US20190195879A1 - Methods for predicting therapeutic benefit of anti-cd19 therapy in patients - Google Patents

Methods for predicting therapeutic benefit of anti-cd19 therapy in patients Download PDF

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US20190195879A1
US20190195879A1 US16/305,482 US201716305482A US2019195879A1 US 20190195879 A1 US20190195879 A1 US 20190195879A1 US 201716305482 A US201716305482 A US 201716305482A US 2019195879 A1 US2019195879 A1 US 2019195879A1
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cells
peripheral
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antibody
lymphoma
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Jan Endell
Mark Winderlich
Rainer BOXHAMMER
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Incyte Corp
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2896—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against molecules with a "CD"-designation, not provided for elsewhere
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/57407—Specifically defined cancers
    • G01N33/57426—Specifically defined cancers leukemia
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/57484—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites
    • G01N33/57492—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites involving compounds localized on the membrane of tumor or cancer cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/705—Assays involving receptors, cell surface antigens or cell surface determinants
    • G01N2333/70503—Immunoglobulin superfamily, e.g. VCAMs, PECAM, LFA-3
    • G01N2333/70535—Fc-receptors, e.g. CD16, CD32, CD64 (CD2314/705F)
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis

Definitions

  • the present disclosure is directed to identifying characteristics and biomarkers in patients that benefit from treatment with anti-CD19 antibodies.
  • CD19 is a 95-kDa transmembrane glycoprotein of the immunoglobulin superfamily containing two extracellular immunoglobulin-like domains and an extensive cytoplasmic tail.
  • the protein is a pan-B lymphocyte surface receptor and is ubiquitously expressed from the earliest stages of pre-B cell development onwards until it is down-regulated during terminal differentiation into plasma cells. It is B-lymphocyte lineage specific and not expressed on hematopoietic stem cells and other immune cells, except some follicular dendritic cells.
  • CD19 functions as a positive regulator of B cell receptor (BCR) signaling and is important for B cell activation and proliferation and in the development of humoral immune responses.
  • BCR B cell receptor
  • CD19 acts as a co-stimulatory molecule in conjunction with CD21 and CD81 and is critical for B cell responses to T-cell-dependent antigens.
  • the cytoplasmic tail of CD19 is physically associated with a family of tyrosine kinases that trigger downstream signaling pathways via the src-family of protein tyrosine kinases.
  • CD19 is an attractive target for cancers of lymphoid origin since it is highly expressed in nearly all chronic lymphocytic leukemia (CLL) and non-Hodgkin's lymphomas (NHL), as well as many other different types of leukemias, including acute lymphocytic leukemia (ALL) and hairy cell leukemia (HCL).
  • CLL chronic lymphocytic leukemia
  • NHL non-Hodgkin's lymphomas
  • ALL acute lymphocytic leukemia
  • HCL hairy cell leukemia
  • MOR00208 (previously named XmAb5574) is an Fc engineered humanized monoclonal antibody that binds CD19.
  • ADCC antibody dependent cell-mediated cytotoxicity
  • ADCP antibody dependent cell-mediated phagocytosis
  • apoptosis direct cytotoxic effects
  • MOR00208 has or is currently being studied in clinical trials in CLL, ALL and NHL. Specifically, a Phase I trial titled Safety and Tolerability of XmAb®5574 in Chronic Lymphocytic Leukemia, and a Phase Ila trial titled Study of Fc-Optimized Anti-CD19 Antibody (MOR00208) to treat B-cell Acute Lymphoblastic Leukemia (B-ALL) are completed. A Phase Ila trial titled Study of Fc-Optimized Anti-CD19 Antibody (MOR00208) to Treat Non-Hodgkin's Lymphoma (NHL) has completed recruitment.
  • B-ALL B-cell Acute Lymphoblastic Leukemia
  • NK natural killer
  • MOR00208 has been studied in patients having CLL, ALL, NHL and SLL. Accordingly, a thorough analysis of clinical data has been completed to date in order to identify characteristics or biomarkers of patients that are more likely to benefit from MOR00208 treatment.
  • MOR00208 specifically targets the CD19 surface antigen and mediates direct tumor cell killing via its enhanced ADCC effector function.
  • MOR00208 has been shown to significantly enhance in vitro ADCC, ADCP, and direct cytotoxic effects (apoptosis) on CD19 + tumor cell lines spanning a broad range of human lymphomas and leukemias (Burkitt's lymphoma, CLL, hairy cell leukemia (HCL), CD19+ chronic myeloid leukemia (CML), diffuse large B cell lymphoma (DLBCL) and acute lymphoblastic leukemia (ALL), expressing levels of CD19 antigen ranging from 15,000 to 105,000 molecules/cell.
  • Burkitt's lymphoma, CLL hairy cell leukemia
  • CML CD19+ chronic myeloid leukemia
  • DLBCL diffuse large B cell lymphoma
  • ALL acute lymphoblastic leukemia
  • DCR Disease Control Rate
  • DCR includes patients have Complete Response (CR)+Partial Response (PR)+Stable Disease (SD). Additionally, such patients had a significantly better Progression Free Survival (PFS) as compared to patients having lower NK cells counts.
  • PFS Progression Free Survival
  • ABS Disease Control Rate
  • DCR Disease Control Rate
  • DCR includes patients have Complete Response (CR)+Partial Response (PR)+Stable Disease (SD).
  • PFS Progression Free Survival
  • ABS Progression Free Survival
  • DCR Disease Control Rate
  • DCR includes patients have Complete Response (CR)+Partial Response (PR)+Stable Disease (SD).
  • PFS Progression Free Survival
  • ABS Progression Free Survival
  • FIG. 1 shows the amino acid sequences of MOR00208 variable domains and CDRs.
  • FIG. 2 shows the amino acid sequences of MOR00208′s full heavy and light chains.
  • FIG. 3 shows the Receive Operating Characteristic (ROC) analysis of peripheral NK cell counts as a predictor for DCR.
  • FIG. 4 shows the ROC analysis of CD16 expression levels on peripheral NK cells (ABCs) as a predictor for DCR.
  • FIG. 5 shows the ROC analysis of peripheral T cell count as a potential predictor for DCR.
  • FIG. 6 shows that peripheral NK cell counts and CD16 expression levels on peripheral NK cells are independent variables and not correlated.
  • FIG. 7 shows the Forest Plot with DCRs in patient subgroups with specific baseline characteristics and biomarkers
  • FIG. 8 shows the progression free survival difference between patients having at least 100 cells/ ⁇ l peripheral NK cell counts versus patients having lower NK cell counts.
  • FIG. 9 shows the progression free survival difference between patients having at least 60,000 ABCs in CD16 expression on peripheral NK cells versus patients having lower CD16 expression on NK cells.
  • FIG. 10 shows the progression free survival difference between patients having at least 500 cells/ ⁇ l peripheral T cell counts versus patients having lower T cell counts.
  • antibody means monoclonal antibodies, including any isotype, such as, IgG, IgM, IgA, IgD and IgE.
  • An IgG antibody is comprised of two identical heavy chains and two identical light chains that are joined by disulfide bonds. Each heavy and light chain contains a constant region and a variable region. Each variable region contains three segments called “complementarity-determining regions” (“CDRs”) or “hypervariable regions”, which are primarily responsible for binding an epitope of an antigen. They are referred to as CDR1, CDR2, and CDR3, numbered sequentially from the N-terminus. The more highly conserved portions of the variable regions outside of the CDRs are called the “framework regions”.
  • an “antibody fragment” means an Fv, scFv, dsFv, Fab, Fab′ F(ab′)2 fragment, or other fragment, which contains at least one variable heavy or variable light chain, each containing CDRs and framework regions.
  • VH refers to the variable region of an immunoglobulin heavy chain of an antibody, or antibody fragment.
  • VL refers to the variable region of the immunoglobulin light chain of an antibody, or antibody fragment.
  • Fc region means the constant region of an antibody, which in humans may be of the IgG1, 2, 3, 4 subclass or others.
  • the sequences of human Fc regions are available at IMGT, Human IGH C-REGIONs, www.imgt.org/IMGTrepertoire/Proteins/protein/human/IGH/IGHC/Hu_IGHCallgenes.html (retrieved on 16 May 2011).
  • patient includes a human.
  • NHL is a heterogeneous malignancy originating from lymphocytes.
  • U.S. United States
  • the incidence is estimated at 65,000/year with mortality of approximately 20,000 (American Cancer Society, 2006; and SEER Cancer Statistics Review).
  • the disease can occur in all ages, the usual onset begins in adults over 40 years, with the incidence increasing with age.
  • NHL is characterized by a clonal proliferation of lymphocytes that accumulate in the lymph nodes, blood, bone marrow and spleen, although any major organ may be involved.
  • the current classification system used by pathologists and clinicians is the World Health Organization (WHO) Classification of Tumours, which organizes NHL into precursor and mature B-cell or T-cell neoplasms.
  • WHO World Health Organization
  • the PDQ is currently dividing NHL as indolent or aggressive for entry into clinical trials.
  • the indolent NHL group is comprised primarily of follicular subtypes, small lymphocytic lymphoma, MALT (mucosa-associated lymphoid tissue), and marginal zone; indolent encompasses approximately 50% of newly diagnosed B-cell NHL patients.
  • Aggressive NHL includes patients with histologic diagnoses of primarily diffuse large B cell (DLBL, DLBCL, or DLCL) (40% of all newly diagnosed patients have diffuse large cell), Burkitt's, and mantle cell.
  • the clinical course of NHL is highly variable. A major determinant of clinical course is the histologic subtype. Most indolent types of NHL are considered to be incurable disease.
  • rituximab anti-CD20 antibody
  • R-CHOP rituximab+CHOP
  • R-CVP rituximab+CVP
  • Rituximab therapy has been shown to be efficacious in several types of NHL, and is currently approved as a first line treatment for both indolent (follicular lymphoma) and aggressive NHL (diffuse large B cell lymphoma).
  • indolent follicular lymphoma
  • aggressive NHL diffuse large B cell lymphoma
  • anti-CD20 monoclonal antibody mAb
  • primary resistance 50% response in relapsed indolent patients
  • acquired resistance 50% response rate upon re-treatment
  • rare complete response 2% complete resonse rate in relapsed population
  • a continued pattern of relapse a continued pattern of relapse.
  • B cells do not express CD20, and thus many B-cell disorders are not treatable using anti-CD20 antibody therapy.
  • Chronic lymphocytic leukemia also known as “chronic lymphoid leukemia” or “CLL”
  • CLL chronic lymphocytic leukemia
  • the malignant lymphocytes may look normal and mature, but they are not able to cope effectively with infection.
  • CLL is the most common form of leukemia in adults. Men are twice as likely to develop CLL as women.
  • the key risk factor is age. Over 75% of new cases are diagnosed in patients over age 50. More than 10,000 cases are diagnosed every year and the mortality is almost 5,000 a year (American Cancer Society, 2006; and SEER Cancer Statistics Review).
  • CLL is an incurable disease but progresses slowly in most cases. Many people with CLL lead normal and active lives for many years. Because of its slow onset, early-stage CLL is generally not treated since it is believed that early CLL intervention does not improve survival time or quality of life. Instead, the condition is monitored over time.
  • Initial CLL treatments vary depending on the exact diagnosis and the progression of the disease. There are dozens of agents used for CLL therapy. Combination chemotherapy regimens such as FCR (fludarabine, cyclophosphamide and rituximab), and BR (Ibrutinib and rituximab) are effective in both newly-diagnosed and relapsed CLL. Allogeneic bone marrow (stem cell) transplantation is rarely used as a first-line treatment for CLL due to its risk.
  • SLL Small lymphocytic lymphoma
  • CLL Small lymphocytic lymphoma
  • the definition of SLL requires the presence of lymphadenopathy and/or splenomegaly.
  • the number of B lymphocytes in the peripheral blood should not exceed 5 ⁇ 109/L.
  • the diagnosis should be confirmed by histopathologic evaluation of a lymph node biopsy whenever possible (Hallek et al., 2008).
  • the incidence of SLL is approximately 25% of CLL in the US (Dores et al., 2007).
  • ALL acute lymphoblastic leukemia
  • ALL is characterized by the overproduction and continuous multiplication of malignant and immature white blood cells (also known as lymphoblasts) in the bone marrow.
  • Acute refers to the undifferentiated, immature state of the circulating lymphocytes (“blasts”), and that the disease progresses rapidly with life expectancy of weeks to months if left untreated.
  • ALL is most common in childhood with a peak incidence of 4-5 years of age. Children of age 12-16 die more easily from it than others. Currently, at least 80% of childhood ALL are considered curable. Under 4,000 cases are diagnosed every year and the mortality is almost 1,500 a year (American Cancer Society, 2006; and SEER Cancer Statistics Review).
  • CD19 antibody in non-specific B cell lymphomas is discussed in WO2007076950 (US2007154473), which are both incorporated by reference.
  • CD19 antibody in CLL, NHL and ALL is described in Scheuermann et al., CD19 Antigen in Leukemia and Lymphoma Diagnosis and Immunotherapy, Leukemia and Lymphoma, Vol. 18, 385-397 (1995), which is incorporated by reference in its entirety.
  • CD19 refers to the protein known as CD19, having the following synonyms: B4, B-lymphocyte antigen CD19, B-lymphocyte surface antigen B4, CVID3, Differentiation antigen CD19, MGC12802, and T-cell surface antigen Leu-12.
  • Human CD19 has the amino acid sequence of:
  • MOR00208 is an anti-CD19 antibody.
  • the amino acid sequence of the variable domains is provided in FIG. 1 .
  • the amino acid sequence of the heavy and light chain Fc regions of MOR00208 are provided in FIG. 2 .
  • “MOR00208” and “XmAb 5574” are used as synonyms to describe the antibody shown in FIGS. 1 and 2 .
  • the MOR00208 antibody is described in U.S. patent application Ser. No. 12/377,251, which is incorporated by reference in its entirety.
  • a pharmaceutical composition includes an active agent, e.g. an antibody for therapeutic use in humans.
  • a pharmaceutical composition may additionally include pharmaceutically acceptable carriers or excipients.
  • administering refers to the delivery of a pharmaceutical composition by an injectable form, such as, for example, an intravenous, intramuscular, intradermal or subcutaneous route or mucosal route, for example, as a nasal spray or aerosol for inhalation or as an ingestable solution, capsule or tablet.
  • injectable form such as, for example, an intravenous, intramuscular, intradermal or subcutaneous route or mucosal route, for example, as a nasal spray or aerosol for inhalation or as an ingestable solution, capsule or tablet.
  • the antibody which is administered according to the present disclosure is administered to the patient in a therapeutically effective amount.
  • a “therapeutically effective amount” refers to an amount sufficient to provide some improvement of the clinical manifestations of a given disease or disorder.
  • patients in the exemplified study received dosing of MOR00208 at 12 mg/kg once weekly, and in maintenance once every two weeks or monthly.
  • the amount that is effective for a particular therapeutic purpose will depend on the severity of the disease or injury as well as on the weight and general state of the subject. It will be understood that determination of an appropriate dosage may be achieved, using routine experimentation, by constructing a matrix of values and testing different points in the matrix, all of which is within the ordinary skills of a trained physician or clinical scientist.
  • Baseline means prior to administration of the desired therapy. For example, prior to administration of the desired anti-CD19 antibody.
  • ROC receiver operating characteristic
  • Optimal Cutpoints An R Package for Selecting Optimal Cutpoints in Diagnostic Tests. Journal of Statistical Software 61(8), 1-36.
  • Antibodies specific to CD19 have also been tested preclinically in combination with other drugs.
  • MOR00208 had been tested in combination with nitrogen mustards, purine analogs, thalidomide analogs, phosphoinositide 3-kinase inhibitor, BCL-2 inhibitors and bruton's tyrosine kinase (BTK) inhibitors.
  • a “nitrogen mustard” is a nonspecific DNA alkylating agent used as chemotherapy.
  • Alkylating agents add an alkyl group (CnH2n+1) to nucleic acid bases, e.g., adding an alkyl group to the guanine base of DNA at the number 7 nitrogen atom of the imidazole ring.
  • the alkylation steps result in the formation of interstrand cross-links (ICLs).
  • ICLs interstrand cross-links
  • Nitrogen mustards include cyclophosphamide, chlorambucil, uramustine, ifosfamide, melphalan and bendamustine.
  • Bendamustine is marketed under the names Ribomustin®,and Treanda®, and is also known as SDX-105, by Mundipharma International Corporation Limited (Licensee of Astellas Pharma GmbH) and Cephalon for the treatment of chronic lymphocytic leukemias (CLL), indolent B-cell non-Hodgkin's lymphoma (NHL), and other lymphomas.
  • Bendamustine has the following structure:
  • a purine analog is an antimetabolite, which mimics the structure of metabolic purines, thereby interfering with the synthesis of nucleic acids.
  • Fludarabine for example, may be incorporated into RNA and DNA by substituting for the purine nucleotides, adenine and guanine.
  • Purine analogs inhibit growth of fast proliferating cells of an individual, e.g. cancer cells, bone marrow cells or cells present in the gastrointestinal tract.
  • Purine analogs include mercaptopurine, azathioprine, thioguanine and fludarabine.
  • Fludarabine or fludarabine phosphate is a chemotherapy drug used in the treatment of chronic lymphocytic leukemia and indolent non-Hodgkins lymphomas. Fludarabine is a purine analog. Fludarabine inhibits DNA synthesis by interfering with ribonucleotide reductase and DNA polymerase and is S phase-specific (since these enzymes are highly active during DNA replication). Fludarabine has the following structure:
  • a “thalidomide analog” includes, but is not limited to, thalidomide itself, lenalidomide (CC-5013, RevlimidTM), Pomalidomide (CC4047, ActimidTM) and the compounds disclosed in WO2002068414 and WO2005016326, which are incorporated by reference in their entireties.
  • the term refers to a synthetic chemical compound using the thalidomide structure as a backbone (e.g., side groups have been added or such groups have been deleted from the parent structure).
  • the analog differs in structure from thalidomide and its metabolite compounds such as by a difference in the length of an alkyl chain, a molecular fragment, by one or more functional groups, or a change in ionization.
  • thalidomide analog also includes the metabolites of thalidomide.
  • Thalidomide analogs include the racemic mixture of the S- and the R-enantiomer of a respective compound and the S-enantiomer or to the R-enantiomer individually. The racemic mixture is preferred.
  • Thalidomide analogs include the compounds of the following structures:
  • a “phosphoinositide 3-kinase inhibitor” is a class of medical drug that functions by inhibiting one or more of the phosphoinositide 3-kinase enzymes, which are part of the PI3K/AKT/mTOR pathway, an important signalling pathway for many cellular functions such as growth control, metabolism and translation initiation.
  • Class 1 PI3Ks have a catalytic subunit known as p110, with four types (isoforms)—p110 alpha, p110 beta, p110 gamma and p110 delta.
  • Current inhibitors being studied inhibit one or more isoforms of the class I PI3Ks.
  • Phosphoinositide 3-kinase inhibitors include at least Idelalisib, Duvelisib and Copanlisib.
  • Idelalisib is marketed by Gilead Sciences, Inc. (trade name Zydelig, also named GS-1101 or CAL-101).
  • Idelalisib is currently labelled for the treatment of relapsed chronic lymphocytic leukemia (CLL), in combination with rituximab, in patients for whom rituximab alone would be considered appropriate therapy due to other co-morbidities; relapsed follicular B-cell non-Hodgkin lymphoma (FL) in patients who have received at least two prior systemic therapies; relapsed small lymphocytic lymphoma (SLL) in patients who have received at least two prior systemic therapies.
  • the substance acts as a phosphoinositide 3-kinase inhibitor; more specifically, it blocks P110 ⁇ , the delta isoform of the enzyme phosphoinositide 3-kinase.
  • BTK Bruton's tyrosine kinase inhibitor
  • PIP3 phosphatidylinositol (3,4,5)-trisphosphate
  • PIP3 binding induces Btk to phosphorylate phospholipase C, which in turn hydrolyzes PIP2, a phosphatidylinositol, into two second messengers, inositol triphosphate (IP3) and diacylglycerol (DAG), which then go on to modulate the activity of downstream proteins during B-cell signalling.
  • IP3 inositol triphosphate
  • DAG diacylglycerol
  • Bruton's tyrosine kinase (BTK) inhibitors include Ibrutinib.
  • Ibrutinib is marketed by Pharmacyclics, Inc and Johnson & Johnson's Janssen Pharmaceutical (trade name Imbruvica, also named PCI-32765).
  • Ibrutinib is currently labelled for the treatment of patients with Mantle cell lymphoma (MCL) who have received at least one prior therapy, Chronic lymphocytic leukemia (CLL) who have received at least one prior therapy, Chronic lymphocytic leukemia with 17p deletion, and Waldenstrom's macroglobulinemia.
  • MCL Mantle cell lymphoma
  • CLL Chronic lymphocytic leukemia
  • Chronic lymphocytic leukemia with 17p deletion and Waldenstrom's macroglobulinemia.
  • Ibrutinib is 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinyl]-2-propen-1-one and has the following structure:
  • a “BCL-2 inhibitor” is a class of drug that functions by inhibiting anti-apoptotic B-cell lymphoma-2 (Bcl-2) protein, leading to programmed cell death of cells.
  • BCL-2 inhibitor include venetoclax. Venetoclax is marketed by Abbvie and Genentech (trade name VENCLEXTATM, also known as GDC-0199, ABT-199, and RG7601). Venetoclax is currently labelled for the treatment of patients with chronic lymphocytic leukemia (CLL) with 17p deletion, as detected by an FDA approved test, who have received at least one prior therapy.
  • CLL chronic lymphocytic leukemia
  • venetoclax is 4-(4- ⁇ [2-(4-Chlorophenyl)-4,4-dimethyl-1-cyclohexen-1-yl]nethyl ⁇ -1-piperazinyl)-N-( ⁇ 3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl ⁇ sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide and has the following structure:
  • Venetoclax “ABT”, and “ABT-199” are used as synonyms herein.
  • An aspect is a method of identifying a subject having chronic lymphocytic leukemia (CLL), non-Hodgkin's lymphoma (NHL), acute lymphoblastic leukemia (ALL) or small lymphocytic lymphoma (SLL) that is responsive to treatment with an anti-CD19 antibody, said method comprising:
  • the sample is a blood sample.
  • said sample comprises peripheral NK cells.
  • the predetermined cut off level of said biomarker is a baseline peripheral NK cell count of at least 50 cells/ ⁇ l, at least 75 cells/ ⁇ l, at least 100 cells/ ⁇ l, at least 125 cells/ ⁇ l, at least 150 cells/ ⁇ l, at least 175 cells/ ⁇ l, at least 200 cells/ ⁇ l, at least 225 cells/ ⁇ l, or at least 250 cells/ ⁇ l.
  • the predetermined cut off level of said biomarker is baseline CD16 expression levels on peripheral NK cells of at least 45,000 ABCs, at least 60,000 ABCs, at least 75,000 ABCs, or at least 90,000 ABCs.
  • the predetermined cut off of said biomarker is:
  • the predetermined cut of said biomarker is:
  • predetermined cut off level a baseline peripheral NK cell count of at least 50 cells/ ⁇ l.
  • the predetermined cut of said biomarker is baseline CD16 expression levels on peripheral NK cells of at least 60,000 (ABCs).
  • the predetermined cut off of said biomarker is:
  • the predetermined cut off of said biomarker is:
  • predetermined cut off level a baseline peripheral NK cell count of at least 70 cells/ ⁇ l.
  • the predetermined cut of said biomarker is baseline CD16 expression levels on peripheral NK cells of at least 60,000 (ABCs).
  • the predetermined cut off of said biomarker is:
  • the predetermined cut off of said biomarker is:
  • predetermined cut off level a baseline peripheral NK cell count of at least 80 cells/ ⁇ l.
  • the predetermined cut of said biomarker is baseline CD16 expression levels on peripheral NK cells of at least 60,000 (ABCs).
  • the predetermined cut off of said biomarker is:
  • the predetermined cut off of said biomarker is:
  • predetermined cut off level a baseline peripheral NK cell count of at least 90 cells/ ⁇ l.
  • the predetermined cut of said biomarker is baseline CD16 expression levels on peripheral NK cells of at least 60,000 (ABCs).
  • the predetermined cut off of said biomarker is:
  • the predetermined cut off of said biomarker is:
  • predetermined cut off level a baseline peripheral NK cell count of at least 100 cells/ ⁇ l.
  • the predetermined cut of said biomarker is baseline CD16 expression levels on peripheral NK cells of at least 60,000 (ABCs).
  • An aspect is a method of identifying a subject having chronic lymphocytic leukemia (CLL), non-Hodgkin's lymphoma (NHL), acute lymphoblastic leukemia (ALL) or small lymphocytic lymphoma (SLL) that is responsive to treatment with an anti-CD19 antibody, said method comprising:
  • An aspect is a method of identifying a subject having chronic lymphocytic leukemia (CLL), non-Hodgkin's lymphoma (NHL), acute lymphoblastic leukemia (ALL) or small lymphocytic lymphoma (SLL) that is responsive to treatment with an anti-CD19 antibody, said method comprising:
  • the predetermined cut of said biomarker is:
  • the predetermined cut off level of said biomarker is a baseline peripheral NK cell count of at least 50 cells/ ⁇ l, at least 75 cells/ ⁇ l, at least 100 cells/ ⁇ l, at least 125 cells/ ⁇ l, at least 150 cells/ ⁇ l, at least 175 cells/ ⁇ l, at least 200 cells/ ⁇ l, at least 225 cells/ ⁇ l, or at least 250 cells/ ⁇ l.
  • the predetermined cut off level of said biomarker is baseline CD16 expression levels on peripheral NK cells of at least 45,000 ABCs, at least 60,000 ABCs, at least 75,000 ABCs, or at least 90,000 ABCs.
  • An aspect is a method of treating a patient having chronic lymphocytic leukemia (CLL), non-Hodgkin's lymphoma (NHL), acute lymphoblastic leukemia (ALL) or small lymphocytic lymphoma (SLL) with an anti-CD19 antibody, the method comprising
  • An aspect is a method of treating a patient having chronic lymphocytic leukemia (CLL), non-Hodgkin's lymphoma (NHL), acute lymphoblastic leukemia (ALL) or small lymphocytic lymphoma (SLL) with an anti-CD19 antibody, the method comprising
  • the method of treating a patient chronic lymphocytic leukemia (CLL), non-Hodgkin's lymphoma (NHL), acute lymphoblastic leukemia (ALL) or small lymphocytic lymphoma (SLL) with an anti-CD19 antibody comprises
  • the method of treating a patient chronic lymphocytic leukemia (CLL), non-Hodgkin's lymphoma (NHL), acute lymphoblastic leukemia (ALL) or small lymphocytic lymphoma (SLL) with an anti-CD19 antibody comprises
  • the method of treating a patient chronic lymphocytic leukemia (CLL), non-Hodgkin's lymphoma (NHL), acute lymphoblastic leukemia (ALL) or small lymphocytic lymphoma (SLL) with an anti-CD19 antibody comprises
  • the method of treating a patient having chronic lymphocytic leukemia (CLL), non-Hodgkin's lymphoma (NHL), acute lymphoblastic leukemia (ALL) or small lymphocytic lymphoma (SLL) with an anti-CD19 antibody comprises
  • the anti-CD19 antibody is administered to patients having both a baseline peripheral NK cell count of of at least 50 cells/ ⁇ l, at least 60 cells/ ⁇ l, at least 70 cells/ ⁇ l, at least 80 cells/ ⁇ l, at least 90 cells/ ⁇ l or at least 100 cells/ ⁇ l, and a baseline CD16 expression level on peripheral NK cells of at least 60,000 (ABCs).
  • ABSCs 60,000
  • the anti-CD19 antibody is administered to patients having both a baseline peripheral NK cell count of at least 100 cells/ ⁇ l, and a baseline CD16 expression level on peripheral NK cells of at least 60,000 (ABCs).
  • the anti-CD19 antibody is administered to patients having a baseline peripheral NK cell count of at least 50 cells/ ⁇ l, at least 75 cells/ ⁇ l, at least 100 cells/ ⁇ l, at least 125 cells/ ⁇ l, at least 150 cells/ ⁇ l, at least 175 cells/ ⁇ l, at least 200 cells/ ⁇ l, at least 225 cells/ ⁇ l, or at least 250 cells/ ⁇ l.
  • the anti-CD19 antibody is administered to patients having baseline CD16 expression levels on peripheral NK cells of at least 45,000 ABCs, at least 60,000 ABCs, at least 75,000 ABCs, or at least 90,000 ABCs.
  • An aspect is a method of treating a patient having chronic lymphocytic leukemia (CLL), non-Hodgkin's lymphoma (NHL), acute lymphoblastic leukemia (ALL) or small lymphocytic lymphoma (SLL) with an anti-CD19 antibody, said method comprising:
  • An aspect is a method of treating a patient having chronic lymphocytic leukemia (CLL), non-Hodgkin's lymphoma (NHL), acute lymphoblastic leukemia (ALL) or small lymphocytic lymphoma (SLL) comprising administering an effective amount of an anti-CD19 antibody to the patient if
  • CLL chronic lymphocytic leukemia
  • NHL non-Hodgkin's lymphoma
  • ALL acute lymphoblastic leukemia
  • SLL small lymphocytic lymphoma
  • An aspect is a method of treating a patient having chronic lymphocytic leukemia (CLL), non-Hodgkin's lymphoma (NHL), acute lymphoblastic leukemia (ALL) or small lymphocytic lymphoma (SLL) comprising
  • An aspect is a method of treating a patient having chronic lymphocytic leukemia (CLL), non-Hodgkin's lymphoma (NHL), acute lymphoblastic leukemia (ALL) or small lymphocytic lymphoma (SLL) comprising
  • anti-CD19 antibody is administered to patients having both a baseline peripheral NK cell count of at least 100 cells/ ⁇ l and a baseline CD16 expression level on peripheral NK cells of at least 60,000 (ABCs).
  • the anti-CD19 antibody is administered to patients having a baseline peripheral NK cell count of at least 50 cells/ ⁇ l, at least 75 cells/ ⁇ l, at least 100 cells/ ⁇ l, at least 125 cells/ ⁇ l, at least 150 cells/ ⁇ l, at least 175 cells/ ⁇ l, at least 200 cells/ ⁇ l at least 225 cells/ ⁇ l, or at least 250 cells/ ⁇ l.
  • the anti-CD19 antibody is administered to patients having baseline CD16 expression levels on peripheral NK cells of at least 45,000 ABCs, at least 60,000 ABCs, at least 75,000 ABCs, or at least 90,000 ABCs.
  • the baseline peripheral NK cell count or baseline CD16 levels (ABCs) on the peripheral NK cells is obtained from a blood sample taken from the patient.
  • the peripheral NK cell count and/or the CD16 expression levels are measured prior to administration of the anti-CD19 antibody.
  • the antibody specific for CD19 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).
  • the baseline peripheral NK cell count or baseline CD16 expression levels on the peripheral NK cells is obtained from a blood sample taken from the patient.
  • the patient has non-Hodgkin's lymphoma.
  • 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.
  • the non-Hodgkin's lymphoma is follicular lymphoma.
  • the non-Hodgkin's lymphoma is indolent non-Hodgkin's lymphoma.
  • the non-Hodgkin's lymphoma is small lymphocytic lymphoma.
  • the non-Hodgkin's lymphoma is mucosa-associated lymphoid tissue. In an embodiment, the non-Hodgkin's lymphoma is marginal zone lymphoma. In an embodiment, the non-Hodgkin's lymphoma is diffuse large B cell lymphoma. In an embodiment, the non-Hodgkin's lymphoma is Burkitt's lymphoma. In an embodiment, the non-Hodgkin's lymphoma is mantle cell lymphoma. In an embodiment, the patient has chronic lymphocytic leukemia. In an embodiment, the patient has acute lymphoblastic leukemia. In an embodiment, the patient has small lymphocytic lymphoma (SLL).
  • SLL small lymphocytic lymphoma
  • the treatment results in the therapeutic effect selected from the group consisting of Disease Control Rate (DCR) and longer duration of Progression Free Survival.
  • DCR Disease Control Rate
  • the treatment further comprises administration of an effective amount of a nitrogen mustard. In an embodiment that nitrogen mustard is bendamustine. In embodiments, the treatment further comprises administration of an effective amount of a purine analog. In embodiments, the purine analog is fludarabine. In embodiments, the treatment further comprises administration of an effective amount of a Bruton's tyrosine kinase (BTK) inhibitor. In embodiments, the Bruton's tyrosine kinase (BTK) inhibitor is ibrutinib. In embodiments, the treatment further comprises administration of an effective amount of a phosphoinositide 3-kinase inhibitor. In an embodiment the phosphoinositide 3-kinase inhibitor is idelalisib.
  • the treatment further comprises administration of an effective amount of a thalidomide analog.
  • the thalidomide analog is lenalidomide.
  • the treatment further comprises administration of an effective amount of a BCL-2 inhibitor.
  • the BCL-2 inhibitor is venetoclax.
  • anti-CD19 antibody and other anti-CD19 antibodies bind CD19, it is believed that similar results may be seen with other anti-CD19 antibodies.
  • Other anti-CD19 antibodies are described in U.S. patent application Ser. No. 12/377,251 (Xencor), WO2005012493, WO2010053716 (Immunomedics); WO2007002223 (Medarex); WO2008022152 (Xencor); WO2008031056 (Medimmune); WO 2007/076950 (Merck Patent GmbH); WO 2009/052431 (Seattle Genetics); and WO2010095031 (Glenmark Pharmaceuticals), all of which are incorporated by reference in their entireties.
  • the antibody specific for CD19 comprises an antibody that cross-competes with the antibody comprising 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).
  • the antibody specific for CD19 comprises an antibody that binds to the same epitope as an antibody comprising 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).
  • the antibody specific for CD19 comprises an HCDR1 region of sequence SYVMH (SEQ ID NO: 1), an HCDR2 region of sequence NPYNDG (SEQ ID NO: 2), an HCDR3 region of sequence GTYYYGTRVFDY (SEQ ID NO: 3), an LCDR1 region of sequence RSSKSLQNVNGNTYLY (SEQ ID NO: 4), an LCDR2 region of sequence RMSNLNS (SEQ ID NO: 5), and an LCDR3 region of sequence MQHLEYPIT (SEQ ID NO: 6).
  • the antibody specific for CD19 comprises a variable heavy chain of the sequence
  • the antibody specific for CD19 comprises a light chain constant domain of the sequence RTVAAPSVFI FP PS DEQLKSGTASVVCLLN N FYPREAKVQWKVDNALQSG NSQESVTEQDS KD STYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC. (SEQ ID NO: 13).
  • the antibody specific for CD19 comprises a heavy chain having the sequence
  • the antibody specific for CD19 comprises a light chain having the sequence
  • Embodiments comprise a pharmaceutical composition.
  • the composition comprises an acceptable carrier.
  • the composition is administered in an effective amount.
  • T cells are a type of lymphocyte (a subtype of white blood cell) that play a central role in cell-mediated immunity. They can be distinguished from other lymphocytes, such as B cells and NK cells, by the presence of a T-cell receptor on the cell surface.
  • NK cells Natural killer cells or NK cells are a type of cytotoxic lymphocyte critical to the innate immune system. NK cells provide rapid responses to viral-infected cells, acting at around 3 days after infection, and respond to tumor formation. Typically, immune cells detect major histocompatibility complex (MHC) presented on infected cell surfaces, triggering cytokine release, causing lysis or apoptosis. NK cells are unique, however, as they have the ability to recognize stressed cells in the absence of antibodies and MHC, allowing for a much faster immune reaction.
  • MHC major histocompatibility complex
  • TriTest CD3 FITC/CD16+CD56 PE/CD45 PerCP (with TruCOUNT tubes), BD Biosciences, Cat: 340403 (US); 342442 (Europe). Pipettors and pipet tips capable of delivering 20 ⁇ L, 50 ⁇ L and 450 ⁇ L, Gilson Inc. FACS Lysing Solutions, BD Biosciences, Cat: 349202.
  • TriTEST reagents Fluorescence triggering, allowing direct fluorescence gating of the NK- and T-cell lymphocyte population to reduce contamination of unlysed or nucleated red blood cells in the gate.
  • a TruCOUNT Tube was labelled with the sample identification number.
  • 20 ⁇ L of TriTEST CD3/CD16+CD56/CD45 reagent was pipetted into the bottom of the tube.
  • 50 ⁇ L of well-mixed, anticoagulated whole blood was pipetted into the bottom of the tube.
  • Anticoagulated blood (EDTA) stored at room temperature (20-25° C.) must be stained within 24 hours of draw and analyzed within 6 hours of staining (keep at room temperature and protected from light).
  • the tube was vortexed gently to mix.
  • the tube was incubated for 15 minutes in the dark at room temperature (20-25° C.).
  • 450 ⁇ L 1 ⁇ FACS Lysing Solution was added to the tube.
  • the tube was vortexed and incubated again for 15 minutes in the dark at room temperature (20-25° C.).
  • TruCOUNT Tubes a known volume of sample is stained directly in a TruCOUNT Tube.
  • the lyophilized pellet in the tube dissolves, releasing a known number of fluorescent beads.
  • the absolute number (cells/ ⁇ L) of positive cells in the sample can be determined by comparing cellular events to bead events.
  • the cells were vortexed thoroughly (at low speed) to reduce aggregation before running them on the flow cytometer.
  • the CD45 vs SSC dot plot was visually inspected. Lymphocytes appear as a bright, compact cell population with low to moderate SSC. Monocytes (M) and granulocytes (G) appear as distinct populations. Analysis was completed when the cell populations of monocytes and lymphocytes showed clear separation.
  • Lymphocytes were first gated as CD45 positive, low SSC cell population.
  • CD16/CD56 vs CD3 were pre-selected.
  • T-cells (T) should appear as a compact bright CD3 positive cluster.
  • NK-cells (NK) should appear as a compact bright CD16/CD56 positive cluster. Gating was completed and the T, and NK cells were counted.
  • Bead event counts were done using a CD16/CD56 vs CD3 plot without any pre-selected gate. Beads should appear as a PE/FITC double positive cluster.
  • the absolute number (cells/ ⁇ L blood) of T cells or NK cells in the sample was determined by comparing cellular events to bead events. Either MultiSET software or manual (using CellQuest or other software) data analysis was done. For manual counting, the number (#) of positive cellular acquired events was divided by the number (#) of acquired bead events, then multiplied by the (total TruCOUNT bead count (lot dependent) divided by whole blood sample volume of 50 ⁇ L). The result is absolute cell numbers per microliter.
  • TruCOUNT ⁇ ⁇ beads 50 ⁇ ⁇ ⁇ ⁇ ⁇ l ⁇ ⁇ whole ⁇ ⁇ blood # ⁇ ⁇ cells / ⁇ ⁇ ⁇ l ⁇ ⁇ blood
  • CD16 an exploratory biomarker was quanitified on peripheral NK Cells centrally by ICON Central Laboratories (Farmingdale, N.Y.).
  • CD45 AmCyan (Clone 2D1, BD Biosciences, Cat #339192); CD3 FITC (Clone UCHT1, BioLegend, Cat #300406); Mouse IgG FITC (Clone MOPC-21, BioLegend, Cat #400110); CD16 PE (Clone 3G8, BioLegend, Cat #302008); MOR00208; Mouse IgG PE (Clone MOPC-21, BioLegend, Cat #400114); CD56 PerCP-Cy5.5 (Clone HCD56, BioLegend, Cat #318322); and Mouse IgG PerCP-Cy5.5 (Clone MOPC-21, BioLegend, Cat #400150).
  • the tubes were centrifuged at 300 ⁇ g for 10 min at 4° C. and supernatant removed. The t ubes were vortexed to resuspend cell pellet. The cell pellet was washed with DBPS, centrifuged, supernatant removed and resuspended by vortexing. The washed PBMC suspension was added into an eppendorf tube containing 1 ⁇ L ViViD stock solution; incubated for 15 min on ice and kept in dark (cover with aluminum foil). The stained ViViD PBMC were transferred into a new labeled conical tube and then ice cold FACS Buffer was added. The cells were centrifuged and vortexed again for resuspension.
  • Polystyrene falcon tubes were labeled for each sample (Table 1).
  • the antibodies or isotype control antibodies were added to the appropriate tubes.
  • the aliquot of ViViD stained PBMCs was added to each tube (Table 1).
  • the tubes were vortexed and incubate.
  • FACS Buffer was added and the cells were centrifuged and vortexed again for resuspension.
  • BD Pharm Lyse Lysing Buffer was added, and the cells were vortexed, centrifuge and aspirated to remove supernatant and vortexed again to resuspend.
  • FACS Buffer was added again and the cells were centrifuged and vortexed again for resuspension.
  • One site of measurable disease by magnetic resonance imaging (MRI) or computed tomography (CT) scan defined as at least one lesion that measures at least 1.5 ⁇ 1.5 cm, with the exception:
  • MRI magnetic resonance imaging
  • CT computed tomography
  • Laboratory criteria at screening a) Absolute neutrophil count (ANC) ⁇ 1.0 (1000/mm3) b) Platelet count ⁇ 75 ⁇ 109/L without previous transfusion within 10 days of first study drug administration. c) Haemoglobin ⁇ 8.0 g/dL (may have been transfused). d) Serum creatinine ⁇ 2.0 ⁇ upper limit of normal (ULN). e) Total bilirubin ⁇ 2.0 ⁇ ULN. f) Alanine transaminase (ALT) and aspartate aminotransferase (AST) ⁇ 2.5 ⁇ ULN.
  • CNS central nervous system
  • MOR00208 was given at a dose of 12 mg/kg on days 1, 8, 15, and 22. At the end of the two cycles, patients having Stable Disease or better were treated with a third 28 day cycle applying the same dosing and schedule as the first two cycles. At the end of the third cycle, patients having Partial Response or better went into Maintenance. In Maintanence, MOR00208 was given at a dose of 12 mg/kg every 14 or 28 days until disease progression.
  • iNHL means a heterogeneous group of not further specified indolent, not aggressive, NHL types, e.g. Marginal Cell Lymphoma, Marginal Zone Lymphoma, and Mucosa associated lymphoid tissue (MALT) lymphoma.
  • NHL types e.g. Marginal Cell Lymphoma, Marginal Zone Lymphoma, and Mucosa associated lymphoid tissue (MALT) lymphoma.
  • DCR disease control rate
  • DLBCL diffuse large B-cell lymphoma
  • iNHL indolent non-Hodgkin's lymphoma
  • MCL mantel cell lymphoma' ORR, overall response rate.
  • DCR (CR+PR+SD) was considered the most relevant efficacy endpoint the analysis of patient characteristic and biomarkers in this trial as the majority of patients with SD had marked target lesion reduction but as per study design were not treated beyond cycle 3. Accordingly, patients having SD included in the analysis.
  • Example 1 and Example 2 above were used to evaluate the baseline peripheral NK cell counts, T cell counts and baseline CD16 expression on peripheral NK cells. The data is shown in Table 2.
  • ROC Receiver Operating Characteristic
  • the area under the curve measures the performance of a classifier and is frequently applied for method comparison. A higher AUC means a better classification.
  • the AUC for peripheral NK/T cell counts and for CD16 expression on NK cells is 0.66, 0.53 and 0.61 respectively ( FIGS. 3, 4 and 5 ).
  • the determination of the cut off depends on the objective the respective method is directed to.
  • Various criteria such as maximum accuracy, maximum diagnostic odds ratio, minimal error rate, maximum sensitivity and/or maximum specificity would lead to a different determination of the cut off.
  • a balance between more of such criteria, e.g. sensitivity and specificity would also lead to a specific determination of the cut off.
  • the AUC is 0.53 and the ROC curve is close to the bisectrix at any value of specificity and sensitivity therefore even selecting a different cut off than 500 cell// ⁇ l had no impact on the negative results of the DCR and PFS subgroup analysis.
  • the determination of the cut off can be balanced either in favor of sensitivity or specificity. If even more weight is assigned to sensitivity for the identification of the optimal cut-off the method would be different and a lower cut-off for the NK cell count is contemplated. In such case a cut off of at least 50 NK cells/ ⁇ l is determined. Alternatively, a cut off of at least 60 NK cells/ ⁇ l, at least 70 NK cells/ ⁇ l, at least 80 NK cells/ ⁇ l, at least 90 NK cells/ ⁇ l or at least 100 NK cells/ ⁇ l is determined.
  • the cut-off for the NK cell count is increased and is determined between at least 100 NK cells/ ⁇ l up to at least 150 NK cells/ ⁇ l. Therefore for maximizing the specificity a cut off of at least 100 NK cells/ ⁇ l, at least 110 NK cells/ ⁇ l, at least 120 NK cells/ ⁇ l, at least 130 NK cells/ ⁇ l, at least 140 NK cells/ ⁇ l or at least 150 NK cells/ ⁇ l is selected.
  • DCR Disease Control Rate
  • PR Partial Response
  • SD Stable Disease
  • PFS Progression Free Survival
  • the PFS comparing patients having NK cell counts having at least 100 cells/ ⁇ l as compared to patients having lower NK cell counts showed a statistically significant difference with a HR of 0.1561 (unadjusted log-rank p value 0.0003). This further confirms the predictivity of NK cells counts in the response of patients treated with MOR00208 of those patients having CLL, NHL, ALL or SLL.

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