TREATMENT PARADIGM FOR AN ANTI-CD19 ANTIBODY AND VENETOCLAX COMBINATION TREATMENT
The instant invention describes pharmaceutical compositions and dosing regimens comprising seviteronel and/or dexamethasone, and methods of treating diseases, disorders or symptoms thereof.
1 : A combination comprising an anti-CD19 antibody and a BCL-2 inhibitor, for use in the treatment of a patient suffering from non-Hodgkin's lymphoma, chronic lymphocytic leukemia and/or small lymphocytic lymphoma, wherein said anti-CD19 antibody is administered at least 7 days prior to the first administration of said BCL-2 inhibitor.
2 : A combination according to claim 1 , wherein the anti-CD19 antibody is administered weekly, bi-weekly or monthly after a first administration on Day 1 and wherein the BCL-2 inhibitor is administered for the first time on Day 8.
3 : A combination according to claim 1 , wherein the anti-CD19 antibody after a first administration on Day 1 is administered weekly for the first 3 months.
4 : A combination according to claim 3 , wherein the anti-CD19 antibody after a first administration on Day 1 is administered weekly for the first 3 months and bi-weekly for at least the next 3 months.
5 : A combination according to claim 4 , wherein the anti-CD19 antibody after a first administration on Day 1 is administered weekly for the first 3 months, bi-weekly for the next 3 months and monthly thereafter.
6 : A combination according to claim 2 , wherein there is an additional dosing of the anti-CD19 antibody on Day 4.
7 : A combination according to claim 2 , wherein the BCL-2 inhibitor is administered for the first time on Day 8 with a starting dose of 20 mg followed by a weekly ramp-up dosing of 50 mg, 100 mg, 200 mg and 400 mg followed by a daily dosing of 400 mg.
8 . (canceled)
9 : A combination according to claim 1 , wherein said BCL-2 inhibitor is venetoclax.
10 : A combination according to claim 1 , wherein the anti-CD19 antibody comprises an HCDR1 region comprising sequence SYVMH (SEQ ID NO: 1), an HCDR2 region comprising sequence NPYNDG (SEQ ID NO: 2), an HCDR3 region comprising sequence GTYYYGTRVFDY (SEQ ID NO: 3), an LCDR1 region comprising sequence RSSKSLQNVNGNTYLY (SEQ ID NO: 4), an LCDR2 region comprising sequence RMSNLNS (SEQ ID NO: 5), and an LCDR3 region comprising sequence MQHLEYPIT (SEQ ID NO: 6)
11 : A combination according to claim 9 , wherein the anti-CD19 antibody comprises a variable heavy chain comprising the sequence
(SEQ ID NO: 10)
EVQLVESGGGLVKPGGSLKLSCAASGYTFTSYVMHWVRQAPGKGLEWIGY
INPYNDGTKYNEKFQGRVTISSDKSISTAYMELSSLRSEDTAMYYCARGT
YYYGTRVFDYWGQGTLVTVSS
and a variable light chain of the sequence
(SEQ ID NO: 11)
DIVMTQSPATLSLSPGERATLSCRSSKSLQNVNGNTYLYWFQQKPGQSPQ
LLIYRMSNLNSGVPDRFSGSGSGTEFTLTISSLEPEDFAVYYCMQHLEYP
ITFGAGTKLEIK.
12 : A combination according to claim 9 , wherein the anti-CD19 antibody comprises a heavy chain constant domain comprising the sequence
(SEQ ID NO: 12)
ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGV
HTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEP
KSCDKTHTCPPCPAPELLGGPDVFLFPPKPKDTLMISRTPEVTCVVVDVS
HEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGK
EYKCKVSNKALPAPEEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTC
LVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRW
QQGNVFSCSVMHEALHNHYTQKSLSLSPGK.
13 : A combination according to claim 10 , wherein the anti-CD19 antibody comprises a light chain constant domain comprising the sequence
(SEQ ID NO: 13)
RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSG
NSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTK
SFNRGEC.
14 : A combination according to claim 10 , wherein the anti-CD19 antibody is administered in a concentration of 12 mg/kg.
15 : A method for treatment of a subject with chronic lymphocytic leukemia, small lymphocytic lymphoma or non-Hodgkin's lymphoma, wherein the non-Hodgkin's lymphoma is selected from the group consisting of follicular lymphoma, small lymphocytic lymphoma, mucosa-associated lymphoid tissue, marginal zone, diffuse large B cell, Burkitt's, and mantle cell, said method comprising administering the subject the combination of claim 1 .
16 : The method of claim 15 wherein said anti-CD19 antibody and said BCL-2 inhibitor are administered separately.
17 : A combination according to claim 10 , wherein the anti-CD19 antibody comprises a heavy chain constant domain comprising the sequence
(SEQ ID NO: 12)
ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGV
HTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEP
KSCDKTHTCPPCPAPELLGGPDVFLFPPKPKDTLMISRTPEVTCVVVDVS
HEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGK
EYKCKVSNKALPAPEEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTC
LVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRW
QQGNVFSCSVMHEALHNHYTQKSLSLSPGK.
18 : A combination according to claim 11 , wherein the anti-CD19 antibody comprises a light chain constant domain comprising the sequence
(SEQ ID NO: 13)
RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSG
NSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTK
SFNRGEC.
19 : A combination according to claim 12 , wherein the anti-CD19 antibody comprises a light chain constant domain comprising the sequence
(SEQ ID NO: 13)
RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSG
NSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTK
SFNRGEC.
20 : A combination according to claim 11 , wherein the anti-CD19 antibody is administered in a concentration of 12 mg/kg.
21 : A combination according to claim 12 , wherein the anti-CD19 antibody is administered in a concentration of 12 mg/kg.