Combinations and uses thereof

Abstract

To provide a pharmaceutical combination for the treatment of non-Hodgkin's lymphoma, chronic lymphocytic leukemia and / or acute lymphoblastic leukemia.SOLUTION: A pharmaceutical combination of an anti-CD19 antibody and a phosphoinositide 3-kinase inhibitor for the treatment of non-Hodgkin's lymphoma, chronic lymphocytic leukemia and / or acute lymphoblastic leukemia is provided.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present disclosure relates to pharmaceutical combinations of anti-CD19 antibodies and phosphoinositide 3-kinase inhibitors for the treatment of non-Hodgkin's lymphoma, chronic lymphocytic leukemia and / or acute lymphoblastic leukemia. [Background technology]

[0002] B cells are lymphocytes that play a major role in humoral immune responses. They are produced in the bone marrow of most mammals and represent 5-15% of the circulating lymphocyte pool. Their primary function is to produce antibodies against various antigens, making them an essential component of the adaptive immune system.

[0003] Due to their critical role in regulating the immune system, dysregulation of B cells is associated with a variety of disorders, such as lymphomas and leukemias, including non-Hodgkin's lymphoma ("NHL"), chronic lymphocytic leukemia ("CLL"), and acute lymphoblastic leukemia ("ALL").

[0004] NHL is a heterogeneous malignant tumor arising from lymphocytes. The incidence in the United States (US) is estimated at 65,000 cases per year, with a mortality rate of approximately 20,000 (American Cancer Society, 2006; and SEER Cancer Statistics Review). The disease can occur at any age, with onset typically beginning in adults over 40 years of age, and incidence increases with age. NHL is characterized by the clonal proliferation of lymphocytes that accumulate in 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 Tumors, which groups NHL into precursor and mature B-cell or mature T-cell neoplasms. PDQ currently categorizes NHL as indolent or aggressive for clinical trial enrollment. The low-grade NHL group consists primarily of follicular subtype, small lymphocytic lymphoma, mucosa-associated lymphoid tissue (MALT), and marginal zone lymphoma; low-grade NHL encompasses approximately 50% of newly diagnosed B-cell NHL patients. High-grade NHL primarily includes patients with histologically diagnosed diffuse large B-cell (DLBL, DLBCL, or DLCL) (40% of all newly diagnosed patients have diffuse large cell), Burkitt cell, and mantle cell lymphoma. The clinical course of NHL is highly variable. The primary determinant of clinical course is the histological subtype. Most low-grade NHL is considered incurable. Patients initially respond to either chemotherapy or antibody therapy, but the majority relapse. Previous studies have not demonstrated improved survival with early intervention. In asymptomatic patients, "watch and wait" is acceptable until the patient becomes symptomatic or the rate of disease progression appears to be accelerating. The disease may evolve to more aggressive histologies over time. Median survival is 8-10 years, and patients with indolent disease often undergo three or more treatments during the course of their disease. Initial treatment for symptomatic indolent NHL has historically been combination chemotherapy.The most commonly used drugs include cyclophosphamide, vincristine, and prednisone (CVP) or cyclophosphamide, adriamycin, vincristine, and prednisone (CHOP). Approximately 70% to 80% of patients respond to these initial chemotherapy regimens, with remissions lasting 2 to 3 years. Ultimately, the majority of patients relapse. The discovery and clinical use of the anti-CD20 antibody, rituximab, has significantly improved response and survival rates. The current standard of care for most patients is rituximab plus CHOP (R-CHOP) or rituximab plus CVP (R-CVP). Interferon, in combination with alkylating agents, has been approved for the initial treatment of NHL, but its use is limited in the United States. Rituximab therapy has been shown to be effective in several types of NHL and is currently approved as first-line treatment for both low-grade (follicular lymphoma) and high-grade (diffuse large B-cell lymphoma) NHL. However, anti-CD20 monoclonal antibodies (mAbs) have significant limitations, including primary resistance (50% response in relapsed low-grade patients), acquired resistance (50% response rate upon retreatment), rare complete responses (2% complete response rate in the relapsed population), and a persistent pattern of relapse. Finally, many B cells do not express CD20, and therefore many B-cell disorders cannot be treated with anti-CD20 antibody therapy.

[0005] In addition to NHL, there are several types of leukemia caused by dysregulation of B cells. CLL is a type of adult leukemia caused by the abnormal accumulation of B lymphocytes. In CLL, malignant lymphocytes may appear normal and mature but are unable to effectively fight infection. CLL is the most common form of leukemia in adults. Men are twice as likely to develop CLL as women. However, age is a significant risk factor. More than 75% of new cases are diagnosed in patients over the age of 50. More than 10,000 cases are diagnosed each year, with nearly 5,000 deaths annually (American Cancer Society, 2006; and SEER Cancer Statistics Review). CLL is an incurable disease, but in most cases it progresses slowly. Many people with CLL lead normal, active lives for many years. Early-stage CLL is generally not treated because of its slow onset, as early intervention is not believed to improve survival or quality of life. Instead, the condition is monitored over time. Initial CLL treatment varies depending on the exact diagnosis and progression of the disease. There are dozens of drugs used in CLL therapy. Combination chemotherapy regimens, such as FCR (fludarabine, cyclophosphamide, and rituximab), and BR (idelalisib and rituximab), are effective for 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 risks.

[0006] Another type of leukemia is ALL, also known as acute lymphocytic leukemia. ALL is characterized by the overproduction and continuous proliferation of malignant immature white blood cells (also called lymphoblasts) in the bone marrow. The "acute" refers to the undifferentiated, immature state of the circulating lymphocytes ("blasts") and the rapid progression of the disease, with a life expectancy of only a few weeks to a few months if left untreated. ALL is most common in childhood, with peak incidence between the ages of 4 and 5. Children aged 12 and 16 are more likely to die from ALL than children of other ages. Currently, at least 80% of childhood ALL cases are considered curable. Fewer than 4,000 cases are diagnosed each year, with approximately 1,500 deaths annually (American Cancer Society, 2006; and SEER Cancer Statistics Review).

[0007] The human CD19 molecule is a structurally distinct cell surface receptor expressed on the surface of human B cells, including, but not limited to, pre-B cells, early developmental B cells (i.e., immature B cells), mature B cells that undergo terminal differentiation to become plasma cells, and malignant B cells. CD19 is expressed on most pre-B acute lymphoblastic leukemias (ALL), non-Hodgkin's lymphomas, B-cell chronic lymphocytic leukemia (CLL), prolymphocytic leukemia, hairy cell leukemia, conventional acute lymphocytic leukemia, and some null cell acute lymphoblastic leukemias (Nadler et al., J. Immunol., 131:244-250 (1983); Loken et al., Blood, 70:1316-1324 (1987); Uckun et al., Blood, 71:13-29 (1988); Anderson et al., Blood, 63:1424-1433 (1984); Scheuermann, Leuk. Lymphoma, 18:385-397 (1995)). Expression of CD19 on plasma cells further suggests that CD19 may be expressed on differentiated B-cell tumors such as multiple myeloma, plasmacytoma, and Waldenstrom's tumor (Grossbard et al., Br. J. Haematol, 102:509-15 (1998); Treon et al., Semin. Oncol, 30:248-52 (2003)).

[0008] Thus, the CD19 antigen is an immunotherapeutic target in the treatment of non-Hodgkin's lymphoma (including each of the subtypes described herein), chronic lymphocytic leukemia, and / or acute lymphoblastic leukemia.

[0009] Several CD19 therapies have been demonstrated. T cells expressing an anti-CD19 chimeric antigen receptor (CAR) containing both CD3-ζ and 4-BB costimulatory domains were administered to three patients with advanced CLL. Kalos et al., "T Cells with Chimeric Antigen Receptors Have Potent Antitumor Effects and Can Establish Memory in Patients with Advanced Leukemia," Science Translational Medicine, vol. 3, no. 95 (10 August 2011), which is incorporated by reference in its entirety. Anti-CD19 chimeric antigen receptors (CARs) are also described in Sadelain et al., "The Promise and Potential Pitfalls of Chimeric Antigen Receptors," Current Opinion in Immunology, Elsevier, vol. 21, no. 2 (2 April 2009), which is incorporated by reference in its entirety.

[0010] The use of CD19 antibodies in non-specific B cell lymphoma is discussed in WO 2007076950 (US 2007154473), both of which are incorporated by reference in their entireties.

[0011] The use of CD19 antibodies 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.

[0012] Additional antibodies specific for CD19 are disclosed in WO 2005012493 (U.S. Patent No. 7,109,304), WO 2010053716 (U.S. Patent Application No. 12 / 266,999) (Immunomedics); WO 2007002223 (U.S. Patent No. 8,097,703) (Medarex); WO 2007002223 (U.S. Patent No. 8,097,703) (Medarex); No. 2008022152 (U.S. Patent Application No. 12 / 377,251) and WO 2008150494 (Xencor), WO 2008031056 (U.S. Patent Application No. 11 / 852,106) (Medimmune); WO 2007076950 (U.S. Patent Application No. 11 / 648,505) (Merck Patent GmbH); WO 2009 / 052431 (U.S. Patent Application No. 12 / 253,895) (Seattle Genetics); and WO 2010095031 (U.S. Patent Application No. 12 / 710,442) (Glenmark Pharmaceuticals), WO 2012010562 and WO 2012010561 (International Drug Development), WO 2011147834 (Roche Glycart), and WO 2012 / 156455 (Sanofi).

[0013] Combinations of antibodies specific for CD19 and other drugs are described in WO 2010151341 (U.S. Patent Application No. 13 / 377,514) (The Feinstein Institute); U.S. Patent No. 5,686,072 (University of Texas), as well as WO 2002022212 (International Application PCT / U.S. Patent Application No. 01 / 29026) (IDEC Pharmaceuticals), WO 2013 / 024097 (U.S. Patent Application No. 14 / 126,928) (MorphoSys AG), and WO 2013 / 024095 (U.S. Patent Application No. 14 / 127,217) (MorphoSys AG), which are incorporated by reference in their entireties. Abstract 4765 from the AACR Annual Meeting 2014, April 5-9, 2014 in San Diego, CA, entitled “Drug synergies observed for antibody and toxin components of SAR3419 ADC contribute to overall conjugate efficacy and can be combination drug or tumor cell line dependent” discloses a PI3K inhibitor and SAR3419 anti-CD19 antibody-drug conjugate (ADC) in specific cell lines.

[0014] Several phosphoinositide 3-kinase inhibitors are commercially available.Idelalisib is also called GS-1101 or CAL-101, and is sold by Gilead, and has the trade name Zydelig in the United States.Idelalisib is described in U.S. Patent No. 6,800,620; U.S. Patent No. 8,865,730; U.S. Patent No. 8,980,901; U.S. Patent No. RE44599; and U.S. Patent No. RE44638, all of which are incorporated by reference in their entirety.

[0015] Despite recent advances in the discovery and development of anti-cancer drugs, it is clear that many forms of cancer associated with CD19-expressing tumors still have poor prognoses. Accordingly, improved methods for treating such forms of cancer are needed. Summary of the Invention

[0016] The prior art does not suggest a synergistic effect of the combination of the exemplified antibodies and idelalisib, either alone or in combination, in the treatment of non-Hodgkin's lymphoma, chronic lymphocytic leukemia and / or acute lymphoblastic leukemia.

[0017] In one aspect, the present disclosure relates to a synergistic combination of an antibody specific for CD19 and a phosphoinositide 3-kinase inhibitor, which is useful for treating B-cell malignancies such as non-Hodgkin's lymphoma (NHL), chronic lymphocytic leukemia, and / or acute lymphoblastic leukemia (ALL).

[0018] In vitro models are believed to suggest how a compound or combination of compounds will behave in humans. Several cell lines were tested, including the chronic B-cell leukemia cell line MEC-1 cells (DSMZ#ACC497). In this in vitro model, MEC-1 cells suggest how this combination will work in treating human chronic lymphocytic leukemia (CLL).

[0019] Furthermore, when the compounds are combined in vitro, the combination is expected to have only additive effects. Surprisingly, the inventors have found that the combination of a particular antibody specific for CD19 and idelalisib mediates synergistic levels of specific cell killing in vitro compared to the antibody and idelalisib alone.

[0020] Specifically, the inventors found that the combination of MOR00208 and idelalisib engaged in synergistic levels of specific cell killing in vitro in MEC-1 cells compared to the antibody and idelalisib alone.

[0021] Additionally and even more surprisingly, the inventors have found that the combination of a particular antibody specific for CD19 and idelalisib has certain superior functional properties compared to the antibody and idelalisib alone.

[0022] In summary, the exemplified combination of anti-CD19 antibodies and idelalisib behaved synergistically in models involving CLL. Because CLL is a B-cell-related disorder and CD19 is highly expressed on B cells, the exemplified combination is likely to have the same mechanism of action and should also behave synergistically in the treatment of other B-cell-related disorders, such as NHL and ALL.

[0023] Therefore, the combination of the exemplary CD19-specific antibodies and idelalisib should be effective in treating non-Hodgkin's lymphoma, chronic lymphocytic leukemia, and / or acute lymphoblastic leukemia in humans. The expected efficacy of the exemplary CD19-specific antibodies and idelalisib combination will be confirmed in clinical trials.

[0024] Because idelalisib and other phosphoinositide 3-kinase inhibitors act by inhibiting one or more phosphoinositide 3-kinase enzymes that are part of the PI3K / AKT / mTOR pathway, a signaling pathway important for many cellular functions, including growth control, metabolism, and translation initiation, their similar mechanisms of action suggest that synergy should also be observed when combining exemplified anti-CD19 antibodies and phosphoinositide 3-kinase inhibitors other than idelalisib to treat humans with non-Hodgkin's lymphoma, chronic lymphocytic leukemia, and / or acute lymphoblastic leukemia.

[0025] Because the exemplified anti-CD19 antibodies and other anti-CD19 antibodies bind to CD19, it is believed that synergy should also be seen when combining any anti-CD19 antibody and a phosphoinositide 3-kinase inhibitor, such as idelalisib, to treat humans with non-Hodgkin's lymphoma, chronic lymphocytic leukemia, and / or acute lymphoblastic leukemia.

[0026] An embodiment of the present disclosure includes a synergistic combination in which an antibody specific for CD19 comprises an HCDR1 region of the sequence SYVMH (SEQ ID NO: 1), an HCDR2 region of the sequence NPYNDG (SEQ ID NO: 2), an HCDR3 region of the sequence GTYYYGTRVFDY (SEQ ID NO: 3), an LCDR1 region of the sequence RSSKSLQNVNGNTYLY (SEQ ID NO: 4), an LCDR2 region of the sequence RMSNLNS (SEQ ID NO: 5), and an LCDR3 region of the sequence MQHLEYPIT (SEQ ID NO: 6), and idelalisib. In a preferred embodiment, the combination is used to treat non-Hodgkin's lymphoma, chronic lymphocytic leukemia, and / or acute lymphoblastic leukemia. [Brief explanation of the drawings]

[0027] [Figure 1] FIG. 1 shows the amino acid sequence of the variable domain of MOR00208. [Figure 2] FIG. 2 shows the amino acid sequence of the Fc region of MOR00208. [Figure 3] FIG. 3 shows ADCC dose-response curves for the combination of MOR00208 and idelalisib in MEC-1 cells from four independent experiments. [Figure 4] FIG. 4 shows ADCC dose-response curves for the combination of MOR00208 and idelalisib in MEC-1 cells from four independent experiments. [Figure 5] FIG. 5 shows ADCC dose-response curves for the combination of MOR00208 and idelalisib in MEC-1 cells from four independent experiments. [Figure 6]FIG. 6 shows ADCC dose-response curves for the combination of MOR00208 and idelalisib in MEC-1 cells from four independent experiments. [Figure 7] Figure 7 shows the CI curves of the combination of MOR00208 and idelalisib at different concentrations obtained from four independent experiments. [Figure 8] FIG. 8 shows the CI curves of the combination of MOR00208 and idelalisib at different concentrations obtained from four independent experiments. [Figure 9] FIG. 9 shows the CI curves of the combination of MOR00208 and idelalisib at different concentrations obtained from four independent experiments. [Figure 10] FIG. 10 shows the CI curves of the combination of MOR00208 and idelalisib at different concentrations obtained from four independent experiments. DETAILED DESCRIPTION OF THE INVENTION

[0028] "Synergy," "cooperation," or "synergistic" means more than the expected additive effect of a combination. The "synergy," "cooperation," or "synergistic" effect of a combination is determined herein by the methods of Chou et al., Clarke et al., and / or Webb et al. See Ting-Chao Chou, "Theoretical Basis, Experimental Design, and Computerized Simulation of Synergism and Antagonism in Drug Combination Studies," Pharmacol Rev 58:621-681 (2006), which is incorporated by reference in its entirety. See also Clarke et al., "Issues in experimental design and endpoint analysis in the study of experimental cytotoxic agents in vivo in breast cancer and other models," Breast Cancer Research and Treatment 46:255-278 (1997), which is incorporated by reference in its entirety. See also Webb, JL (1963) Enzyme and Metabolic Inhibitors, Academic Press, New York, which is incorporated by reference in its entirety.

[0029] The term "antibody" refers to monoclonal antibodies, including any isotype, such as IgG, IgM, IgA, IgD, and IgE. IgG antibodies consist of two identical heavy chains and two identical light chains linked by disulfide bonds. The heavy and light chains each contain 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 to an antigen epitope. These are numbered sequentially from the N-terminus and are designated CDR1, CDR2, and CDR3. The more highly conserved portions of the variable region outside the CDRs are called "framework regions." An "antibody fragment" refers to Fv, scFv, dsFv, Fab, Fab', F(ab')2 fragments, or other fragments containing at least one variable heavy chain or variable light chain, each containing a CDR and framework region.

[0030] "Phosphoinositide 3-kinase inhibitors" are a class of pharmaceutical agents that function by inhibiting one or more of the phosphoinositide 3-kinase enzymes that are part of the PI3K / AKT / mTOR pathway, a signaling pathway important for many cellular functions, including growth control, metabolism, and translation initiation.

[0031] There are several different classes and isoforms of PI3K. Class 1 PI3K has a catalytic subunit called p110, which exists in four isoforms: p110α, p110β, p110γ, and p110δ. Currently studied inhibitors block one or more isoforms of class I PI3K.

[0032] Phosphoinositide 3-kinase inhibitors include at least idelalisib, duvelisib, and copanlisib.

[0033] Idelalisib is marketed by Gilead Sciences, Inc. (trade name Zydelig, also known as GS-1101 or CAL-101). Idelalisib is currently labeled for the treatment of relapsed chronic lymphocytic leukemia (CLL) in combination with rituximab in patients for whom rituximab alone is considered appropriate therapy due to other comorbidities; for the treatment of relapsed follicular B-cell non-Hodgkin's lymphoma (FL) in patients who have received at least two prior systemic therapies; and for the treatment of 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, and more specifically, it blocks the delta isoform P110δ of the enzyme phosphoinositide 3-kinase. The formula for idelalisib is: TIFF2025131697000001.tif65161

[0034] Duvelisib (IPI-145, INK1197) is a novel selective PI3Kδ / γ (delta and gamma) inhibitor. The formula of duvelisib is: TIFF2025131697000002.tif65161

[0035] Copanlisib (BAY 80-6946), developed by Bayer, is a selective class I phosphoinositide 3-kinase inhibitor. The formula for copanlisib is: TIFF2025131697000003.tif49161

[0036] "VH" refers to the variable region of the 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.

[0037] The term "CD19" refers to the protein known as CD19, which has 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.

[0038] Human CD19 has the following amino acid sequence: TIFF2025131697000004.tif43169

[0039] "MOR00208" is an anti-CD19 antibody. The amino acid sequences of the variable domains are set forth in Figure 1. The amino acid sequences of the heavy and light chain Fc regions of MOR00208 are set forth in Figure 2. "MOR00208," "XmAb 5574," and "MOR208" are used synonymously to refer to the antibody shown in Figures 1 and 2. The MOR00208 antibody is described in U.S. Patent Application Serial No. 12 / 377,25 (the entire light chain is SEQ ID NO: 106 and the entire heavy chain is SEQ ID NO: 87), which is incorporated by reference in its entirety.

[0040] MOR00208 has been studied in human clinical trials for ALL, NHL, CLL, and small lymphocytic lymphoma (SLL).

[0041] Additional antibodies specific for CD19 are described in U.S. Patent No. 7,109,30 (Immunomedics), which is incorporated by reference in its entirety; U.S. Patent Application No. 11 / 917,75 (Medarex), which is incorporated by reference in its entirety; U.S. Patent Application No. 11 / 852,10 (Medimmune), which is incorporated by reference in its entirety; U.S. Patent Application No. 11 / 648,50 (Merck Patent GmbH), which is incorporated by reference in its entirety; U.S. Patent No. 7,968,68 (Seattle Genetics), which is incorporated by reference in its entirety; and U.S. Patent Application No. 12 / 710,44 (Glenmark Pharmaceuticals), which is incorporated by reference in its entirety.

[0042] "Fc region" means the constant region of an antibody, which in humans may be an IgG1, 2, 3, 4 subclass or other constant region. The sequence of the human Fc region is available at IMGT, Human IGH C-REGIONs, http: / / www.imgt.org / IMGTrepertoire / Proteins / protein / human / IGH / IGHC / Hu_IGHCallgenes.html (retrieved May 16, 2011).

[0043] "RefmAb33" is an antibody whose amino acid sequence is as follows: Heavy chain containing the Fc region: TIFF2025131697000005.tif42170

[0044] Light chain containing the Fc region: TIFF2025131697000006.tif21169

[0045] RefmAb33 is used as an isotype control as it is specific for RSV and shares the same Fc region as MOR00208.

[0046] "Combination" means two or more items, for example, an antibody and a compound, such as idelalisib.

[0047] The present disclosure further relates to combinations, medicaments and pharmaceutical compositions comprising the described combinations. The two components of the synergistic combination of the present invention, e.g., the CD19-specific antibody and idelalisib, may be administered physically or temporally together, simultaneously, separately or sequentially.

[0048] Idelalisib is currently administered orally at 150 mg twice daily. MOR00208 is currently administered intravenously, once a week or once every two weeks. In one embodiment, idelalisib is administered prior to administration of a CD19-specific antibody, e.g., MOR00208. In one embodiment, idelalisib is administered after administration of a CD19-specific antibody, e.g., MOR00208.

[0049] Preferably, administration of both agents allows both agents to be effective in the patient simultaneously, for example, if MOR00208 is administered once a week and idelalisib is administered once a day, it is desirable that the active agents of both agents be present in the patient at the same time, even if they are not necessarily both administered on the same day.

[0050] "Concurrently" or "administered together" means that two components are administered when both components (drugs) are available to the patient at the same time. "Synergy" means that both drugs are available to the patient at the same time. "Concurrently" or "administered together" does not necessarily mean that the drugs are administered at the exact same time or always on the same day.

[0051] The two components may be formulated in different pharmaceutical compositions.

[0052] The pharmaceutical composition comprises an active agent, such as an antibody, for use in human therapy. The pharmaceutical composition may include an acceptable carrier or excipient.

[0053] "Administered" or "administration" includes, but is not limited to, delivery in an injectable form, such as by intravenous, intramuscular, intradermal, topical, transdermal, intraperitoneal, intraorbital, implant or subcutaneous routes, or by mucosal routes, such as as a nasal spray or aerosol for inhalation, or as an ingestible solution, or orally as a capsule or tablet.

[0054] A "therapeutically effective amount" of a compound or combination refers to an amount sufficient to produce a measurable improvement in, alleviate, or partially prevent the clinical symptoms of a given disease or disorder. The amount that is effective for a particular therapeutic purpose will vary depending on the severity of the disease or injury, as well as the weight and general condition of the subject. It will be understood that determining an appropriate dosage may be accomplished by constructing a matrix of values ​​using routine experimentation and testing various points within the matrix. All of this is within the ordinary skill of a trained physician or clinical scientist.

[0055] "CDR" herein is defined by Chothia et al. or Kabat et al. See Chothia C, Lesk AM. (1987) Canonical structures for the hypervariable regions of immunoglobulins. J Mol Biol., 196(4):901-17, which is incorporated by reference in its entirety. See Kabat EA, Wu TT, Perry HM, Gottesman KS and Foeller C. (1991). Sequences of Proteins of Immunological Interest. 5th edition, NIH Publication no. 91-3242, US Dept. of Health and Human Services, Washington, DC, which is incorporated by reference in its entirety.

[0056] "Cross-competition" refers to the ability of an antibody or other binding agent to interfere with the binding of another antibody or binding agent to CD19 in a standard competitive binding assay. The ability or extent to which an antibody or other binding agent can interfere with the binding of another antibody or binding molecule to CD19, and therefore whether it can be considered cross-competitive according to the present invention, can be determined using standard competitive binding assays. One suitable assay uses Biacore technology (e.g., by using a BIAcore 3000 instrument (Biacore, Uppsala, Sweden)), which can measure the degree of interaction using surface plasmon resonance technology. Another assay for measuring cross-competition uses an ELISA-based approach. A high-throughput process for "epitope binning" antibodies based on their cross-competition is described in WO 2003 / 48731.

[0057] The term "epitope" includes any protein determinant capable of specific binding to an antibody or otherwise interacting with a molecule. Epitope determinants generally consist of chemically active surface groupings of molecules such as amino acids or carbohydrate or sugar side chains and may have specific three-dimensional structural and charge characteristics. Epitopes can be "linear" or "conformational." The term "linear epitope" refers to an epitope in which all of the points of interaction between the protein and the interacting molecule (such as an antibody) occur linearly along the primary amino acid sequence of the protein (continuous). The term "conformational epitope" refers to an epitope in which discontinuous amino acids are grouped together in a three-dimensional structure. In a conformational epitope, the points of interaction occur across amino acid residues that are spaced apart from one another on the protein.

[0058] "Binds to the same epitope" refers to the ability of an antibody or other binding agent to bind to the same epitope as CD19 and the exemplified antibody. The epitopes of the exemplified antibodies and other antibodies to CD19 can be determined using standard epitope mapping techniques. Epitope mapping techniques are well known in the art and include "Epitope Mapping Protocols in Methods in Molecular Biology," Vol. 66 (Glenn E. Morris, Ed., 1996) Humana Press, Totowa, New Jersey. For example, linear epitopes may be determined by, for example, simultaneously synthesizing large numbers of peptides corresponding to portions of a protein molecule on a solid support and reacting the peptides with an antibody while the peptides are still bound to the support. Such techniques are known in the art and are described, for example, in U.S. Pat. No. 4,708,87; Geysen et al. (1984) Proc. Natl. Acad. Sci. USA 8:3998-4002; Geysen et al. (1985) Proc. Natl. Acad. Sci. USA 82:78-182; Geysen et al. (1986) Mol. Immunol. 23:709-715. Similarly, conformational epitopes are readily identified by determining the spatial structure of amino acids, for example, by hydrogen / deuterium exchange, X-ray crystallography, and two-dimensional nuclear magnetic resonance. See, for example, Epitope Mapping Protocols, supra. Antigenic regions of proteins can also be identified using standard antigenicity and hydropathy plots, such as those calculated using the Omiga version 1.0 software program available from the Oxford Molecular Group.This computer program utilizes the Hopp / Woods method, Hopp et al. (1981) Proc. Natl. Acad. Sci USA 78:3824-3828, for determining antigenic profiles and the Kyte-Doolittle technique, Kyte et al. (1982) J. Mol. Biol. 157:105-132, for hydropathy plots.

[0059] Embodiment Aspects of the present disclosure include a combination of an antibody specific for CD19 and a phosphoinositide 3-kinase inhibitor for use in the treatment of non-Hodgkin's lymphoma, chronic lymphocytic leukemia, and / or acute lymphoblastic leukemia. In embodiments, the combination is synergistic.

[0060] The combination of the exemplified anti-CD19 antibody and idelalisib behaves synergistically in an in vitro model related to CLL. Because CLL is a B cell-related disorder and CD19 is highly expressed on B cells, the exemplified combination should have the same mechanism of action and should also behave synergistically in the treatment of other B cell-related disorders, such as NHL and ALL. Therefore, the exemplified combination of the CD19-specific antibody and idelalisib should be effective in the treatment of non-Hodgkin's lymphoma, chronic lymphocytic leukemia, and / or acute lymphoblastic leukemia in humans. The expected effectiveness of the exemplified combination of the CD19-specific antibody and idelalisib will be confirmed in clinical trials.

[0061] Chronic B-cell leukemia cell line MEC-1 cells (DSMZ#ACC497) were tested.

[0062] The following additional cell lines will also be evaluated: human Burkitt's lymphoma cells, Ramos cells (ATCC No. CRL-1596); HG-3 (DSMZ#ACC765) and C11 (DSMZ#ACC773) are chronic lymphocytic leukemia cell lines; Su-DHL 6 (DSMZ#ACC572) and U2932 (DSMZ#ACC633) are diffuse large B-cell lymphoma (DLBCL) cell lines; JVM-2 (ATCC® CRL-3002) is a mantle cell lymphoma cell line; and BALL-1 (DSMZ#ACC742) is an acute lymphoblastic leukemia cell line.

[0063] The MEC-1 cell in vitro model suggests how this combination will work in treating human chronic lymphocytic leukemia (CLL). The Ramos cell in vitro model suggests how this combination will work in treating human non-Hodgkin's lymphoma (NHL). The HG-3 and Cll cell in vitro models suggest how this combination will work in treating human chronic lymphocytic leukemia (CLL). The Su-DHL 6 and U2932 cell in vitro models suggest how this combination will work in treating human non-Hodgkin's lymphoma. The JVM-2 cell in vitro model suggests how this combination will work in treating human non-Hodgkin's lymphoma. The BALL-1 cell in vitro model suggests how this combination will work in treating human acute lymphoblastic leukemia.

[0064] The Chou index and Clarke et al. values ​​show a clear synergistic effect of the combination of MOR00208 and idelalisib in specific killing of MEC-1 cells compared to MOR00208 and idelalisib alone.

[0065] In summary, the combination of the exemplified anti-CD19 antibodies and idelalisib behaves synergistically in models relevant to CLL. Therefore, the combination of the exemplified CD19-specific antibodies and idelalisib should be effective in treating humans with non-Hodgkin's lymphoma, chronic lymphocytic leukemia, and / or acute lymphoblastic leukemia.

[0066] Because idelalisib and other phosphoinositide 3-kinase inhibitors all act by inhibiting one or more phosphoinositide 3-kinase enzymes, which are part of the PI3K / AKT / mTOR pathway, a signaling pathway important for many cellular functions, including growth control, metabolism, and translation initiation, the mechanisms of action of idelalisib and other phosphoinositide 3-kinase inhibitors are similar, and therefore synergistic effects should be observed when combining exemplified anti-CD19 antibodies and phosphoinositide 3-kinase inhibitors other than idelalisib to treat humans with non-Hodgkin's lymphoma, chronic lymphocytic leukemia, and / or acute lymphoblastic leukemia.

[0067] The exemplified anti-CD19 antibodies and other anti-CD19 antibodies bind to CD19 and are therefore described in, for example, U.S. Patent Application Serial No. 12 / 377,25 (Xencor), WO 2005012493, WO 2010053716 (Immunomedics); WO 2007002223 (Medarex); WO 2008022152 (Xencor); WO 2008031056 (Medimmune); WO 2007 / 076950 (Merck Patent GmbH); WO 2009 / 052431 (Seattle Genetics); and WO 2010095031 (Glenmark), all of which are incorporated by reference in their entirety. It is believed that synergy should also be seen when a combination of any of the anti-CD19 antibodies described in the Journal of Clinical Oncology (Clinical Oncology, Inc.) and a phosphoinositide 3-kinase inhibitor is used to treat humans with non-Hodgkin's lymphoma, chronic lymphocytic leukemia, and / or acute lymphoblastic leukemia.

[0068] In embodiments, antibodies specific for CD19 include antibodies that cross-compete with an antibody comprising an HCDR1 region of the sequence SYVMH (SEQ ID NO: 1), an HCDR2 region of the sequence NPYNDG (SEQ ID NO: 2), an HCDR3 region of the sequence GTYYYGTRVFDY (SEQ ID NO: 3), an LCDR1 region of the sequence RSSKSLQNVNGNTYLY (SEQ ID NO: 4), an LCDR2 region of the sequence RMSNLNS (SEQ ID NO: 5), and an LCDR3 region of the sequence MQHLEYPIT (SEQ ID NO: 6).

[0069] In embodiments, antibodies specific for CD19 include antibodies that bind to the same epitope as an antibody comprising an HCDR1 region of the sequence SYVMH (SEQ ID NO: 1), an HCDR2 region of the sequence NPYNDG (SEQ ID NO: 2), an HCDR3 region of the sequence GTYYYGTRVFDY (SEQ ID NO: 3), an LCDR1 region of the sequence RSSKSLQNVNGNTYLY (SEQ ID NO: 4), an LCDR2 region of the sequence RMSNLNS (SEQ ID NO: 5), and an LCDR3 region of the sequence MQHLEYPIT (SEQ ID NO: 6).

[0070] In embodiments, the antibody specific for CD19 comprises an HCDR1 region of the sequence SYVMH (SEQ ID NO: 1), an HCDR2 region of the sequence NPYNDG (SEQ ID NO: 2), an HCDR3 region of the sequence GTYYYGTRVFDY (SEQ ID NO: 3), an LCDR1 region of the sequence RSSKSLQNVNGNTYLY (SEQ ID NO: 4), an LCDR2 region of the sequence RMSNLNS (SEQ ID NO: 5), and an LCDR3 region of the sequence MQHLEYPIT (SEQ ID NO: 6).

[0071] In embodiments, the antibody specific for CD19 has the sequence The variable heavy chain of TIFF2025131697000007.tif23170, and sequence Contains the variable light chain of TIFF2025131697000008.tif21170.

[0072] In certain embodiments, the antibody comprises the sequence Contains the heavy chain constant domain of TIFF2025131697000009.tif40169.

[0073] In embodiments, the antibody specific for CD19 has the sequence Contains the light chain constant domain of TIFF2025131697000010.tif20169.

[0074] In embodiments, the phosphoinositide 3-kinase inhibitor is idelalisib.

[0075] In one embodiment, the components of the combination, the CD19-specific antibody and idelalisib, are administered separately. In one embodiment, idelalisib is administered before the administration of the CD19-specific antibody. In one embodiment, idelalisib is administered after the administration of the CD19-specific antibody. In one embodiment, the components of the combination, the CD19-specific antibody and idelalisib, are administered simultaneously or together.

[0076] In embodiments, the combination is a pharmaceutical composition. In embodiments, the composition includes an acceptable carrier. In embodiments, the combination is administered in an effective amount.

[0077] In another embodiment, a synergistic combination of an antibody specific for CD19 comprising an HCDR1 region of the sequence SYVMH (SEQ ID NO: 1), an HCDR2 region of the sequence NPYNDG (SEQ ID NO: 2), an HCDR3 region of the sequence GTYYYGTRVFDY (SEQ ID NO: 3), an LCDR1 region of the sequence RSSKSLQNVNGNTYLY (SEQ ID NO: 4), an LCDR2 region of the sequence RMSNLNS (SEQ ID NO: 5), and an LCDR3 region of the sequence MQHLEYPIT (SEQ ID NO: 6), with idelalisib, can mediate killing of MEC-1 cells by ADCC with efficacy that is at least 2-fold, 3-fold, 4-fold, or 5-fold greater than idelalisib alone in the presence of isolated human PBMCs.

[0078] Aspects of the present disclosure include a synergistic combination of an antibody specific for CD19, comprising an HCDR1 region of the sequence SYVMH (SEQ ID NO: 1), an HCDR2 region of the sequence NPYNDG (SEQ ID NO: 2), an HCDR3 region of the sequence GTYYYGTRVFDY (SEQ ID NO: 3), an LCDR1 region of the sequence RSSKSLQNVNGNTYLY (SEQ ID NO: 4), an LCDR2 region of the sequence RMSNLNS (SEQ ID NO: 5), and an LCDR3 region of the sequence MQHLEYPIT (SEQ ID NO: 6), with idelalisib for the treatment of non-Hodgkin's lymphoma, chronic lymphocytic leukemia, and / or acute lymphoblastic leukemia. In embodiments, 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 cell, and mantle cell.

[0079] Another aspect includes a method of treating non-Hodgkin's lymphoma, chronic lymphocytic leukemia, and / or acute lymphoblastic leukemia in an individual in need thereof, comprising administering an antibody specific for CD19 and a phosphoinositide 3-kinase inhibitor. In an embodiment of the method, the antibody specific for CD19 comprises an HCDR1 region of the sequence SYVMH (SEQ ID NO: 1), an HCDR2 region of the sequence NPYNDG (SEQ ID NO: 2), an HCDR3 region of the sequence GTYYYGTRVFDY (SEQ ID NO: 3), an LCDR1 region of the sequence RSSKSLQNVNGNTYLY (SEQ ID NO: 4), an LCDR2 region of the sequence RMSNLNS (SEQ ID NO: 5), and an LCDR3 region of the sequence MQHLEYPIT (SEQ ID NO: 6). In an embodiment of the method, the antibody comprises an exemplary CD19-specific antibody. In an embodiment of this method, the phosphoinositide 3-kinase inhibitor is idelalisib.

[0080] Another aspect includes the use of an antibody specific for CD19 and a phosphoinositide 3-kinase inhibitor in the manufacture of a medicament for the treatment of non-Hodgkin's lymphoma, chronic lymphocytic leukemia, and / or acute lymphoblastic leukemia in an individual in need thereof, the method comprising administering the medicament comprising an antibody specific for CD19 and a phosphoinositide 3-kinase inhibitor. In an embodiment of the method, the antibody specific for CD19 comprises an HCDR1 region of the sequence SYVMH (SEQ ID NO: 1), an HCDR2 region of the sequence NPYNDG (SEQ ID NO: 2), an HCDR3 region of the sequence GTYYYGTRVFDY (SEQ ID NO: 3), an LCDR1 region of the sequence RSSKSLQNVNGNTYLY (SEQ ID NO: 4), an LCDR2 region of the sequence RMSNLNS (SEQ ID NO: 5), and an LCDR3 region of the sequence MQHLEYPIT (SEQ ID NO: 6). In an embodiment of this method, the antibody includes an exemplary antibody specific for CD19. In an embodiment of this method, the phosphoinositide 3-kinase inhibitor is idelalisib. [Example]

[0081] Example 1: Cytotoxicity of MEC-1 cells using MOR00208 and idelalisib alone and in combination material Cell lines: MEC-1 cells (DSMZ#ACC497) are a chronic B-cell leukemia cell line; JVM-2 (ATCC® CRL-3002) are a mantle cell lymphoma cell line; Ramos cells (ATCC No. CRL-1596) are human Burkitt lymphoma cells; HG-3 (DSMZ#ACC765) and C11 (DSMZ#ACC773) are chronic lymphocytic leukemia cell lines; Su-DHL 6 (DSMZ#ACC572) and U2932 (DSMZ#ACC633) are diffuse large B-cell lymphoma (DLBCL) cell lines; and BALL-1 (DSMZ#ACC742) is an acute lymphoblastic leukemia cell line.

[0082] The culture conditions for the cell lines used were in accordance with the supplier's information.

[0083] Cell culture media: Iscove's Modified Dulbecco's Medium (IMDM), Invitrogen, Catalog Number: 31980-048; RPMI1640, Invitrogen, Catalog Number: 31870-074; GlutaMAX, Invitrogen, Catalog Number: 35050-38 Lot Number: 1654740; FCS: Sigma Catalog Number: F7524 Lot Number: 111M3396.

[0084] NK: RPMI 1640 with GlutaMAX™, Invitrogen, Catalog No. 31870-074, 10% FCS; Biocoll: Biochrome AG, Catalog No. L6115, Lot No. 0034D; MACS NK Cell Isolation Kit: Miltenyi Biotec, Catalog No. 130-092-657, Lot No. 5150327376; idelalisib: Selleck Chem, Catalog No. S2226; FCS: Sigma, Catalog No. F7524, Lot No. 111M3396; and RefmAb33 (anti-RSV), which contains the same Fc region as MOR00208.

[0085] method The cytotoxicity of MOR00208 and idelalisib alone and in combination was tested in the MEC-1 cell line.

[0086] Idelalisib is a phosphoinositide 3-kinase inhibitor, specifically, it blocks the delta isoform P110δ of the enzyme phosphoinositide 3-kinase. Idelalisib alone has little or no cytotoxic effect on MEC-1 cells. MOR00208 targets CD19 and mediates target cell killing via ADCC.

[0087] The following were used as controls: a) MEC-1 cells + RefmAb33 + DMSO + NK cells, b) MEC-1 cells + DMSO + NK cells, c) MEC-1 cells + DMSO.

[0088] Target cell killing was measured using the following parameters: idelalisib at concentrations of 0.3 μM, 1 μM, 3 μM and 10 μM; MOR00208 at concentrations of 1.5 μg / ml, 0.015 μg / ml and 0.0015 μg / ml and the combination of MOR00208 and idelalisib at the same concentrations.

[0089] For the idelalisib group, the MOR00208 alone group, and the MOR00208 + idelalisib combination group, target cells were pretreated with idelalisib for 7 days before the ADCC assay. Target cells were counted and stained with CFSE at a final concentration of 10 μM. For DMSO-treated target cells, 5 × 10 5 An effector:target (E:T) ratio of 2:1 was selected, corresponding to a cell density of 1 × 10 / ml. The E:T ratio of inhibitor-treated cells was adjusted to include the proliferative effect on target cells caused by idelalisib treatment. NK cells were counted and 1 × 10 6The target cell killing assay was performed as follows: 100 μl of target cell suspension was added per well of a 96-well plate, followed by 100 μl of NK cell suspension, resulting in an E:T ratio of 2:1. Antibodies were diluted in medium over a range of 10–0.00001 nM (corresponding to 1.5–0.0000015 μg / ml). Cells were centrifuged, and the target:effector cell pellet was resuspended in 100 μl of antibody-containing medium or the corresponding control solution. The assay was incubated for 4 hours at 37°C in a CO2 incubator. After a 10-minute incubation on ice, 50 μl of DAPI solution was added to each well (final concentration 1 μg / ml) and incubated on ice for 10 minutes. Cell killing was measured using a FACS-Verse. Dead target cells were DAPI-positive.

[0090] data A total of six experiments were performed to determine the effect of ADCC on MEC-1 cells by the combination of MOR00208 and idelalisib. In two of the six experiments, the RefmAb control and DMSO-only control demonstrated 25% greater killing compared to the MEC-1 cell-only control, and data were therefore excluded from analysis. In these two experiments, NK cell autoreactivity prevented proper analysis.

[0091] The ADCC dose-response curves for Experiments 1 to 4 are shown in Figures 3 to 6.

[0092] The cell death rates (%) (raw data) for Experiments 1 to 4 are shown in Tables 1 to 16 below.

[0093] Experiment 1 TIFF2025131697000011.tif83170TIFF2025131697000012.tif69170TIFF2025131697000013.tif70170TIFF2025131697000014.tif67170

[0094] Experiment 2 TIFF2025131697000015.tif70170TIFF2025131697000016.tif71170TIFF2025131697000017.tif71170TIFF2025131697000018.tif71170

[0095] Experiment 3 TIFF2025131697000019.tif83170TIFF2025131697000020.tif69170TIFF2025131697000021.tif72170TIFF2025131697000022.tif68170

[0096] Experiment 4 TIFF2025131697000023.tif68170TIFF2025131697000024.tif71170TIFF2025131697000025.tif70170TIFF2025131697000026.tif68170

[0097] Calculating synergy: Clarke et al. When an agent has low activity, as in this case when idelalisib alone has low cytotoxicity activity against MEC-1 cells, synergy can be determined by statistical evidence that the combination is significantly different from the inhibitor alone. See Clarke et al., "Issues in experimental design and endpoint analysis in the study of experimental cytotoxic agents in vivo in breast cancer and other models," Breast Cancer Research and Treatment 46:255-278 (1997), incorporated herein by reference in its entirety.

[0098] The % dead cells (raw data) in Tables 1 to 16 were analyzed as follows. Antagonistic (AB) / C<(A / C)×(B / C) Additive (AB) / C=(A / C)×(B / C) Synergistic (AB) / C>(A / C)×(B / C) A is treatment with MOR00208 alone; B is treatment with idelalisib alone; C is the response to control DMSO+RefMab33; AB is the combination of treatments A and B.

[0099] Experiment 1 TIFF2025131697000027.tif63170TIFF2025131697000028.tif58170TIFF2025131697000029.tif55170TIFF2025131697000030.tif52170

[0100] Experiment 2 TIFF2025131697000031.tif55170TIFF2025131697000032.tif54170TIFF2025131697000033.tif60170TIFF2025131697000034.tif53170

[0101] Experiment 3 TIFF2025131697000035.tif55170TIFF2025131697000036.tif53170TIFF2025131697000037.tif54170TIFF2025131697000038.tif55170

[0102] Experiment 4 TIFF2025131697000039.tif58170TIFF2025131697000040.tif50170TIFF2025131697000041.tif55170TIFF2025131697000042.tif54170

[0103] result Experiments 2-4 at each concentration demonstrated clear synergistic activity of the MOR00208 + idelalisib combination using the method of Clarke et al. However, Experiment 1 at a few concentrations demonstrated no synergistic activity, as the idelalisib group (see Tables 1-3) showed a slight effect slightly greater than the control (approximately 4% greater than the control). This slight difference compared to the control (approximately 4%) is well within the range of the other controls and may be attributable to the experimental setup.

[0104] Calculation of synergy: Combination Index (CI) To confirm the synergy results calculated using Clarke et al. above, the combination index (CI) method was applied to the % cell deaths (raw data) in Tables 1 to 16. For CI calculations, we used 0.3 μM, 1 μM, 3 μM, and 10 μM idelalisib and three concentrations of MOR208 (1.5 μg / ml, 0.015 μg / ml, and 0.0015 μg / ml).

[0105] Such calculations are described in Ting-Chao Chou, Theoretical Basis, Experimental Design, and Computerized Simulation of Synergism and Antagonism in Drug Combination Studies, Pharmacol Rev 58:621-681 (2006), which is incorporated by reference in its entirety, and Chou TC, Talalay P, Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul 22:27-55 (1984), which is incorporated by reference in its entirety. The Chou-Talalay method is performed using the CI-isobol method.

[0106] Median effect equation The median effect equation is to calculate the effect of an inhibitor (such as a drug) as F a / F u= (D / D50)^m, where D is the dose and F a and F u is the proportion of systems affected or not affected by dose D (F a +F u = 1); D50 is the dose that exerts half the median effect (e.g., IC50, ED50, LD50). The constant m determines the shape of the dose-response curve.

[0107] We use GraphPad Prism to perform nonlinear regression calculations to estimate the parameters m and D50.

[0108] CI-isobol method The CI-isobol method provides a quantitative assessment of synergy between drugs. The combination index (CI) is estimated from dose-effect data for single and combined drug treatments. A CI < 1 indicates synergism; a CI = 1 indicates additivity; and a CI > 1 indicates antagonism. The more significant the drug interaction (synergism or antagonism), the more the CI value deviates from 1.

[0109] Formally, the combination index (CI) for a combination drug treatment is CI = D1 / D x1 +D2 / D x2 It is defined as follows. where D1 and D2 are the doses of drug 1 and drug 2 in the combination, respectively; Dx1 and Dx2 are the doses of drug 1 and drug 2 treatment alone that are expected to have the same effect as the combination. Doses Dx1 and Dx2 must be estimated from the dose-effect data of the single drug treatments. Essentially, a median effect equation is fitted to the data for each drug. From the median effect equation for a drug, we can estimate the dose (i.e., D) required to exert an effect (i.e., Fa, Fu). The further a point is from the additivity line, the greater the difference between 1 and its CI, and therefore the stronger the effect (synergistic or antagonistic).

[0110] result The curves generated for the calculation of synergy using Chou are shown in Figures 7 to 10. The Chou index values ​​show a clear synergistic effect in all experiments 1 to 4 of the combination of MOR00208 and idelalisib compared to MOR00208 and idelalisib alone in the specific killing of MEC-1 cells.

[0111] The combination of MOR00208 and idelalisib behaved synergistically in the MEC-1 CLL cell line, and therefore, the combination of MOR00208 and idelalisib is likely to be synergistic in the treatment of CLL in humans.

[0112] Furthermore, it is believed that the combination of MOR00208 and idelalisib will also behave synergistically in the treatment of human non-Hodgkin's lymphoma (NHL), chronic lymphocytic leukemia (CLL) and acute lymphoblastic leukemia (ALL).

[0113] It will be understood that the present description, specific examples, and data, while indicating exemplary embodiments, are given by way of illustration and are not intended to limit the invention. Various changes and modifications in the invention will become apparent from the discussion, disclosure, and data contained herein and are therefore considered a part of the invention.

Claims

1. 1. A synergistic combination comprising an antibody specific for CD19, the antibody comprising an HCDR1 region of the sequence SYVMH (SEQ ID NO: 1), an HCDR2 region of the sequence NPYNDG (SEQ ID NO: 2), an HCDR3 region of the sequence GTYYYGTRVFDY (SEQ ID NO: 3), an LCDR1 region of the sequence RSSKSLQNVNGNTYLY (SEQ ID NO: 4), an LCDR2 region of the sequence RMSNLNS (SEQ ID NO: 5), and an LCDR3 region of the sequence MQHLEYPIT (SEQ ID NO: 6), and a phosphoinositide 3-kinase inhibitor, for use in the treatment of non-Hodgkin's lymphoma, chronic lymphocytic leukemia, and / or acute lymphoblastic leukemia.

2. 3. The combination of claim 2, wherein the antibody has the sequence and the variable heavy chain of sequence a combination comprising a variable light chain of

3. 3. The combination of claim 1 or 2, wherein the antibody has the sequence A combination comprising a heavy chain constant domain of

4. 4. The combination according to claim 1, wherein the antibody has the sequence a light chain constant domain of

5. The combination according to any one of claims 1 to 4, wherein the antibody specific for CD19 and the phosphoinositide 3-kinase inhibitor are administered separately.

6. 6. The combination of claim 5, wherein the antibody specific for CD19 and the phosphoinositide 3-kinase inhibitor are administered physically separately.

7. 6. The combination of claim 5, wherein the antibody specific for CD19 and the phosphoinositide 3-kinase inhibitor are administered temporally separately.

8. 5. The combination according to any one of claims 1 to 4, wherein the antibody specific for CD19 and the phosphoinositide 3-kinase inhibitor are administered together.

9. 9. The combination according to any one of claims 1 to 8, wherein the phosphoinositide 3-kinase inhibitor is administered before the administration of the antibody specific for CD19.

10. 10. The combination according to any one of claims 1 to 9, wherein the phosphoinositide 3-kinase inhibitor is administered after the administration of the antibody specific for CD19.

11. The combination according to any one of claims 1 to 4, wherein the phosphoinositide 3-kinase inhibitor and the antibody specific for CD19 are administered simultaneously.

12. 12. The combination according to any one of claims 1 to 11, wherein the phosphoinositide 3-kinase inhibitor is idelalisib.

13. 13. The combination of any one of claims 1 to 12, for use in the treatment of 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 cell, and mantle cell.

14. 14. The combination according to any one of claims 1 to 13, characterized in that it is used in the treatment of chronic lymphocytic leukemia.

15. 15. The combination according to any one of claims 1 to 14, for use in the treatment of acute lymphoblastic leukemia.

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