Obinutuzumab treatment of a dlbcl patient subgroup

Abstract

The present invention relates to obinutuzumab (or its functional equivalents) for use in the treatment of a particular biomarker-defined DLBCL patient and a novel DLBCL patient subgroup, respectively. The present invention further relates to a method for treating DLBCL with obinutuzumab (or its functional equivalents) in a patient in need thereof, wherein said patient is a particular biomarker-defined DLBCL patient or belongs to a novel biomarker-defined DLBCL patient subgroup. The present invention further relates to the use of obinutuzumab (or its functional equivalents) for the preparation of a pharmaceutical composition for the treatment of DLBCL in the particular biomarker-defined DLBCL patient/novel DLBCL patient subgroup. The present invention further relates to a method for identifying a particular DLBCL patient/novel DLBCL patient subgroup and a method for diagnosing a novel form of DLBCL and a particular DLBCL patient/novel DLBCL patient subgroup, respectively.

1 - 28 . (canceled) 
     
     
         29 . A method of treating a patient having a diffuse large B-cell lymphoma (DLBCL), the method comprising administering to the patient a therapeutically effective amount of a humanized Type II anti-CD20 antibody, wherein a tumor sample from the patient has one or more of:
 (a) a germinal center B-cell-like (GCB) cell-of-origin (COO) status;   (b) a GCB COO status and molecular follicular lymphoma (FL)-like features;   (c) one or more mutations in one or more of CREBBP, EP300, MEF2B, MYC, EZH2, and TNFRSF14;   (d) one or more mutations in CD58;   (e) an expression level of CD58 that is less than 5.3 log 2(nRPKM);   (f) a translocation of BCL2; and   (g) expression of BCL2 in at least 50% of tumor cells;   wherein the humanized Type II anti-CD20 antibody comprises a heavy chain variable region having the specificity determining residues of the heavy chain variable region of SEQ ID NO:1 and a light chain variable region having the specificity determining residues of the light chain variable region of SEQ ID NO:2.   
     
     
         30 . The method of  claim 29 , wherein the GCB COO status is a strong GCB COO status. 
     
     
         31 . The method of  claim 29 , wherein the humanized Type II anti-CD20 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 90% identity to SEQ ID NO:
 1 and a light chain variable region comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 2.   
     
     
         32 . The method of  claim 29 , wherein the tumor sample from the patient has (a) one or more mutations in one or more of CREBBP, EP300, MEF2B, MYC, EZH2, and TNFRSF14 and (b) one or both of (i) one or more genetic mutations in CD58 and (ii) an expression level of CD58 that is less than 5.3 log 2(nRPKM). 
     
     
         33 . The method of  claim 29 , wherein the tumor sample from the patient has (a) a GCB COO status and (b) one or both of (i) a translocation of BCL2 and (ii) a high expression level of BCL2. 
     
     
         34 . The method of  claim 29 , wherein the patient reaches an improved clinical outcome as compared to a patient treated with rituximab. 
     
     
         35 . The method of  claim 34 , wherein the clinical outcome is progression-free survival (PFS), overall survival (OS), or event-free survival (EFS). 
     
     
         36 . The method of  claim 29 , wherein the humanized Type II anti-CD20 antibody comprises a glycoengineered Fc region. 
     
     
         37 . The method of  claim 36 , wherein the humanized Type II anti-CD20 antibody has an increase in the fraction of non-fucosylated oligosaccharides attached to the glycoengineered Fc region relative to the non-glycoengineered antibody. 
     
     
         38 . The method of  claim 37 , wherein the non-fucosylated oligosaccharides are bisected non-fucosylated oligosaccharides. 
     
     
         39 . The method of  claim 29 , wherein:
 (a) the humanized Type II anti-CD20 antibody has an increased affinity for human FcγRIII receptors relative to the non-glycoengineered antibody or rituximab;   (b) the humanized Type II anti-CD20 antibody is capable of causing increased antibody-dependent cellular cytotoxicity (ADCC) relative to the non-glycoengineered antibody; or   (c) the humanized Type II anti-CD20 antibody is capable of causing increased ADCC relative to rituximab.   
     
     
         40 . The method of  claim 29 , wherein the antibody is obinutuzumab or a functional equivalent thereof. 
     
     
         41 . The method of  claim 29 , further comprising administering to the patient one or more additional cytotoxic agents or chemotherapeutic agents. 
     
     
         42 . The method of  claim 41 , further comprising administering to the patient ionizing radiation enhancing the effects of the one or more cytotoxic agents or the one or more chemotherapeutic agents. 
     
     
         43 . The method of  claim 41 , comprising administering to the patient the chemotherapeutic agents cyclophosphamide; doxorubicin; vincristine; and prednisone or prednisolone. 
     
     
         44 . The method of  claim 29 , wherein the humanized Type II anti-CD20 antibody is administered to the patient in a pharmaceutical composition comprising a pharmaceutically acceptable carrier. 
     
     
         45 . The method of  claim 29 , wherein the humanized Type II anti-CD20 antibody is administered intravenously at a dose of 1000 mg every three weeks. 
     
     
         46 . The method of  claim 45 , wherein the humanized Type II anti-CD20 antibody is administered on days 1, 8, and 15 of a first 21-day treatment cycle and on day 1 of one or more additional 21-day treatment cycles. 
     
     
         47 . The method of  claim 46 , wherein 8 cycles of treatment are administered. 
     
     
         48 . The method of  claim 29 , wherein the tumor sample from the patient has an expression level of CD58 that is less than or equal to 5.2 log 2(nRPKM). 
     
     
         49 . The method of  claim 30 , wherein a strong GCB COO status of a tumor sample from the patient is identified by an overexpression of one or more of MME, SERPINA9, ASB13, MAML3, ITPKB, MYBL1, and S1PR2 in the tumor sample. 
     
     
         50 . The method of  claim 49 , wherein the overexpression is mRNA overexpression. 
     
     
         51 . The method of  claim 30 , wherein a strong GCB COO status of a tumor sample from the patient is identified by a linear predictor score (LPS) for the tumor sample that is less than 1141, wherein the LPS is a weighted sum of the expression levels of the genes TNFRSF13B, LIMD1, IRF4, CREB3L2, PIM2, CYB5R2, RAB7L1, CCDC50, MME, SERPINA9, ASB13, MAML3, ITPKB, MYBL1, S1PR2, R3HDM1, WDR55, ISY1, UBXN4, and TRIM56 and is calculated according the formula:
     LPS ( X )=Σ j α j   X   j ,
   wherein X j  is the gene expression for gene j and a 1  is the coefficient for gene j.   
     
     
         52 . The method of  claim 51 , wherein a strong GCB COO status of a tumor sample from the patient is identified by a LPS for the tumor sample that is less than or equal to 1100, less than or equal to 749, or less than or equal to 725. 
     
     
         53 . The method of  claim 51 , wherein a strong GCB COO status of a tumor sample from the patient is identified by a LPS for the tumor sample that is less than the 25th percentile of LPS scores in a population of patients having DLBCL. 
     
     
         54 . A method of identifying a patient having a diffuse large B-cell lymphoma (DLBCL) who is likely to respond to a treatment with a therapeutically effective amount of a humanized Type II anti-CD20 antibody by reaching an improved clinical outcome as compared to a patient treated with rituximab, the method comprising determining whether a tumor sample from the patient has one or more of:
 (a) a germinal center B-cell-like (GCB) COO status;   (b) a GCB COO status and molecular follicular lymphoma (FL)-like features;   (c) one or more mutations in one or more of CREBBP, EP300, MEF2B, MYC, EZH2, and TNFRSF14;   (d) one or more mutations in CD58;   (e) an expression level of CD58 that is less than 5.3 log 2(nRPKM);   (f) a translocation of BCL2; or   (g) expression of BCL2 in at least 50% of tumor cells;   wherein the presence of one or more of (a)-(g) in a tumor sample from the patient identifies the patient as one who is likely to respond to a treatment with a therapeutically effective amount of a humanized Type II anti-CD20 antibody by reaching an improved clinical outcome as compared to a patient treated with rituximab; and wherein the humanized Type II anti-CD20 antibody comprises a heavy chain variable region having the specificity determining residues of the heavy chain variable region of SEQ ID NO:1 and a light chain variable region having the specificity determining residues of the light chain variable region of SEQ ID NO:2.