ANTI-CD47 AGENT-BASED TREATMENT OF CD20-POSITIVE CANCER
Methods, kits, and compositions are provided herein that can be used to treat CD20+ cancer using an anti-CD47 agent such as an antibody. The anti-CD47 agent can be used alone or in combination with one or more additional agent such as an anti-CD20 antibody.
1 . A method of treating a human subject having a CD20+ cancer or reducing the size of the CD20+ cancer in the human subject, comprising: (a) administering an anti-CD47 antibody to the subject at a dose of greater than or equal to 10 mg of antibody per kg of body weight; and (b) administering an anti-CD20 antibody to the subject.
2 . The method of claim 1 , wherein the CD20+ cancer is a B cell cancer, Non-Hodgkin's lymphoma (NHL), indolent lymphoma, follicular lymphoma (FL), double hit lymphoma, myc-rearranged lymphoma, marginal zone lymphoma, diffuse large B cell lymphoma (DLBCL), mantle cell lymphoma, chronic lymphocytic leukemia/small lymphocytic leukemia, waldenstrom's macroglobulinemia/lymphoplasmacytic lymphoma, primary mediastinal B-cell lymphoma, Burkitt's lymphoma, B-cell lymphoma unclassified, B-cell acute lymphoblastic leukemia, or post-transplant lymphoproliferative disease (PTLD), optionally wherein the CD20+ cancer is classified based on histopathology, flow cytometry, molecular classification, one or more equivalent assays, or a combination thereof.
3 . The method of claim 1 , wherein subject is relapsed or refractory to at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or greater than 10 prior lines of cancer therapy.
4 . The method of claim 3 , wherein the subject is refractory to rituximab.
5 . The method of claim 1 , wherein the anti-CD47 antibody comprises or consists of Hu5F9-G4.
6 . The method of claim 1 , wherein the anti-CD47 antibody is administered at a dose of 10-30, 20-30, 10, 20, or 30 mg of antibody per kg of body weight.
7 . The method of claim 1 , wherein the anti-CD20 antibody comprises an Fc capable of at least one of ADCC and ADCP.
8 . The method of claim 1 , wherein the anti-CD20 antibody comprises or consists of rituximab.
9 . The method of claim 1 , wherein the anti-CD20 antibody is administered at a dose of 375 mg/m 2 of antibody.
10 . The method of claim 1 , wherein the anti-CD47 antibody is administered to the subject in a first cycle comprising a priming dose of 1 mg of antibody per kg of body weight on day 1 followed by a dose of 30 mg of antibody per kg of body weight once every week with an additional (optional) loading dose of at least 30 mg/kg on Day 11 (week 2).
11 . The method of claim 10 , wherein the first cycle is 4 weeks in duration.
12 . The method of claim 10 , wherein the anti-CD20 antibody is administered to the subject in the first cycle once every week at a dose of 375 mg/m 2 of antibody.
13 . The method of claim 10 , wherein the anti-CD47 antibody is administered to the subject in a second cycle comprising a dose of 30 mg of antibody per kg of body weight once every 2 weeks.
14 . The method of claim 13 , wherein the second cycle is 4 weeks in duration.
15 . The method of claim 13 , wherein the anti-CD20 antibody is administered to the subject in the second cycle once every four weeks at a dose of 375 mg/m 2 of antibody.
16 . The method of claim 1 , wherein the subject is refractory to rituximab and the method results in a reversal of refractoriness to rituximab.
17 . The method of claim 1 , wherein the subject is a human subject having a CD20+ cancer, and the method comprises administering the anti-CD47 antibody and the anti-CD20 antibody to the subject for at least two distinct cycles of four weeks each, the first cycle comprising (1) administering a priming dose of anti-CD47 antibody at 1 mg of antibody per kg of body weight at time 0 (T0), (2) administering a dose of 30 mg of anti-CD47 antibody per kg of body weight once every week beginning one week after T0 with an additional (optional) loading dose of at least 30 mg/kg on Day 11 (week 2), and (3) administering a dose of 375 mg/m 2 of anti-CD20 antibody once every week; and the second cycle comprising (1) administering a dose of 30 mg of anti-CD47 antibody per kg of body weight once every two weeks, and (2) administering a dose of 375 mg/m 2 of anti-CD20 antibody once every four weeks; optionally the second cycle is repeated as one or more additional cycles without limit or until a clinical benefit is reduced or lost; optionally, when reached and starting at Cycle 6 and beyond, anti-CD20 antibody is administered to the subject at a dose of 375 mg/m 2 once every eight weeks; optionally anti-CD47 antibody and anti-CD20 antibody are administered to the subject until the subject loses a clinical benefit; optionally the anti-CD47 antibody is Hu5F9-G4; optionally the anti-CD20 antibody is rituximab.
18 . The method of claim 1 , wherein the subject is a human subject having lymphoma, and the method comprises administering the anti-CD47 antibody and the anti-CD20 antibody to the subject for at least two distinct cycles of four weeks each, the first cycle comprising (1) administering a priming dose of anti-CD47 antibody at 1 mg of antibody per kg of body weight at time 0 (T0), (2) administering a dose of 30 mg of anti-CD47 antibody per kg of body weight once every week beginning one week after T0 with an additional (optional) loading dose of at least 30 mg/kg on Day 11 (week 2), and (3) administering a dose of 375 mg/m 2 of anti-CD20 antibody once every week; and the second cycle comprising (1) administering a dose of 30 mg of anti-CD47 antibody per kg of body weight once every two weeks, and (2) administering a dose of 375 mg/m 2 of anti-CD20 antibody once every four weeks; optionally the second cycle is repeated as one or more additional cycles without limit or until a clinical benefit is reduced or lost; optionally, when reached and starting at Cycle 6 and beyond, anti-CD20 antibody is administered to the subject at a dose of 375 mg/m 2 once every eight weeks; optionally anti-CD47 antibody and anti-CD20 antibody are administered to the subject until the subject loses a clinical benefit; optionally the anti-CD47 antibody is Hu5F9-G4; optionally the anti-CD20 antibody is rituximab.
19 . The method of claim 1 , wherein the subject is a human subject having DLBCL, and the method comprises administering the anti-CD47 antibody and the anti-CD20 antibody to the subject for at least two distinct cycles of four weeks each, the first cycle comprising (1) administering a priming dose of anti-CD47 antibody at 1 mg of antibody per kg of body weight at time 0) (T0), (2) administering a dose of 30 mg of anti-CD47 antibody per kg of body weight once every week beginning one week after T0 with an additional (optional) loading dose of at least 30 mg/kg on Day II (week 2), and (3) administering a dose of 375 mg/m 2 of anti-CD20 antibody once every week; and the second cycle comprising (1) administering a dose of 30 mg of anti-CD47 antibody per kg of body weight once every two weeks, and (2) administering a dose of 375 mg/m 2 of anti-CD20 antibody once every four weeks; optionally the second cycle is repeated as one or more additional cycles without limit or until a clinical benefit is reduced or lost; optionally, when reached and starting at Cycle 6 and beyond, anti-CD20 antibody is administered to the subject at a dose of 375 mg/m 2 once every eight weeks; optionally anti-CD47 antibody and anti-CD20 antibody are administered to the subject until the subject loses a clinical benefit; optionally the anti-CD47 antibody is Hu5F9-G4; optionally the anti-CD20 antibody is rituximab.
20 . The method of claim 1 , wherein the subject is a human subject having indolent lymphoma, and the method comprises administering the anti-CD47 antibody and the anti-CD20 antibody to the subject for at least two distinct cycles of four weeks each, the first cycle comprising (1) administering a priming dose of anti-CD47 antibody at 1 mg of antibody per kg of body weight at time 0 (T0), (2) administering a dose of 30 mg of anti-CD47 antibody per kg of body weight once every week beginning one week after T0 with an additional (optional) loading dose of at least 30 mg/kg on Day 11 (week 2), and (3) administering a dose of 375 mg/m 2 of anti-CD20 antibody once every week; and the second cycle comprising (1) administering a dose of 30 mg of anti-CD47 antibody per kg of body weight once every two weeks, and (2) administering a dose of 375 mg/m 2 of anti-CD20 antibody once every four weeks; optionally the second cycle is repeated as one or more additional cycles without limit or until a clinical benefit is reduced or lost; optionally, when reached and starting at Cycle 6 and beyond, anti-CD20 antibody is administered to the subject at a dose of 375 mg/m 2 once every eight weeks; optionally anti-CD47 antibody and anti-CD20 antibody are administered to the subject until the subject loses a clinical benefit; optionally the anti-CD47 antibody is Hu5F9-G4; optionally the anti-CD20 antibody is rituximab.
21 . The method of claim 20 , wherein the subject is a human subject having FL, and the method comprises administering the anti-CD47 antibody and the anti-CD20 antibody to the subject for at least two distinct cycles of four weeks each, the first cycle comprising (1) administering a priming dose of anti-CD47 antibody at 1 mg of antibody per kg of body weight at time 0 (T0), (2) administering a dose of 30 mg of anti-CD47 antibody per kg of body weight once every week beginning one week after T0 with an additional (optional) loading dose of at least 30 mg/kg on Day 11 (week 2), and (3) administering a dose of 375 mg/m 2 of anti-CD20 antibody once every week; and the second cycle comprising (1) administering a dose of 30 mg of anti-CD47 antibody per kg of body weight once every two weeks, and (2) administering a dose of 375 mg/m 2 of anti-CD20 antibody once every four weeks; optionally the second cycle is repeated as one or more additional cycles without limit or until a clinical benefit is reduced or lost; optionally, when reached and starting at Cycle 6 and beyond, anti-CD20 antibody is administered to the subject at a dose of 375 mg/m 2 once every eight weeks; optionally anti-CD47 antibody and anti-CD20 antibody are administered to the subject until the subject loses a clinical benefit; optionally the anti-CD47 antibody is Hu5F9-G4; optionally the anti-CD20 antibody is rituximab.
22 . The method of claim 20 , wherein the subject is a human subject having marginal zone lymphoma, and the method comprises administering the anti-CD47 antibody and the anti-CD20 antibody to the subject for at least two distinct cycles of four weeks each, the first cycle comprising (1) administering a priming dose of anti-CD47 antibody at 1 mg of antibody per kg of body weight at time 0 (T0), (2) administering a dose of 30 mg of anti-CD47 antibody per kg of body weight once every week beginning one week after T0 with an additional (optional) loading dose of at least 30 mg/kg on Day 11 (week 2), and (3) administering a dose of 375 mg/m 2 of anti-CD20 antibody once every week; and the second cycle comprising (1) administering a dose of 30 mg of anti-CD47 antibody per kg of body weight once every two weeks, and (2) administering a dose of 375 mg/m 2 of anti-CD20 antibody once every four weeks; optionally the second cycle is repeated as one or more additional cycles without limit or until a clinical benefit is reduced or lost; optionally, when reached and starting at Cycle 6 and beyond, anti-CD20 antibody is administered to the subject at a dose of 375 mg/m 2 once every eight weeks; optionally anti-CD47 antibody and anti-CD20 antibody are administered to the subject until the subject loses a clinical benefit; optionally the anti-CD47 antibody is Hu5F9-G4; optionally the anti-CD20 antibody is rituximab.