JPWO2022098648A5 - - Google Patents

Claims (98)

(a) an anti-CD79b antibody drug conjugate; (b) a bispecific antibody that binds to CD20 and CD3; or (c) an anti-CD79b antibody drug conjugate and a bispecific antibody that binds to CD20 and CD3. A medicament for treating a subject with a B cell proliferative disorder, the medicament comprising :
the anti-CD79b antibody drug conjugate and the bispecific antibody that binds CD20 and CD3 are administered to the subject in a regimen comprising at least a first cycle of administration and a second cycle of administration;
(a) said first administration cycle comprises a first dose of said bispecific antibody (C1D1), a second dose of said bispecific antibody (C1D2), and a second dose of said bispecific antibody (C1D2); 3 doses (C1D3), wherein the C1D1 of the bispecific antibody is about 1 mg , the C1D2 of the bispecific antibody is about 2 mg, and the C1D2 of the bispecific antibody is about 2 mg ; a first dose of said bispecific antibody (C1D1), a second dose of said bispecific antibody, wherein C1D3 is about 9 mg, about 13.5 mg, about 20 mg, about 40 mg , or about 60 mg; (C1D2), and a third dose (C1D3) of said bispecific antibody; and
(b) said bispecific antibody, wherein said second administration cycle is a single dose (C2D1) of said bispecific antibody, wherein said C2D1 of said bispecific antibody is greater than or equal to said C1D3; (C2D1) ,
the bispecific antibody is a full-length bispecific antibody, the bispecific antibody is administered intravenously;
The bispecific antibody is
The following six hypervariable regions (HVR):
(a) HVR-H1 comprising the amino acid sequence of GYTFTSYNMH (SEQ ID NO: 1);
(b) HVR-H2 comprising the amino acid sequence of AIYPGNGDTSYNQKFKG (SEQ ID NO: 2);
(c) HVR-H3 comprising the amino acid sequence of VVYYSNSYWYFDV (SEQ ID NO: 3);
(d) HVR-L1 comprising the amino acid sequence of RASSSVSYMH (SEQ ID NO: 4);
(e) HVR-L2 comprising the amino acid sequence of APSNLAS (SEQ ID NO: 5); and
(f) HVR-L3 containing the amino acid sequence of QQWSFNPPT (SEQ ID NO: 6)
an anti-CD20 arm comprising a first binding domain comprising; and
The following six HVRs:
(a) HVR-H1 comprising the amino acid sequence of NYYIH (SEQ ID NO: 17);
(b) HVR-H2 comprising the amino acid sequence of WIYPGDGNTKYNEKFKG (SEQ ID NO: 18);
(c) HVR-H3 comprising the amino acid sequence of DSYSNYYFDY (SEQ ID NO: 19);
(d) HVR-L1 comprising the amino acid sequence of KSSQSLLNSRTRKNYLA (SEQ ID NO: 20);
(e) HVR-L2 comprising the amino acid sequence of WASTRES (SEQ ID NO: 21); and
(f) HVR-L3 containing the amino acid sequence of TQSFILRT (SEQ ID NO: 22)
an anti-CD3 arm comprising a second binding domain comprising; and
The anti-CD79b antibody drug conjugate can be used for the following six HVRs:
(a) HVR-H1 comprising the amino acid sequence of GYTFSSYWIE (SEQ ID NO: 65);
(b) HVR-H2 comprising the amino acid sequence of GEILPGGDTNYNEIFKG (SEQ ID NO: 66);
(c) HVR-H3 comprising the amino acid sequence of TRRVPIRLDY (SEQ ID NO: 67);
(d) HVR-L1 comprising the amino acid sequence of KASQSVDYEGDSFLN (SEQ ID NO: 68);
(e) HVR-L2 comprising the amino acid sequence of AASNLES (SEQ ID NO: 69); and
(f) HVR-L3 containing the amino acid sequence of QQSNEDPLT (SEQ ID NO: 70)
comprising an anti-CD79b antibody comprising;
Medicine . (a) the C1D1 of the bispecific antibody is about 1 mg, the C1D2 of the bispecific antibody is about 2 mg , and the C1D3 of the bispecific antibody is about 9 mg ; and /or the C2D1 of the bispecific antibody is about 9 mg;
(b) the C1D1 of the bispecific antibody is about 1 mg, the C1D2 of the bispecific antibody is about 2 mg, and the C1D3 of the bispecific antibody is about 13.5 mg. and/or the C2D1 of the bispecific antibody is about 13.5 mg;
(c) the C1D1 of the bispecific antibody is about 1 mg, the C1D2 of the bispecific antibody is about 2 mg, and the C1D3 of the bispecific antibody is about 20 mg; and /or the C2D1 of the bispecific antibody is about 20 mg; and/or
(d) the C1D1 of the bispecific antibody is about 1 mg, the C1D2 of the bispecific antibody is about 2 mg, and the C1D3 of the bispecific antibody is about 40 mg; and /or the C2D1 of the bispecific antibody is about 40 mg ;
The medicament according to claim 1. the C1D1 of the bispecific antibody is about 1 mg, the C1D2 of the bispecific antibody is about 2 mg, and the C1D3 of the bispecific antibody is about 60 mg ; and/ Alternatively, the medicament according to claim 1 or 2 , wherein the C2D1 of the bispecific antibody is about 60 mg . said first administration cycle comprises a single dose C1D1 of said anti-CD79b antibody drug conjugate ; and/or
the second administration cycle comprises a single dose C2D1 of the anti-CD79b antibody drug conjugate;
The medicament according to any one of claims 1 to 3 . The single dose C1D1 of the anti-CD79b antibody drug conjugate is 0 . 5mg/kg to 10mg/kg ; and/or
the single dose C2D1 of the anti-CD79b antibody drug conjugate is from 0.5 mg/kg to 10 mg/kg;
The medicament according to claim 4 . the single dose C1D1 of the anti-CD79b antibody drug conjugate is about 1.8 mg/kg ; and/or
the single dose C2D1 of the anti-CD79b antibody drug conjugate is about 1.8 mg/kg;
The medicament according to claim 5 . (a) the C1D1 of the bispecific antibody, the C1D2 of the bispecific antibody, and the C1D3 of the bispecific antibody are administered on day 1 and day 8, respectively, of the first administration cycle; and/or the C2D1 of the bispecific antibody is administered to the subject on day 1 of the second administration cycle; and/ or
(b) said C1D1 of said anti-CD79b antibody drug conjugate is administered to said subject on day 1 of said first administration cycle; and/or said C2D1 of said anti-CD79b antibody drug conjugate is administered to said subject on day 1 of said first administration cycle; administered to said subject on day 1 of an administration cycle of
The medicament according to any one of claims 1 to 6 . The medicament according to any one of claims 1 to 7 , wherein the first administration cycle and the second administration cycle are 21 day administration cycles. Medicament according to any one of claims 1 to 8 , wherein the dosing regimen comprises one or more additional dosing cycles. A medicament according to claim 9 , wherein the dosing regimen comprises 4 to 15 additional dosing cycles. 11. A medicament according to claim 9 or 10 , wherein the additional administration cycle is a 21 day administration cycle. One or more of said additional administration cycles include:
(a) comprising an additional single dose of said bispecific antibody and an additional single dose of said anti-CD79b antibody drug conjugate ; and/or
(b) comprising an additional single dose of said bispecific antibody and not comprising administering said anti-CD79b antibody drug conjugate;
The medicament according to any one of claims 9 to 11 . the additional single dose of the anti-CD79b antibody drug conjugate is equivalent to the C2D1 of the anti-CD79b antibody drug conjugate ; and/or
13. The additional single dose of the anti-CD79b antibody drug conjugate is administered to the subject on day 1 of each additional administration cycle that includes an additional dose of the anti-CD79b antibody drug conjugate. medicine . 13. The medicament of claim 12 , wherein the additional single dose of the bispecific antibody is equivalent to the C2D1 of the bispecific antibody. 15. The medicament of claim 14, wherein the additional single dose of the bispecific antibody is about 9 mg, about 13.5 mg, about 20 mg, or about 40 mg. 13. The medicament of claim 12 , wherein the additional single dose of the bispecific antibody is less than the C2D1 of the bispecific antibody. 17. The medicament of claim 16 , wherein the additional single dose of the bispecific antibody is about 30 mg . Claims 12 and 14-17 , wherein the additional single dose of the bispecific antibody is administered to the subject on the first day of each additional administration cycle comprising the additional dose of the bispecific antibody. The medicament according to any one of . wherein said dosing regimen comprises six or more additional cycles of administration, each of said six or more additional dosing cycles comprising a single dose of said bispecific antibody, and said six or more additional dosing cycles 13. The medicament of claim 12 , wherein no more than four of the administration cycles comprise administration of the anti-CD79b antibody drug conjugate. wherein said dosing regimen comprises four or more additional dosing cycles, each of said four or more additional dosing cycles comprising a single dose of said bispecific antibody, and said four or more additional dosing cycles 13. The medicament of claim 12 , wherein no more than four of the administration cycles comprise administration of the anti-CD79b antibody drug conjugate. (a) an anti-CD79b antibody drug conjugate; (b) a bispecific antibody that binds to CD20 and CD3; or (c) an anti-CD79b antibody drug conjugate and a bispecific antibody that binds to CD20 and CD3. A medicament for treating a subject with a B cell proliferative disorder, the medicament comprising:
the anti-CD79b antibody drug conjugate and the bispecific antibody that binds CD20 and CD3 are administered to the subject in a regimen comprising eight or more administration cycles;
(a) the first administration cycle comprises:
(i) a first dose of said bispecific antibody (C1D1), a second dose of said bispecific antibody (C1D2), and a third dose of said bispecific antibody (C1D3); The C1D1 of the bispecific antibody is about 1 mg , the C1D2 of the bispecific antibody is about 2 mg , and the C1D3 of the bispecific antibody is about 9 mg, about 13.5 mg, about 20 mg, or about 40 mg of said bispecific antibody C1D1, said bispecific antibody C1D2, and said bispecific antibody C1D3; and (ii) of said anti-CD79b antibody drug conjugate. Single dose (C1D1)
including;
(b) a second administration cycle comprises a single dose of said bispecific antibody (C2D1) and a single dose of said anti-CD79b antibody drug conjugate (C2D1);
(c) a third administration cycle comprises a single dose of said bispecific antibody (C3D1) and a single dose of said anti-CD79b antibody drug conjugate (C3D1);
(d) a fourth administration cycle comprises a single dose of said bispecific antibody (C4D1) and a single dose of said anti-CD79b antibody drug conjugate (C4D1);
(e) a fifth administration cycle comprises a single dose of said bispecific antibody (C5D1) and a single dose of said anti-CD79b antibody drug conjugate (C5D1);
(f) a sixth administration cycle comprises a single dose of said bispecific antibody (C6D1) and a single dose of said anti-CD79b antibody drug conjugate (C6D1);
(g) a seventh administration cycle comprising a single dose of said bispecific antibody (C7D1) and no administration of said anti-CD79b antibody drug conjugate; and (h) an eighth administration cycle comprising: comprising a single dose of said bispecific antibody (C8D1) and not comprising administration of said anti-CD79b antibody drug conjugate;
each single dose C2D1-C8D1 of said bispecific antibody is equivalent to said C1D3;
the bispecific antibody is a full-length bispecific antibody, the bispecific antibody is administered intravenously;
The bispecific antibody is
The following six hypervariable regions (HVR):
(a) HVR-H1 comprising the amino acid sequence of GYTFTSYNMH (SEQ ID NO: 1);
(b) HVR-H2 comprising the amino acid sequence of AIYPGNGDTSYNQKFKG (SEQ ID NO: 2);
(c) HVR-H3 comprising the amino acid sequence of VVYYSNSYWYFDV (SEQ ID NO: 3);
(d) HVR-L1 comprising the amino acid sequence of RASSSVSYMH (SEQ ID NO: 4);
(e) HVR-L2 comprising the amino acid sequence of APSNLAS (SEQ ID NO: 5); and
(f) HVR-L3 containing the amino acid sequence of QQWSFNPPT (SEQ ID NO: 6)
an anti-CD20 arm comprising a first binding domain comprising; and
The following six HVRs:
(a) HVR-H1 comprising the amino acid sequence of NYYIH (SEQ ID NO: 17);
(b) HVR-H2 comprising the amino acid sequence of WIYPGDGNTKYNEKFKG (SEQ ID NO: 18);
(c) HVR-H3 comprising the amino acid sequence of DSYSNYYFDY (SEQ ID NO: 19);
(d) HVR-L1 comprising the amino acid sequence of KSSQSLLNSRTRKNYLA (SEQ ID NO: 20);
(e) HVR-L2 comprising the amino acid sequence of WASTRES (SEQ ID NO: 21); and
(f) HVR-L3 containing the amino acid sequence of TQSFILRT (SEQ ID NO: 22)
an anti-CD3 arm comprising a second binding domain comprising; and
The anti-CD79b antibody drug conjugate can be used for the following six HVRs:
(a) HVR-H1 comprising the amino acid sequence of GYTFSSYWIE (SEQ ID NO: 65);
(b) HVR-H2 comprising the amino acid sequence of GEILPGGDTNYNEIFKG (SEQ ID NO: 66);
(c) HVR-H3 comprising the amino acid sequence of TRRVPIRLDY (SEQ ID NO: 67);
(d) HVR-L1 comprising the amino acid sequence of KASQSVDYEGDSFLN (SEQ ID NO: 68);
(e) HVR-L2 comprising the amino acid sequence of AASNLES (SEQ ID NO: 69); and
(f) HVR-L3 containing the amino acid sequence of QQSNEDPLT (SEQ ID NO: 70)
comprising an anti-CD79b antibody comprising;
Medicine . (a) an anti-CD79b antibody drug conjugate; (b) a bispecific antibody that binds to CD20 and CD3; or (c) an anti-CD79b antibody drug conjugate and a bispecific antibody that binds to CD20 and CD3. A medicament for treating a subject with a B cell proliferative disorder, the medicament comprising:
the anti-CD79b antibody drug conjugate and the bispecific antibody that binds CD20 and CD3 are administered to the subject in a regimen comprising eight or more administration cycles;
(a) the first administration cycle comprises:
(i) a first dose of said bispecific antibody (C1D1), a second dose of said bispecific antibody (C1D2), and a third dose of said bispecific antibody (C1D3); and the C1D1 of the bispecific antibody is about 1 mg , the C1D2 of the bispecific antibody is about 2 mg , and the C1D3 of the bispecific antibody is about 60 mg. C1D1 of the specific antibody, C1D2 of the bispecific antibody, and C1D3 of the bispecific antibody; and (ii) a single dose of the anti-CD79b antibody drug conjugate (C1D1)
including;
(b) a second administration cycle comprises a single dose (C2D1) of said bispecific antibody and a single dose (C2D1) of said anti-CD79b antibody drug conjugate; is about 60 mg ;
(c) a third administration cycle comprises a single dose of said bispecific antibody (C3D1) and a single dose of said anti-CD79b antibody drug conjugate (C3D1);
(d) a fourth administration cycle comprises a single dose of said bispecific antibody (C4D1) and a single dose of said anti-CD79b antibody drug conjugate (C4D1);
(e) a fifth administration cycle comprises a single dose of said bispecific antibody (C5D1) and a single dose of said anti-CD79b antibody drug conjugate (C5D1);
(f) a sixth administration cycle comprises a single dose of said bispecific antibody (C6D1) and a single dose of said anti-CD79b antibody drug conjugate (C6D1);
(g) a seventh administration cycle comprising a single dose of said bispecific antibody (C7D1) and no administration of said anti-CD79b antibody drug conjugate; and (h) an eighth administration cycle comprising: comprising a single dose of said bispecific antibody (C8D1) and not comprising administration of said anti-CD79b antibody drug conjugate;
each single dose of said C3D1 to C8D1 of said bispecific antibody is less than said C1D3;
the bispecific antibody is a full-length bispecific antibody, the bispecific antibody is administered intravenously;
The bispecific antibody is
The following six hypervariable regions (HVR):
(a) HVR-H1 comprising the amino acid sequence of GYTFTSYNMH (SEQ ID NO: 1);
(b) HVR-H2 comprising the amino acid sequence of AIYPGNGDTSYNQKFKG (SEQ ID NO: 2);
(c) HVR-H3 comprising the amino acid sequence of VVYYSNSYWYFDV (SEQ ID NO: 3);
(d) HVR-L1 comprising the amino acid sequence of RASSSVSYMH (SEQ ID NO: 4);
(e) HVR-L2 comprising the amino acid sequence of APSNLAS (SEQ ID NO: 5); and
(f) HVR-L3 containing the amino acid sequence of QQWSFNPPT (SEQ ID NO: 6)
an anti-CD20 arm comprising a first binding domain comprising; and
The following six HVRs:
(a) HVR-H1 comprising the amino acid sequence of NYYIH (SEQ ID NO: 17);
(b) HVR-H2 comprising the amino acid sequence of WIYPGDGNTKYNEKFKG (SEQ ID NO: 18);
(c) HVR-H3 comprising the amino acid sequence of DSYSNYYFDY (SEQ ID NO: 19);
(d) HVR-L1 comprising the amino acid sequence of KSSQSLLNSRTRKNYLA (SEQ ID NO: 20);
(e) HVR-L2 comprising the amino acid sequence of WASTRES (SEQ ID NO: 21); and
(f) HVR-L3 containing the amino acid sequence of TQSFILRT (SEQ ID NO: 22)
an anti-CD3 arm comprising a second binding domain comprising; and
The anti-CD79b antibody drug conjugate can be used for the following six HVRs:
(a) HVR-H1 comprising the amino acid sequence of GYTFSSYWIE (SEQ ID NO: 65);
(b) HVR-H2 comprising the amino acid sequence of GEILPGGDTNYNEIFKG (SEQ ID NO: 66);
(c) HVR-H3 comprising the amino acid sequence of TRRVPIRLDY (SEQ ID NO: 67);
(d) HVR-L1 comprising the amino acid sequence of KASQSVDYEGDSFLN (SEQ ID NO: 68);
(e) HVR-L2 comprising the amino acid sequence of AASNLES (SEQ ID NO: 69); and
(f) HVR-L3 containing the amino acid sequence of QQSNEDPLT (SEQ ID NO: 70)
A medicament comprising an anti-CD79b antibody comprising . 23. The medicament of claim 22 , wherein each single dose of C3D1-C8D1 of the bispecific antibody is about 30 mg . the C1D1 to C6D1 of the anti-CD79b antibody drug conjugate are in equal amounts , and/or
each of the C1D1 to C6D1 of the anti-CD79b antibody drug conjugate is 0.5 mg/kg to 10 mg/kg;
The medicament according to any one of claims 21 to 23 . 25. The medicament of claim 24 , wherein each of the C1D1-C6D1 of the anti-CD79b antibody drug conjugate is about 1.8 mg/kg. (a) the C1D1 of the bispecific antibody, the C1D2 of the bispecific antibody, and the C1D3 of the bispecific antibody on day 1 and day 8, respectively, of the first administration cycle; , and administered to said subject on day 15 ;
(b) each of said C2D1-C8D1 of said bispecific antibody is administered to said subject on day 1 of each administration cycle; and/or
(c) each of said C1D1-C6D1 of said anti-CD79b antibody drug conjugate is administered to said subject on day 1 of each administration cycle;
The medicament according to any one of claims 21 to 25 . A medicament according to any one of claims 21 to 26 , wherein each administration cycle is a 21 day administration cycle. (a) an anti-CD79b antibody drug conjugate; (b) a bispecific antibody that binds to CD20 and CD3; or (c) an anti-CD79b antibody drug conjugate and a bispecific antibody that binds to CD20 and CD3. A medicament for treating a subject with a B cell proliferative disorder, the medicament comprising:
the anti-CD79b antibody drug conjugate and the bispecific antibody that binds CD20 and CD3 are administered to the subject in a regimen comprising eight or more administration cycles;
(a) a first administration cycle comprises a first dose of said bispecific antibody (C1D1), a second dose of said bispecific antibody (C1D2), and a third dose of said bispecific antibody; of the bispecific antibody, wherein the C1D1 of the bispecific antibody is about 1 mg , the C1D2 is about 2 mg, and the C1D3 is about 9 mg, about 13.5 mg, about 20 mg , or about a first dose of said bispecific antibody (C1D1), a second dose of said bispecific antibody (C1D2), and a third dose of said bispecific antibody (C1D3), which are 40 mg. including;
(b) a second administration cycle comprises a single dose of said bispecific antibody (C2D1) and a single dose of said anti-CD79b antibody drug conjugate (C2D1);
(c) a third administration cycle comprises a single dose of said bispecific antibody (C3D1) and a single dose of said anti-CD79b antibody drug conjugate (C3D1);
(d) a fourth administration cycle comprises a single dose of said bispecific antibody (C4D1) and a single dose of said anti-CD79b antibody drug conjugate (C4D1);
(e) a fifth administration cycle comprises a single dose of said bispecific antibody (C5D1) and a single dose of said anti-CD79b antibody drug conjugate (C5D1);
(f) a sixth administration cycle comprises a single dose of said bispecific antibody (C6D1) and a single dose of said anti-CD79b antibody drug conjugate (C6D1);
(g) a seventh administration cycle comprising a single dose of said bispecific antibody (C7D1) and no administration of said anti-CD79b antibody drug conjugate; and (h) an eighth administration cycle comprising: comprising a single dose of said bispecific antibody (C8D1) and not comprising administration of said anti-CD79b antibody drug conjugate;
each single dose C2D1-C8D1 of said bispecific antibody is equivalent to said C1D3;
the bispecific antibody is a full-length bispecific antibody, the bispecific antibody is administered intravenously;
The bispecific antibody is
The following six hypervariable regions (HVR):
(a) HVR-H1 comprising the amino acid sequence of GYTFTSYNMH (SEQ ID NO: 1);
(b) HVR-H2 comprising the amino acid sequence of AIYPGNGDTSYNQKFKG (SEQ ID NO: 2);
(c) HVR-H3 comprising the amino acid sequence of VVYYSNSYWYFDV (SEQ ID NO: 3);
(d) HVR-L1 comprising the amino acid sequence of RASSSVSYMH (SEQ ID NO: 4);
(e) HVR-L2 comprising the amino acid sequence of APSNLAS (SEQ ID NO: 5); and
(f) HVR-L3 containing the amino acid sequence of QQWSFNPPT (SEQ ID NO: 6)
an anti-CD20 arm comprising a first binding domain comprising; and
The following six HVRs:
(a) HVR-H1 comprising the amino acid sequence of NYYIH (SEQ ID NO: 17);
(b) HVR-H2 comprising the amino acid sequence of WIYPGDGNTKYNEKFKG (SEQ ID NO: 18);
(c) HVR-H3 comprising the amino acid sequence of DSYSNYYFDY (SEQ ID NO: 19);
(d) HVR-L1 comprising the amino acid sequence of KSSQSLLNSRTRKNYLA (SEQ ID NO: 20);
(e) HVR-L2 comprising the amino acid sequence of WASTRES (SEQ ID NO: 21); and
(f) HVR-L3 containing the amino acid sequence of TQSFILRT (SEQ ID NO: 22)
an anti-CD3 arm comprising a second binding domain comprising; and
The anti-CD79b antibody drug conjugate can be used for the following six HVRs:
(a) HVR-H1 comprising the amino acid sequence of GYTFSSYWIE (SEQ ID NO: 65);
(b) HVR-H2 comprising the amino acid sequence of GEILPGGDTNYNEIFKG (SEQ ID NO: 66);
(c) HVR-H3 comprising the amino acid sequence of TRRVPIRLDY (SEQ ID NO: 67);
(d) HVR-L1 comprising the amino acid sequence of KASQSVDYEGDSFLN (SEQ ID NO: 68);
(e) HVR-L2 comprising the amino acid sequence of AASNLES (SEQ ID NO: 69); and
(f) HVR-L3 containing the amino acid sequence of QQSNEDPLT (SEQ ID NO: 70)
comprising an anti-CD79b antibody comprising;
Medicine . (a) an anti-CD79b antibody drug conjugate; (b) a bispecific antibody that binds to CD20 and CD3; or (c) an anti-CD79b antibody drug conjugate and a bispecific antibody that binds to CD20 and CD3. A medicament for treating a subject with a B cell proliferative disorder, the medicament comprising:
the anti-CD79b antibody drug conjugate and the bispecific antibody that binds CD20 and CD3 are administered to the subject in a regimen comprising eight or more administration cycles;
(a) a first administration cycle comprises a first dose of said bispecific antibody (C1D1), a second dose of said bispecific antibody (C1D2), and a third dose of said bispecific antibody; of the bispecific antibody, wherein the C1D1 of the bispecific antibody is about 1 mg , the C1D2 is about 2 mg , and the C1D3 is about 60 mg. a first dose (C1D1), a second dose (C1D2) of said bispecific antibody, and a third dose (C1D3) of said bispecific antibody;
(b) a second administration cycle comprising a single dose (C2D1) of said bispecific antibody and a single dose (C2D1) of said anti-CD79b antibody drug conjugate , wherein said bispecific antibody of said C2D1 is about 60 mg ;
(c) a third administration cycle comprises a single dose of said bispecific antibody (C3D1) and a single dose of said anti-CD79b antibody drug conjugate (C3D1);
(d) a fourth administration cycle comprises a single dose of said bispecific antibody (C4D1) and a single dose of said anti-CD79b antibody drug conjugate (C4D1);
(e) a fifth administration cycle comprises a single dose of said bispecific antibody (C5D1) and a single dose of said anti-CD79b antibody drug conjugate (C5D1);
(f) a sixth administration cycle comprises a single dose of said bispecific antibody (C6D1) and a single dose of said anti-CD79b antibody drug conjugate (C6D1);
(g) a seventh administration cycle comprising a single dose of said bispecific antibody (C7D1) and no administration of said anti-CD79b antibody drug conjugate; and (h) an eighth administration cycle comprising: comprising a single dose of said bispecific antibody (C8D1) and not comprising administration of said anti-CD79b antibody drug conjugate;
each single dose of said bispecific antibody C3D1-C8D1 is less than said C1D3;
the bispecific antibody is a full-length bispecific antibody, the bispecific antibody is administered intravenously;
The bispecific antibody is
The following six hypervariable regions (HVR):
(a) HVR-H1 comprising the amino acid sequence of GYTFTSYNMH (SEQ ID NO: 1);
(b) HVR-H2 comprising the amino acid sequence of AIYPGNGDTSYNQKFKG (SEQ ID NO: 2);
(c) HVR-H3 comprising the amino acid sequence of VVYYSNSYWYFDV (SEQ ID NO: 3);
(d) HVR-L1 comprising the amino acid sequence of RASSSVSYMH (SEQ ID NO: 4);
(e) HVR-L2 comprising the amino acid sequence of APSNLAS (SEQ ID NO: 5); and
(f) HVR-L3 containing the amino acid sequence of QQWSFNPPT (SEQ ID NO: 6)
an anti-CD20 arm comprising a first binding domain comprising; and
The following six HVRs:
(a) HVR-H1 comprising the amino acid sequence of NYYIH (SEQ ID NO: 17);
(b) HVR-H2 comprising the amino acid sequence of WIYPGDGNTKYNEKFKG (SEQ ID NO: 18);
(c) HVR-H3 comprising the amino acid sequence of DSYSNYYFDY (SEQ ID NO: 19);
(d) HVR-L1 comprising the amino acid sequence of KSSQSLLNSRTRKNYLA (SEQ ID NO: 20);
(e) HVR-L2 comprising the amino acid sequence of WASTRES (SEQ ID NO: 21); and
(f) HVR-L3 containing the amino acid sequence of TQSFILRT (SEQ ID NO: 22)
an anti-CD3 arm comprising a second binding domain comprising; and
The anti-CD79b antibody drug conjugate can be used for the following six HVRs:
(a) HVR-H1 comprising the amino acid sequence of GYTFSSYWIE (SEQ ID NO: 65);
(b) HVR-H2 comprising the amino acid sequence of GEILPGGDTNYNEIFKG (SEQ ID NO: 66);
(c) HVR-H3 comprising the amino acid sequence of TRRVPIRLDY (SEQ ID NO: 67);
(d) HVR-L1 comprising the amino acid sequence of KASQSVDYEGDSFLN (SEQ ID NO: 68);
(e) HVR-L2 comprising the amino acid sequence of AASNLES (SEQ ID NO: 69); and
(f) HVR-L3 containing the amino acid sequence of QQSNEDPLT (SEQ ID NO: 70)
comprising an anti-CD79b antibody comprising;
Medicine . A medicament according to claim 29, wherein each single dose C3D1-C8D1 of said bispecific antibody is about 30 mg. the C2D1 to C6D1 of the anti-CD79b antibody drug conjugate are in equal amounts , and/or
each of the C2D1 to C6D1 of the anti-CD79b antibody drug conjugate is 0.5 mg/kg to 10 mg/kg;
The medicament according to any one of claims 28 to 30 . 32. The medicament of claim 31 , wherein each of the C2D1-C6D1 of the anti-CD79b antibody drug conjugate is about 1.8 mg/kg. (a) the C1D1 of the bispecific antibody, the C1D2 of the bispecific antibody, and the C1D3 of the bispecific antibody are administered on day 1 and day 8, respectively, of the first administration cycle; , and administered to said subject on day 15 ;
(b) each of said bispecific antibodies C2D1-C8D1 is administered to said subject on day 1 of each administration cycle; and/or
(c) each of said C2D1-C6D1 of said anti-CD79b antibody drug conjugate is administered to said subject on day 1 of each administration cycle;
The medicament according to any one of claims 28 to 32 . A medicament according to any one of claims 28 to 33 , wherein each administration cycle is a 21 day administration cycle. Medicament according to any one of claims 21 to 34 , wherein the dosing regimen comprises one or more additional dosing cycles comprising a single dose of the bispecific antibody. said dosing regimen comprises 1 to 9 additional dosing cycles comprising a single dose of said bispecific antibody ; and/or
each of said additional administration cycles does not include administration of said anti-CD79b antibody drug conjugate;
The medicament according to claim 35 . each single dose of said bispecific antibody is equivalent to C2D1; or
the additional single dose of said bispecific antibody is less than C2D1 of said bispecific antibody;
The medicament according to claim 36. 38. A medicament according to any one of claims 35 to 37 , wherein each of said additional administration cycles is a 21 day administration cycle. 39. A medicament according to any one of claims 1 to 38 , wherein the dosage regimen further comprises the administration of one or more additional therapeutic agents. 40. The medicament of claim 39 , wherein the one or more additional therapeutic agents are corticosteroids or IL- 6R antagonists. (a) tocilizumab is administered intravenously to said subject as a single dose of about 8 mg/kg, and said single dose does not exceed 800 mg ; and/or
(b) the corticosteroid is dexamethasone, prednisone, or methylprednisolone;
The medicament according to claim 40 . 40. The medicament of claim 39 , wherein the one or more additional therapeutic agents include one or more chemotherapeutic agents. 43. A medicament according to claim 42 , wherein the one or more chemotherapeutic agents comprises cyclophosphamide or doxorubicin. (a) an anti-CD79b antibody drug conjugate; (b) a bispecific antibody that binds to CD20 and CD3; or (c) an anti-CD79b antibody drug conjugate and a bispecific antibody that binds to CD20 and CD3. A medicament for reducing the rate of cytokine release syndrome in a population of subjects with a B cell proliferative disorder, the method comprising:
The anti -CD79b antibody drug conjugate and the bispecific antibody that binds CD20 and CD3 are administered to one or more subjects of the population in a regimen comprising at least a first cycle of administration and a second cycle of administration. is ,
(a) said first administration cycle comprises a first dose of said bispecific antibody (C1D1), a second dose of said bispecific antibody (C1D2), and a second dose of said bispecific antibody (C1D2); 3 doses (C1D3), wherein the C1D1 of the bispecific antibody is about 1 mg , the C1D2 of the bispecific antibody is about 2 mg, and the C1D2 of the bispecific antibody is about 2 mg ; a first dose of said bispecific antibody (C1D1), a second dose of said bispecific antibody (C1D2), wherein C1D3 is about 9 mg, about 13.5 mg, about 20 mg or about 40 mg ; and a third dose (C1D3) of said bispecific antibody;
(b) said second administration cycle is a single dose (C2D1) of said bispecific antibody, said C2D1 of said bispecific antibody being equivalent to said C1D3; comprising a single dose of specific antibody (C2D1);
the rate of cytokine release syndrome is reduced in the population of subjects compared to a reference population of subjects to which the anti-CD79b antibody drug conjugate is not administered ;
the bispecific antibody is a full-length bispecific antibody, the bispecific antibody is administered intravenously;
The bispecific antibody is
The following six hypervariable regions (HVR):
(a) HVR-H1 comprising the amino acid sequence of GYTFTSYNMH (SEQ ID NO: 1);
(b) HVR-H2 comprising the amino acid sequence of AIYPGNGDTSYNQKFKG (SEQ ID NO: 2);
(c) HVR-H3 comprising the amino acid sequence of VVYYSNSYWYFDV (SEQ ID NO: 3);
(d) HVR-L1 comprising the amino acid sequence of RASSSVSYMH (SEQ ID NO: 4);
(e) HVR-L2 comprising the amino acid sequence of APSNLAS (SEQ ID NO: 5); and
(f) HVR-L3 containing the amino acid sequence of QQWSFNPPT (SEQ ID NO: 6)
an anti-CD20 arm comprising a first binding domain comprising; and
The following six HVRs:
(a) HVR-H1 comprising the amino acid sequence of NYYIH (SEQ ID NO: 17);
(b) HVR-H2 comprising the amino acid sequence of WIYPGDGNTKYNEKFKG (SEQ ID NO: 18);
(c) HVR-H3 comprising the amino acid sequence of DSYSNYYFDY (SEQ ID NO: 19);
(d) HVR-L1 comprising the amino acid sequence of KSSQSLLNSRTRKNYLA (SEQ ID NO: 20);
(e) HVR-L2 comprising the amino acid sequence of WASTRES (SEQ ID NO: 21); and
(f) HVR-L3 containing the amino acid sequence of TQSFILRT (SEQ ID NO: 22)
an anti-CD3 arm comprising a second binding domain comprising; and
The anti-CD79b antibody drug conjugate can be used for the following six HVRs:
(a) HVR-H1 comprising the amino acid sequence of GYTFSSYWIE (SEQ ID NO: 65);
(b) HVR-H2 comprising the amino acid sequence of GEILPGGDTNYNEIFKG (SEQ ID NO: 66);
(c) HVR-H3 comprising the amino acid sequence of TRRVPIRLDY (SEQ ID NO: 67);
(d) HVR-L1 comprising the amino acid sequence of KASQSVDYEGDSFLN (SEQ ID NO: 68);
(e) HVR-L2 comprising the amino acid sequence of AASNLES (SEQ ID NO: 69); and
(f) HVR-L3 containing the amino acid sequence of QQSNEDPLT (SEQ ID NO: 70)
A medicament comprising an anti-CD79b antibody comprising . (a) an anti-CD79b antibody drug conjugate; (b) a bispecific antibody that binds to CD20 and CD3; or (c) an anti-CD79b antibody drug conjugate and a bispecific antibody that binds to CD20 and CD3. A medicament for reducing the rate of cytokine release syndrome in a population of subjects with a B cell proliferative disorder, the method comprising:
the anti-CD79b antibody drug conjugate and the bispecific antibody that binds CD20 and CD3 are administered to one or more subjects of said population in a regimen comprising eight or more administration cycles;
(a) the first administration cycle comprises:
(i) a first dose of said bispecific antibody (C1D1), a second dose of said bispecific antibody (C1D2), and a third dose of said bispecific antibody (C1D3); The C1D1 of the bispecific antibody is about 1 mg , the C1D2 of the bispecific antibody is about 2 mg , and the C1D3 of the bispecific antibody is about 9 mg, about 13.5 mg, about 20 mg or about 40 mg of C1D1 of said bispecific antibody, C1D2 of said bispecific antibody, and C1D3 of said bispecific antibody; and (ii) a monomer of said anti-CD79b antibody drug conjugate. Dose (C1D1)
including;
(b) a second administration cycle comprises a single dose of said bispecific antibody (C2D1) and a single dose of said anti-CD79b antibody drug conjugate (C2D1);
(c) a third administration cycle comprises a single dose of said bispecific antibody (C3D1) and a single dose of said anti-CD79b antibody drug conjugate (C3D1);
(d) a fourth administration cycle comprises a single dose of said bispecific antibody (C4D1) and a single dose of said anti-CD79b antibody drug conjugate (C4D1);
(e) a fifth administration cycle comprises a single dose of said bispecific antibody (C5D1) and a single dose of said anti-CD79b antibody drug conjugate (C5D1);
(f) a sixth administration cycle comprises a single dose of said bispecific antibody (C6D1) and a single dose of said anti-CD79b antibody drug conjugate (C6D1);
(g) a seventh administration cycle comprising a single dose of said bispecific antibody (C7D1) and no administration of said anti-CD79b antibody drug conjugate; and (h) an eighth administration cycle comprising: comprising a single dose of said bispecific antibody (C8D1) and not comprising administration of said anti-CD79b antibody drug conjugate;
Each single dose C2D1-C8D1 of said bispecific antibody is equivalent to C1D3 and said rate of cytokine release syndrome is compared to a reference population of subjects to which no anti-CD79b antibody drug conjugate has been administered. and is decreased in the target population,
the bispecific antibody is a full-length bispecific antibody, the bispecific antibody is administered intravenously;
The bispecific antibody is
The following six hypervariable regions (HVR):
(a) HVR-H1 comprising the amino acid sequence of GYTFTSYNMH (SEQ ID NO: 1);
(b) HVR-H2 comprising the amino acid sequence of AIYPGNGDTSYNQKFKG (SEQ ID NO: 2);
(c) HVR-H3 comprising the amino acid sequence of VVYYSNSYWYFDV (SEQ ID NO: 3);
(d) HVR-L1 comprising the amino acid sequence of RASSSVSYMH (SEQ ID NO: 4);
(e) HVR-L2 comprising the amino acid sequence of APSNLAS (SEQ ID NO: 5); and
(f) HVR-L3 containing the amino acid sequence of QQWSFNPPT (SEQ ID NO: 6)
an anti-CD20 arm comprising a first binding domain comprising; and
The following six HVRs:
(a) HVR-H1 comprising the amino acid sequence of NYYIH (SEQ ID NO: 17);
(b) HVR-H2 comprising the amino acid sequence of WIYPGDGNTKYNEKFKG (SEQ ID NO: 18);
(c) HVR-H3 comprising the amino acid sequence of DSYSNYYFDY (SEQ ID NO: 19);
(d) HVR-L1 comprising the amino acid sequence of KSSQSLLNSRTRKNYLA (SEQ ID NO: 20);
(e) HVR-L2 comprising the amino acid sequence of WASTRES (SEQ ID NO: 21); and
(f) HVR-L3 containing the amino acid sequence of TQSFILRT (SEQ ID NO: 22)
an anti-CD3 arm comprising a second binding domain comprising; and
The anti-CD79b antibody drug conjugate can be used for the following six HVRs:
(a) HVR-H1 comprising the amino acid sequence of GYTFSSYWIE (SEQ ID NO: 65);
(b) HVR-H2 comprising the amino acid sequence of GEILPGGDTNYNEIFKG (SEQ ID NO: 66);
(c) HVR-H3 comprising the amino acid sequence of TRRVPIRLDY (SEQ ID NO: 67);
(d) HVR-L1 comprising the amino acid sequence of KASQSVDYEGDSFLN (SEQ ID NO: 68);
(e) HVR-L2 comprising the amino acid sequence of AASNLES (SEQ ID NO: 69); and
(f) HVR-L3 containing the amino acid sequence of QQSNEDPLT (SEQ ID NO: 70)
A medicament comprising an anti-CD79b antibody comprising . (a) an anti-CD79b antibody drug conjugate; (b) a bispecific antibody that binds to CD20 and CD3; or (c) an anti-CD79b antibody drug conjugate and a bispecific antibody that binds to CD20 and CD3. A medicament for reducing the rate of cytokine release syndrome in a population of subjects with a B cell proliferative disorder, the method comprising:
the anti -CD79b antibody drug conjugate and the bispecific antibody that binds CD20 and CD3 are administered to one or more subjects of said population in a regimen comprising eight or more administration cycles;
(a) the first administration cycle comprises:
(i) a first dose of said bispecific antibody (C1D1), a second dose of said bispecific antibody (C1D2), and a third dose of said bispecific antibody (C1D3); and the C1D1 of the bispecific antibody is about 1 mg , the C1D2 of the bispecific antibody is about 2 mg , and the C1D3 of the bispecific antibody is about 60 mg. C1D1 of the specific antibody, C1D2 of the bispecific antibody, and C1D3 of the bispecific antibody; and (ii) a single dose of the anti-CD79b antibody drug conjugate (C1D1)
including;
(b) a second administration cycle comprises a single dose of said bispecific antibody (C2D1) and a single dose of said anti-CD79b antibody drug conjugate (C2D1);
(c) a third administration cycle comprises a single dose of said bispecific antibody (C3D1) and a single dose of said anti-CD79b antibody drug conjugate (C3D1);
(d) a fourth administration cycle comprises a single dose of said bispecific antibody (C4D1) and a single dose of said anti-CD79b antibody drug conjugate (C4D1);
(e) a fifth administration cycle comprises a single dose of said bispecific antibody (C5D1) and a single dose of said anti-CD79b antibody drug conjugate (C5D1);
(f) a sixth administration cycle comprises a single dose of said bispecific antibody (C6D1) and a single dose of said anti-CD79b antibody drug conjugate (C6D1);
(g) a seventh administration cycle comprising a single dose of said bispecific antibody (C7D1) and no administration of said anti-CD79b antibody drug conjugate; and (h) an eighth administration cycle comprising: comprising a single dose of said bispecific antibody (C8D1) and not comprising administration of said anti-CD79b antibody drug conjugate;
said single dose C2D1 of said bispecific antibody is equivalent to said C1D3, each single dose C3D1-C8D1 of said bispecific antibody is less than said C1D3, and said rate of cytokine release syndrome is , is reduced in the population of subjects compared to a reference population of subjects to which the anti-CD79b antibody drug conjugate has not been administered;
the bispecific antibody is a full-length bispecific antibody, the bispecific antibody is administered intravenously;
The bispecific antibody is
The following six hypervariable regions (HVR):
(a) HVR-H1 comprising the amino acid sequence of GYTFTSYNMH (SEQ ID NO: 1);
(b) HVR-H2 comprising the amino acid sequence of AIYPGNGDTSYNQKFKG (SEQ ID NO: 2);
(c) HVR-H3 comprising the amino acid sequence of VVYYSNSYWYFDV (SEQ ID NO: 3);
(d) HVR-L1 comprising the amino acid sequence of RASSSVSYMH (SEQ ID NO: 4);
(e) HVR-L2 comprising the amino acid sequence of APSNLAS (SEQ ID NO: 5); and
(f) HVR-L3 containing the amino acid sequence of QQWSFNPPT (SEQ ID NO: 6)
an anti-CD20 arm comprising a first binding domain comprising; and
The following six HVRs:
(a) HVR-H1 comprising the amino acid sequence of NYYIH (SEQ ID NO: 17);
(b) HVR-H2 comprising the amino acid sequence of WIYPGDGNTKYNEKFKG (SEQ ID NO: 18);
(c) HVR-H3 comprising the amino acid sequence of DSYSNYYFDY (SEQ ID NO: 19);
(d) HVR-L1 comprising the amino acid sequence of KSSQSLLNSRTRKNYLA (SEQ ID NO: 20);
(e) HVR-L2 comprising the amino acid sequence of WASTRES (SEQ ID NO: 21); and
(f) HVR-L3 containing the amino acid sequence of TQSFILRT (SEQ ID NO: 22)
an anti-CD3 arm comprising a second binding domain comprising; and
The anti-CD79b antibody drug conjugate can be used for the following six HVRs:
(a) HVR-H1 comprising the amino acid sequence of GYTFSSYWIE (SEQ ID NO: 65);
(b) HVR-H2 comprising the amino acid sequence of GEILPGGDTNYNEIFKG (SEQ ID NO: 66);
(c) HVR-H3 comprising the amino acid sequence of TRRVPIRLDY (SEQ ID NO: 67);
(d) HVR-L1 comprising the amino acid sequence of KASQSVDYEGDSFLN (SEQ ID NO: 68);
(e) HVR-L2 comprising the amino acid sequence of AASNLES (SEQ ID NO: 69); and
(f) HVR-L3 containing the amino acid sequence of QQSNEDPLT (SEQ ID NO: 70)
A medicament comprising an anti-CD79b antibody comprising : (a) an anti-CD79b antibody drug conjugate; (b) a bispecific antibody that binds to CD20 and CD3; or (c) an anti-CD79b antibody drug conjugate and a bispecific antibody that binds to CD20 and CD3. A medicament for reducing the rate of cytokine release syndrome in a population of subjects with a B cell proliferative disorder, the method comprising:
the anti -CD79b antibody drug conjugate and the bispecific antibody that binds CD20 and CD3 are administered to one or more subjects of said population in a regimen comprising eight or more administration cycles;
(a) a first administration cycle comprises a first dose of said bispecific antibody (C1D1), a second dose of said bispecific antibody (C1D2), and a third dose of said bispecific antibody; of the bispecific antibody, wherein the C1D1 of the bispecific antibody is about 1 mg , the C1D2 is about 2 mg, and the C1D3 is about 9 mg, about 13.5 mg, about 20 mg , or about a first dose of said bispecific antibody (C1D1), a second dose of said bispecific antibody (C1D2), and a third dose of said bispecific antibody (C1D3), which are 40 mg. including;
(b) a second administration cycle comprises a single dose of said bispecific antibody (C2D1) and a single dose of said anti-CD79b antibody drug conjugate (C2D1);
(c) a third administration cycle comprises a single dose of said bispecific antibody (C3D1) and a single dose of said anti-CD79b antibody drug conjugate (C3D1);
(d) a fourth administration cycle comprises a single dose of said bispecific antibody (C4D1) and a single dose of said anti-CD79b antibody drug conjugate (C4D1);
(e) a fifth administration cycle comprises a single dose of said bispecific antibody (C5D1) and a single dose of said anti-CD79b antibody drug conjugate (C5D1);
(f) a sixth administration cycle comprises a single dose of said bispecific antibody (C6D1) and a single dose of said anti-CD79b antibody drug conjugate (C6D1);
(g) a seventh administration cycle comprising a single dose of said bispecific antibody (C7D1) and no administration of said anti-CD79b antibody drug conjugate; and (h) an eighth administration cycle comprising: comprising a single dose of said bispecific antibody (C8D1) and not comprising administration of said anti-CD79b antibody drug conjugate;
Each single dose C2D1-C8D1 of said bispecific antibody is equivalent to C1D3, and said rate of cytokine release syndrome is compared to a reference population of subjects to which no anti-CD79b antibody drug conjugate has been administered. decreased in said target population ;
the bispecific antibody is a full-length bispecific antibody, the bispecific antibody is administered intravenously;
The bispecific antibody is
The following six hypervariable regions (HVR):
(a) HVR-H1 comprising the amino acid sequence of GYTFTSYNMH (SEQ ID NO: 1);
(b) HVR-H2 comprising the amino acid sequence of AIYPGNGDTSYNQKFKG (SEQ ID NO: 2);
(c) HVR-H3 comprising the amino acid sequence of VVYYSNSYWYFDV (SEQ ID NO: 3);
(d) HVR-L1 comprising the amino acid sequence of RASSSVSYMH (SEQ ID NO: 4);
(e) HVR-L2 comprising the amino acid sequence of APSNLAS (SEQ ID NO: 5); and
(f) HVR-L3 containing the amino acid sequence of QQWSFNPPT (SEQ ID NO: 6)
an anti-CD20 arm comprising a first binding domain comprising; and
The following six HVRs:
(a) HVR-H1 comprising the amino acid sequence of NYYIH (SEQ ID NO: 17);
(b) HVR-H2 comprising the amino acid sequence of WIYPGDGNTKYNEKFKG (SEQ ID NO: 18);
(c) HVR-H3 comprising the amino acid sequence of DSYSNYYFDY (SEQ ID NO: 19);
(d) HVR-L1 comprising the amino acid sequence of KSSQSLLNSRTRKNYLA (SEQ ID NO: 20);
(e) HVR-L2 comprising the amino acid sequence of WASTRES (SEQ ID NO: 21); and
(f) HVR-L3 containing the amino acid sequence of TQSFILRT (SEQ ID NO: 22)
an anti-CD3 arm comprising a second binding domain comprising; and
The anti-CD79b antibody drug conjugate can be used for the following six HVRs:
(a) HVR-H1 comprising the amino acid sequence of GYTFSSYWIE (SEQ ID NO: 65);
(b) HVR-H2 comprising the amino acid sequence of GEILPGGDTNYNEIFKG (SEQ ID NO: 66);
(c) HVR-H3 comprising the amino acid sequence of TRRVPIRLDY (SEQ ID NO: 67);
(d) HVR-L1 comprising the amino acid sequence of KASQSVDYEGDSFLN (SEQ ID NO: 68);
(e) HVR-L2 comprising the amino acid sequence of AASNLES (SEQ ID NO: 69); and
(f) HVR-L3 containing the amino acid sequence of QQSNEDPLT (SEQ ID NO: 70)
A medicament comprising an anti-CD79b antibody comprising . (a) an anti-CD79b antibody drug conjugate; (b) a bispecific antibody that binds to CD20 and CD3; or (c) an anti-CD79b antibody drug conjugate and a bispecific antibody that binds to CD20 and CD3. A medicament for reducing the rate of cytokine release syndrome in a population of subjects with a B cell proliferative disorder, the method comprising:
the anti -CD79b antibody drug conjugate and the bispecific antibody that binds CD20 and CD3 are administered to one or more subjects of said population in a regimen comprising eight or more administration cycles;
(a) a first administration cycle comprises a first dose of said bispecific antibody (C1D1), a second dose of said bispecific antibody (C1D2), and a third dose of said bispecific antibody; of the bispecific antibody, wherein the C1D1 of the bispecific antibody is about 1 mg , the C1D2 is about 2 mg , and the C1D3 is about 60 mg. a first dose (C1D1), a second dose (C1D2) of said bispecific antibody, and a third dose (C1D3) of said bispecific antibody;
(b) a second administration cycle comprises a single dose of said bispecific antibody (C2D1) and a single dose of said anti-CD79b antibody drug conjugate (C2D1);
(c) a third administration cycle comprises a single dose of said bispecific antibody (C3D1) and a single dose of said anti-CD79b antibody drug conjugate (C3D1);
(d) a fourth administration cycle comprises a single dose of said bispecific antibody (C4D1) and a single dose of said anti-CD79b antibody drug conjugate (C4D1);
(e) a fifth administration cycle comprises a single dose of said bispecific antibody (C5D1) and a single dose of said anti-CD79b antibody drug conjugate (C5D1);
(f) a sixth administration cycle comprises a single dose of said bispecific antibody (C6D1) and a single dose of said anti-CD79b antibody drug conjugate (C6D1);
(g) a seventh administration cycle comprising a single dose of said bispecific antibody (C7D1) and no administration of said anti-CD79b antibody drug conjugate; and (h) an eighth administration cycle comprising: comprising a single dose of said bispecific antibody (C8D1) and not comprising administration of said anti-CD79b antibody drug conjugate;
said single dose C2D1 of said bispecific antibody is equivalent to said C1D3, and each single dose C3D1-C8D1 of said bispecific antibody is about 30 mg , and said rate of cytokine release syndrome is reduced in the population of subjects compared to a reference population of subjects to which the anti-CD79b antibody drug conjugate has not been administered;
the bispecific antibody is a full-length bispecific antibody, the bispecific antibody is administered intravenously;
The bispecific antibody is
The following six hypervariable regions (HVR):
(a) HVR-H1 comprising the amino acid sequence of GYTFTSYNMH (SEQ ID NO: 1);
(b) HVR-H2 comprising the amino acid sequence of AIYPGNGDTSYNQKFKG (SEQ ID NO: 2);
(c) HVR-H3 comprising the amino acid sequence of VVYYSNSYWYFDV (SEQ ID NO: 3);
(d) HVR-L1 comprising the amino acid sequence of RASSSVSYMH (SEQ ID NO: 4);
(e) HVR-L2 comprising the amino acid sequence of APSNLAS (SEQ ID NO: 5); and
(f) HVR-L3 containing the amino acid sequence of QQWSFNPPT (SEQ ID NO: 6)
an anti-CD20 arm comprising a first binding domain comprising; and
The following six HVRs:
(a) HVR-H1 comprising the amino acid sequence of NYYIH (SEQ ID NO: 17);
(b) HVR-H2 comprising the amino acid sequence of WIYPGDGNTKYNEKFKG (SEQ ID NO: 18);
(c) HVR-H3 comprising the amino acid sequence of DSYSNYYFDY (SEQ ID NO: 19);
(d) HVR-L1 comprising the amino acid sequence of KSSQSLLNSRTRKNYLA (SEQ ID NO: 20);
(e) HVR-L2 comprising the amino acid sequence of WASTRES (SEQ ID NO: 21); and
(f) HVR-L3 containing the amino acid sequence of TQSFILRT (SEQ ID NO: 22)
an anti-CD3 arm comprising a second binding domain comprising; and
The anti-CD79b antibody drug conjugate can be used for the following six HVRs:
(a) HVR-H1 comprising the amino acid sequence of GYTFSSYWIE (SEQ ID NO: 65);
(b) HVR-H2 comprising the amino acid sequence of GEILPGGDTNYNEIFKG (SEQ ID NO: 66);
(c) HVR-H3 comprising the amino acid sequence of TRRVPIRLDY (SEQ ID NO: 67);
(d) HVR-L1 comprising the amino acid sequence of KASQSVDYEGDSFLN (SEQ ID NO: 68);
(e) HVR-L2 comprising the amino acid sequence of AASNLES (SEQ ID NO: 69); and
(f) HVR-L3 containing the amino acid sequence of QQSNEDPLT (SEQ ID NO: 70)
A medicament comprising an anti-CD79b antibody comprising . 49. Any one of claims 44-48 , wherein said population of subjects exhibits cytokine release syndrome after administration of said bispecific antibody, and said proportion of said cytokine release syndrome in said population of subjects is 20 % or less. Medicines listed in. 50. The medicament according to claim 49 , wherein the proportion of cytokine release syndrome in the population of subjects is 10 % or less. 51. The medicament according to claim 50 , wherein the proportion of cytokine release syndrome in the population of subjects is 5 % or less. 52. The medicament of claim 51 , wherein the proportion of cytokine release syndrome in the population of subjects is 3 % or less. 53. The medicament according to any one of claims 44 to 52 , wherein the proportion of cytokine release syndrome of grade 2 or higher (as defined by American Society for Transplantation and Cellular Therapy, 2019; ASTCT) is 20 % or less. 54. The medicament according to claim 53 , wherein the proportion of cytokine release syndrome of grade 2 or higher (as defined by ASTCT) is 5% or less. 55. The medicament according to claim 54 , wherein the proportion of cytokine release syndrome of grade 2 or higher (as defined by ASTCT) is about 0%. 56. The medicament according to any one of claims 1 to 55 , wherein the B cell proliferative disorder is non-Hodgkin's lymphoma (NHL), chronic lymphocytic leukemia (CLL), or central nervous system lymphoma (CNSL). The NHL is diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma (PMLBCL). 57. The medicament according to claim 56 , which is diffuse B-cell lymphoma, small lymphocytic lymphoma, marginal zone lymphoma (MZL), Burkitt's lymphoma, or lymphoplasmacytic lymphoma. 58. The medicament according to claim 56 or 57 , wherein the NHL is relapsed or refractory NHL. 58. The medicament according to claim 56 or 57 , wherein the NHL is DLBCL. 60. The medicament according to claim 59 , wherein the DLBCL is relapsed or refractory DLBCL. 60. The medicament according to claim 59 , wherein the DLBCL is a Richter transformation. 58. The medicament according to claim 56 or 57 , wherein the NHL is FL. 63. The medicament according to claim 62 , wherein the FL is relapsed or refractory FL. 63. The medicament according to claim 62 , wherein the FL is a transformed FL. 58. The medicament according to claim 56 or 57 , wherein the NHL is MCL. 66. The medicament according to claim 65 , wherein the MCL is relapsed or refractory MCL. The medicament according to any one of claims 1 to 55 , wherein the B cell proliferative disorder is relapsed and/or refractory. The bispecific antibody is
(a) a heavy chain variable (VH) domain comprising (i) an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 7; and/or ( ii ) at least to the amino acid sequence of SEQ ID NO: 8; A light chain variable (VL) domain comprising an amino acid sequence with 95% sequence identity
an anti-CD20 arm comprising a first binding domain comprising ; and/or
(b) a VH domain comprising (i) an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 23; and/or (ii) at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 24; VL domain containing an amino acid sequence with
an anti-CD3 arm comprising a second binding domain comprising;
68. The medicament according to any one of claims 1 to 67 , comprising : the first binding domain comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 7 and a VL domain comprising the amino acid sequence of SEQ ID NO: 8, and/or
69. The medicament according to claim 68 , wherein the second binding domain comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 23 and a VL domain comprising the amino acid sequence of SEQ ID NO: 24 . The bispecific antibody is
(a) is a humanized or chimeric antibody, and/or
(b) is an IgG antibody;
The medicament according to any one of claims 1 to 69. The IgG antibody is IgG ₁ 71. The medicament according to claim 70, which is an antibody. 71. A medicament according to claim 70, wherein the IgG antibody comprises a mutation at amino acid residue N297 (EU numbering) resulting in the absence of glycosylation. 73. The medicament according to claim 72, wherein the mutation at amino acid residue N297 is a substitution mutation and/or reduces the effector function of the Fc region. 74. The medicament according to claim 73, wherein the mutation is the N297G or N297A mutation. 71. The medicament of claim 70, wherein the IgG antibody comprises a mutation in the Fc region that reduces effector function. 76. The medicament according to claim 75, wherein the mutation is a substitution mutation. 77. The medicament according to claim 76, wherein the substitution mutations are at amino acid residues L234, L235, D265 and/or P329 (EU numbering). 78. The medicament according to claim 77, wherein the substitution mutation is selected from the group consisting of L234A, L235A, D265A and P329G. The bispecific antibody comprises one or more heavy chain constant domains, the one or more heavy chain constant domains comprising a first CH1 (CH1 ₁ ) domain, the first CH2 (CH2 ₁ ) domain, the first CH3 (CH3 ₁ ) domain, second CH1 (CH1 ₂ ) domain, second CH2 (CH2 ₂ ) domain, and a second CH3 (CH3 ₂ ) domain, and
79. A medicament according to any preceding claim, wherein at least one of the one or more heavy chain constant domains is paired with another heavy chain constant domain. (a) Said CH3 ₁ domain and the CH3 ₂ the domains each include a protrusion or a cavity, and the CH3 ₁ The protrusion or cavity of the domain ₂ can be arranged in the cavity or protrusion of the domain, and the CH3 ₁ domain and the CH3 ₂ domains associate at an interface between the protrusion and the cavity; or
(b) Said CH2 ₁ domain and the CH2 ₂ The domains each include a protrusion or a cavity, and the CH2 ₁ The protrusion or cavity of the domain is ₂ can be arranged in the cavity or protrusion of the domain, and the CH2 ₁ domain and the CH2 ₂ domains associate at an interface between the protrusion and the cavity;
The medicament according to claim 79. the anti-CD20 arm further comprises T366W and N297G substitution mutations (EU numbering), and/or
the anti-CD3 arm further comprises T366S, L368A, Y407V, and N297G substitution mutations (EU numbering);
The medicament according to any one of claims 1 to 80. The bispecific antibody is
(a) a heavy chain comprising (i) an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 85; and (ii) an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 86. and (b) (i) a heavy chain comprising an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 83, and (ii) the amino acid sequence of SEQ ID NO: 84. and a light chain comprising an amino acid sequence having at least 95 % sequence identity . (a) the anti-CD20 arm comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 85 and a light chain comprising the amino acid sequence of SEQ ID NO: 86; and (b) the anti-CD3 arm comprises the amino acid sequence of SEQ ID NO: 83. 83. A medicament according to claim 82 , comprising a heavy chain comprising the sequence and a light chain comprising the amino acid sequence of SEQ ID NO: 84. The anti-CD79b antibody drug conjugate is
(a) a VH domain comprising an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 71;
(b) a VL domain comprising an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 72; or (c) an antibody comprising a VH domain according to (a) and a VL domain according to (b). 84. The medicament according to any one of claims 1 to 83 , comprising the CD79b antibody. 85. The medicament according to claim 84 , wherein the anti-CD79b antibody comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 71 and a VL domain comprising the amino acid sequence of SEQ ID NO: 72. The anti-CD79b antibody drug conjugate comprises: (a) a heavy chain comprising an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 81, and (b) at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 82. 86. The medicament according to any one of claims 1 to 85 , comprising an anti-CD79b antibody comprising a light chain comprising an amino acid sequence having sequence identity. 87. The medicament according to claim 86 , wherein the anti-CD79b antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 81 and a light chain comprising the amino acid sequence of SEQ ID NO: 82. the anti-CD79b antibody drug conjugate is administered intravenously, and/or
the bispecific antibody is administered by intravenous infusion;
The medicament according to any one of claims 1 to 87. 89. The medicament of claim 88, wherein the anti-CD79b antibody drug conjugate is administered by intravenous infusion. On each day that includes administration of the dose of bispecific antibody and administration of the dose of anti-CD79b antibody drug conjugate, the dose of anti-CD79b antibody drug conjugate is administered before,
The medicament according to any one of claims 1 to 89. the dose of anti-CD79b antibody drug conjugate is administered at least 60 minutes prior to the administration of the dose of bispecific antibody;
The medicament according to claim 90. 91. The anti-CD79b antibody drug conjugate is polatuzumab vedotin or anti-CD79b-MC-vc-PAB-MMAE, and/or the bispecific antibody is monetuzumab. The medicament according to any one of the above. 93. The medicament of claim 92, wherein the anti-CD79b antibody drug conjugate is polatuzumab vedotin. A medicament for treating a subject with NHL , comprising (a) polatuzumab vedotin, (b) monetuzumab, or (c) polatuzumab vedotin and monetuzumab ,
Polatuzumab vedotin and monetuzumab are administered to the subject in a regimen comprising eight or more dosing cycles;
(a) the first administration cycle comprises:
(i) the first dose of monetuzumab (C1D1), the second dose of monetuzumab (C1D2), and the third dose of monetuzumab (C1D3), wherein the C1D1 of monetuzumab is about 1 mg; , the C1D2 of the monetuzumab is about 2 mg, and the C1D3 of the monetuzumab is about 9 mg, about 13.5 mg, about 20 mg , or about 40 mg . and (ii) a single dose of said polatuzumab vedotin (C1D1)
including;
(b) a second administration cycle comprises a single dose of said monetuzumab (C2D1) and a single dose of said polatuzumab vedotin (C2D1);
(c) a third administration cycle comprises a single dose of said monetuzumab (C3D1) and a single dose of said polatuzumab vedotin (C3D1);
(d) a fourth administration cycle comprises a single dose of said monetuzumab (C4D1) and a single dose of said polatuzumab vedotin (C4D1);
(e) a fifth administration cycle comprises a single dose of said monetuzumab (C5D1) and a single dose of said polatuzumab vedotin (C5D1);
(f) a sixth administration cycle comprises a single dose of said monetuzumab (C6D1) and a single dose of said polatuzumab vedotin (C6D1);
(g) a seventh administration cycle comprises a single dose of said monetuzumab (C7D1) and no administration of said polatuzumab vedotin; and (h) an eighth administration cycle comprises a single dose of said monetuzumab (C7D1); (C8D1) and does not include administration of said polatuzumab vedotin;
Each single dose C2D1-C8D1 of said monetuzumab is equivalent to said C1D3, and each single dose C1D1-C6D1 of polatuzumab vedotin is about 1.8 mg/kg, and each single dose of monetuzumab and polatuzumab Tuzumab vedotin is a drug administered intravenously . A medicament for treating a subject with NHL , comprising (a) polatuzumab vedotin, (b) monetuzumab, or (c) polatuzumab vedotin and monetuzumab ,
Polatuzumab vedotin and monetuzumab are administered to the subject in a regimen comprising eight or more dosing cycles;
(a) the first administration cycle comprises:
(i) the first dose of monetuzumab (C1D1), the second dose of monetuzumab (C1D2), and the third dose of monetuzumab (C1D3), wherein the C1D1 of monetuzumab is about 1 mg; , the C1D2 of the monetuzumab is about 2 mg, and the C1D3 of the monetuzumab is about 60 mg, the C1D1 of the monetuzumab, the C1D2 of the monetuzumab, and the C1D3 of the monetuzumab; and (ii) the polatuzumab vedotin. A single dose of (C1D1)
including;
(b) a second administration cycle comprises a single dose (C2D1) of said monetuzumab and a single dose (C2D1) of said polatuzumab vedotin, wherein said C2D1 of said monetuzumab is about 60 mg;
(c) a third administration cycle comprises a single dose of said monetuzumab (C3D1) and a single dose of said polatuzumab vedotin (C3D1);
(d) a fourth administration cycle comprises a single dose of said monetuzumab (C4D1) and a single dose of said polatuzumab vedotin (C4D1);
(e) a fifth administration cycle comprises a single dose of said monetuzumab (C5D1) and a single dose of said polatuzumab vedotin (C5D1);
(f) a sixth administration cycle comprises a single dose of said monetuzumab (C6D1) and a single dose of said polatuzumab vedotin (C6D1);
(g) a seventh administration cycle comprises a single dose of said monetuzumab (C7D1) and no administration of said polatuzumab vedotin; and (h) an eighth administration cycle comprises a single dose of said monetuzumab (C7D1); (C8D1) and does not include administration of said polatuzumab vedotin;
each single dose C3D1-C8D1 of mosnetuzumab is about 30 mg, and each single dose C1D1-C6D1 of polatuzumab vedotin is about 1.8 mg/kg; Mabvedotin is a drug that is administered intravenously . A medicament for treating a subject with NHL , comprising (a) polatuzumab vedotin, (b) monetuzumab, or (c) polatuzumab vedotin and monetuzumab ,
Polatuzumab vedotin and monetuzumab are administered to the subject in a regimen comprising eight or more dosing cycles;
(a) a first administration cycle comprising: a first dose (C1D1) of said monetuzumab, a second dose (C1D2) of said monetuzumab, and a third dose (C1D3) of said monetuzumab; the first dose of mosnetuzumab (C1D1), the second dose of mosnetuzumab (C1D2), wherein the C1D1 is about 1 mg , the C1D2 is about 2 mg , and the C1D3 is about 60 mg; comprising a third dose (C1D3) of said monetuzumab;
(b) a second administration cycle comprises a single dose of monetuzumab (C2D1) and a single dose of polatuzumab vedotin (C2D1) , and the C2D1 of monetuzumab is about 60 mg ;
(c) a third administration cycle comprises a single dose of said monetuzumab (C3D1) and a single dose of said polatuzumab vedotin (C3D1);
(d) a fourth administration cycle comprises a single dose of said monetuzumab (C4D1) and a single dose of said polatuzumab vedotin (C4D1);
(e) a fifth administration cycle comprises a single dose of said monetuzumab (C5D1) and a single dose of said polatuzumab vedotin (C5D1);
(f) a sixth administration cycle comprises a single dose of said monetuzumab (C6D1) and a single dose of said polatuzumab vedotin (C6D1);
(g) a seventh administration cycle comprises a single dose of said monetuzumab (C7D1) and no administration of said polatuzumab vedotin; and (h) an eighth administration cycle comprises a single dose of said monetuzumab (C7D1); (C8D1) and does not include administration of said polatuzumab vedotin;
Each single dose C 3 D1-C8D1 of mosnetuzumab is about 30 mg , each single dose C2D1-C6D1 of polatuzumab vedotin is about 1.8 mg/kg, and Zumabvedotin is a drug administered intravenously . The medicament according to any one of claims 94 to 96 , wherein the NHL is aggressive NHL , DLBCL and/or R/R MCL . 98. The medicament according to any one of claims 1 to 97 , wherein the subject is a human.