stable molecules with favorable in vivo half-life and allowing the use of standard antibody production methods.

[0396] Paramatuzumab (XmAb13676) is formatted as Fab-scFv-Fc (scFv, single-chain variable fragment), an Fc-based heterodimeric format that can only bind its bispecific antigen monovalently, as opposed to the bivalent binding of standard antibodies. The monovalency of CD3 is a key design constraint because bivalent binding of CD3 results in T cell activation in the absence of target cells expressing CD20. The Fc region of paramatuzumab has also been engineered to silence its affinity for Fc gamma receptors (FcγRs), which is critical to prevent T cell activation by cross-linking of paramatuzumab by FcγR-expressing cells. Xencor’s antibody discovery program has demonstrated that several bsAbs based on this format are highly but selectively active against target cells in primate models.

[0397] IV Solution Stabilizer (IVSS) is a concentrated form of the paramatuzumab (XmAb13676) buffer that also minimizes protein binding to administration equipment when paramatuzumab is administered at lower concentrations.

[0398] Paramatuzumab (XmAb13676) drug product (DP) is a sterile liquid supplied in 5 mg vials. Each 2 mL disposable glass vial contains 1.0 mL of drug product, which contains 5.0 mg paramatuzumab (XmAb13676) dissolved in 10 mM sodium succinate, 5% sucrose (weight to volume ratio, w / v) and 0.01% (w / v) polysorbate-80 (pH 5.5). Each product bottle is intended to deliver 1.0 mL of drug solution. Dilution instructions for any alternative fill volumes required during the study will be provided in the pharmacy manual.

[0399] IVSS will be supplied in disposable glass vials. Each vial contains 10.0 mL of a solution containing 250 mM sodium succinate and 0.25% (w / v) polysorbate-80 at pH 5.5. Each vial is intended to deliver 10.0 mL of IVSS solution.

[0400] Vials containing paramatuzumab and IVSS must be stored under refrigeration at 2°C to 8°C in an appropriately secure area accessible only to pharmacists, researchers, or duly designated personnel. Since paramatuzumab does not contain a preservative, an opened paramatuzumab vial must be used within 24 hours.

[0401] Tafacitumomab-cxix (tafacitumomab)

[0402] Tafacitumomab (tafacitumomab-cxix) is a cytolytic antibody directed against CD19 indicated in the US in combination with lenalidomide for the treatment of adult patients with R / R DLBCL not otherwise specified (NOS) (including DLBCL arising from low-grade lymphoma) who are ineligible for ASCT. Tafacitumomab is also approved in the EU in combination with lenalidomide and tafacitumomab monotherapy sequentially for the treatment of adult patients with relapsed or refractory DLBCL who are ineligible for ASCT. Tafacitumomab is a humanized cytolytic monoclonal antibody directed against CD19 containing a hybrid IgG1 / 2 Fc domain with 2 amino acid substitutions to alter the Fc-mediated function of the antibody. It is produced in mammalian cells (Chinese hamster ovary) by recombinant DNA technology. The molecular weight of tafacitumomab is approximately 150 kDa

[0403] Tafacitumab-cxix for injection is provided in 200 mg vials, which contain a sterile, preservative-free, white to slightly yellow 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 and the pH is 6.0. Each single-dose vial contains 200 mg of tafacitumab, citric acid monohydrate (3.7 mg), polysorbate 20 (1 mg), sodium citrate dihydrate (31.6 mg) and trehalose dihydrate (378.3 mg).

[0404] Vials containing tadalafil should be stored according to the package insert or SmPC (MONJU VIPI, 2021; MONJUVI smPC, 2021).

[0405] Lenalidomide

[0406] Lenalidomide (thalidomide analogue) is an immunomodulatory agent with antiangiogenic and antitumor properties It is indicated for the treatment of adult patients with multiple myeloma, myelodysplastic syndrome, mantle cell lymphoma, follicular lymphoma, and marginal zone lymphoma (see REVLIMID PI, 2021 or REVLIMID SmPC, 2022).

[0407] Lenalidomide may be provided by the investigator or as clinical trial material / study drug (REVLIMID or regionally approved generic lenalidomide).

[0408] Lenalidomide should be stored according to the package labeling of REVLIMID or generic lenalidomide.

[0409] 5.7 Study Drug Preparation and Handling

[0410] Paramatuzumab (XmAb13676)

[0411] Please note that palamuxomab has pharmacodynamic effects in vivo at very low concentrations, so each vial of product must be highly diluted prior to administration.

[0412] Paramatuzumab solutions are prepared under sterile conditions. Prior to administration, paramatuzumab will be diluted to the desired 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. Prior to dilution, vials containing parenteral drug product should be visually inspected. If particulate matter and / or discoloration are observed, the drug should not be administered and the sponsor should be notified. After dilution, the bag containing paramatuzumab (XmAb13676) should be gently inverted 2 to 3 times to mix the solution. Be sure not to shake the bag.

[0413] Paramatuzumab has been previously used in humans in a Phase 1 clinical study (XmAb13676-01). In the XmAb13676-01 study, CRS was frequently observed, especially at the Cycle 1 Day 1 dose. The Principal Investigator or a Deputy Investigator (MD) must be available at all times during and for at least 24 hours after administration of Paramatuzumab doses.

[0414] All subjects will be pre-treated with 20 mg of dexamethasone by IV approximately 30 to 60 minutes prior to the start of the tafacictumab infusion during Cycle 1. If the tafacictumab infusion is suspended for any reason during Cycle 1, dexamethasone will be given 1 hour prior to the start of paramedicum administration. After Cycle 1, pre-treatment with dexamethasone is not necessary and is permitted at the discretion of the investigator. (Cetirizine or other antihistamines may be used instead of diphenhydramine).

[0415] Administration of palamuximab should be started as soon as possible after preparation of the dosing solution. If administration is delayed, it may be stored at room temperature for no more than 4 hours or at 2°C to 8°C for no more than 12 hours prior to infusion.

[0416] Paramatuzumab should not be administered as an IV bolus or injection.

[0417] Study drug will be administered as an open-label solution at a constant rate over at least 2 hours (-5 minute window) using a dedicated infusion set. Care should be taken to prevent CRS or infusion reactions / allergic reactions during tocilizumab administration. Because CRS or allergic / infusion reactions may occur, emergency resuscitation equipment ("crash carts") and medications, including steroids and tocilizumab, should be available in the vicinity of the area where subjects receive infusions. Other supportive measures should be taken, including but not limited to acetaminophen, antihistamines, corticosteroids, IV fluids, bronchodilators, epinephrine, vasopressors, and oxygen.

[0418] Tafacitinib

[0419] Tafacitinib was prepared and administered according to the package insert or SmPC (MONJUVIPI, 2021; MONJUVI smPC, 2021).

[0420] Lenalidomide

[0421] Lenalidomide comes as an oral capsule that the study center will dispense to participants.

[0422] Lenalidomide will be assigned to subjects for oral administration in the evening according to the package insert or SmPC (REVLIMID PI, 2021; REVLIMID SmPC, 2022). Subjects will be given a diary to record the date and time of each lenalidomide administration and provide product records.

[0423] If a subject misses a dose of lenalidomide and it is less than 12 hours before the usual dosing time, the subject should be instructed to make up the missed dose and then take the next dose on their regular schedule.

[0424] 5.8 Pharmacokinetics, Pharmacodynamics, and Biomarker Assessment

[0425] Pharmacokinetic analysis, serum assessment of antidrug antibodies, cytokines, and rituximab levels

[0426] Venous blood samples will be obtained according to the schedule listed in Tables 6 and 7 for analysis of serum paramatuzumab and tafacitumab PK, paramatuzumab and tafacitumab ADA, cytokines, and rituximab levels. The remaining samples will be stored for additional testing of biomarkers associated with pharmacodynamic activity, clinical response, or study drug resistance. In Table 6, paramatuzumab PK, cytokines, and ADA, as well as ECG, will be performed on subjects in Part 1 and subjects randomized to Arm A in Part 2. All times are relative to paramatuzumab infusion. On the days of administration of tafacitumab and paramatuzumab, pre-dose samples will be drawn and ECGs performed before starting tafacitumab infusion. Tafacitumab anti-drug antibodies and pharmacokinetics will be studied in all subjects in Table 7. All times are relative to tafacitumab infusion.

[0427]

[0428]

[0429]

[0431] Pharmacodynamics and biomarker assessment

[0432] Peripheral blood assessment

[0433] Blood samples will be collected to explore the pharmacodynamic effects of parametuzumab, tafacitinib, 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. The frequencies of circulating T cells, B cells, and NK cells will also be monitored. Additional blood samples will be drawn into PAXGENE RNA tubes and stored for potential exploratory studies of leukocyte function and pharmacodynamic effects by RNA sequencing and transcriptome gene and pathway analysis. Peripheral baseline and pharmacodynamic markers will be evaluated for correlation with CRS and AE incidence, as well as clinical response and resistance. CRS assessment within 24 hours after each dose will include monitoring of serum cytokines and flow cytometry evaluation of changes in T cell numbers and activation status in peripheral blood.

[0434] Blood samples will be collected at screening and treatment to measure ctDNA. By using DNA sequencing methods to track the levels and mutations of ctDNA during treatment, ctDNA, as a measure of MRD, will be explored as a marker of clinical response. Blood samples can also be used to evaluate germline DNA variations across the genome to account for tumor-specific DNA mutations.

[0435] Detailed instructions for handling and shipping peripheral blood samples are provided in the laboratory manual. Please refer to Table 9 (Evaluation Schedule) for the sampling schedule. Non-scheduled samples may be collected and sent to the designated central laboratory at the discretion of the investigator. Remaining peripheral blood mononuclear cells, plasma samples, and serum samples will be stored at the designated central laboratory and may be used to evaluate additional future exploratory biomarkers associated with pharmacodynamic activity, clinical response, or resistance to the study drug.

[0436] Tumor biopsy

[0437] Archival tissue - Archival blocks (preferred) or unstained slides will be requested from lymph node biopsy to confirm the DLBCL diagnosis, determine cell of origin status, and perform genomic mutation analysis. Cell of origin analysis (COO), germinal center B cell (GCB), or activated B cell type (ABC) origin will be determined using transcriptional analysis, NANOSTRING LYMPHC2X, or other gene expression methods. Immunohistochemistry analysis will be performed using relevant markers from the Hans algorithm (Yoon, 2017).

[0438] Archival tissue of diagnostic tumor mass or lymph nodes must be confirmed to be available at study entry and will be collected and sent to the designated central laboratory within 8 weeks after the first dose of study drug or randomization. The sampling schedule is shown in Table 9 (Assessment Schedule). If archival tissue is not available, a fresh tumor biopsy will be requested at baseline.

[0439] Baseline and On-Treatment Tumor Biopsies: Baseline Biopsy: Fresh tumor biopsies (excisional or core needle biopsies) are encouraged because they allow for an unbiased analysis of tumor status, whereas archival biopsies may not reflect the effects of therapy prior to the start of the study. Therefore, if the subject consents and there is palpable lymph node involvement (e.g., superficial lymphadenopathy), a pre-treatment baseline biopsy will be requested to allow for low-risk surgery to obtain tissue. Excisional or core needle biopsies are acceptable, but fine needle aspiration is not acceptable.

[0440] Baseline and During Treatment Tumor Biopsies: During Treatment Biopsies: During treatment biopsies are required for subjects with palpable lymphadenopathy. During treatment biopsies should be obtained during the fourth week of treatment (after the C1D22 dose, but before the C2D1 dose). For responding subjects, additional biopsies are recommended at the time of progression to determine the molecular and cellular basis of progression and specifically exclude loss of CD19 or CD20 expression as a mechanism of acquired resistance.

[0441] Tumor tissue from archival, pre-treatment, during-treatment, and progression biopsies will be processed to enable analyses including, but not limited to: (1) DNA sequencing to identify acquired genetic alterations in tumor cells; (2) RNA analysis of the tumor and tumor microenvironment; and (3) immunostaining of the tumor for CD19 and CD20 expression, as well as for inflammatory cells (including T cells) in the microenvironment.

[0442] Biopsies will be collected at baseline and during treatment and sent to a central laboratory. The sampling schedule is shown in Table 8.

[0443]

[0444]

[0445]

[0446]

[0447]

[0448]

[0449]

[0450]

[0451] Following analysis of study-specified tumor biopsies, remaining archival and fresh biopsy samples will be stored at a designated central laboratory for evaluation of additional future exploratory biomarkers associated with pharmacodynamic activity, clinical response, or resistance to study drug.

[0452] 5.9 Efficacy evaluation

[0453] Efficacy evaluation

[0454] Response assessment will be determined as specified in Table 9.

[0455] Table 9. Response Assessment

[0456]

[0457]

[0458]

[0459] 5PS = 5-point scale; CT = computed tomography; FDG = fluorodeoxyglucose; IHC = immunohistochemistry; LDi = longest transverse diameter of lesion; MRI = magnetic resonance imaging; PET = positron emission tomography; PPD = cross product of LDi and perpendicular diameter; SDi = shortest axis perpendicular to LDi; SPD = sum of the products of perpendicular diameters of multiple lesions.

[0460] a In the Waldeyer's ring or extranodal sites (eg, GI tract, liver, bone marrow), FDG uptake may be higher than in the mediastinum in the setting of a complete metabolic response but should not be higher than normal physiologic uptake in the periphery (eg, due to bone marrow activation caused by chemotherapy or myeloid growth factors).

[0461] b PET 5PS: 1, no uptake above background; 2, uptake ≤ mediastinum; 3, uptake > mediastinum but ≤ liver; 4, moderate uptake > liver; 5, uptake significantly above liver and / or new lesions; X, new area of ​​uptake is unlikely to be related to lymphoma.

[0462] Main lesions measured: Select up to the six largest primary nodules, nodal masses, and extranodal lesions that can be clearly measured in two diameters. Nodules should preferably be from different regions of the body and should include the mediastinum and retroperitoneum, if applicable. Non-nodal lesions include lesions of solid organs (e.g., liver, spleen, kidney, lung), GI involvement, skin lesions, or lesions found on palpation. Recent biopsy lesions should not be used as primary lesions for measurement.

[0463] Lesions not measured: Any disease not selected for measurement, primary disease, and truly evaluable disease should be considered unmeasured. These sites include any nodules, nodular masses, and extranodal sites that were not selected as primary or measurable or that did not meet the requirements for measurability but were still considered abnormal, as well as truly evaluable disease, which is any suspected site of disease that is difficult to quantitatively track with measurement, including pleural effusions, ascites, bone lesions, leptomeningeal disease, abdominal masses, and other lesions that cannot be confirmed and tracked with imaging.

[0464] The investigators and BIRC will assess the response to study drug at each efficacy time point. The following endpoints will be reported:

[0465] Progression-free survival: defined as the time from randomization to the first documented progressive disease or death, whichever comes first. Investigators and BIRC will determine progressive disease events in all randomized subjects. PFS assessed by the BIRC is the primary endpoint of Part 2 of this study. To determine the sample size, it was assumed that the triple combination therapy would improve the median PFS from 12 months (with tafacitinib + lenalidomide treatment (Duell Haematologica. 2021; 106(9): 2417-26)) to 23.5 months (with triple combination therapy (palamotuzumab + tafacitinib + lenalidomide)), corresponding to a hazard ratio (HR) of 0.51 for all randomized subjects (an estimated 90% of subjects will be diagnosed with DLBCL by central pathology). The power of the log-rank test was 90% and the sample size was 200 (93 events) to maintain a type I error of 0.025 (one-sided). The sample size calculation assumes a loss to follow-up rate of 1.5% / month. Subjects will be randomized 1:1 and stratified by baseline IPI risk score (3 to 5 vs. 0 to 2), number of prior lines of therapy (1 vs. ≥2), and primary refractory (yes vs. no). A maximum of 36 primary refractory subjects will be enrolled in the sample size of 200. Enrollment of 200 subjects is expected to take 27 months, with a minimum follow-up of 6 months. A 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 at the time of the final PFS analysis will be performed using a group sequential design.

[0466] Duration of Response: Defined as the time from first response (CR or PR) to progression or death from any cause in subjects who achieve a CR or PR and in subjects with a CR. DOR will be derived using disease progression as determined by BIRC for subjects with a response (CR or PR).

[0467] Overall survival: defined as the time from randomization to death from any cause. All randomized subjects will receive up to 5 years of survival follow-up. Overall survival will be assessed in the randomized population (Part 2). The one-sided alpha level for the test OS is 0.025. Assuming that the median OS of Arm B in Part 2 is 34 months, Arm A in Part 2 will improve by 40% over Arm B (ie, median OS = 56.6 months, HR = 0.60). In addition, assuming that enrollment is completed within 27 months, the minimum follow-up time is 24 months, and the OS censoring rate (missing rate) is approximately 1% per month, the study will produce a statistical significance with a power of 60%. Once 65% of the information (death events) is available, an interim analysis of OS will be planned. Advantage analysis will be performed during the interim and final analysis.

[0468] 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 determined by the investigator and BIRC.

[0469] Additionally, adverse events and other safety parameters, including the incidence of cytokine release syndrome (CRS), will be assessed.

[0470] 5.10 Toxicity Management

[0471] Toxicity from the 3-drug regimens (pamostatin, tafamidis, and lenalidomide) may be identified during the study. Management of known toxicities (eg, CRS, infusion-related reactions, hematologic toxicity, and tumor lysis syndrome) is outlined below.

[0472] Cytokine Release Syndrome : ASTCT defines CRS as a supraphysiological reaction after any immunotherapy that results in the activation or involvement 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 leakage (hypoxia), and end-organ dysfunction (Lee DW, Santomasso BD, Locke FL, et al. ASTCT consensus grading for cytokinerelease syndrome and neurologic toxicity associated with immune effector cells. Biol Blood Marrow Transplant. 2019; 25(4)625–38).

[0473] CRS can present with a wide range of symptoms, from mild flu-like symptoms to severe, life-threatening manifestations of an inflammatory response. Mild symptoms of CRS include fever, fatigue, headache, rash, arthralgia, and myalgia. More severe cases are characterized by hypotension and high fever and may progress to an uncontrolled systemic inflammatory response with circulatory shock requiring vasopressors, vascular leak, disseminated intravascular coagulation, and multi-organ system failure (Shimabukuro-Vornhagen A, Cytokine release syndrome, P, Subklewe M, et al. J Immunother Cancer. 2018; 6(1): 56). CRS is more likely to occur after the first dose of paramatuzumab than after subsequent doses, tends to start slightly later than hypersensitivity reactions, and is more likely to be associated with liver and neurological complications. Symptoms of paramatuzumab-associated CRS observed in the Phase 1 study include:

[0474] Aphasia or difficulty finding words

[0475] Joint pain

[0476] Confusion / altered mental status / delirium Increased serum creatinine

[0477] ·sweat

[0478] ·Dizziness

[0479] Difficulty breathing

[0480] Fatigue (weakness, drowsiness, malaise)

[0481] ·fever

[0482] ·Gait disorders / dysmetria

[0483] ·Headache

[0484] Hypotension / hypertension

[0485] Hypoxia

[0486] Myalgia

[0487] Nausea / vomiting

[0488] Chills / chills

[0489] Tachycardia

[0490] Shortness of breath

[0491] ·epilepsy

[0492] Elevated transaminases / hyperbilirubinemia

[0493] Tremor

[0494] CRS toxicity was defined using the ASTCT CRS consensus grading (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). The relevant definitions are shown in Table 10.

[0495] Table 10. American Society for Transplantation and Cellular Therapy consensus classification of cytokine release syndrome

[0496]

[0497] BiPAP = bilevel positive airway pressure; CPAP = continuous positive airway pressure; CRS = cytokine release syndrome; CTCAE = Common Terminology Criteria for Adverse Events.

[0498] Organ toxicities associated with CRS can be graded according to CTCAE v5.0, but they do not affect the CRS grade.

[0499] a Fever was defined as a temperature ≥ 38°C not attributable to any other cause. For subjects who had CRS and received antipyretics or anti-cytokine therapy (such as tocilizumab or steroids), fever was no longer required to grade the severity of subsequent CRS. In this setting, CRS grade was determined by hypotension and / or hypoxia.

[0500] b The CRS grade was determined by the more severe event: hypotension or hypoxia not attributable to any other cause. For example, a subject with a temperature of 39.5°C, hypotension requiring 1 vasopressor, and hypoxia requiring a low-flow nasal cannula was classified as Grade 3 CRS.

[0501] c Low-flow nasal cannula is defined as oxygen delivered ≤6 L / min. Low flow also includes insufflation-based oxygen delivery, which is sometimes used in pediatrics. High-flow nasal cannula is defined as oxygen delivered >6 L / min.

[0502] Safety run-in and part 2, Arm A (palamotuzumab, tafamidis, and lenalidomide) : Paramatuzumab can cause CRS. CRS has not been observed in clinical trials with tadalafil and lenalidomide. However, lenalidomide, through its potential to activate T cells, may enhance CRS in combination with paramatuzumab. In addition, to avoid overlap of CRS caused by paramatuzumab with infusion-related reactions induced by tadalafil, paramatuzumab should always be given after tadalafil if administered on the same day. See section 5.11 for dose adjustments of lenalidomide and paramatuzumab in the setting of CRS.

[0503] Part 2, Arm B (tafamidis and lenalidomide) : If CRS is observed while using tadalafil, treatment guidelines provided for palamuxolizumab should be followed.

[0504] Cytokine Release Syndrome for 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 im munomodulatory monoclonal antibodies. MAbs. 2010; 2(3): 233–55), but some manifestations are common to both AEs, and both have been reported to occur with therapeutic antibodies. Although cytokine release may be associated with immune cell activation, how it is triggered is unclear; in this setting, CD3-expressing lymphocytes may be the primary effectors of CRS.

[0505] Tocilizumab for cytokine release syndrome :Tocilizumab It is a therapeutic antibody that interferes with the binding of interleukin 6 (IL-6) to the IL-6 receptor. Tocilizumab can be used to reduce the severity of severe CRS and may reduce mortality, and early administration can be used to improve outcomes. Tocilizumab (at a dose of 8 mg / kg) should be available at all times if needed, and repeated doses of tocilizumab may be required if signs and symptoms persist or recur after initial treatment. In some cases, another treatment (instead of tocilizumab) can be used to treat CRS.

[0506] Fluid Management : CRS may be associated with myocardial dysfunction, pulmonary edema, or capillary leak syndrome (Shimabukuro-Vornhagen A, P, Subklewe M, et al. Cytokine release syndrome. J Immunother Cancer. 2018;6(1):56). Monitor subjects for weight gain and, in acute settings, for intravenous (IV) fluid administration. The following are guidelines for administering fluids:

[0507] If a subject is noted to have gained ≥10% body weight in the past 2 weeks and develops new or significantly increased bilateral lower extremity edema, dosing should be delayed until this finding is evaluated and treated, if indicated.

[0508] For acute hypotension, IV fluid boluses should be limited to 500 to 1000 mL of normal saline or equivalent.

[0509] If the response to fluids is inadequate, treatment with tocilizumab (and vasopressors, if necessary) should be considered rather than additional fluid boluses.

[0510] Guidelines for the treatment of cytokine release syndrome according to ASTCT CRS consensus level:CRS treatment guidelines are listed by level as follows

[0511] Level 1

[0512] Symptomatic management is recommended: 650 mg of acetaminophen orally as an antipyretic or analgesic, and / or 25 to 50 mg of diphenhydramine intravenously or orally for rash, pruritus, or other signs and symptoms of hypersensitivity (allergy), as clinically indicated.

[0513] Measure vital signs every 15 minutes or less, or as clinically indicated.

[0514] Obtain unscheduled blood samples for cytokine analysis during the event and approximately 4 hours afterward, unless scheduled cytokine monitoring is already being performed on the same visit day.

[0515] Monitor the subject for worsening of his or her condition; if the event increases in severity to a higher grade, stop the infusion and administer steroids.

[0516] Level 2

[0517] Hypotension responsive to fluids not requiring vasopressors or mild respiratory symptoms treatable with low-flow oxygen are signs of Grade 2 toxicity. Older subjects or subjects with severe comorbidities may be at increased risk for decompensation in this setting.

[0518] - Stop the infusion, and / or administer additional dexamethasone at a dose of 10 to 20 mg IV, and / or acetaminophen 650 mg orally, and / or diphenhydramine 25 to 50 mg IV or orally to treat signs and symptoms.

[0519] Once symptoms subside, restart the infusion at 50% of the baseline rate. If after 1 hour, the subject has no recurrence of symptoms and vital signs are stable, the infusion rate may be increased every 30 minutes as tolerated until the baseline rate is reached.

[0520] Measure vital signs every 15 minutes or less frequently as clinically indicated. For subjects who can tolerate an increase in the infusion rate back to baseline and maintain normotension within 30 minutes of the rate increase, vital sign assessments may be reduced to every 30 minutes during the infusion.

[0521] Obtain unscheduled blood samples for cytokine analysis during the event and approximately 4 hours afterward, unless scheduled cytokine monitoring is already being performed on the same visit day.

[0522] Monitor the subject for worsening of his or her condition; if the event increases in severity to a higher grade, stop the infusion and administer appropriate treatment, and follow guidelines for Grade 3 and 4 reactions if necessary.

[0523] In this setting, older subjects or subjects with severe comorbidities may be at higher risk of decompensation. When these vulnerable subjects develop a response or rapidly progress to a response, treatment with tocilizumab 8 mg / kg IV for 1 hour with or without dexamethasone 10 to 20 mg IV (or equivalent) should be considered.

[0524] Level 3 and 4

[0525] Stop the infusion and disconnect the subject's IV line.

[0526] An additional 10 mg of dexamethasone was administered intravenously.

[0527] Provide aggressive supportive care immediately. Use vasopressors, fluids, oxygen, epinephrine or bronchodilators, ventilatory support, antipyretics, and analgesics as indicated.

[0528] Due to the higher risk of progression and permanent organ dysfunction, tocilizumab therapy (8 mg / kg IV for 1 hour) is recommended for CRS (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).

[0529] Admission to hospital for observation, usually to an intensive care unit, is almost always necessary because initial improvement may quickly lead to rapid decompensation.

[0530] Subjects with Grade 3 CRS or infusion reactions, once resolved, may be re-challenged as described in Section 5.11 and Table 14. Subjects with recurrent Grade 3 or any Grade 4 reactions should not receive further palamuximab treatment but will continue to be followed per protocol (i.e., for long-term survival follow-up).

[0531] Obtain unscheduled blood samples for cytokine analysis during the event and approximately 4 hours afterward, unless scheduled cytokine monitoring is already being performed on the same visit day.

[0532] Obtain unscheduled samples for antidrug antibody (ADA) testing as close to the onset of an event as possible, at resolution of an event, and approximately 28 days after an event unless scheduled cytokine monitoring is being performed on the same visit date.

[0533] ·Physician and / or medical monitor should be contacted.

[0534] 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 present with delirium, encephalopathy, aphasia, lethargy, inattention, agitation, tremor, seizures, and rarely, cerebral edema (Lee DW, Santomasso BD, Locke FL, et al. ASTCT consensus grading for cytokine release syndrome and neurologictoxicity associated with immune effector cells. Biol Blood Marrow Transplant. 2019; 25(4)625–38). Due to the timing of treatment and treatment response of neurotoxicity, its treatment is separate from CRS.

[0535] Neurological symptoms may develop during or after CRS symptoms but rarely precede them. The earliest manifestations of ICANS are tremor, dysgraphia, mild expressive speech difficulties (especially naming objects), impaired attention, apraxia, and mild somnolence. Headache is a nonspecific symptom that often occurs during fever or after chemotherapy in patients without other neurological deficits. Therefore, headache alone is not an appropriate marker for ICANS. Expressive aphasia, on the other hand, appears to be a very specific symptom of ICANS.

[0536] The consensus grading scheme is a slightly modified version of the CARTOX-10 screening tool that incorporates key elements of the Mini-Mental State Examination, the immune effector cell-associated encephalopathy (ICE) score, for grading ICANS (Table 11). The 10-point ICE screening tool helps assess whether a subject has encephalopathy; however, grading ICANS requires the 10-point ICE score assessment as well as other neurologic domain assessments, such as level of consciousness, motor symptoms, seizures, and signs of increased intracranial pressure / cerebral edema, which may or may not be present with 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.

[0537] Table 11. Immune effector cell-related encephalopathy scores

[0538]

[0539] ICANS = immune effector cell-associated neurotoxicity syndrome; ICE = immune effector cell-associated encephalopathy (score).

[0540] Rating: 10, no damage;

[0541] 7–9, ICANS level 1;

[0542] 3–6, Level 2 ICANS;

[0543] 0–2, 3-level ICANS;

[0544] 0, because the patient cannot be aroused and ICE assessment is not possible, 4 ICANS

[0545] Table 12. American Society for Transplantation and Cellular Therapy consensus toxicity grades for immune effector cell-related neurotoxicity syndromes in adults

[0546]

[0547]

[0548] EEG = electroencephalogram; ICANS = immune effector cell-associated neurotoxicity syndrome; ICE = immune effector cell-associated encephalopathy (score); ICP = intracranial pressure; N / A = not applicable; VI = sixth.

[0549] The ICANS grade is determined by the most severe event (ICE score, level of consciousness, seizures, motor manifestations, increased ICP / cerebral edema) that cannot be attributed to any other cause; for example, a patient with an ICE score of 3 who presents with a generalized seizure is classified as a grade 3 ICANS.

[0550] a A patient with an ICE score of 0 might be classified as a grade 3 ICANS if they had complete aphasia while awake, but a patient with an ICE score of 0 might be classified as a grade 4.

[0551] b A decreased level of consciousness should not be attributed to other causes (eg, absence of sedative medications).

[0552] c Tremor and myoclonus associated with immune effector cell therapy can be graded according to CTCAE v5.0, but they do not affect the ICANS grade.

[0553] dIntracranial hemorrhage with or without associated edema is not considered a neurotoxic feature and is excluded from the ICANS classification. It can be graded according to CTCAE v5.0

[0554] High levels of IL-6 may directly mediate neurotoxicity. The human anti-IL-6 monoclonal antibody tocilizumab 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 mainstay of therapy and may be considered if corticosteroids are ineffective.

[0555] Clinical Management of Neurotoxicity:

[0556] Monitor subjects for signs and symptoms of events (including use of mental status and neurologic examinations).

[0557] If neurotoxicity becomes evident, an unscheduled blood sample will be drawn for cytokine analysis at that time and again 4 hours later unless scheduled cytokine monitoring has already occurred on the same visit day.

[0558] If neurotoxicity was grade 4, palamuxomab was discontinued.

[0559] For grade 3 neurologic toxicity, withhold until toxicity recovers to ≤ grade 1 (mild) and remains ≤ grade 1 for at least 3 days before restarting therapy. Restart therapy at 75% of the previous dose. If grade ≥2 toxicity does not recur, increase dose back to full dose at next dose. Permanently discontinue if grade ≥2 toxicity recurs at 75% dose, or if grade <2 toxicity takes more than 7 days to resolve. Permanently discontinue palamuximab if grade 3 neurologic toxicity persists for more than 7 days.

[0560] For severe neurologic symptoms, if symptoms do not resolve rapidly, administer 10 mg additional dexamethasone intravenously and repeat every 12 hours.

[0561] For recurrent seizures, anticonvulsant therapy may be required.

[0562] Allergic / hypersensitivity / infusion-related reactions : Infusion-related reactions can occur with both tafacitinib and palamectomy. Allergic reactions are usually caused by a type 1 hypersensitivity mechanism resulting from immunoglobulin E (IgE)-mediated release of histamine and prostaglandins, but direct interactions with mast cells and basophils may also occur. 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.

[0563] Signs and symptoms usually develop during or shortly after the drug infusion in a hypersensitivity reaction, are more likely to develop after a few doses, and are strongly related to histamine release. Typical signs and symptoms include rash / hives, flushing, itching, fever, difficulty breathing, cough, and low blood pressure, but the following symptoms may also occur

[0564] Joint pain

[0565] Bronchospasm

[0566] Confusion / altered mental status / delirium

[0567] ·Dizziness

[0568] Fatigue (weakness, drowsiness, malaise)

[0569] Hallucinations

[0570] ·Headache

[0571] ·hypertension

[0572] Myalgia

[0573] Nausea / vomiting

[0574] Chills / chills

[0575] ·sweat

[0576] Tachycardia

[0577] Allergic / hypersensitivity / infusion-related reactions were managed according to institutional practices and guidelines. Allergic / hypersensitivity reactions were defined according to the NCI-CTCAE version 5.0 (NCI-CTCAE, 2017) definition of anaphylaxis.

[0578] Safety run-in and part 2, Arm A (palamotuzumab, tafamidis, and lenalidomide) : Infusion-related reactions may occur with the use of palamuxetumab and tafacitinib. To mitigate overlapping toxicities with palamuxetumab, tafacitinib should be administered first on a given treatment day, and at least 2 hours should elapse between the end of the tafacitinib infusion and the start of the palamuxetumab infusion. If a grade >1 infusion reaction occurs with tafacitinib, the administration of palamuxetumab should be delayed until all symptoms of the reaction resolve. Depending on the time to resolution of all symptoms, palamuxetumab may need to be administered the following day.

[0579] Part 2, Arm B (tafamidis and lenalidomide) : Infusion-related reactions may occur with the use of tafamidis and lenalidomide. Instructions for toxicity management provided in the tafamidis prescribing information may be followed. For dose modifications, see section 5.11.

[0580] Hematological toxicityHematologic toxicity, particularly decreases in absolute neutrophil count (ANC) and platelet count, has been observed in clinical trials with tadalafil and lenalidomide. Decreases in platelets and ANC were observed with palamuxetin (see Table 13).

[0581] Table 13: Adverse events of neutropenia and thrombocytopenia (all grades) with tafamidis / lenalidomide and palamuxomab

[0582] <![CDATA[Talacetamab a / lenalidomide]]> <![CDATA[Paramotomab b > Neutropenia 51％ 20.8％ Thrombocytopenia 31％ 24.0％

[0583] a [SmPC]. Noord-Holland, Netherlands: Incyte Biosciences Distribution BV2021; (tafas) [Packaging Instructions]. Boston, MA: MORPHOSYS USINC. 2021.

[0584] b Plamotamab Investigator's Brochure,2021

[0585] These declines may be exacerbated or last longer when these products are given in combination. Carefully monitor blood counts and follow institutional guidelines for management 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 drug until counts have recovered to at least Grade 2 levels. Refer to Section 5.11 for any dose adjustments of study drug.

[0586] Safety run-in and part 2, Arm A (palamotuzumab, tafamidis, and lenalidomide) : Hematologic toxicities may occur in clinical trials of tadalafil and lenalidomide; specifically, ANC and platelet counts may decrease. Decreases in platelets and ANC may also occur with the use of tadalafil. The magnitude of these decreases may be exacerbated or last longer when these products are given in combination. Monitor blood counts carefully and follow institutional guidelines for treatment of neutropenia and thrombocytopenia, which may include growth factors and whole blood / blood product transfusions. Management may also include delaying administration of study drug until counts have recovered to at least Grade 2 levels. Refer to section 5.11 for any dose adjustments of study drug.

[0587] Part 2, Arm B (tafamidis and lenalidomide) : Hematologic toxicity may occur with the use of tafamidis and lenalidomide. Instructions for toxicity management provided in the tafamidis prescribing information should be followed. Refer to section 5.11 for any dose adjustments of study drug.

[0588] Tumor lysis syndrome Tumor Lysis Syndrome (TLS) is a rare but serious and life-threatening condition resulting from the rapid release of tumor cell contents following lysis; the resulting metabolic imbalance may lead to acute renal failure and / or other life-threatening conditions. Subjects with high tumor burden, hyperproliferative disease, and / or certain pre-existing conditions (e.g., renal disease) are at increased risk for TLS.

[0589] Safety run-in and part 2, Arm A (palamotuzumab, tafamidis, and lenalidomide) : It is unknown whether treatment with paramatuzumab, tafamidis, and lenalidomide leads to the development of TLS in R / R DLBCL. A Phase 1 study of paramatuzumab monotherapy in CD20-expressing hematological malignancies reported TLS of any grade in 4 of 96 subjects (4.2%), with only 2 of 80 subjects with R / R NHL (2.5%) experiencing TLS; importantly, no serious or fatal TLS events were reported with paramatuzumab monotherapy in R / R DLBCL. Similarly, no TLS events were reported in a Phase 2, open-label, single-arm, tafamidis plus lenalidomide study in R / RDLBCL (L-MIND). However, fatal cases of TLS have been reported with lenalidomide in other indications and combinations. Prior to initiating study medication, all subjects should be assessed for TLS risk based on laboratory parameters and tumor volume, per institutional practice

[0590] Prevention, Monitoring, and Treatment of Tumor Lysis Syndrome: For subjects at high risk for TLS, prophylaxis should be initiated prior to initiation of treatment. Hospitalization may be considered for subjects considered at higher risk for TLS and / or creatinine clearance <80 mL / min. Allopurinol (or other xanthine oxidase inhibitors) should be initiated at least 48 hours prior to C1D1 for 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 prior to administration of study medication, including uric acid, potassium, phosphorus, calcium, and creatinine. Laboratory results should be evaluated in real time. If a subject is unable to take in adequate oral fluids, IV fluids should be added.

[0591] If a subject experiences laboratory changes or symptoms suggestive of TLS, treatment with palamuximab, tafacizumab, and lenalidomide should be interrupted. Study treatment will continue until resolution of TLS. If moderate or high risk of TLS persists after resolution, additional precautions and / or continued interruption or reduction of palamuximab, tafacizumab, or lenalidomide doses may be considered.

[0592] Part 2, Arm B (tafamidis and lenalidomide)TLS should be prevented, monitored, and treated following the guidelines outlined above in “Prevention, Monitoring, and Treatment of Tumor Lysis Syndrome.”

[0593] 5.11 Dosage Adjustment Guidelines

[0594] Subjects who experience severe toxicity will be treated with standard medical interventions as appropriate (e.g., filgrastim for neutropenia and / or acetaminophen for fever). Standard treatment practices may be used for the management of infusion reactions / cytokine release syndrome (CRS) and neurotoxicity.

[0595] In general, subjects may need to discontinue palamuximab or tafacitinib treatment if > Grade 2 toxicity prevents dosing for > 14 days and / or 2 consecutive doses are missed (this applies to weekly and Q2W dosing). Subjects may restart study drug even after 2 or more consecutive doses of palamuximab or tafacitinib are missed if the benefits are determined to outweigh the risks and toxicity (if applicable) can be managed with concomitant medications or other means. Medical monitoring approval is required for delays of > 14 days and / or 2 consecutive doses.

[0596] During weekly dosing of paramatuzumab and / or tamiflu, a subject's dose was considered missed if it was paused for ≥7 days. During Q2W dosing of paramatuzumab and / or tamiflu, a subject's dose was considered missed if it was paused for ≥14 days. If a subject's dose was outside the window or delayed due to safety issues (including AEs), it was not considered a protocol deviation.

[0597] After an extended dosing delay of more than one cycle for reasons other than toxicity (e.g., comorbidities, pseudoprogression, or delayed response), palamuxomab may be resumed. Resumption of the initial course of treatment may be permitted on a case-by-case basis if it is considered to be in the best interest of the subject. As a safety measure, the dose may be reduced to the initial dose for re-adjustment. Study assessments (including local and / or central laboratories) should be collected according to the assessment schedule shown, for example, in Table 14.

[0598] For potentially overlapping toxicities (e.g., CRS, infusion reactions, hematologic toxicities), detailed dose modifications by grade are listed in Table 14 below.

[0599] Table 14. Dose Modifications for Specific Toxicity

[0600]

[0601]

[0602]

[0603]

[0604]

[0605]

[0606] ALT = alanine aminotransferase; AST = aspartate aminotransferase; C#D#, e.g. C1D1 = cycle # day #; CBC = complete blood count; CRS = cytokine release syndrome.

[0607] For other AEs ≥ Grade 3, additional dose modifications will be considered on a case-by-case basis.

[0608] 5.12 Results

[0609] It is expected that subjects who receive the combination of palamuxetumab, tafacizumab, and lenalidomide will have improved treatment outcomes compared to subjects who receive tafacizumab and lenalidomide alone.

[0610] DLBCL Baseline Disease Assessment : Prior to the start of the study (17 days prior to the start of the study), the subject was given a PET-CT scan (5-point scale test) and a grade or score of 5 was obtained (Table 16). 61 days after the start of the study, the PET-CT scan showed that the score of the same subject decreased from 5 points to 2 points (Table 17). A PET-CT scan grade of 2 was also observed when measured on the 117th day after the start of the study (Table 17). From 177 days after the start of the study until the end of treatment, the subject's PET-CT scan score decreased to 1 (Table 18). The results show that the subject had a complete metabolic response at the end of treatment (as well as the 2nd, 4th, 6th or later, and / or 8th cycle or later of the study).

[0611]

[0612]

[0613]

[0614] *****

[0615] Those skilled in the art will appreciate that changes may be made to the above embodiments without departing from the broad inventive concept of the present invention. Therefore, it should be understood that the present invention is not limited to the specific embodiments disclosed, but is intended to cover modifications within the spirit and scope of the present invention as defined by this specification.

[0616] Although the present invention has been described in detail with reference to its specific embodiments, it will be appreciated that functionally equivalent variations are within the scope of the present invention. In fact, various modifications to the present invention other than those shown and described herein will become apparent to those skilled in the art from the description and drawings above. Such modifications are intended to be within the scope of the appended claims. Those skilled in the art will recognize or be able to determine many equivalents of the specific embodiments of the invention described herein using only routine experimentation. Such equivalents are intended to be encompassed in the appended claims.

Claims

1. A method of treating lymphoma in a subject in need thereof, the method comprising administering to the subject: (a) Antibodies that bind to CD19 (CD19 antibodies); (b) a multispecific antibody, wherein the multispecific antibody comprises a first binding domain that binds to CD3 and a second binding domain that binds to CD20 (CD3xCD20 antibody); and (c) A compound having the following structure: (Compound A), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof; wherein a first dose of the CD19 antibody is administered to the subject at least one day prior to administering to the subject: (i) a first dose of Compound A or a pharmaceutically acceptable salt, solvate or stereoisomer thereof; or (ii) a first dose of said CD3xCD20 antibody.

2. The method of claim 1, wherein (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 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; (b) the first binding domain of the CD3xCD20 antibody that binds to CD3 comprises: (i) a VH domain 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) a VL domain 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; and / or (c) the second binding domain of the CD3xCD20 antibody that binds to CD20 comprises: (i) a VH domain 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) a VL 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.

3. The method of claim 2, wherein: (a) the CD19 antibody comprises 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 comprises 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 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: 22; (e) the second binding domain of the CD3xCD20 antibody that binds to 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; and / or (f) the second binding domain of the CD3xCD20 antibody that binds to 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.

4. The method of any one of claims 1-3, wherein the CD3xCD20 antibody comprises: (a) a first monomer comprising, from N-terminus to C-terminus, a scFv-linker-CH2-CH3 having an amino acid sequence of SEQ ID NO: 25; (b) a second monomer comprising, from N-terminus to C-terminus, 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, VL-CL having the amino acid sequence of SEQ ID NO:

27.

5. The method of any one of claims 1 to 4, wherein the compound is 6. The method of any one of claims 1-5, wherein the lymphoma is non-Hodgkin's lymphoma.

7. The method of claim 6, wherein the non-Hodgkin lymphoma is diffuse large cell lymphoma (DLBCL).

8. The method of claim 7, wherein the DLBCL is relapsed, refractory, or relapsed and refractory DLBCL.

9. The method of claim 7, wherein the DLBCL is primary refractory DLBCL.

10. The method of claim 7, wherein the DLBCL is first-line DLBCL.

11. The method of any one of claims 1-10, wherein the lymphoma is a CD20-expressing lymphoma.

12. The method of any one of claims 1-11, wherein the lymphoma is a CD19 expressing lymphoma.

13. The method of any one of claims 1-12, wherein the subject has not received a stem cell transplant.

14. The method of any one of claims 1-13, wherein the subject is not suitable for stem cell transplantation.

15. The method of claim 13 or 14, wherein the stem cell transplant is an autologous stem cell transplant.

16. The method of any one of claims 1-15, wherein the method comprises cyclic administration of the CD19 antibody, the Compound A or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, and the CD3xCD20 antibody.

17. The method of claim 16, wherein each cycle of said cyclic administration is 28 days.

18. The method of claim 17, wherein the cyclic administration comprises about one cycle, two cycles, three cycles, four cycles, five cycles, six cycles, seven cycles, eight cycles, nine cycles, ten cycles, eleven cycles, twelve cycles, or more than twelve cycles.

19. The method of any one of claims 16-18, wherein the first dose of the CD 19 antibody is administered to the subject prior to day 1 of the first cycle of the cycle administration.

20. The method of claim 19, wherein the first dose of the CD 19 antibody is administered to the subject at least one, two, three, four, five, six, seven, eight, nine, ten, or more days prior to day 1 of the first cycle of said cycle administration.

21. The method of any one of claims 16-20, wherein the first dose of the CD 19 antibody is administered to the subject four days prior to day 1 of the first cycle of said cycle administration.

22. The method of any one of claims 16-20, wherein the first dose of the CD 19 antibody is administered to the subject eight days prior to day 1 of the first cycle of said cycle administration.

23. The method of any one of claims 16-20, wherein the CD 19 antibody is administered to the subject four and eight days prior to day 1 of the first cycle of said cycle administration.

24. The method of any one of claims 16-23, wherein the CD19 antibody is administered to the subject on day 1, day 8, day 15, and / or day 22 of the cycle of cyclic administration.

25. The method of any one of claims 16-24, wherein the CD19 antibody is administered to the subject on day 1, day 8, day 15, and day 22 of the cycle of cyclic administration.

26. The method of any one of claims 16-24, wherein the CD19 antibody is administered to the subject on day 1 and day 15 of the cycle of cyclic administration.

27. The method of any one of claims 16-26, wherein the CD19 antibody is administered to the subject on day 1, day 8, day 15, and day 22 of each of cycles 1-3 of the cyclic administration.

28. The method of any one of claims 16-27, wherein the CD19 antibody is administered to the subject on days 1 and 15 of cycle 4 and subsequent cycles of the cyclic administration.

29. The method of any one of claims 16-28, wherein the CD19 antibody is administered to the subject on Day 1 and Day 15 of Cycle 4-6 of the cyclic administration.

30. The method of any one of claims 16-23, wherein the CD 19 antibody is administered to the subject every 6 to 8 days in the cycle of cyclic administration.

31. The method of any one of claims 16-30, wherein the Compound A or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is administered to the subject for 21 days in the cycle administration.

32. The method of any one of claims 16-31, wherein the Compound A or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is administered to the subject on day 1 to day 21 of the cycle of administration.

33. The method of any one of claims 16-32, wherein the Compound A or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is administered to the subject for 21 days in a 28-day cycle of the cycle administration, followed by a seven-day rest period.

34. The method of any one of claims 16-33, wherein the CD3xCD20 antibody is administered to the subject on day 1, day 8, day 15 and / or day 22 of the cycle of cyclic administration.

35. The method of any one of claims 16-34, wherein the CD3xCD20 antibody is administered to the subject on day 1, day 8, day 15, and day 22 of the cycle of cyclic administration.

36. The method of any one of claims 16-35, wherein the CD3xCD20 antibody is administered to the subject on day 1 and day 15 of the cycle of cyclic administration.

37. The method of any one of claims 16-36, wherein the CD3xCD20 antibody is administered to the subject on Day 1, Day 8, Day 15, and Day 22 of Cycle 1 and Cycle 2 of the cyclic administration.

38. The method of any one of claims 16-37, wherein the CD3xCD20 antibody is administered to the subject on days 1 and 15 of cycle 3 and subsequent cycles of the cyclic administration.

39. The method of any one of claims 16-38, wherein the CD3xCD20 antibody is administered to the subject on Day 1 and Day 15 of Cycles 3-6 of the cyclic administration.

40. The method of any one of claims 16-33, wherein the CD3xCD20 antibody is administered to the subject every 6 to 8 days in the cycle of cyclic administration.

41. The method of any one of claims 1-40, wherein the CD 19 antibody is administered to the subject in an amount of about 1 mg / kg / day to about 20 mg / kg / day.

42. The method of any one of claims 1-41, wherein the CD 19 antibody is administered to the subject in an amount of about 12 mg / kg / day.

43. The method of any one of claims 1-41, wherein the CD 19 antibody is administered to the subject in an amount of about 5 mg / kg / day.

44. The method of any one of claims 1-41, wherein the CD 19 antibody is administered to the subject in an amount of about 10 mg / kg / day.

45. The method of any one of claims 1-44, wherein the Compound A, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is administered to the subject in an amount of about 1 mg / day to about 30 mg / day.

46. ​​The method of any one of claims 1-45, wherein the Compound A, or a pharmaceutically 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.

47. The method of any one of claims 1-46, wherein the Compound A, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is administered to the subject in an amount of about 2.5 mg / day.

48. The method of any one of claims 1-46, wherein the Compound A, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is administered to the subject in an amount of about 5 mg / day.

49. The method of any one of claims 1-46, wherein the Compound A, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is administered to the subject in an amount of about 10 mg / day.

50. The method of any one of claims 1-46, wherein the Compound A, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is administered to the subject in an amount of about 15 mg / day.

51. The method of any one of claims 1-46, wherein the Compound A, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is administered to the subject in an amount of about 20 mg / day.

52. The method of any one of claims 1-46, wherein the Compound A, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is administered to the subject in an amount of about 25 mg / day.

53. The method of any one of claims 1-52, wherein the CD3xCD20 antibody is administered to the subject in an amount of about 0.8 mg / day to about 100 mg / day.

54. The method of any one of claims 1-53, wherein the CD3xCD20 antibody is administered to the subject in an amount of about 0.8 mg / day to about 50 mg / day.

55. The method of any one of claims 1-54, wherein the CD3xCD20 antibody is administered to the subject in an amount of about 0.8 mg / day to about 20 mg / day.

56. The method of any one of claims 1-55, wherein the CD3xCD20 antibody is administered to the subject in an amount of about 0.8 mg / day.

57. The method of any one of claims 1-55, wherein the CD3xCD20 antibody is administered to the subject in an amount of about 2 mg / day.

58. The method of any one of claims 1-55, wherein the CD3xCD20 antibody is administered to the subject in an amount of about 20 mg / day.

59. The method of any one of claims 1-54, wherein the CD3xCD20 antibody is administered to the subject in an amount of about 35 mg / day.

60. The method of any one of claims 1-54, wherein the CD3xCD20 antibody is administered to the subject in an amount of about 50 mg / day.

61. The method of any one of claims 16-60, wherein said first dose of said CD3xCD20 antibody is administered on day 1 of said first cycle in said cycle.

62. The method of any one of claims 1-55, wherein 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.

63. The method of any one of claims 1-54, wherein 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.

64. The method of any one of claims 16-63, wherein said first dose of Compound A, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is administered on day 1 of said first cycle during said cycle.

65. The method of any one of claims 16-64, wherein said first dose of said CD3xCD20 antibody and said first dose of said Compound A or a pharmaceutically acceptable salt, solvate or stereoisomer thereof are both administered on day 1 of said first cycle of said cycle.

66. The method of any one of claims 16-65, wherein the CD 19 antibody is administered to the subject once per week during the cycle of cyclic administration.

67. The method of any one of claims 16-66, wherein the CD 19 antibody is administered to the subject once weekly in cycles 1-3 of the cycle administration.

68. The method of any one of claims 16-67, wherein the CD 19 antibody is administered to the subject every two weeks during the cycle of cyclic administration.

69. The method of any one of claims 16-68, wherein the CD19 antibody is administered to the subject every two weeks in cycle 4 and thereafter of the cycle administration.

70. The method of any one of claims 16-69, wherein the CD3xCD20 antibody is administered to the subject once per week during the cycle of cyclic administration.

71. The method of any one of claims 16-70, wherein the CD3xCD20 antibody is administered to the subject once weekly in cycle 1 and cycle 2 of the cycle administration.

72. The method of any one of claims 16-71, wherein the CD3xCD20 antibody is administered to the subject every two weeks during the cycle of cyclic administration.

73. The method of any one of claims 16-72, wherein the CD3xCD20 antibody is administered to the subject every two weeks in cycle 3 and thereafter of the cycle administration.

74. The method of any one of claims 16-73, wherein the CD3xCD20 antibody and the CD19 antibody are each administered to the subject within a maximum of 4 days in a cycle of cyclic administration.

75. The method of any one of claims 1-17, wherein the method comprises cyclically administering the CD3xCD20 antibody to the subject, wherein the first cycle comprises administering to the subject about 0.8 mg on day 1, about 2 mg on about day 8, about 20 mg on about day 15, and about 20 mg of the CD3xCD20 antibody on about day 22, wherein the subject is administered about 20 mg of the CD3xCD20 antibody on day 1 and every 6 to 8 days of the second cycle of cyclic administration, wherein the subject is administered four doses of the CD3xCD20 antibody in each of the first 2 cycles, wherein the subject is administered about 20 mg of the CD3xCD20 antibody on day 1 and every 12 to 16 days in cycle 3 and any subsequent cycles during treatment, and wherein each cycle of cyclic administration is 28 days.

76. The method of any one of claims 1-17, wherein the method comprises cyclically administering the CD3xCD20 antibody to the subject, wherein the first cycle comprises administering to the subject about 0.8 mg on day 1, about 2 mg on about day 8, about 20 mg on about day 15, and about 35 mg of the CD3xCD20 antibody on about day 22, wherein the subject is administered about 50 mg of the CD3xCD20 antibody on day 1 and every 6 to 8 days of the second cycle of cyclic administration, wherein the subject is administered four doses of the CD3xCD20 antibody in each of the first 2 cycles, wherein the subject is administered about 50 mg of the CD3xCD20 antibody on day 1 and every 12 to 16 days in cycle 3 and any subsequent cycles during treatment, and wherein each cycle of cyclic administration is 28 days.

77. The method of any one of claims 1-17, wherein the method comprises cyclically administering the CD3xCD20 antibody to the subject, wherein the first cycle comprises administering to the subject about 0.8 mg on day 1, about 2 mg on day 8, about 20 mg on day 15, and about 20 mg on day 22 of the CD3xCD20 antibody, wherein the subject is administered about 20 mg of the CD3xCD20 antibody on day 1 and every 7 days for the first 2 cycles of cyclic administration, wherein the subject is administered four doses of the CD3xCD20 antibody in each of the first 2 cycles, wherein the subject is administered about 20 mg of the CD3xCD20 antibody on day 1 and every 14 days in cycle 3 and any subsequent cycles during treatment, and wherein each cycle of cyclic administration is 28 days.

78. The method of any one of claims 1-17, wherein the method comprises cyclically administering the CD3xCD20 antibody to the subject, wherein the first cycle comprises administering to the subject about 0.8 mg on day 1, about 2 mg on day 8, about 20 mg on day 15, and about 35 mg of the CD3xCD20 antibody on day 22, wherein the subject is administered about 50 mg of the CD3xCD20 antibody on day 1 and every 7 days for the first 2 cycles of cyclic administration, wherein the subject is administered four doses of the CD3xCD20 antibody in each of the first 2 cycles, wherein the subject is administered about 50 mg of the CD3xCD20 antibody on day 1 and every 14 days in cycle 3 and any subsequent cycles during treatment, and wherein each cycle of cyclic administration is 28 days.

79. The method of any one of claims 1-17 and 75-78, wherein the method comprises cyclically administering the 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 to 8 days for the first 3 cycles of the cyclic administration, wherein four doses of the CD19 antibody are administered to the subject in each of the first 3 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 to 16 days for Cycle 4 and any subsequent cycles during treatment, wherein about 10 mg / kg to about 15 mg / kg of the CD19 antibody is administered to the subject on the 8 days and 4 days prior to Day 1 of the first cycle of the cyclic administration, and wherein each cycle of the cyclic administration is 28 days.

80. The method of any one of claims 1-17 and 75-78, wherein the method comprises cyclically administering the CD19 antibody to the subject, wherein about 12 mg / kg of the CD19 antibody is administered to the subject on Day 1 and every 7 days for the first 3 cycles of the cyclic administration, wherein four doses of the CD19 antibody are administered to the subject in each of the first 3 cycles, wherein about 12 mg / kg of the CD19 antibody is administered to the subject on Day 1 and every 14 days for Cycle 4 and any subsequent cycles during treatment, wherein about 12 mg / kg of the CD19 antibody is administered to the subject on the 8 days and 4 days prior to Day 1 of the first cycle of the cyclic administration, and wherein each cycle of the cyclic administration is 28 days.

81. The method of any one of claims 1-17 and 75-78, wherein the method comprises cyclically administering Compound A or a pharmaceutically acceptable salt, solvate or stereoisomer thereof to the subject, wherein about 25 mg of Compound A or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is administered to the subject daily on day 1 of each cycle of cyclic administration and for 21 days, followed by a 7-day rest, and wherein each cycle of cyclic administration is 28 days.

82. The method of any one of claims 1-17, wherein the method comprises cyclically administering the CD19 antibody, the CD3xCD20 antibody, and the Compound A or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof to the subject, and wherein the method comprises: (a) administering to the subject about 0.6 to about 1 mg of the CD3xCD20 antibody on Day 1 of the first cycle, about 1.8 to about 2.2 mg on about Day 8, and about 18 to about 22 mg on about Days 15 and 22; administering to the subject about 20 mg of the CD3xCD20 antibody on Day 1 and every 6 to 8 days of the second cycle of said cycle administration, wherein the subject is administered four doses of the CD3xCD20 antibody in each of the first 2 cycles, wherein the subject is administered about 20 mg of the CD3xCD20 antibody on Day 1 and every 12 to 16 days of Cycle 3 and any subsequent cycles during treatment; (b) administering to the subject about 10 mg / kg to about 15 mg / kg of the CD19 antibody on Day 1 and every 6 to 8 days for the first 3 cycles of cycle administration, wherein in each of the first 3 cycles, the subject is administered four doses of the CD19 antibody, wherein on Cycle 4 and any subsequent cycles during treatment, the subject is administered about 10 mg / kg to about 15 mg / kg of the CD19 antibody on Day 1 and every 12 to 16 days, wherein the subject is administered about 10 mg / kg to about 15 mg / kg of the CD19 antibody on the 8 days and 4 days prior to Day 1 of the first cycle of cycle administration; and (c) administering to the subject about 25 mg of the compound A or a pharmaceutically acceptable salt, solvate or stereoisomer thereof on the first day of each cycle of the cycle administration and for 21 consecutive days per day, followed by a rest period of 7 days; and wherein each cycle of said cyclic administration is 28 days.

83. The method of any one of claims 1-17, wherein the method comprises cyclically administering the CD19 antibody, the CD3xCD20 antibody, and the Compound A or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof to the subject, and wherein the method comprises: (a) administering to the subject about 0.6 to about 1 mg of the CD3xCD20 antibody on Day 1 of the first cycle, about 1.8 to about 2.2 mg on about Day 8, about 18 to about 22 mg on about Days 15 and 22, and about 33 to about 36 mg on Day 22; administering to the subject about 50 mg of the CD3xCD20 antibody on Day 1 and every 6 to 8 days of the second cycle of said cycle administration, wherein the subject is administered four doses of the CD3xCD20 antibody in each of the first 2 cycles, wherein the subject is administered about 50 mg of the CD3xCD20 antibody on Day 1 and every 12 to 16 days of Cycle 3 and any subsequent cycles during treatment; (b) administering to the subject about 10 mg / kg to about 15 mg / kg of the CD19 antibody on Day 1 and every 6 to 8 days for the first 3 cycles of said cycle administration, wherein in each of the first 3 cycles, four doses of the CD19 antibody are administered to the subject, wherein on Cycle 4 and any subsequent cycles during treatment, about 10 mg / kg to about 15 mg / kg of the CD19 antibody is administered to the subject on Day 1 and every 12 to 16 days, wherein the subject is administered about 10 mg / kg to about 15 mg / kg of the CD19 antibody on the 8 days and 4 days prior to Day 1 of the first cycle of said cycle administration, and (c) administering to the subject about 25 mg of the compound A or a pharmaceutically acceptable salt, solvate or stereoisomer thereof on the first day of each cycle of the cycle administration and for 21 consecutive days per day, followed by a rest period of 7 days; and wherein each cycle of said cyclic administration is 28 days.

84. The method of any one of claims 1-17, wherein the method comprises cyclically administering the CD19 antibody, the CD3xCD20 antibody, and the Compound A or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof to the subject, and wherein the method comprises: (a) administering to the subject about 0.8 mg of the CD3xCD20 antibody on Day 1 of the first cycle, about 2 mg on Day 8, and about 20 mg on Days 15 and 22; administering to the subject about 20 mg of the CD3xCD20 antibody on Day 1 and every 7 days of the second cycle of said cycle administration, wherein the subject is administered four doses of the CD3xCD20 antibody in each of the first 2 cycles, wherein the subject is administered about 20 mg of the CD3xCD20 antibody on Day 1 and every 14 days of Cycle 3 and any subsequent cycles during treatment; (b) administering to the subject about 12 mg / kg of the CD19 antibody on Day 1 and every 7 days for the first 3 cycles of said cycle administration, wherein the subject is administered four doses of the CD19 antibody in each of the first 3 cycles, wherein the subject is administered about 12 mg / kg of the CD19 antibody on Day 1 and every 14 days for the 4th cycle and any subsequent cycles during treatment, wherein the subject is administered about 12 mg / kg of the CD19 antibody on the 8 days and 4 days prior to Day 1 of the first cycle of said cycle administration; and (c) administering to the subject about 25 mg of Compound A or a pharmaceutically acceptable salt, solvate or stereoisomer thereof daily on the first day of each cycle of cyclic administration during the treatment and for 21 consecutive days, followed by a rest period of 7 days; and wherein each cycle of said cyclic administration is 28 days.

85. The method of any one of claims 1-17, wherein the method comprises cyclically administering the CD19 antibody, the CD3xCD20 antibody, and the Compound A or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof to the subject, and wherein the method comprises: (a) administering to the subject about 0.8 mg of the CD3xCD20 antibody on Day 1 of the first cycle, about 2 mg on about Day 8, about 20 mg on Day 15, and about 35 mg on Day 22; administering to the subject about 50 mg of the CD3xCD20 antibody on Day 1 and every 7 days of the second cycle of said cycle administration, wherein the subject is administered four doses of the CD3xCD20 antibody in each of the first 2 cycles, wherein the subject is administered about 50 mg of the CD3xCD20 antibody on Day 1 and every 14 days of Cycle 3 and any subsequent cycles during treatment; (b) administering to the subject about 12 mg / kg of the CD19 antibody on Day 1 and every 7 days for the first 3 cycles of said cycle administration, wherein the subject is administered four doses of the CD19 antibody in each of the first 3 cycles, wherein the subject is administered about 12 mg / kg of the CD19 antibody on Day 1 and every 14 days for the 4th cycle and any subsequent cycles during treatment, wherein the subject is administered about 12 mg / kg of the CD19 antibody on the 8 days and 4 days prior to Day 1 of the first cycle of said cycle administration; and (c) administering to the subject about 25 mg of Compound A or a pharmaceutically acceptable salt, solvate or stereoisomer thereof daily on the first day of each cycle of cyclic administration during the treatment and for 21 consecutive days, followed by a rest period of 7 days; and wherein each cycle of said cyclic administration is 28 days.

86. The method of any one of claims 1-17, wherein the method comprises cyclically administering the CD19 antibody, the CD3xCD20 antibody, and the Compound A or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof to the subject, and wherein the method comprises: (a) administering to said subject about 0.8 mg on day 1, about 2 mg on day 8, and about 20 mg on days 15 and 22 of said first cycle; administering to said subject about 20 mg of said CD3xCD20 antibody on days 1, 8, 15 and 22 of said second cycle of said cycle administration, wherein said subject is administered about 20 mg of said CD3xCD20 antibody on days 1 and 15 of cycle 3 and any subsequent cycles during treatment; (b) administering to the subject about 12 mg / kg of the CD19 antibody on Day 1, Day 8, Day 15, and Day 22 of the first 3 cycles of said cycle administration, wherein the subject is administered about 12 mg / kg of the CD19 antibody on Day 1 and Day 15 of Cycle 4 and any subsequent cycles during treatment, wherein the subject is administered about 12 mg / kg of the CD19 antibody on the 8 days and 4 days prior to Day 1 of the first cycle of said cycle administration; and (c) administering to the subject about 25 mg of Compound A or a pharmaceutically acceptable salt, solvate or stereoisomer thereof daily on the first day of each cycle of cyclic administration during the treatment and for 21 consecutive days, followed by a rest period of 7 days; and wherein each cycle of said cyclic administration is 28 days.

87. The method of any one of claims 1-17, wherein the method comprises cyclically administering the CD19 antibody, the CD3xCD20 antibody, and the Compound A or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof to the subject, and wherein the method comprises: (a) administering to said subject about 0.8 mg on day 1, about 2 mg on day 8, about 20 mg on day 15, and about 35 mg on day 22 of said first cycle; administering to said subject about 50 mg of said CD3xCD20 antibody on days 1, 8, 15, and 22 of said second cycle of said cycle administration, wherein said subject is administered about 50 mg of said CD3xCD20 antibody on days 1 and 15 of cycle 3 and any subsequent cycles during treatment; (b) administering to the subject about 12 mg / kg of the CD19 antibody on Day 1, Day 8, Day 15, and Day 22 of the first 3 cycles of said cycle administration, wherein the subject is administered about 12 mg / kg of the CD19 antibody on Day 1 and Day 15 of Cycle 4 and any subsequent cycles during treatment, wherein the subject is administered about 12 mg / kg of the CD19 antibody on the 8 days and 4 days prior to Day 1 of the first cycle of said cycle administration; and (c) administering to the subject about 25 mg of Compound A or a pharmaceutically acceptable salt, solvate or stereoisomer thereof daily on the first day of each cycle of cyclic administration during the treatment and for 21 consecutive days, followed by a rest period of 7 days; and wherein each cycle of said cyclic administration is 28 days.

88. The method of any one of claims 1-87, wherein the CD19 antibody is tafacitinib.

89. The method of any one of claims 1-88, wherein the CD3xCD20 antibody is palamutumomab.

90. The method of any one of claims 1-89, wherein the Compound A, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is administered to the subject orally.

91. The method of any one of claims 1-90, wherein the Compound A or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is administered to the subject in the form of a capsule or tablet.

92. The method of any one of claims 1-91, wherein the CD 19 antibody is administered intravenously.

93. The method of any one of claims 16-92, wherein the CD 19 antibody is not administered to the subject on day 4 of the first cycle of said cycle administration.

94. The method of any one of claims 16-93, wherein the CD3xCD20 antibody is not administered to the subject on day 4 of the first cycle of said cycle administration.

95. The method of any one of claims 16-94, wherein the method further comprises determining a positron emission tomography-computed tomography (PET-CT) after every two cycles of the cycle administration.

96. The method of any one of claims 1-95, wherein the subject has received prior CAR-T therapy.

97. The method of any one of claims 1-96, wherein the method results in enhanced therapeutic efficacy relative to administering the CD19 antibody and Compound A or a pharmaceutically acceptable salt, solvate or stereoisomer thereof to the subject without administering the CD3xCD20 antibody.

98. The method of claim 97, wherein the enhanced therapeutic efficacy is measured by increased overall survival time.

99. The method of claim 97, wherein the enhanced therapeutic efficacy is measured by increased progression-free survival.

100. The method of claim 97, wherein the enhanced therapeutic efficacy is measured by a decrease in the number of cancer cells in a biological sample obtained from the subject compared to a reference.

101. The method of claim 100, wherein the reference is the number of cancer cells in a biological sample obtained from the subject at an earlier time point.

102. The method of claim 100, wherein the reference is a predetermined value.

103. The method of claim 100, wherein the reference is the number of cancer cells in a biological sample obtained from another subject suffering from lymphoma.

104. The method of claim 100, wherein the reference is the number of cancer cells in a biological sample obtained from a population of subjects suffering from lymphoma.

105. The method of any one of claims 100-104, wherein the biological sample is blood.

106. The method of any one of claims 100-104, wherein the biological sample is serum.

107. The method of any one of claims 100-104, wherein the biological sample is plasma.

108. The method of any one of claims 97-107, wherein the enhanced therapeutic efficacy is measured by an improved overall response rate and / or increased quality of life of the subject.

109. The method of any one of claims 1-108, wherein the subject has received prior treatment for lymphoma.

110. The method of claim 109, wherein the prior treatment comprises chemoimmunotherapy, anti-CD20 antibodies, or a combination thereof.

111. A method of treating lymphoma in a subject in need thereof, the method comprising administering to the subject: (a) Antibodies that bind to CD19 (CD19 antibodies); (b) a multispecific antibody, wherein the multispecific antibody comprises a first binding domain that binds to CD3 and a second binding domain that binds to CD20 (CD3xCD20 antibody); and (c) A compound having the following structure: (Compound A), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

112. The method of claim 111, wherein (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 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; (b) the multispecific antibody comprises: (i) an anti-CD3 epsilon heavy chain having the amino acid sequence of SEQ ID NO: 30, an anti-CD3 epsilon 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-CD3 epsilon heavy chain having the amino acid sequence of SEQ ID NO: 34, an anti-CD3 epsilon 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.

113. The method of claim 112, wherein (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; (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.

114. The method of any one of claims 111-113, wherein the compound is 115. The method of any one of claims 111-114, wherein the lymphoma is non-Hodgkin's lymphoma.

116. The method of claim 115, wherein the non-Hodgkin lymphoma is diffuse large cell lymphoma (DLBCL).

117. The method of claim 116, wherein the DLBCL is relapsed, refractory, or relapsed and refractory DLBCL.

118. The method of claim 116, wherein the DLBCL is primary refractory DLBCL.

119. The method of claim 116, wherein the DLBCL is first-line DLBCL.

120. The method of any one of claims 1-119, wherein the subject achieves a complete metabolic response as determined by positron emission tomography (PET)-computed tomography (CT).

121. The method of claim 120, wherein the subject achieves a complete metabolic response at or after cycle 2, cycle 4, cycle 6, cycle 8, and / or the end of treatment.

122. The method of claim 120 or 121, wherein the subject achieves a complete metabolic response on or after Day 26 of Cycle 2, Day 26 of Cycle 4, Day 26 of Cycle 6, Day 26 of Cycle 8, and / or the end of treatment.

123. The method of claim 120 or 121, wherein the subject achieves a complete metabolic response at or after 61 days, 117 days, 177 days, 233 days, or 299 days from the first administration of the multispecific antibody to the subject.

Images