METHODS FOR PREDICTING THERAPEUTIC BENEFIT OF ANTI-CD19 THERAPY IN PATIENTS
The present disclosure is directed to a method of identifying a subject having chronic lymphocytic leukemia (CLL), non-Hodgkin's lymphoma (NHL), small lymphocytic lymphoma (SLL) or acute lymphoblastic leukemia (ALL) that is responsive to treatment with an anti-CD19 antibody, said method comprising: a) providing a blood sample obtained from said subject prior to treatment with said anti-CD19 antibody, b) determining the level of at least one biomarker in said sample selected from the group consisting of: i) peripheral NK cell count, and ii) CD16 expression levels on peripheral NK cells, c) comparing the level of said at least one biomarker in said sample to a predetermined cut off level, wherein levels of said at least one biomarker at or above the predetermined cut off level is indicative of a subject who would benefit from treatment with an anti-CD19 antibody. The present disclosure is also directed to a method for selecting a patient for treatment according to the above and to the use of an anti-CD19 antibody for the treatment of such a patient.
1 . A method of identifying a subject having chronic lymphocytic leukemia (CLL), non-Hodgkin's lymphoma (NHL), small lymphocytic lymphoma (SLL) or acute lymphoblastic leukemia (ALL) that is responsive to treatment with an anti-CD19 antibody, said method comprising:
a. providing a blood sample obtained from said subject prior to treatment with said anti-CD19 antibody,
b. determining the level of at least one biomarker in said sample selected from the group consisting of:
i. peripheral NK cell count, and
ii. CD16 expression levels on peripheral NK cells,
c. comparing the level of said at least one biomarker in said sample to a predetermined cut off level,
wherein levels of said at least one biomarker at or above the predetermined cut off level is indicative of a subject who would benefit from treatment with an anti-CD19 antibody.
2 . The method according to claim 1 , wherein the predetermined cut off of said biomarker is:
a. a baseline NK cell count within at least 50 cells/μl, or
b. baseline CD16 expression levels on peripheral NK cells of at least 60,000 ABCs.
3 . The method according to claim 1 , wherein the predetermined cut of said biomarker is:
a. a baseline peripheral NK cell count of at least 60 cells/μl.
4 . The method according to claim 1 , wherein the predetermined cut of said biomarker is:
a. a baseline peripheral NK cell count of at least 70 cells/μl.
5 . The method according to claim 1 , wherein the predetermined cut of said biomarker is:
a. a baseline peripheral NK cell count of at least 80 cells/μl.
6 . The method according to claim 1 , wherein the predetermined cut of said biomarker is:
a. a baseline peripheral NK cell count of at least 100 cells/μl.
7 . The method according to claim 1 , wherein the predetermined cut of said biomarker is:
a. baseline CD16 expression levels on peripheral NK cells of at least 60,000 ABCs.
8 . The method according to claim 1 , wherein the anti-CD19 antibody comprises an HCDR1 region comprising the sequence SYVMH (SEQ ID NO: 1), an HCDR2 region comprising the sequence NPYNDG (SEQ ID NO: 2), an HCDR3 region comprising the sequence GTYYYGTRVFDY (SEQ ID NO: 3), an LCDR1 region comprising the sequence RSSKSLQNVNGNTYLY (SEQ ID NO: 4), an LCDR2 region comprising the sequence RMSNLNS (SEQ ID NO: 5), and an LCDR3 region comprising the sequence MQHLEYPIT (SEQ ID NO: 6).
9 . The method according to claim 1 , wherein the anti-CD19 antibody comprises a variable heavy chain of the sequence EVQLVESGGGLVKPGGSLKLSCAASGYTFTSYVMHWVRQAPGKGLEWIGYINPY NDGTKYNEKFQGRVTISSDKSISTAYMELSSLRSEDTAMYYCARGTYYYGTRVFDYWG QGTLVTVSS (SEQ ID NO: 10) and a variable light chain of the sequence DIVMTQSPATLSLSPGERATLSCRSSKSLQNVNGNTYLYWFQQKPGQSPQLLIYR MSNLNSGVPDRFSGSGSGTEFTLTISSLEPEDFAVYYCMQHLEYPITFGAGTKLEIK (SEQ ID NO: 11).
10 . The method according to claim 1 , wherein the anti-CD19 comprises a heavy chain having the sequence EVQLVESGGGLVKPGGSLKLSCAASGYTFTSYVMHWVRQAPGKGLEWIGYINPYNDGTKYNEKF QGRVTISSDKSISTAYMELSSLRSEDTAMYYCARGTYYYGTRVFDYWGQGTLVTVSSASTKGPS VFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTV PSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPDVFLFPPKPKDTLM ISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNG KEYKCKVSNKALPAPEEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPMLDSDOSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLS PGK (SEQ ID NO: 8) and a light chain having the sequence DIVMTQSPATLSLSPGERATLSCRSSKSLQNVNGNTYLYWFQQKPGQSPQLLIYRMSNLNSGVP DRFSGSGSGTEFTLTISSLEPEDFAVYYCMQHLEYPITFGAGTKLEIKRTVAAPSVFIFPPSDE QLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSK ADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 9).
11 . A method for selecting a patient for treatment according to claim 1 , wherein said patient has non-Hodgkin's lymphoma.
12 . A method for selecting a patient for treatment according to claim 6 , 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.
13 . A method for the treatment of a patient having chronic lymphocytic leukemia (CLL), non-Hodgkin's lymphoma (NHL), small lymphocytic lymphoma (SLL) or acute lymphoblastic leukemia (ALL) identified according to a method of claim 1 , said method comprising administering an anti-CD19 antibody to the patient.