WO2024115935A1 - Methods for the treatment of b-cell lymphoma using cd39 inhibitors - Google Patents
Methods for the treatment of b-cell lymphoma using cd39 inhibitors Download PDFInfo
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- WO2024115935A1 WO2024115935A1 PCT/IB2022/000688 IB2022000688W WO2024115935A1 WO 2024115935 A1 WO2024115935 A1 WO 2024115935A1 IB 2022000688 W IB2022000688 W IB 2022000688W WO 2024115935 A1 WO2024115935 A1 WO 2024115935A1
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Classifications
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- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
Definitions
- LF Follicular Lymphoma
- Diffuse Large B-Cell Lymphoma NDL
- Rituximab an anti-CD20 monoclonal antibody often used in combination with chemotherapy.
- TIL Tumor Infiltrating Lymphocytes
- IEGS33 the Tumor Infiltrating Lymphocytes
- IEGS33 score based on the collective overexpression of 33 genes specifically involved in IE of lymphoma: Stage I corresponding to non-immunogenic tumors poorly infiltrated with low IE (IEGS33-/T cell activation-). Stage II corresponds to immunogenic tumors with no or low IE signature (IEGS-/ T cell activation+), Stage III to immunogenic tumors with high IE (IEGS+/T cell activation+), and stage IV corresponding to no or little infiltrated tumors with high IE (IEGS+/T cell activation-) [4,6].
- TIL Tumor Infiltrating Lymphocytes
- the present invention relates to a method of treating a B-cell lymphoma in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a CD39 inhibitor.
- the present invention relates to a method of treating a B-cell lymphoma in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a CD39 inhibitor.
- a CD39 inhibitor As used herein, the term “subject” or “patient” denotes a mammal.
- a subject according to the invention refers to any subject (preferably human) afflicted with or susceptible to be afflicted with a B-cell lymphoma, in particular a non-Hodgkin lymphoma, in particular a Follicular Lymphoma (FL), a Diffuse Large B-Cell Lymphoma (DLBCL) or a Mantle Cell Lymphoma (MCL).
- a B-cell lymphoma in particular a non-Hodgkin lymphoma, in particular a Follicular Lymphoma (FL), a Diffuse Large B-Cell Lymphoma (DLBCL) or a Mantle Cell Lymphoma (MCL).
- the subject is treated with an anti-CD20 monoclonal antibody therapy.
- the subject is treated with an anti-PD1 monoclonal antibody therapy.
- the term “lymphoma” refers to a group of blood cell tumours that develop from lymphoid cells.
- lymphomas are Hodgkin lymphomas (HL) and non-Hodgkin lymphomas (NHL).
- HL Hodgkin lymphomas
- NHL non-Hodgkin lymphomas
- NHL lymphomas are categorized by affected cell type: B-cell lymphoma or T-cell lymphoma.
- B-cell lymphoma comprises different subtypes such as Follicular Lymphoma (FL), Diffuse Large B-cell Lymphoma (DLBCL), Mantle cell lymphoma (MCL), Waldenstrom Macroglobulinemia (WM), lymphoblastic lymphoma, Primary Mediastinal Large B-Cell Lymphoma (PMBCL), Marginal Zone B-cell Lymphoma (MZL) or Burkitt lymphoma.
- the B-cell lymphoma is a non-Hodgkin lymphoma.
- the B-cell lymphoma is a Follicular Lymphoma (FL).
- the B-cell lymphoma is a Diffuse Large B Cell Lymphoma (DLBCL). In some embodiments, the B-cell lymphoma is a Mantle Cell Lymphoma (MCL).
- DLBCL Diffuse Large B Cell Lymphoma
- MCL Mantle Cell Lymphoma
- FL or “Follicular Lymphoma” refers to the most common type of low-grade non-Hodgkin lymphoma. Under a microscope, FL is characterised by tumour cells that appear in a circular, or clump-like, pattern.
- the term “DLBCL” or “Diffuse Large B Cell Lymphoma” is a non- Hodgkin lymphoma developed from B lymphocytes, where B cells are abnormally larger than normal and healthy B cells.
- DLBCL is the most common form of adult lymphoma worldwide.
- a DLBCL may be diagnosed with an excisional biopsy of an abnormal lymph node, the excisional biopsy showing a disrupted structural integrity of the lymph node architecture with large cells.
- MCL or “Mantle Cell Lymphoma” is a non-Hodgkin lymphoma that arises from cells originating in the mantle zone.
- the mantle zone is the outer ring of small lymphocytes surrounding the center of a lymphatic nodule.
- the B-cell lymphoma is resistant to a CD20 inhibitor.
- the B-cell lymphoma is resistant to an anti-CD20 monoclonal antibody.
- anti-CD20 monoclonal antibodies include, but are not limited to, Rituximab (Roche), Ocrelizumab (Roche), Obinutuzumab (Roche), Ibritumomab (Bayer Schering), Ofatumumab (HuMax-CD20, Gemnab), Ublituximab (TG Therapeutics), IMMU-106 (Immunomedics), AME-133v (Applied Molecular Evolution), TRU-015 (Trubion) or Tositumomab (GlaxoSmithKline).
- the anti-CD20 antibody is Obinutuzumab.
- the anti-CD20 monoclonal antibody is rituximab.
- the B-cell lymphoma is resistant to rituximab.
- the B-cell lymphoma is resistant to a chemotherapy.
- the B-cell lymphoma is a chemoresistant lymphoma.
- the term "chemoresistant” refers to the clinical situation in a subject suffering from a lymphoma when the proliferation of cancer cells cannot be prevented or inhibited by means of a chemotherapeutic agent or a combination of chemotherapeutic agents usually used to treat lymphoma, at an acceptable dose for the subject.
- the lymphoma can be intrinsically resistant prior to chemotherapy, or resistance may be acquired during treatment of lymphoma that is initially sensitive to chemotherapy.
- chemotherapeutic agent refers to any chemical agent with therapeutic usefulness in the treatment of cancer, in particular B-cell lymphoma.
- Chemotherapeutic agents as used herein encompass both chemical and biological agents. These agents function to inhibit a cellular activity upon which the cancer cell depends for continued survival. Categories of chemotherapeutic agents include alkylating/alkaloid agents, antimetabolites, hormones or hormone analogs, and miscellaneous antineoplastic drugs. Most if not all of these drugs are directly toxic to cancer cells and do not require immune stimulation.
- Suitable chemotherapeutic agents are described, for example, in Slapak and Kufe, Principles of Cancer Therapy, Chapter 86 in Harrison's Principles of Internal medicine, 14th edition; Perry et al, Chemotherapeutic, Ch 17 in Abeloff, Clinical Oncology 2nd ed., 2000 ChrchillLivingstone, Inc.; Baltzer L. and Berkery R. (eds): Oncology Pocket Guide to Chemotherapeutic, 2nd ed. St. Louis, mosby-Year Book, 1995; Fischer D. S., Knobf M. F., Durivage HJ. (eds): The Cancer Chemotherapeutic Handbook, 4th ed. St. Louis, Mosby-Year Handbook.
- the chemotherapeutic agent is cytarabine (cytosine arabinoside, Ara-C, Cytosar-U), quizartinib (AC220), sorafenib (BAY 43-9006), lestaurtinib (CEP-701), midostaurin (PKC412), carboplatin, carmustine, chlorambucil, dacarbazine, ifosfamide, lomustine, mechlorethamine, procarbazine, pentostatin, (2'deoxycoformycin), etoposide, teniposide, topotecan, vinblastine, vincristine, paclitaxel, dexamethasone, methylprednisolone, prednisone, all-trans retinoic acid, arsenic trioxide, interferon-alpha, rituximab (Rituxan®), gemtuzumab ozogamicin, imatin
- the B-cell lymphoma is resistant to an anti-CD20 monoclonal antibody combined with a chemotherapy. In some embodiments, the B-cell lymphoma is resistant to a chemotherapy comprising at least one selected in the group consisting in cyclophosphamide, doxorubicin, vincristine and prednisone. In some embodiments, the B-cell lymphoma is resistant to R-CHOP therapy.
- R-CHOP refers to a therapy consisting essentially in rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone.
- the R- CHOP therapy consists in rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone.
- CD39 has its general meaning in the art and refers to the CD39 protein, also named as EctoNucleoside TriphosPhate Diphosphohydrolase-1 (ENTPD1).
- ENTPD1 EctoNucleoside TriphosPhate Diphosphohydrolase-1
- CD39 is an ectoenzyme that hydrolyzes ATP/UTP and ADP/UDP to AMP.
- CD39 is encoded by ENTPD1 gene (Entre Gene: 953; Ensembl: ENSG00000138185).
- An exemplary amino acid sequence for CD39 is represented in SEQ ID NO:1.
- a CD39 inhibitor can be a molecule of any type that interferes with the signalling associated with CD39 in a cell, for example, either by decreasing transcription or translation of CD39-encoding nucleic acid, or by inhibiting or blocking CD39 polypeptide activity, or both.
- CD39 inhibitors include, but are not limited to, antisense polynucleotides, interfering RNAs, catalytic RNAs, RNA-DNA chimeras, CD39-specific aptamers, anti-CD39 antibodies, CD39-binding fragments of anti-CD39 antibodies, CD39-binding small molecules, CD39-binding peptides, and other polypeptides that specifically bind CD39 (including, but not limited to, CD39-binding fragments of one or more CD39 ligands, optionally fused to one or more additional domains), such that the interaction between the CD39 inhibitor and CD39 results in a reduction or cessation of CD39 activity or expression.
- the CD39 inhibitor is an antibody having specificity for CD39.
- antibody is thus used to refer to any antibody-like molecule that has an antigen binding region, and this term includes antibody fragments that comprise an antigen binding domain such as Fab', Fab, F(ab')2, single domain antibodies (DABs), TandAbs dimer, Fv, scFv (single chain Fv), dsFv, ds-scFv, Fd, linear antibodies, minibodies, diabodies, bispecific antibody fragments, bibody, tribody (scFv-Fab fusions, bispecific or trispecific, respectively); sc-diabody; kappa(lamda) bodies (scFv-CL fusions); BiTE (Bispecific T-cell Engager, scFv-scFv tandems to attract T cells); DVD-Ig (dual variable domain antibody, bispecific format); SIP (small immunoprotein, a kind of minibody); SMIP ("small modular immunopharmaceutical" sc
- Antibodies can be fragmented using conventional techniques. For example, F(ab')2 fragments can be generated by treating the antibody with pepsin. The resulting F(ab')2 fragment can be treated to reduce disulfide bridges to produce Fab' fragments. Papain digestion can lead to the formation of Fab fragments.
- Fab, Fab' and F(ab')2, scFv, Fv, dsFv, Fd, dAbs, TandAbs, ds-scFv, dimers, minibodies, diabodies, bispecific antibody fragments and other fragments can also be synthesized by recombinant techniques or can be chemically synthesized. Techniques for producing antibody fragments are well known and described in the art. For example, each of Beckman et al., 2006; Holliger & Hudson, 2005; Le Gall et al., 2004; Reff & Heard, 2001; Reiter et al., 1996; and Young et al., 1995 further describe and enable the production of effective antibody fragments.
- the residues in antibody variable domains are conventionally numbered according to a system devised by Kabat et al. This system is set forth in Kabat et al., 1987, in Sequences of Proteins of Immunological Interest, US Department of Health and Human Services, NIH, USA (hereafter “Kabat et al.”). This numbering system is used in the present specification.
- the Kabat residue designations do not always correspond directly with the linear numbering of the amino acid residues in SEQ ID sequences.
- the actual linear amino acid sequence may contain fewer or additional amino acids than in the strict Kabat numbering corresponding to a shortening of, or insertion into, a structural component, whether framework or complementarity determining region (CDR), of the basic variable domain structure.
- the correct Kabat numbering of residues may be determined for a given antibody by alignment of residues of homology in the sequence of the antibody with a “standard” Kabat numbered sequence.
- the CDRs of the heavy chain variable domain are located at residues 31-35B (H- - 9 - CDR1), residues 50-65 (H-CDR2) and residues 95-102 (H-CDR3) according to the Kabat numbering system.
- the CDRs of the light chain variable domain are located at residues 24-34 (L-CDR1), residues 50-56 (L-CDR2) and residues 89-97 (L-CDR3) according to the Kabat numbering system.
- the amino acid residues of the antibody of the invention are numbered according to the IMGT numbering system.
- the IMGT unique numbering has been defined to compare the variable domains whatever the antigen receptor, the chain type, or the species (Lefranc M.-P., "Unique database numbering system for immunogenetic analysis” Immunology Today, 18, 509 (1997) ; Lefranc M.-P., "The IMGT unique numbering for Immunoglobulins, T cell receptors and Ig-like domains" The Immunologist, 7, 132-136 (1999).; Lefranc, M.-P., Pommié, C., Ruiz, M., Giudicelli, V., Foulquier, E., Truong, L., Thouvenin- Contet, V.
- IMGT unique numbering 15 for immunoglobulin and T cell receptor variable domains and Ig superfamily V-like domains Dev. Comp. Immunol., 27, 55- 77 (2003).
- conserved amino acids always have the same position, for instance cysteine 23, tryptophan 41, hydrophobic amino acid 89, cysteine 104, phenylalanine or tryptophan 118.
- the IMGT unique numbering provides a standardized delimitation of the framework regions (FR1- 20 IMGT: positions 1 to 26, FR2-IMGT: 39 to 55, FR3-IMGT: 66 to 104 and FR4-IMGT: 118 to 128) and of the complementarity determining regions: CDR1-IMGT: 27 to 38, CDR2-IMGT: 56 to 65 and CDR3-IMGT: 105 to 117. If the CDR3-IMGT length is less than 13 amino acids, gaps are created from the top of the loop, in the following order 111, 112, 110, 113, 109, 114, etc.
- the term “specificity” refers to the ability of an antibody to detectably bind an epitope presented on an antigen, such as CD39, while having relatively little detectable reactivity with non-CD39 proteins or structures (such as other proteins presented on B-cell lymphoma cells).
- Specificity can be relatively determined by binding or competitive binding assays, using, e.g., Biacore instruments, as described elsewhere herein. Specificity can be exhibited by, e.g., an about 10:1, about 20:1, about 50:1, about 100:1, 10.000:1 or greater ratio of affinity/avidity in binding to the specific antigen versus nonspecific binding to other irrelevant molecules (in this case the specific antigen is a CD39 polypeptide).
- affinity as used herein, means the strength of the binding of an antibody to an epitope.
- the affinity of an antibody is given by the dissociation constant Kd, defined as [Ab] x [Ag] / [Ab-Ag], where [Ab-Ag] is the molar concentration of the antibody-antigen complex, [Ab] is the molar concentration of the unbound antibody and [Ag] is the molar concentration of the unbound antigen.
- Kd dissociation constant
- Ka is defined by 1/Kd.
- the light chain includes two domains, a variable domain (VL) and a constant domain (CL).
- the heavy chain includes four domains, a variable domain (VH) and three constant domains (CH1, CH2 and CH3, collectively referred to as CH).
- the variable regions of both light (VL) and heavy (VH) chains determine binding recognition and specificity to the antigen.
- the constant region domains of the light (CL) and heavy (CH) chains confer important biological properties such as antibody chain association, secretion, trans-placental mobility, complement binding, and binding to Fc receptors (FcR).
- the Fv fragment is the N-terminal part of the Fab fragment of an immunoglobulin and consists of the variable portions of one light chain and one heavy chain.
- CDRs complementarity determining regions
- FR framework regions
- Complementarity Determining Regions or CDRs refer to amino acid sequences which together define the binding affinity and specificity of the natural Fv region of a native immunoglobulin binding site.
- the light and heavy chains of an immunoglobulin each have three CDRs, designated L-CDR1, L-CDR2, L-CDR3 and H-CDR1, H-CDR2, H-CDR3, respectively.
- An antigen-binding site therefore, includes six CDRs, comprising the CDR set from each of a heavy and a light chain V region.
- Framework Regions refer to amino acid sequences interposed between CDRs.
- Fab denotes an antibody fragment having a molecular weight of about 50,000Da and antigen binding activity, in which about a half of the N-terminal side of H chain and the entire L chain, among fragments obtained by treating IgG with a protease, papaine, are bound together through a disulfide bond.
- F(ab')2 refers to an antibody fragment having a molecular weight of about 100,000Da and antigen binding activity, which is slightly larger than the Fab bound via a disulfide bond of the hinge region, among fragments obtained by treating IgG with a protease, pepsin.
- Fab' refers to an antibody fragment having a molecular weight of about 50,000 and antigen binding activity, which is obtained by cutting a disulfide bond of the hinge region of the F(ab')2.
- a single chain Fv (“scFv”) polypeptide is a covalently linked VH::VL heterodimer which is usually expressed from a gene fusion including VH and VL encoding genes linked by a peptide-encoding linker.
- dsFv is a VH::VL heterodimer stabilised by a disulfide bond.
- Divalent and multivalent antibody fragments can form either spontaneously by association of monovalent scFvs, or can be generated by coupling monovalent scFvs by a peptide linker, such as divalent sc(Fv)2.
- diabodies refers to small antibody fragments with two antigen-binding sites, which fragments comprise a heavy-chain variable domain (VH) connected to a light-chain variable domain (VL) in the same polypeptide chain (VH-VL).
- VH heavy-chain variable domain
- VL light-chain variable domain
- VH-VL polypeptide chain
- a mouse or other appropriate host animal is immunized at suitable intervals (e.g., twice-weekly, weekly, twice-monthly or monthly) with the appropriate antigenic forms (i.e. CD39 or cell that express CD39).
- suitable intervals e.g., twice-weekly, weekly, twice-monthly or monthly
- lymphocytes are isolated from the spleen, lymph node or other organ of the animal and fused with a suitable myeloma cell line using an agent such as polyethylene glycol to form a hydridoma.
- cells are placed in media permissive for growth of hybridomas but not the fusion partners using standard methods.
- cell supernatants are analyzed for the presence of antibodies of the desired specificity, i.e., that selectively bind the antigen.
- Suitable analytical techniques include ELISA, flow cytometry, immunoprecipitation, and western blotting. Other screening techniques are well-known in the field. Preferred techniques are those that confirm binding of antibodies to conformationally intact, natively folded antigen, such as non- denaturing ELISA, flow cytometry, and immunoprecipitation.
- the Fc' and Fc regions are effectors of the complement cascade but are not involved in antigen binding.
- an antibody from which the Fc region has been enzymatically cleaved, or which has been produced without the Fc region designated as Fab fragment, retains one of the antigen binding sites of an intact antibody molecule.
- Fab fragments consist of a covalently bound antibody light chain and a portion of the antibody heavy chain denoted Fd.
- the Fd fragments are the major determinant of antibody specificity (a single Fd fragment may be associated with up to ten different light chains without altering antibody specificity) and Fd fragments retain epitope-binding ability in isolation.
- the antibody is a humanized antibody.
- humanized describes antibodies wherein some, most or all of the amino acids outside the CDR regions are replaced with corresponding amino acids derived from human immunoglobulin molecules.
- Methods of humanization include, but are not limited to, those described in U.S. Pat. Nos. 4,816,567, 5,225,539, 5,585,089, 5,693,761, 5,693,762 and 5,859,205, which are hereby incorporated by reference.
- the antibody is a fully human antibody.
- Fully human monoclonal antibodies also can be prepared by immunizing mice transgenic for large portions of human immunoglobulin heavy and light chain loci. See, e.g., U.S. Pat. Nos.
- mice have been genetically modified such that there is a functional deletion in the production of endogenous (e.g., murine) antibodies.
- the animals are further modified to contain all or a portion of the human germ-line immunoglobulin gene locus such that immunization of these animals will result in the production of fully human antibodies to the antigen of interest.
- monoclonal antibodies can be prepared according to standard hybridoma technology.
- the antibody of the present invention may be of any isotype.
- the choice of isotype typically will be guided by the desired effector functions, such as ADCC induction.
- Exemplary isotypes are IgGl, IgG2, IgG3, and IgG4.
- Either of the human light chain constant regions, kappa or lambda may be used.
- the class of a human monoclonal antibody of the present invention may be switched by known methods. Typical, class switching techniques may be used to convert one IgG subclass to another, for instance from IgG1 to IgG2.
- the effector function of the human monoclonal antibodies of the present invention may be changed by isotype switching to, e.g., an IgGl, IgG2, IgG3, IgG4, IgD, IgA, IgE, or IgM antibody for various therapeutic uses.
- the antibody of the present invention is a full- length antibody. In some embodiments, the full-length antibody is an IgG1 antibody.
- the full-length antibody is an IgG4 antibody.
- the specific IgG4 antibody is a stabilized IgG4 antibody.
- suitable stabilized IgG4 antibodies are antibodies wherein arginine at position 409 in a heavy chain constant region of human IgG4, which is indicated in the EU index as in Kabat et al. supra, is substituted with lysine, threonine, methionine, or leucine, preferably lysine (described in WO2006/033386) and/or wherein the hinge region comprises a Cys-Pro-Pro-Cys sequence.
- Monoclonal antibodies that are CD39 inhibitors are well known in the art and includes as example those described in the international patent applications WO2009/095478, WO2012/085132, WO2016/073845, WO2019/027935, WO2021/055329, WO2021/056610, WO2022/111576.
- antibodies having specificity for CD39 includes, but are not limited to, TTX-030 (Trishula Therapeutics), TTX-030-001 (Trishula Therapeutics), TTX-030- 002 (Trishula Therapeutics), IPH52 (Innate Pharma), IPH5201 (Innate Pharma), OREG- 103/BY40 (Orega Biotech), BA54g (Orega Biotech), BY12 (Orega Biotech), SRF370 (Surface Oncology), SRF365 (Surface Oncology), SRF367 (Surface Oncology), SRF617 (Surface Oncology), 9-8B (Igenica Therapeutics), ES014 (Elpiscience Biopharma), ES002 (Elpiscience Biopharma), ES002023 (Elpiscience Biopharma), EMB04 (EpimAb Biotherapeutics) or AB598 (Arcus Biosciences).
- the antibody having specificity for CD39 is TTX-030, IPH5201, BY40, BA54g, BY12, SRF617, 9-8B, ES002023 or ES014.
- the VH region of the TTX-030 antibody consists in the sequence of SEQ ID NO:2.
- the VH-CDR1 of the TTX-030 antibody is defined by SEQ ID NO:3 (SYEMH)
- the VH-CDR2 of the TTX-030 antibody is defined by SEQ ID NO:4 (RINPSVGSTWYAQKFQG)
- the VH-CDR3 of the TTX-030 antibody is defined by SEQ ID NO:5 (GKREGGTEYLRK).
- SEQ ID NO: 2 > VH domain of TTX-030 (FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4) QVQLVQSGAEVKKPGASVKVSCKASGYTFKSYEMHWVRQAPGQGLEWMGRINPSVGSTWYAQKFQGRVT MTRDTSTSTVYMELSSLRSEDTAVYYCARGKREGGTEYLRKWGQGTLVTVSS
- the VL region of the TTX-030 antibody consists of the sequence of SEQ ID NO:6.
- the VL-CDR1 of TTX-030 antibody is defined by SEQ ID NO:7 (RASQSVASSYLA)
- the VL-CDR2 of the TTX-030 antibody is defined by SEQ ID NO:8 (GASNRHT)
- the VL-CDR3 of the TTX-030 antibody is defined by SEQ ID NO:9 (QQYHNAIT).
- VH region of the IPH52 antibody consists in the sequence of SEQ ID NO:10.
- the VH-CDR1 of IPH52 antibody is defined by SEQ ID NO:11 (DYNMH)
- the VH-CDR2 of the IPH52 antibody is defined by SEQ ID NO:12 (YIVPLNGGSTFNQKFKG)
- the VH-CDR3 of the IPH52 antibody is defined by SEQ ID NO:13 (GGTRFAY).
- the VL-CDR1 of the IPH52 antibody is defined by SEQ ID NO:15 (RASESVDNFGVSFMY)
- the VL-CDR2 of the IPH52 antibody is defined by SEQ ID NO:16 (GASNQGS)
- the VL-CDR3 of the IPH52 antibody is defined by SEQ ID NO:17 (QQTKEVPYT).
- SEQ ID NO: 14 > VL domain of IPH52 (FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4) DIVLTQSPASLAVSLGQRATISCRASESVDNFGVSFMYWFQQKPGQPPNLLIYGASNQGSGVPARFRGS GSGTDFSLNIHPMEADDTAMYFCQQTKEVPYTFGGGTKLEIK
- the VH region of the SRF617 antibody consists in the sequence of SEQ ID NO:18.
- the VH-CDR1 of the SRF617 antibody is defined by SEQ ID NO:19 (GTFSSEGIS)
- the VH-CDR2 of the SRF617 antibody is defined by SEQ ID NO:20 (SILPIFGTANYAQKFQG)
- the VH-CDR3 of the SRF617 antibody is defined by SEQ ID NO:21 (AREAGYYRYRYFDL).
- SEQ ID NO: 18 > VH domain of SRF617 (FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4) QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSEGISWVRQAPGQGLEWMGSILPIFGTANYAQKFQGRVT ITADESTSTAYMELSSLRSEDTAVYYCAREAGYYRYRYFDLWGKGTLVTVSS
- the VL region of the SRF617 antibody consists of the sequence of SEQ ID NO:22.
- the VL-CDR1 of the SRF617 antibody is defined by SEQ ID NO:23 (RASQSVSSNLA)
- the VL-CDR2 of the SRF617 antibody is defined by SEQ ID NO:24 (GASTRAT)
- the VL-CDR3 of the SRF617 antibody is defined by SEQ ID NO:25 (QQHALWPLT).
- SEQ ID NO: 22 > VL domain of SRF617 (FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4) EIVMTQSPATLSVSPGERATLSCRASQSVSSNLAWYQQKPGQAPRLLIYGASTRATGIPARFSGSGSGT EFTLTISSLQSEDFAVYYCQQHALWPLTFGGGTKVEIK
- the VH region of the BY40 antibody consists in the sequence of SEQ ID NO:26.
- the VH-CDR1 of the BY40 antibody is defined by SEQ ID NO:27 (GYTFTHYG)
- the VH-CDR2 of the BY40 antibody is defined by SEQ ID NO:28 (INTYTGEP)
- the VH-CDR3 of the BY40 antibody is defined by SEQ ID NO:29 (ARRRYEGNYVFYYFDYWGQGTTLTVSS).
- SEQ ID NO: 26 > VH domain of BY40 (FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4) TRVKKPRETVKISCKASGYTFTHYGMNWVKQAPGKGLKWMGWINTYTGEPTYADDFKGRFAFSLEASVS TAYLQINNLKNEDTATYFCARRRYEGNYVFYYFDYWGQGTTLTVSSAKTTPPSVYPLAPGSAAQTNSMV TLGCLVKGYFPEQVTVTWNSGSLSSGVHTFPAVLQSDLYTLSSSVTVPS
- the VL region of the BY40 antibody consists of the sequence of SEQ ID NO:30.
- the VL-CDR1 of the BY40 antibody is defined by SEQ ID NO:31 (RASENIYSYFS)
- the VL-CDR2 of the BY40 antibody is defined by SEQ ID NO:32 (TAKTLAE)
- the VL-CDR3 of the BY40 antibody is defined by SEQ ID NO:33 (QHHYVTPYTFGGGTKLEIKR).
- SEQ ID NO:30 VL domain of BY40 (FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4) DIQMTGSPASLSASVGETVTITCRASENIYSYFSWYQQKQGKSPQLLVYTAKTLAEGVPSRFSGSGSGT QFSLKINSLQPEDFGSYYCQHHYVTPYTFGGGTKLEIKRADAAPTVSIFPPSSEQLTSGGASVVCFLNN FYPKDINVKWKIDGSERQNGVLNSWTD
- the VH region of the BA54g antibody consists in the sequence of SEQ ID NO:34.
- the VH-CDR1 of the BA54g antibody is defined by SEQ ID NO:35 (GGSRKLSCAASGFTFSSFGMH)
- the VH-CDR2 of the BA54g antibody is defined by SEQ ID NO:36 (YISSGSSIIYYADTVKG)
- the VH-CDR3 of the BA54g antibody is defined by SEQ ID NO:37 (WSTTVVATDYWGQGTTLTVS).
- SEQ ID NO: 34 VH domain of BA54g (FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4) DVQLVESGGGLVQPGGSRKLSCAASGFTFSSFGMHWVRQAPEKGLEWVAYISSGSSIIYYADTVKGRFT ISRDNPKNTLFLQMTSLGSEDTAMYYCARWSTTVVATDYWGQGTTLTVS
- the VL region of the BA54g antibody consists of the sequence of SEQ ID NO:38.
- the VL-CDR1 of the BA54g antibody is defined by SEQ ID NO:39 (KASENVVTYVS), the VL-CDR2 of the BA54g antibody is defined by SEQ ID NO:40 (GASNRYT) and the VL-CDR3 of the BA54g antibody is defined by SEQ ID NO:41 (CGQGYSYPYTFGGGTKLEIKR).
- VH region of the 9-8B antibody consists in the sequence of SEQ ID NO:42.
- the VH-CDR1 of the 9-8B antibody is defined by SEQ ID NO:43 (HYGMN)
- the VH-CDR2 of the 9-8B antibody is defined by SEQ ID NO:44 (WINTYTGELTYADDFKG)
- the VH-CDR3 of the 9-8B antibody is defined by SEQ ID NO:45 (RAYYRYDYVMDY).
- SEQ ID NO: 42 > VH domain of 9-8B (FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4) QIQLVQSGPELKKPGETVKISCKASGYTFTHYGMNWVKQAPGKGLKWMGWINTYTGELTYADDFKGRFA FSLETSASTAYLQINNLKNEDTATYFCARRAYYRYDYVMDYWGQGTSVTVSS
- the VL region of the 9-8B antibody consists of the sequence of SEQ ID NO:46.
- the VL-CDR1 of the 9-8B antibody is defined by SEQ ID NO:47 (KASHNVGTNVA)
- the VL-CDR2 of the 9-8B antibody is defined by SEQ ID NO:48 (SASYRYS)
- the VL-CDR3 of the 9-8B antibody is defined by SEQ ID NO:49 (HQYNNYPYT).
- the antibody of the present invention is a single chain antibody.
- single domain antibody has its general meaning in the art and refers to the single heavy chain variable domain of antibodies of the type that can be found in Camelid mammals which are naturally devoid of light chains. Such single domain antibody are also “nanobody®”.
- the amino acid sequence and structure of a single domain antibody can be considered to be comprised of four framework regions or "FRs” which are referred to in the art and herein as “Framework region 1" or “FRl "; as “Framework region 2” or “FR2”; as “Framework region 3 “ or “FR3”; and as “Framework region 4" or “FR4” respectively; which framework regions are interrupted by three complementary determining regions or "CDRs”, which are referred to in the art as "Complementarity Determining Region for "CDRl”; as Complementarity Determining Region 2 or CDR2 and as Complementarity Determining Region 3" or “CDR3”, respectively.
- CDRs complementary determining regions
- the single domain antibody can be defined as an amino acid sequence with the general structure: FRl - CDRl - FR2 - CDR2 - FR3 - CDR3 - FR4 in which FRl to FR4 refer to framework regions 1 to 4 respectively, and in which CDRl to CDR3 refer to the complementarity determining regions 1 to 3.
- the antibody leads to the depletion of CD39 expressing cancer cells.
- the term “depletion” with respect to cancer cells refers to a measurable decrease in the number of CD39 expressing cancer cells in the patient.
- the reduction can be at least about 10%, e.g., at least about 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or more.
- the term refers to a decrease in the number of CD39 cancer cells in the patient below detectable limits.
- the antibody suitable for depletion of CD39 cancer cells mediates antibody-dependant cell-mediated cytotoxicity.
- ADCC antibody-dependent cell-mediated cytotoxicity
- non-specific cytotoxic cells e.g., T gamma delta lymphocytes, Natural Killer (NK) cells, neutrophils, and macrophages
- NK Natural Killer
- these cytotoxic cells that mediate ADCC generally express Fc receptors (FcRs).
- FcRs Fc receptors
- the CD39 inhibitor is an inhibitor of CD39 expression.
- An “inhibitor of expression” refers to a natural or synthetic compound that has a biological effect to inhibit the expression of a gene.
- said inhibitor of gene expression is a siRNA, an antisense oligonucleotide or a ribozyme.
- anti- sense oligonucleotides including anti-sense RNA molecules and anti-sense DNA molecules, would act to directly block the translation of CD39 mRNA by binding thereto and thus preventing protein translation or increasing mRNA degradation, thus decreasing the level of CD39, and thus activity, in a cell.
- antisense oligonucleotides of at least about 15 bases and complementary to unique regions of the mRNA transcript sequence encoding CD39 can be synthesized, e.g., by conventional phosphodiester techniques.
- RNA interference small double stranded RNA
- Antisense oligonucleotides, siRNAs, shRNAs and ribozymes of the invention may be delivered in vivo alone or in association with a vector.
- a "vector" is any vehicle capable of facilitating the transfer of the antisense oligonucleotide, siRNA, shRNA or ribozyme nucleic acid to the cells and typically cells expressing CD39.
- the vector transports the nucleic acid to cells with reduced degradation relative to the extent of degradation that would result in the absence of the vector.
- the vectors useful in the invention include, but are not limited to, plasmids, phagemids, viruses, other vehicles derived from viral or bacterial sources that have been manipulated by the insertion or incorporation of the antisense oligonucleotide, siRNA, shRNA or ribozyme nucleic acid sequences.
- Viral vectors are a preferred type of vector and include, but are not limited to nucleic acid sequences from the following viruses: retrovirus, such as moloney murine leukemia virus, harvey murine sarcoma virus, murine mammary tumor virus, and rous sarcoma virus; adenovirus, adeno-associated virus; SV40-type viruses; polyoma viruses; Epstein-Barr viruses; papilloma viruses; herpes virus; vaccinia virus; polio virus; and RNA virus such as a retrovirus.
- retrovirus such as moloney murine leukemia virus, harvey murine sarcoma virus, murine mammary tumor virus, and rous sarcoma virus
- adenovirus adeno-associated virus
- SV40-type viruses polyoma viruses
- Epstein-Barr viruses Epstein-Barr viruses
- papilloma viruses herpes virus
- vaccinia virus
- the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment.
- the specific therapeutically effective dose level for any particular subject will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed, the age, body weight, general health, sex and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidential with the specific polypeptide employed; and like factors well known in the medical arts.
- the daily dosage of the products may be varied over a wide range from 0.01 to 1,000 mg per adult per day.
- the compositions contain 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 250 and 500 mg of the active ingredient for the symptomatic adjustment of the dosage to the subject to be treated.
- a medicament typically contains from about 0.01 mg to about 500 mg of the active ingredient, preferably from 1 mg to about 100 mg of the active ingredient.
- an effective amount of the drug is ordinarily supplied at a dosage level from 0.0002 mg/kg to about 20 mg/kg of body weight per day, especially from about 0.001 mg/kg to 7 mg/kg of body weight per day.
- the inhibitor of the present invention is combined with pharmaceutically acceptable excipients, and optionally sustained-release matrices, such as biodegradable polymers, to form pharmaceutical compositions.
- pharmaceutically acceptable excipients such as biodegradable polymers
- a pharmaceutically acceptable carrier or excipient refers to a non-toxic solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.
- the pharmaceutical compositions contain vehicles, which are pharmaceutically acceptable for a formulation capable of being injected. These may be in particular isotonic, sterile, saline solutions (monosodium or disodium phosphate, sodium, potassium, calcium or magnesium chloride and the like or mixtures of such salts), or dry, especially freeze-dried compositions which upon addition, depending on the case, of sterilized water or physiological saline, permit the constitution of injectable solutions.
- the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions; formulations including sesame oil, peanut oil or aqueous propylene glycol; and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
- the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi.
- Sterile injectable solutions are prepared by incorporating the inhibitor at the required amount in the appropriate solvent with several of the other ingredients enumerated above, as required, followed by filtered sterilization.
- dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
- sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
- treatment or treat refer to both prophylactic or preventive treatment as well as curative or disease modifying treatment, including treatment of subject at risk of contracting the disease or suspected to have contracted the disease as well as subjects who are ill or have been diagnosed as suffering from a disease or medical condition, and includes suppression of clinical relapse.
- the treatment may be administered to a subject having a medical disorder or who ultimately may acquire the disorder, in order to prevent, cure, delay the onset of, reduce the severity of, or ameliorate one or more symptoms of a disorder or recurring disorder, or in order to prolong the survival of a subject beyond that expected in the absence of such treatment.
- therapeutic regimen is meant the pattern of treatment of an illness, e.g., the pattern of dosing used during therapy.
- a therapeutic regimen may include an induction regimen and a maintenance regimen.
- the phrase "induction regimen” or “induction period” refers to a therapeutic regimen (or the portion of a therapeutic regimen) that is used for the initial treatment of a disease.
- An induction regimen may employ (in part or in whole) a "loading regimen", which may include administering a greater dose of the drug than a physician would employ during a maintenance regimen, administering a drug more frequently than a physician would administer the drug during a maintenance regimen, or both.
- loading regimen may include administering a greater dose of the drug than a physician would employ during a maintenance regimen, administering a drug more frequently than a physician would administer the drug during a maintenance regimen, or both.
- the phrase "maintenance regimen” or “maintenance period” refers to a therapeutic regimen (or the portion of a therapeutic regimen) that is used for the maintenance of a subject during treatment of an illness, e.g., to keep the subject in remission for long periods of time (months or years).
- a maintenance regimen may employ continuous therapy (e.g., administering a drug at a regular intervals, e.g., weekly, monthly, yearly, etc.) or intermittent therapy (e.g., interrupted treatment, intermittent treatment, treatment at relapse, or treatment upon achievement of a particular predetermined criteria [e.g., pain, disease manifestation, etc.]).
- continuous therapy e.g., administering a drug at a regular intervals, e.g., weekly, monthly, yearly, etc.
- intermittent therapy e.g., interrupted treatment, intermittent treatment, treatment at relapse, or treatment upon achievement of a particular predetermined criteria [e.g., pain, disease manifestation, etc.].
- the Inventors also herein demonstrate that CD39 inhibition potentiate anti-CD20 monoclonal antibody therapy.
- the present invention relates to a method of treating a B-cell lymphoma in a subject in need thereof comprising administering said subject with a CD39 inhibitor and an anti-CD20 monoclonal
- the present invention relates to i) a CD39 inhibitor, and ii) an anti-CD20 monoclonal antibody, as a combined preparation for simultaneous, separate or sequential use in the treatment of a B-cell lymphoma.
- the use of the CD39 inhibitor of the present invention is particularly useful to improve anti-CD20 monoclonal antibody efficacy.
- the CD39 inhibitor according to the present invention is particularly suitable for improving anti-CD20 monoclonal antibody efficacy in a subject suffering from a B-cell lymphoma.
- anti-CD20 monoclonal antibodies include, but are not limited to, Rituximab (Roche), Ocrelizumab (Roche), Obinutuzumab (Roche), Ibritumomab (Bayer Schering), Ofatumumab (HuMax-CD20, Gemnab), Ublituximab (TG Therapeutics), IMMU- 106 (Immunomedics), AME-133v (Applied Molecular Evolution), TRU-015 (Trubion) or Tositumomab (GlaxoSmithKline).
- the anti-CD20 antibody is Obinutuzumab.
- the B-cell lymphoma is resistant to obinutuzumab.
- the anti-CD20 monoclonal antibody is rituximab.
- the B-cell lymphoma is resistant to rituximab.
- the Inventors demonstrate that CD39 inhibition potentiates anti-PD1 monoclonal antibody therapy. Accordingly, in a third aspect, the present invention relates to a method of treating a B-cell lymphoma in a subject in need thereof comprising administering said subject with a CD39 inhibitor and an anti-PD1 monoclonal antibody.
- the present invention relates to a method of treating a B-cell lymphoma in a subject in need thereof comprising administering said subject with a CD39 inhibitor, an anti- PD1 monoclonal antibody and Ibrutinib.
- the present invention relates to i) a CD39 inhibitor, and ii) an anti-PD1 monoclonal antibody, as a combined preparation for simultaneous, separate or sequential use in the treatment of a B-cell lymphoma.
- the use of the CD39 inhibitor of the present invention is particularly useful to improve anti-PD1 monoclonal antibody efficacy.
- the CD39 inhibitor according to the present invention is particularly suitable for improving anti-PD1 monoclonal antibody efficacy in a subject suffering from a B-cell lymphoma.
- anti-PD1 monoclonal antibodies include, but are not limited to, Pembrolizumab (Merck), Nivolumab (Ono Pharmaceutical), BMS-936559 (Bristol-Myers Squibb), Cemiplimab (Regeneron), Cemiplimab-rwlc (Sanofi), Avelumab (Merck), Durvalumab (AstraZeneca), Atezolizumab (Roche) or Spartalizumab (Novartis).
- the anti-PD1 monoclonal antibody is nivolumab.
- the B-cell lymphoma is resistant to nivolumab.
- the present invention relates to a method of treating a B-cell lymphoma in a subject in need thereof comprising administering said subject with a CD39 inhibitor, an anti-CD20 monoclonal antibody and an anti-PD1 monoclonal antibody.
- the present invention relates to i) a CD39 inhibitor, ii) an anti-CD20 monoclonal antibody and iii) an anti-PD1 monoclonal antibody as a combined preparation for simultaneous, separate or sequential use in the treatment of a B-cell lymphoma.
- the use of the CD39 inhibitor of the present invention is particularly useful to improve anti-CD20 monoclonal antibody efficacy and anti-PD1 monoclonal antibody efficacy.
- the CD39 inhibitor according to the present invention is particularly suitable for improving anti-CD20 monoclonal antibody efficacy and anti-PD1 monoclonal antibody efficacy in a subject suffering from a B-cell lymphoma.
- the present invention relates to a method of treating a B-cell lymphoma in a subject in need thereof comprising administering said subject with a CD39 inhibitor and a PDE-4 inhibitor.
- the PDE-4 inhibitor is Roflumilast.
- the present invention relates to a method of treating a B-cell lymphoma in a subject in need thereof comprising administering said subject with a CD39 inhibitor and a BTK inhibitor.
- the BTK inhibitor is Ibrutinib.
- the present invention relates to a method of treating a B-cell lymphoma in a subject in need thereof comprising administering said subject with a CD39 inhibitor and a chemotherapy.
- the present invention relates to a method of treating a B-cell lymphoma in a subject in need thereof comprising administering said subject with a CD39 inhibitor and at least a chemotherapy.
- the B-cell lymphoma is Follicular Lymphoma (FL), Diffuse Large B-cell Lymphoma (DLBCL), Mantle cell lymphoma (MCL), Waldenstrom Macroglobulinemia (WM), lymphoblastic lymphoma, Primary Mediastinal Large B-Cell Lymphoma (PMBCL), Marginal Zone B-cell Lymphoma (MZL) or Burkitt lymphoma.
- the B-cell lymphoma is a non-Hodgkin lymphoma. In some embodiments, the B-cell lymphoma is a Follicular Lymphoma (FL). In some embodiment, the B-cell lymphoma is a Diffuse Large B Cell Lymphoma (DLBCL). In some embodiment, the B-cell lymphoma is a Mantle Cell Lymphoma.
- the term “simultaneous use” denotes the use of the CD39 inhibitor, the anti-CD20 monoclonal antibody and/or the anti-PD1 monoclonal antibody occurring at the same time.
- the term “separate use” denotes the use of the CD39 inhibitor, the anti-CD20 monoclonal antibody and/or the anti-PD1 monoclonal antibody not occurring at the same time.
- the term “sequential use” denotes the use of the CD39 inhibitor, the anti-CD20 monoclonal antibody and/or the anti-PD1 monoclonal antibody occurring by following an order.
- the CD39 inhibitor according to the present invention is particularly suitable for preventing B-cell lymphoma relapse.
- the CD39 inhibitor of the present invention is particularly useful to prevent relapse after putatively successful treatment with anti-CD20 monoclonal antibody (e.g.
- the CD39 inhibitor of the present invention is particularly useful to prevent relapse after putatively successful treatment with anti- PD1 monoclonal antibody (e.g. nivolumab) and/or a chemotherapy.
- the CD39 inhibitor of the present invention is particularly useful to prevent relapse after putatively successful treatment with a PDE-4 inhibitor.
- the CD39 inhibitor of the present invention is particularly useful to prevent relapse after putatively successful treatment with a BTK inhibitor.
- the CD39 inhibitor according to the present invention is particularly suitable for treating a B-cell lymphoma relapse.
- the present invention also relates to a method for preventing relapse of a subject suffering from a B-cell lymphoma comprising administering said subject with a therapeutically effective amount of a CD39 inhibitor.
- the present invention also relates to a method for preventing relapse of a subject suffering from a B-cell lymphoma who was treated with anti-CD20 monoclonal antibody and/or a chemotherapy comprising administering said subject with a therapeutically effective amount of a CD39 inhibitor.
- the present invention also relates to a method for preventing relapse of a subject suffering from a B-cell lymphoma who was treated with anti-PD1 monoclonal antibody and/or a chemotherapy comprising administering said subject with a therapeutically effective amount of a CD39 inhibitor.
- the present invention also relates to a method for preventing relapse of a subject suffering from a B-cell lymphoma who was treated with anti-CD20 monoclonal antibody comprising administering said subject with a therapeutically effective amount of a CD39 inhibitor.
- the present invention also relates to a method for preventing relapse of a subject suffering from a B-cell lymphoma who was treated with anti-PD1 monoclonal antibody comprising administering said subject with a therapeutically effective amount of a CD39 inhibitor.
- the anti-CD20 monoclonal antibody is obinutuzumab.
- the anti-CD20 monoclonal antibody is a rituximab.
- the anti-PD1 monoclonal antibody is nivolumab.
- the chemotherapy is CHOP therapy.
- the term "relapse" refers to the return of cancer after a period of improvement in which no cancer could be detected.
- the present invention relates to a method for predicting the survival time of a subject suffering from a B-cell lymphoma comprising determining the level of expression of ENTPD1 gene in a sample from said subject.
- sample refers to any biological sample of a subject and can include, by way of example and not limitation, bodily fluids and/or tissue extracts such as homogenates or solubilized tissue obtained from a subject. Tissue extracts are obtained routinely from tissue biopsy.
- a biological sample may be a tumor sample, bodily fluids such as blood sample, plasma sample, serum sample, cerebrospinal fluid, pleural effusion, ascetic effusion, urinary sample, saliva sample, or in case of fetus, amniotic fluid or chorionic villy or any other bodily secretion or derivative thereof.
- the biological sample is a tumor sample or a bodily fluid sample which may contain cell free DNA/RNA associated tumour (circulating tumour DNA/RNA).
- the sample is a lymphatic tissue, bone, cerebrospinal fluid, digestive tract, sinus, testicles, thyroid gland or skin.
- the present invention relates to a method for predicting the survival time of subject suffering from a B-cell lymphoma comprising i) determining the expression level of ENTPD1 gene in a sample obtained from a subject ii) comparing the expression level determined at step i) with a predetermined reference value and iii) providing a good prognosis when the expression level determined at step i) is lower than the predetermined reference value, or providing a bad prognosis when the expression level determined at step i) is higher than the predetermined reference value.
- the B-cell lymphoma is Follicular Lymphoma (FL), Diffuse Large B-cell Lymphoma (DLBCL), Mantle cell lymphoma (MCL), Waldenstrom Macroglobulinemia (WM), lymphoblastic lymphoma, Primary Mediastinal Large B-Cell Lymphoma (PMBCL), Marginal Zone B-cell Lymphoma (MZL) or Burkitt lymphoma.
- the B-cell lymphoma is a non-Hodgkin lymphoma.
- the B-cell lymphoma is a Follicular Lymphoma (FL).
- the B-cell lymphoma is a Diffuse Large B Cell Lymphoma (DLBCL). In some embodiments, the B-cell lymphoma is a Mantle Cell Lymphoma (MCL).
- survival time denotes the percentage of people in a study or treatment group who are still alive for a certain period of time after they were diagnosed with or started treatment for a disease, such as B-cell lymphoma (according to the invention). The survival time rate is often stated as a five-year survival rate, which is the percentage of people in a study or treatment group who are alive five years after their diagnosis or the start of treatment.
- the term “survival time” can regroup the term “Overall survival (OS)”.
- OS denotes the time from diagnosis of a disease such as B- cell lymphoma (according to the invention) until death from any cause.
- the overall survival rate is often stated as a two-year survival rate, which is the percentage of people in a study or treatment group who are alive two years after their diagnosis or the start of treatment.
- Measuring the expression level of CD39 can be done by measuring the gene expression level of CD39 or by measuring the level of the protein CD39 and can be performed by a variety of techniques well known in the art. Typically, the expression level of a gene may be determined by determining the quantity of mRNA.
- the nucleic acid contained in the samples e.g., cell or tissue prepared from the patient
- the samples e.g., cell or tissue prepared from the patient
- the extracted mRNA is then detected by hybridization (e. g., Northern blot analysis, in situ hybridization) and/or amplification (e.g., RT-PCR).
- hybridization e. g., Northern blot analysis, in situ hybridization
- amplification e.g., RT-PCR.
- Other methods of Amplification include ligase chain reaction (LCR), transcription-mediated amplification (TMA), strand displacement amplification (SDA) and nucleic acid sequence based amplification (NASBA).
- LCR ligase chain reaction
- TMA transcription-mediated amplification
- SDA strand displacement amplification
- NASBA nucleic acid sequence based amplification
- nucleic acids having at least 10 nucleotides and exhibiting sequence complementarity or homology to the mRNA of interest herein find utility as hybridization probes or amplification primers. It is understood that such nucleic acids need not be identical, but are typically at least about 80% identical to the homologous region of comparable size, more preferably 85% identical and even more preferably 90-95% identical. In certain embodiments, it will be advantageous to use nucleic acids in combination with appropriate means, such as a detectable label, for detecting hybridization. Typically, the nucleic acid probes include one or more labels, for example to permit detection of a target nucleic acid molecule using the disclosed probes.
- a nucleic acid probe includes a label (e.g., a detectable label).
- a “detectable label” is a molecule or material that can be used to produce a detectable signal that indicates the presence or concentration of the probe (particularly the bound or hybridized probe) in a sample.
- a labeled nucleic acid molecule provides an indicator of the presence or concentration of a target nucleic acid sequence (e.g., genomic target nucleic acid sequence or mRNA) (to which the labeled uniquely specific nucleic acid molecule is bound or hybridized) in a sample.
- a label associated with one or more nucleic acid molecules can be detected either directly or indirectly.
- a label can be detected by any known or yet to be discovered mechanism including absorption, emission and/ or scattering of a photon (including radio frequency, microwave frequency, infrared frequency, visible frequency and ultra-violet frequency photons).
- Detectable labels include colored, fluorescent, phosphorescent and luminescent molecules and materials, catalysts (such as enzymes) that convert one substance into another substance to provide a detectable difference (such as by converting a colorless substance into a colored substance or vice versa, or by producing a precipitate or increasing sample turbidity), haptens that can be detected by antibody binding interactions, and paramagnetic and magnetic molecules or materials.
- detectable labels include fluorescent molecules (or fluorochromes).
- fluorochromes are known to those skilled in the art, and can be selected, for example from Life Technologies (formerly Invitrogen), e.g., see, The Handbook— A Guide to Fluorescent Probes and Labeling Technologies). Examples of particular fluorophores that can be attached (for example, chemically conjugated) to a nucleic acid molecule (such as a uniquely specific binding region) are provided in U.S. Pat.
- No.5,866, 366 to Nazarenko et al. such as 4-acetamido-4'-isothiocyanatostilbene-2,2' disulfonic acid, acridine and derivatives such as acridine and acridine isothiocyanate, 5-(2'-aminoethyl) aminonaphthalene-1-sulfonic acid (EDANS), 4-amino -N- [3 vinylsulfonyl)phenyl]naphthalimide-3,5 disulfonate (Lucifer Yellow VS), N-(4-anilino-1- naphthyl)maleimide, antl1ranilamide, Brilliant Yellow, coumarin and derivatives such as coumarin, 7-amino-4-methylcoumarin (AMC, Coumarin 120), 7-amino-4- trifluoromethylcouluarin (Coumarin 151); cyanosine; 4',6-diarninidino-2-phen
- fluorophores include thiol-reactive europium chelates which emit at approximately 617 nm (Heyduk and Heyduk, Analyt. Biochem.248:216-27, 1997; J. Biol. Chem.274:3315-22, 1999), as well as GFP, LissamineTM, diethylaminocoumarin, fluorescein chlorotriazinyl, naphthofluorescein, 4,7-dichlororhodamine and xanthene (as described in U.S. Pat. No. 5,800,996 to Lee et al.) and derivatives thereof.
- fluorophores known to those skilled in the art can also be used, for example those available from Life Technologies (Invitrogen; Molecular Probes (Eugene, Oreg.)) and including the ALEXA FLUOR® series of dyes (for example, as described in U.S. Pat. Nos. 5,696,157, 6, 130, 101 and 6,716,979), the BODIPY series of dyes (dipyrromethene boron difluoride dyes, for example as described in U.S. Pat. Nos.
- a fluorescent label can be a fluorescent nanoparticle, such as a semiconductor nanocrystal, e.g., a QUANTUM DOT® (obtained, for example, from Life Technologies (Quantum Dot Corp, Invitrogen Nanocrystal Technologies, Eugene, Oreg.); see also, U.S. Pat.
- a fluorescent nanoparticle such as a semiconductor nanocrystal, e.g., a QUANTUM DOT® (obtained, for example, from Life Technologies (Quantum Dot Corp, Invitrogen Nanocrystal Technologies, Eugene, Oreg.); see also, U.S. Pat.
- Semiconductor nanocrystals are microscopic particles having size-dependent optical and/or electrical properties.
- a secondary emission of energy occurs of a frequency that corresponds to the band gap of the semiconductor material used in the semiconductor nanocrystal. This emission can he detected as colored light of a specific wavelength or fluorescence.
- Semiconductor nanocrystals with different spectral characteristics are described in e.g., U.S. Pat. No. 6,602,671.
- Semiconductor nanocrystals that can he coupled to a variety of biological molecules (including dNTPs and/or nucleic acids) or substrates by techniques described in, for example, Bruchez et al., Science 281 :20132016, 1998; Chan et al., Science 281:2016-2018, 1998; and U.S. Pat. No. 6,274,323. Formation of semiconductor nanocrystals of various compositions are disclosed in, e.g., U.S. Pat. Nos.
- quantum dots that emit light at different wavelengths based on size (565 nm, 655 nm, 705 nm, or 800 nm emission wavelengths), which are suitable as fluorescent labels in the probes disclosed herein are available from Life Technologies (Carlsbad, Calif.). Additional labels include, for example, radioisotopes (such as 3 H), metal chelates such as DOTA and DPTA chelates of radioactive or paramagnetic metal ions like Gd3+.
- radioisotopes such as 3 H
- metal chelates such as DOTA and DPTA chelates of radioactive or paramagnetic metal ions like Gd3+.
- Detectable labels that can be used with nucleic acid molecules also include enzymes, for example horseradish peroxidase, alkaline phosphatase, acid phosphatase, glucose oxidase, beta-galactosidase, beta-glucuronidase, or beta-lactamase.
- an enzyme can be used in a metallographic detection scheme.
- silver in situ hybridization (SISH) procedures involve metallographic detection schemes for identification and localization of a hybridized genomic target nucleic acid sequence.
- Metallographic detection methods include using an enzyme, such as alkaline phosphatase, in combination with a water-soluble metal ion and a redox-inactive substrate of the enzyme.
- the substrate is converted to a redox-active agent by the enzyme, and the redoxactive agent reduces the metal ion, causing it to form a detectable precipitate.
- Metallographic detection methods also include using an oxido-reductase enzyme (such as horseradish peroxidase) along with a water soluble metal ion, an oxidizing agent and a reducing agent, again to form a detectable precipitate.
- an oxido-reductase enzyme such as horseradish peroxidase
- Probes made using the disclosed methods can be used for nucleic acid detection, such as ISH procedures (for example, fluorescence in situ hybridization (FISH), chromogenic in situ hybridization (CISH) and silver in situ hybridization (SISH)) or comparative genomic hybridization (CGH).
- FISH fluorescence in situ hybridization
- CISH chromogenic in situ hybridization
- SISH silver in situ hybridization
- CGH comparative genomic hybridization
- Numerous procedures for FISH, CISH, and SISH are known in the art.
- procedures for performing FISH are described in U.S. Pat. Nos. 5,447,841; 5,472,842; and 5,427,932; and for example, in Pinkel et al., Proc. Natl. Acad. Sci. 83:2934- 2938, 1986; Pinkel et al., Proc. Natl. Acad.
- CISH is described in, e.g., Tanner et al., Am.1. Pathol. 157:1467-1472, 2000 and U.S. Pat. No.6,942,970. Additional detection methods are provided in U.S. Pat. No. 6,280,929. Numerous reagents and detection schemes can be employed in conjunction with FISH, CISH, and SISH procedures to improve sensitivity, resolution, or other desirable properties. As discussed above probes labeled with fluorophores (including fluorescent dyes and QUANTUM DOTS®) can be directly optically detected when performing FISH.
- fluorophores including fluorescent dyes and QUANTUM DOTS®
- the probe can be labeled with a nonfluorescent molecule, such as a hapten (such as the following non-limiting examples: biotin, digoxigenin, DNP (dinitrophenol), and various oxazoles, pyrrazoles, thiazoles, nitroaryls, benzofurazans, triterpenes, ureas, thioureas, rotenones, coumarin, courmarin-based compounds, Podophyllotoxin, Podophyllotoxin-based compounds, and combinations thereof), ligand or other indirectly detectable moiety.
- a hapten such as the following non-limiting examples: biotin, digoxigenin, DNP (dinitrophenol), and various oxazoles, pyrrazoles, thiazoles, nitroaryls, benzofurazans, triterpenes, ureas, thioureas, rotenones, coumarin, courmarin-based compounds, Pod
- Probes labeled with such non-fluorescent molecules (and the target nucleic acid sequences to which they bind) can then be detected by contacting the sample (e.g., the cell or tissue sample to which the probe is bound) with a labeled detection reagent, such as an antibody (or receptor, or other specific binding partner) specific for the chosen hapten or ligand.
- a labeled detection reagent such as an antibody (or receptor, or other specific binding partner) specific for the chosen hapten or ligand.
- the detection reagent can be labeled with a fluorophore (e.g., QUANTUM DOT®) or with another indirectly detectable moiety, or can be contacted with one or more additional specific binding agents (e.g., secondary or specific antibodies), which can be labeled with a fluorophore.
- the probe, or specific binding agent (such as an antibody, e.g., a primary antibody, receptor or other binding agent) is labeled with an enzyme that is capable of converting a fluorogenic or chromogenic composition into a detectable fluorescent, colored or otherwise detectable signal (e.g., as in deposition of detectable metal particles in SISH).
- the enzyme can be attached directly or indirectly via a linker to the relevant probe or detection reagent. Examples of suitable reagents (e.g., binding reagents) and chemistries (e.g., linker and attachment chemistries) are described in U.S. Patent Application Publication Nos.2006/0246524; 2006/0246523, and 2007/ 0117153.
- multiplex detection schemes can be produced to facilitate detection of multiple target nucleic acid sequences (e.g., genomic target nucleic acid sequences) in a single assay (e.g., on a single cell or tissue sample or on more than one cell or tissue sample).
- a first probe that corresponds to a first target sequence can be labelled with a first hapten, such as biotin, while a second probe that corresponds to a second target sequence can be labelled with a second hapten, such as DNP.
- the bound probes can he detected by contacting the sample with a first specific binding agent (in this case avidin labelled with a first fluorophore, for example, a first spectrally distinct QUANTUM DOT®, e.g., that emits at 585 nm) and a second specific binding agent (in this case an anti- DNP antibody, or antibody fragment, labelled with a second fluorophore (for example, a second spectrally distinct QUANTUM DOT®, e.g., that emits at 705 nm).
- a first specific binding agent in this case avidin labelled with a first fluorophore, for example, a first spectrally distinct QUANTUM DOT®, e.g., that emits at 585 nm
- a second specific binding agent in this case an anti- DNP antibody, or antibody fragment, labelled with a second fluorophore (for example, a second spectrally distinct QUANTUM DOT®,
- Probes typically comprise single-stranded nucleic acids of between 10 to 1000 nucleotides in length, for instance of between 10 and 800, more preferably of between 15 and 700, typically of between 20 and 500.
- Primers typically are shorter single-stranded nucleic acids, of between 10 to 25 nucleotides in length, designed to perfectly or almost perfectly match a nucleic acid of interest, to be amplified.
- the probes and primers are “specific” to the nucleic acids they hybridize to, i.e.
- the nucleic acid primers or probes used in the above amplification and detection method may be assembled as a kit.
- a kit includes consensus primers and molecular probes.
- a preferred kit also includes the components necessary to determine if amplification has occurred.
- the kit may also include, for example, PCR buffers and enzymes; positive control sequences, reaction control primers; and instructions for amplifying and detecting the specific sequences.
- the expression level is determined by DNA chip analysis.
- Such DNA chip or nucleic acid microarray consists of different nucleic acid probes that are chemically attached to a substrate, which can be a microchip, a glass slide or a microsphere- sized bead.
- a microchip may be constituted of polymers, plastics, resins, polysaccharides, silica or silica-based materials, carbon, metals, inorganic glasses, or nitrocellulose.
- Probes comprise nucleic acids such as cDNAs or oligonucleotides that may be about 10 to about 60 base pairs.
- a sample from a test subject optionally first subjected to a reverse transcription, is labelled and contacted with the microarray in hybridization conditions, leading to the formation of complexes between target nucleic acids that are complementary to probe sequences attached to the microarray surface.
- the labelled hybridized complexes are then detected and can be quantified or semi-quantified. Labelling may be achieved by various methods, e.g. by using radioactive or fluorescent labelling. Many variants of the microarray hybridization technology are available to the man skilled in the art (see e.g. the review by Hoheisel, Nature Reviews, Genetics, 2006, 7:200-210).
- Expression level of a gene may be expressed as absolute expression level or normalized expression level.
- expression levels are normalized by correcting the absolute expression level of a gene by comparing its expression to the expression of a gene that is not a relevant for determining the cancer stage of the patient, e.g., a housekeeping gene that is constitutively expressed.
- Suitable genes for normalization include housekeeping genes such as the actin gene ACTB, ribosomal 18S gene, GUSB, PGK1, TFRC, GAPDH, GUSB, TBP and ABL1.
- This normalization allows the comparison of the expression level in one sample, e.g., a patient sample, to another sample, or between samples from different sources.
- the level of CD39 proteins may also be measured and can be performed by a variety of techniques well known in the art.
- the detection of the expression level of CD39 can be performed by flow cytometry.
- the method consists of determining the amount of CD39 expressed on tumor cells.
- the flow cytometry method when the florescence intensity is high or bright, the level of CD39 express on tumor cells is high and thus the expression level of CD39 is high and when the florescence intensity is low or dull, the level of CD39 express on tumor cells is low and thus the expression level of CD39 is low.
- techniques like ELISA (see below) or ELLA allowing to measure the level of the soluble proteins are also suitable.
- the “level of protein” or the “protein level expression” or the “protein concentration” means the quantity or concentration of said protein.
- the “level of protein” means the level of CD39 protein fragments.
- the “level of protein” means the quantitative measurement of CD39 protein expression relative to an internal control.
- protein concentration may be measured for example by capillary electrophoresis-mass spectroscopy technique (CE-MS) or ELISA performed on the sample.
- CE-MS capillary electrophoresis-mass spectroscopy technique
- ELISA ELISA
- the presence of the protein can be detected using standard electrophoretic and immunodiagnostic techniques, including immunoassays such as competition, direct reaction, or sandwich type assays.
- immunoassays such as competition, direct reaction, or sandwich type assays.
- assays include, but are not limited to, Western blots; agglutination tests; enzyme-labeled and mediated immunoassays, such as ELISAs; biotin/avidin type assays; radioimmunoassays; immunoelectrophoresis; immunoprecipitation, capillary electrophoresis- mass spectroscopy technique (CE-MS), etc.
- the reactions generally include revealing labels such as fluorescent, chemioluminescent, radioactive, enzymatic labels or dye molecules, or other methods for detecting the formation of a complex between the antigen and the antibody or antibodies reacted therewith.
- the aforementioned assays generally involve separation of unbound protein in a liquid phase from a solid phase support to which antigen-antibody complexes are bound.
- Solid supports which can be used in the practice of the invention include substrates such as nitrocellulose (e. g., in membrane or microtiter well form); polyvinylchloride (e.
- an ELISA method can be used, wherein the wells of a microtiter plate are coated with a set of antibodies against the proteins to be tested. A sample containing or suspected of containing the marker protein is then added to the coated wells. After a period of incubation sufficient to allow the formation of antibody-antigen complexes, the plate(s) can be washed to remove unbound moieties and a detectably labeled secondary binding molecule is added.
- the secondary binding molecule is allowed to react with any captured sample marker protein, the plate is washed and the presence of the secondary binding molecule is detected using methods well known in the art.
- Predetermined reference values used for comparison of the expression levels may comprise “cut-off” or “threshold” values that may be determined as described herein.
- Each reference (“cut-off”) value for CD39 level may be predetermined by carrying out a method comprising the steps of: a) providing a collection of samples from patients suffering of a cancer and/or samples of the corresponding uninvolved tissues as described in the invention; b) determining the level of CD39 for each sample contained in the collection provided at step a); c) ranking the tumor tissue samples according to said level d) classifying said samples in pairs of subsets of increasing, respectively decreasing, number of members ranked according to their expression level, e) providing, for each sample provided at step a), information relating to the actual clinical outcome for the corresponding cancer patient; f) for each pair of subsets of samples, obtaining a Kaplan Meier percentage of survival curve; g) for each pair of subsets of samples calculating the statistical significance (p value) between both subsets h) selecting as reference value for the level, the value of level for which the p value is the smallest.
- the expression level of CD39 may be assessed for 100 cancer samples of 100 patients.
- the 100 samples are ranked according to their expression level.
- Sample 1 has the highest expression level and sample 100 has the lowest expression level.
- a first grouping provides two subsets: on one side sample Nr 1 and on the other side the 99 other samples.
- the next grouping provides on one side samples 1 and 2 and on the other side the 98 remaining samples etc., until the last grouping: on one side samples 1 to 99 and on the other side sample Nr 100.
- Kaplan Meier curves are prepared for each of the 99 groups of two subsets. Also for each of the 99 groups, the p value between both subsets was calculated.
- the reference value is selected such as the discrimination based on the criterion of the minimum p value is the strongest. In other terms, the expression level corresponding to the boundary between both subsets for which the p value is minimum is considered as the reference value. It should be noted that the reference value is not necessarily the median value of expression levels. In routine work, the reference value (cut-off value) may be used in the present method to discriminate cancer samples and therefore the corresponding patients. Kaplan–Meier curves of percentage of survival as a function of time are commonly used to measure the fraction of patients living for a certain amount of time after treatment and are well known by the man skilled in the art.
- FIGURES Figure 1.
- B CD39 expression followed by flow cytometry upon ⁇ T cell primary cell culture.
- Upper panel represents ratio of mean fluorescence and lower panel CD39+ percent of expressing ⁇ T cells.
- Figure 2. MALC were co-cultured or not with LT ⁇ cells (ratio E/T: 0.5/1) and treated or not by GA101 (10 ⁇ g/ml), POM1 (10 or 100 ⁇ M) or combination.
- GA101 10 ⁇ g/ml
- POM1 10 or 100 ⁇ M
- A Viability was determined by Trypan blue assay on 5 MALC dissociated and pooled.
- B Depletion was determined by comparison to cell number of UT condition. Each symbol and color represents a donor and an experiment, SD represents 3 independent experiments.
- PDLS PDLS morphology after CD39 targeting.
- PDLS were established from 8 different FL patients and after 3 days of culture were treated by GA101 at 10 ⁇ g/mL and/or Nivolumab at 10 ⁇ g/mL and/or POM1 at 10 ⁇ M or 100 ⁇ M. Quantification of center and periphery areas ( ⁇ m2) was performed with the Columbus software.
- Figure 5. CD19+ cell depletion 72h post-treatment.
- PDLS were established from 8 different FL patients and after 3 days of culture were treated by GA101 at 10 ⁇ g/mL and/or Nivolumab at 10 ⁇ g/mL and/or POM1 at 10 ⁇ M or 100 ⁇ M.10 PDLS were pooled, dissociated, stained and analyzed by flow cytometry.
- Figure 6. FL Patient survival depending on their level of CD39 expression (high or low).
- Figure 7. Characterization of CD39, CD73 and A2aR expression on MCL cell lines.
- Figure 8. Viability of MCL cell lines treated or not with POM1 at 2,5 ⁇ M, 5 ⁇ M or 10 ⁇ M.
- ULA-MALC a scaffold-free model adapted for drug screening MALC were produced by adaptation of the HD method where RL cell’s suspension was prepared in complete medium containing 1% methylcellulose (a gelling agent that forces cell- cell interaction) 13 . 20 ⁇ L of this suspension were dropped into coverslips of a 24-well culture plate and after 24 hours’ incubation, all drops were transferred by returning the coverslip to a dish previously coated with 4% agarose. All of the MALC culture medium was then renewed every 5 days.
- the HD method allowed a better understanding of FL biology and drug responses in a more relevant model than 2D cultures, it was not suitable for drug screening due to the manual transfer of neoaggregates into agarose-precoated wells.
- the “ultra-low attachment method” was the most adapted 12 .
- 100 ⁇ L of cell suspension were placed into 96-wells plate ultra-low attachment plate and a centrifugation (1000rpm, 10 min) was than performed to promote cell aggregation.
- the plate was placed into an incubator at 37°C and 5% CO2.
- 100 ⁇ L of medium were renewed every 3 days in order to provide sufficient nutriments to the cell culture and spheroid growth.3D culture of several B- NHL cell lines were tested (RL, WSU, DOHH-2 for follicular lymphoma and Ocily-7, Ocily- 1, Ocily-10, Ocily-3 for DLBCL).
- RL MALC were the most compact and spherical models obtained.
- Fresh tissues from lymph nodes were dissociated using the gentleMACSTM Octo Dissociator (Miltenyi, Paris, France).
- Cell suspensions were frozen in 4% human albumin (VIALEBEX 40 mg/ml, LFB Biomedicaments)/10% DMSO until FL diagnosis. After diagnosis, cells were thawed in complete medium and their phenotypes were analysed by Fortessa X20 (BD Biosciences Le Pont de Claix, France) after staining by fluorochrome- labelled antibodies (see flow cytometry section).
- PDLS were established according to the following protocol: 25000 cells in 100 ⁇ l of enriched medium supplemented with cytokines (IMDM medium + 10% HiClone serum, 5.10-5M 2-ME, 50 ⁇ g/ml gentamicin, 40 ⁇ g/ml apotransferrin, 1 mM sodium pyruvate, 1X nonessential amino acids and 20 mM HEPES, 0.2 ⁇ M ODN, 15ng/mL IL-15, 10ng/mL IL-2, 50ng/mL IL-4, 50ng/mL CD40L) were seeded in 96-well round bottom ULA plates (Corning, Samois sur Seine, France), centrifuged 10 minutes at 1000 rpm and cultured at 37 °C in a humidified 5% CO2 atmosphere.
- cytokines IMDM medium + 10% HiClone serum, 5.10-5M 2-ME, 50 ⁇ g/ml gentamicin, 40 ⁇ g/ml apotrans
- CD39 targeting was evaluated from the cells of these patients, grown for 3 days and treated for 24 hours with POM1.
- POM1 potentiates the effect of GA101 (anti-CD20) and/or Nivolumab (anti-PD1).
- CD39 is also overexpressed in MCL cell lines ( Figure 7).
- the effect of CD39 targeting was evaluated from MCL cell lines treated with POM1 ( Figure 8).
- POM1 potentiates the effect of Roflutinib and Ibrutinib in PDLS.
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Abstract
The Inventors herein demonstrate that CD39 is a relevant therapeutic target in B-cell lymphoma, in particular Follicular Lymphoma (FL), Diffuse Large B-Cell Lymphoma (DLBCL) and Mantle Cell Lymphoma (MCL). They also demonstrate that CD39 potentiate anti-CD20 monoclonal antibody therapy and/or anti-PD1 monoclonal antibody therapy, and that ENTPD1 overexpression is correlated with poor prognosis in FL patients. Accordingly, the present invention relates to a method of treating a B-cell lymphoma in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a CD39 inhibitor.
Description
METHODS FOR THE TREATMENT OF B-CELL LYMPHOMA FIELD OF THE INVENTION: The present invention is in the field of medicine, in particular oncology. BACKGROUND OF THE INVENTION: Follicular Lymphoma (LF) and Diffuse Large B-Cell Lymphoma (DLBCL) are the two most common non-Hodgkin lymphoma (NHL) subtypes that have benefited greatly from the introduction of Rituximab, an anti-CD20 monoclonal antibody often used in combination with chemotherapy. Despite these significant therapeutic advances, a significant fraction of patients relapses, and some patients do not respond to standard treatment [1,2]. This is due in particular to anti-CD20 monoclonal antibody resistance mechanisms such as Fc receptor polymorphism, dose, CD20 loss of expression, antigenic modulation and overactivation of survival pathways (anti-apoptotic) [3]. These pitfalls have led to major advances in the development of new treatments (new anti-CD20 monoclonal antibodies, bi-specific monoclonal antibodies, small molecules, etc.) but also in the exploration of the mechanisms that characterize the immuno- escape (IE) of these tumors. It was recently shown that NHLs frequently express some immune checkpoint (ICP) and have a specific gene signature [4-6]. Transcriptomic analyses identified 4 different stages according to the Tumor Infiltrating Lymphocytes (TIL) activation score and the IEGS33 score based on the collective overexpression of 33 genes specifically involved in IE of lymphoma: Stage I corresponding to non-immunogenic tumors poorly infiltrated with low IE (IEGS33-/T cell activation-). Stage II corresponds to immunogenic tumors with no or low IE signature (IEGS-/ T cell activation+), Stage III to immunogenic tumors with high IE (IEGS+/T cell activation+), and stage IV corresponding to no or little infiltrated tumors with high IE (IEGS+/T cell activation-) [4,6]. At least in DLBCL, the most common NHL, these stages correlate with the clinical outcome of patients. Patients with better overall survival have immunogenic tumours without IE (stage II), while conversely, patients with very short overall survival have tumours that are not infiltrated (stage I and IV). In the FL, most patients have stage III tumours (infiltrated with high IE levels) [6.7]. Recently, it has been shown that the T gamma delta lymphocytes (LTγδ) infiltrate FL tumors and strongly express the PD-1 ICP [7]. Thus, it appears that the targeting of these IE pathways could represent a major challenge in the
management of patients. This is supported by the fact that the PD-1 blockade increases the efficacy of anti-CD20 monoclonal antibodies in the LF both in vitro on 3D models but also in vivo on xenograft mice without however completely eradicating tumor cells [7]. Thus, other targets must be discovered and other therapeutic perspectives must be proposed. SUMMARY OF THE INVENTION: The invention is defined by the claims. In particular, the present invention relates to a method of treating a B-cell lymphoma in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a CD39 inhibitor. DETAILED DESCRIPTION OF THE INVENTION: In a first aspect, the present invention relates to a method of treating a B-cell lymphoma in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a CD39 inhibitor. As used herein, the term “subject” or “patient” denotes a mammal. Typically, a subject according to the invention refers to any subject (preferably human) afflicted with or susceptible to be afflicted with a B-cell lymphoma, in particular a non-Hodgkin lymphoma, in particular a Follicular Lymphoma (FL), a Diffuse Large B-Cell Lymphoma (DLBCL) or a Mantle Cell Lymphoma (MCL). In some embodiments, the subject is treated with an anti-CD20 monoclonal antibody therapy. In some embodiments, the subject is treated with an anti-PD1 monoclonal antibody therapy. As used herein, the term “lymphoma” refers to a group of blood cell tumours that develop from lymphoid cells. The two main categories of lymphomas are Hodgkin lymphomas (HL) and non-Hodgkin lymphomas (NHL). In some embodiments, the lymphoma is a non- Hodgkin lymphoma. NHL lymphomas are categorized by affected cell type: B-cell lymphoma or T-cell lymphoma. The term “B-cell lymphoma” comprises different subtypes such as Follicular Lymphoma (FL), Diffuse Large B-cell Lymphoma (DLBCL), Mantle cell lymphoma (MCL), Waldenstrom Macroglobulinemia (WM), lymphoblastic lymphoma, Primary Mediastinal Large B-Cell Lymphoma (PMBCL), Marginal Zone B-cell Lymphoma (MZL) or Burkitt lymphoma. In some embodiments, the B-cell lymphoma is a non-Hodgkin lymphoma. In some embodiments, the B-cell lymphoma is a Follicular Lymphoma (FL). In some
embodiment, the B-cell lymphoma is a Diffuse Large B Cell Lymphoma (DLBCL). In some embodiments, the B-cell lymphoma is a Mantle Cell Lymphoma (MCL). As used herein, the term “FL” or “Follicular Lymphoma” refers to the most common type of low-grade non-Hodgkin lymphoma. Under a microscope, FL is characterised by tumour cells that appear in a circular, or clump-like, pattern. As used herein, the term “DLBCL” or “Diffuse Large B Cell Lymphoma” is a non- Hodgkin lymphoma developed from B lymphocytes, where B cells are abnormally larger than normal and healthy B cells. DLBCL is the most common form of adult lymphoma worldwide. As example, a DLBCL may be diagnosed with an excisional biopsy of an abnormal lymph node, the excisional biopsy showing a disrupted structural integrity of the lymph node architecture with large cells. As used herein, the term “MCL” or “Mantle Cell Lymphoma” is a non-Hodgkin lymphoma that arises from cells originating in the mantle zone. The mantle zone is the outer ring of small lymphocytes surrounding the center of a lymphatic nodule. In some embodiments, the B-cell lymphoma is resistant to a CD20 inhibitor. In a more particular embodiment, the B-cell lymphoma is resistant to an anti-CD20 monoclonal antibody. As example, anti-CD20 monoclonal antibodies include, but are not limited to, Rituximab (Roche), Ocrelizumab (Roche), Obinutuzumab (Roche), Ibritumomab (Bayer Schering), Ofatumumab (HuMax-CD20, Gemnab), Ublituximab (TG Therapeutics), IMMU-106 (Immunomedics), AME-133v (Applied Molecular Evolution), TRU-015 (Trubion) or Tositumomab (GlaxoSmithKline). In some embodiments, the anti-CD20 antibody is Obinutuzumab. In some embodiments, the anti-CD20 monoclonal antibody is rituximab. Thus, in some embodiments, the B-cell lymphoma is resistant to rituximab. In some embodiments, the B-cell lymphoma is resistant to a chemotherapy. According to this embodiment, the B-cell lymphoma is a chemoresistant lymphoma. As used herein, the term "chemoresistant” refers to the clinical situation in a subject suffering from a lymphoma when the proliferation of cancer cells cannot be prevented or inhibited by means of a chemotherapeutic agent or a combination of chemotherapeutic agents usually used to treat lymphoma, at an acceptable dose for the subject. The lymphoma can be intrinsically resistant
prior to chemotherapy, or resistance may be acquired during treatment of lymphoma that is initially sensitive to chemotherapy. As used herein, the term "chemotherapeutic agent" refers to any chemical agent with therapeutic usefulness in the treatment of cancer, in particular B-cell lymphoma. Chemotherapeutic agents as used herein encompass both chemical and biological agents. These agents function to inhibit a cellular activity upon which the cancer cell depends for continued survival. Categories of chemotherapeutic agents include alkylating/alkaloid agents, antimetabolites, hormones or hormone analogs, and miscellaneous antineoplastic drugs. Most if not all of these drugs are directly toxic to cancer cells and do not require immune stimulation. Suitable chemotherapeutic agents are described, for example, in Slapak and Kufe, Principles of Cancer Therapy, Chapter 86 in Harrison's Principles of Internal medicine, 14th edition; Perry et al, Chemotherapeutic, Ch 17 in Abeloff, Clinical Oncology 2nd ed., 2000 ChrchillLivingstone, Inc.; Baltzer L. and Berkery R. (eds): Oncology Pocket Guide to Chemotherapeutic, 2nd ed. St. Louis, mosby-Year Book, 1995; Fischer D. S., Knobf M. F., Durivage HJ. (eds): The Cancer Chemotherapeutic Handbook, 4th ed. St. Louis, Mosby-Year Handbook. In some embodiments the chemotherapeutic agent is cytarabine (cytosine arabinoside, Ara-C, Cytosar-U), quizartinib (AC220), sorafenib (BAY 43-9006), lestaurtinib (CEP-701), midostaurin (PKC412), carboplatin, carmustine, chlorambucil, dacarbazine, ifosfamide, lomustine, mechlorethamine, procarbazine, pentostatin, (2'deoxycoformycin), etoposide, teniposide, topotecan, vinblastine, vincristine, paclitaxel, dexamethasone, methylprednisolone, prednisone, all-trans retinoic acid, arsenic trioxide, interferon-alpha, rituximab (Rituxan®), gemtuzumab ozogamicin, imatinib mesylate, Cytosar-U), melphalan, busulfan (Myleran®), thiotepa, bleomycin, platinum (cisplatin), cyclophosphamide, Cytoxan®), daunorubicin, doxorubicin, idarubicin, mitoxantrone, 5-azacytidine, cladribine, fludarabine, hydroxyurea, 6-mercaptopurine, methotrexate, 6-thioguanine, or any combination thereof. In some embodiments, the B-cell lymphoma is resistant to an anti-CD20 monoclonal antibody combined with a chemotherapy. In some embodiments, the B-cell lymphoma is resistant to a chemotherapy comprising at least one selected in the group consisting in cyclophosphamide, doxorubicin, vincristine and prednisone. In some embodiments, the B-cell lymphoma is resistant to R-CHOP therapy. As used herein, the term “R-CHOP” refers to a therapy consisting essentially in rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone. In some embodiments, the R-
CHOP therapy consists in rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone. As used herein, the term “CD39” has its general meaning in the art and refers to the CD39 protein, also named as EctoNucleoside TriphosPhate Diphosphohydrolase-1 (ENTPD1). CD39 is an ectoenzyme that hydrolyzes ATP/UTP and ADP/UDP to AMP. CD39 is encoded by ENTPD1 gene (Entre Gene: 953; Ensembl: ENSG00000138185). An exemplary amino acid sequence for CD39 is represented in SEQ ID NO:1. SEQ ID NO:1 >sp|P49961|ENTP1_HUMAN OS=Homo sapiens OX=9606 GN=ENTPD1 PE=1 SV=1 MEDTKESNVK TFCSKNILAI LGFSSIIAVI ALLAVGLTQN KALPENVKYG IVLDAGSSHT SLYIYKWPAE KENDTGVVHQ VEECRVKGPG ISKFVQKVNE IGIYLTDCME RAREVIPRSQ HQETPVYLGA TAGMRLLRME SEELADRVLD VVERSLSNYP FDFQGARIIT GQEEGAYGWI TINYLLGKFS QKTRWFSIVP YETNNQETFG ALDLGGASTQ VTFVPQNQTI ESPDNALQFR LYGKDYNVYT HSFLCYGKDQ ALWQKLAKDI QVASNEILRD PCFHPGYKKV VNVSDLYKTP CTKRFEMTLP FQQFEIQGIG NYQQCHQSIL ELFNTSYCPY SQCAFNGIFL PPLQGDFGAF SAFYFVMKFL NLTSEKVSQE KVTEMMKKFC AQPWEEIKTS YAGVKEKYLS EYCFSGTYIL SLLLQGYHFT ADSWEHIHFI GKIQGSDAGW TLGYMLNLTN MIPAEQPLST PLSHSTYVFL MVLFSLVLFT VAIIGLLIFH KPSYFWKDMV As used herein, the term “CD39 inhibitor” refers to a molecule that partially or fully blocks, inhibits, or neutralizes a biological activity or expression of CD39. A CD39 inhibitor can be a molecule of any type that interferes with the signalling associated with CD39 in a cell, for example, either by decreasing transcription or translation of CD39-encoding nucleic acid, or by inhibiting or blocking CD39 polypeptide activity, or both. Examples of CD39 inhibitors include, but are not limited to, antisense polynucleotides, interfering RNAs, catalytic RNAs, RNA-DNA chimeras, CD39-specific aptamers, anti-CD39 antibodies, CD39-binding fragments of anti-CD39 antibodies, CD39-binding small molecules, CD39-binding peptides, and other polypeptides that specifically bind CD39 (including, but not limited to, CD39-binding fragments of one or more CD39 ligands, optionally fused to one or more additional domains), such that the interaction between the CD39 inhibitor and CD39 results in a reduction or cessation of CD39 activity or expression. In some embodiments, the CD39 inhibitor is an antibody having specificity for CD39. As used herein, the term "antibody" is thus used to refer to any antibody-like molecule that has an antigen binding region, and this term includes antibody fragments that comprise an antigen binding domain such as Fab', Fab, F(ab')2, single domain antibodies (DABs), TandAbs dimer, Fv, scFv (single chain Fv), dsFv, ds-scFv, Fd, linear antibodies, minibodies, diabodies, bispecific antibody fragments, bibody, tribody (scFv-Fab fusions, bispecific or trispecific,
respectively); sc-diabody; kappa(lamda) bodies (scFv-CL fusions); BiTE (Bispecific T-cell Engager, scFv-scFv tandems to attract T cells); DVD-Ig (dual variable domain antibody, bispecific format); SIP (small immunoprotein, a kind of minibody); SMIP ("small modular immunopharmaceutical" scFv-Fc dimer; DART (ds-stabilized diabody "Dual Affinity ReTargeting"); small antibody mimetics comprising one or more CDRs and the like. The techniques for preparing and using various antibody-based constructs and fragments are well known in the art (see Kabat et al., 1991, specifically incorporated herein by reference). Diabodies, in particular, are further described in EP 404, 097 and WO 93/11161; whereas linear antibodies are further described in Zapata et al. (1995). Antibodies can be fragmented using conventional techniques. For example, F(ab')2 fragments can be generated by treating the antibody with pepsin. The resulting F(ab')2 fragment can be treated to reduce disulfide bridges to produce Fab' fragments. Papain digestion can lead to the formation of Fab fragments. Fab, Fab' and F(ab')2, scFv, Fv, dsFv, Fd, dAbs, TandAbs, ds-scFv, dimers, minibodies, diabodies, bispecific antibody fragments and other fragments can also be synthesized by recombinant techniques or can be chemically synthesized. Techniques for producing antibody fragments are well known and described in the art. For example, each of Beckman et al., 2006; Holliger & Hudson, 2005; Le Gall et al., 2004; Reff & Heard, 2001; Reiter et al., 1996; and Young et al., 1995 further describe and enable the production of effective antibody fragments. The residues in antibody variable domains are conventionally numbered according to a system devised by Kabat et al. This system is set forth in Kabat et al., 1987, in Sequences of Proteins of Immunological Interest, US Department of Health and Human Services, NIH, USA (hereafter “Kabat et al.”). This numbering system is used in the present specification. The Kabat residue designations do not always correspond directly with the linear numbering of the amino acid residues in SEQ ID sequences. The actual linear amino acid sequence may contain fewer or additional amino acids than in the strict Kabat numbering corresponding to a shortening of, or insertion into, a structural component, whether framework or complementarity determining region (CDR), of the basic variable domain structure. The correct Kabat numbering of residues may be determined for a given antibody by alignment of residues of homology in the sequence of the antibody with a “standard” Kabat numbered sequence. The CDRs of the heavy chain variable domain are located at residues 31-35B (H- - 9 - CDR1), residues 50-65 (H-CDR2) and residues 95-102 (H-CDR3) according to the Kabat numbering system. The CDRs of the light chain variable domain are located at residues 24-34 (L-CDR1), residues 50-56 (L-CDR2) and
residues 89-97 (L-CDR3) according to the Kabat numbering system. (http://www.bioinf.org.uk/abs/#cdrdef) In some embodiments, the amino acid residues of the antibody of the invention are numbered according to the IMGT numbering system. The IMGT unique numbering has been defined to compare the variable domains whatever the antigen receptor, the chain type, or the species (Lefranc M.-P., "Unique database numbering system for immunogenetic analysis" Immunology Today, 18, 509 (1997) ; Lefranc M.-P., "The IMGT unique numbering for Immunoglobulins, T cell receptors and Ig-like domains" The Immunologist, 7, 132-136 (1999).; Lefranc, M.-P., Pommié, C., Ruiz, M., Giudicelli, V., Foulquier, E., Truong, L., Thouvenin- Contet, V. and Lefranc, G., "IMGT unique numbering 15 for immunoglobulin and T cell receptor variable domains and Ig superfamily V-like domains" Dev. Comp. Immunol., 27, 55- 77 (2003).). In the IMGT unique numbering, the conserved amino acids always have the same position, for instance cysteine 23, tryptophan 41, hydrophobic amino acid 89, cysteine 104, phenylalanine or tryptophan 118. The IMGT unique numbering provides a standardized delimitation of the framework regions (FR1- 20 IMGT: positions 1 to 26, FR2-IMGT: 39 to 55, FR3-IMGT: 66 to 104 and FR4-IMGT: 118 to 128) and of the complementarity determining regions: CDR1-IMGT: 27 to 38, CDR2-IMGT: 56 to 65 and CDR3-IMGT: 105 to 117. If the CDR3-IMGT length is less than 13 amino acids, gaps are created from the top of the loop, in the following order 111, 112, 110, 113, 109, 114, etc. If the CDR3-IMGT length is more than 13 amino acids, additional positions are created between positions 111 and 112 at the top of the CDR3-IMGT loop in the following order 112.1,111.1, 112.2, 111.2, 112.3, 111.3, etc. (http://www.imgt.org/IMGTScientificChart/Nomenclature/IMGT-FRCDRdefinition.html). As used herein, the term “specificity” refers to the ability of an antibody to detectably bind an epitope presented on an antigen, such as CD39, while having relatively little detectable reactivity with non-CD39 proteins or structures (such as other proteins presented on B-cell lymphoma cells). Specificity can be relatively determined by binding or competitive binding assays, using, e.g., Biacore instruments, as described elsewhere herein. Specificity can be exhibited by, e.g., an about 10:1, about 20:1, about 50:1, about 100:1, 10.000:1 or greater ratio of affinity/avidity in binding to the specific antigen versus nonspecific binding to other irrelevant molecules (in this case the specific antigen is a CD39 polypeptide).
The term affinity , as used herein, means the strength of the binding of an antibody to an epitope. The affinity of an antibody is given by the dissociation constant Kd, defined as [Ab] x [Ag] / [Ab-Ag], where [Ab-Ag] is the molar concentration of the antibody-antigen complex, [Ab] is the molar concentration of the unbound antibody and [Ag] is the molar concentration of the unbound antigen. The affinity constant Ka is defined by 1/Kd. Preferred methods for determining the affinity of mAbs can be found in Harlow, et al., Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1988), Coligan et al., eds., Current Protocols in Immunology, Greene Publishing Assoc. and Wiley Interscience, N.Y., (1992, 1993), and Muller, Meth. Enzymol. 92:589-601 (1983), which references are entirely incorporated herein by reference. One preferred and standard method well known in the art for determining the affinity of mAbs is the use of Biacore instruments. In natural antibodies, two heavy chains are linked to each other by disulfide bonds and each heavy chain is linked to a light chain by a disulfide bond. There are two types of light chain, lambda (l) and kappa (k). There are five main heavy chain classes (or isotypes) which determine the functional activity of an antibody molecule: IgM, IgD, IgG, IgA and IgE. Each chain contains distinct sequence domains. The light chain includes two domains, a variable domain (VL) and a constant domain (CL). The heavy chain includes four domains, a variable domain (VH) and three constant domains (CH1, CH2 and CH3, collectively referred to as CH). The variable regions of both light (VL) and heavy (VH) chains determine binding recognition and specificity to the antigen. The constant region domains of the light (CL) and heavy (CH) chains confer important biological properties such as antibody chain association, secretion, trans-placental mobility, complement binding, and binding to Fc receptors (FcR). The Fv fragment is the N-terminal part of the Fab fragment of an immunoglobulin and consists of the variable portions of one light chain and one heavy chain. The specificity of the antibody resides in the structural complementarity between the antibody combining site and the antigenic determinant. Antibody combining sites are made up of residues that are primarily from the hypervariable or complementarity determining regions (CDRs). Occasionally, residues from nonhypervariable or framework regions (FR) influence the overall domain structure and hence the combining site. Complementarity Determining Regions or CDRs refer to amino acid sequences which together define the binding affinity and specificity of the natural Fv region of a native immunoglobulin binding site. The light and heavy chains of an immunoglobulin each have three CDRs, designated L-CDR1, L-CDR2, L-CDR3 and H-CDR1, H-CDR2, H-CDR3, respectively. An antigen-binding site, therefore, includes six CDRs, comprising the CDR set
from each of a heavy and a light chain V region. Framework Regions (FRs) refer to amino acid sequences interposed between CDRs. The term “Fab” denotes an antibody fragment having a molecular weight of about 50,000Da and antigen binding activity, in which about a half of the N-terminal side of H chain and the entire L chain, among fragments obtained by treating IgG with a protease, papaine, are bound together through a disulfide bond. The term “F(ab')2” refers to an antibody fragment having a molecular weight of about 100,000Da and antigen binding activity, which is slightly larger than the Fab bound via a disulfide bond of the hinge region, among fragments obtained by treating IgG with a protease, pepsin. The term “Fab' “ refers to an antibody fragment having a molecular weight of about 50,000 and antigen binding activity, which is obtained by cutting a disulfide bond of the hinge region of the F(ab')2. A single chain Fv (“scFv”) polypeptide is a covalently linked VH::VL heterodimer which is usually expressed from a gene fusion including VH and VL encoding genes linked by a peptide-encoding linker. “dsFv” is a VH::VL heterodimer stabilised by a disulfide bond. Divalent and multivalent antibody fragments can form either spontaneously by association of monovalent scFvs, or can be generated by coupling monovalent scFvs by a peptide linker, such as divalent sc(Fv)2. The term "diabodies" refers to small antibody fragments with two antigen-binding sites, which fragments comprise a heavy-chain variable domain (VH) connected to a light-chain variable domain (VL) in the same polypeptide chain (VH-VL). By using a linker that is too short to allow pairing between the two domains on the same chain, the domains are forced to pair with the complementary domains of another chain and create two antigen-binding sites. Monoclonal antibodies may be generated using the method of Kohler and Milstein (Nature, 256:495, 1975). To prepare monoclonal antibodies useful in the invention, a mouse or other appropriate host animal is immunized at suitable intervals (e.g., twice-weekly, weekly, twice-monthly or monthly) with the appropriate antigenic forms (i.e. CD39 or cell that express CD39). Following the immunization regimen, lymphocytes are isolated from the spleen, lymph node or other organ of the animal and fused with a suitable myeloma cell line using an agent such as polyethylene glycol to form a hydridoma. Following fusion, cells are placed in media permissive for growth of hybridomas but not the fusion partners using standard methods. Following culture of the hybridomas, cell supernatants are analyzed for the presence of antibodies of the desired specificity, i.e., that selectively bind the antigen. Suitable analytical
techniques include ELISA, flow cytometry, immunoprecipitation, and western blotting. Other screening techniques are well-known in the field. Preferred techniques are those that confirm binding of antibodies to conformationally intact, natively folded antigen, such as non- denaturing ELISA, flow cytometry, and immunoprecipitation. Significantly, as is well-known in the art, only a small portion of an antibody molecule, the paratope, is involved in the binding of the antibody to its epitope (see, in general, Clark, W. R. (1986) The Experimental Foundations of Modern Immunology Wiley & Sons, Inc., New York; Roitt, I. (1991) Essential Immunology, 7th Ed., Blackwell Scientific Publications, Oxford). The Fc' and Fc regions, for example, are effectors of the complement cascade but are not involved in antigen binding. An antibody from which the pFc' region has been enzymatically cleaved, or which has been produced without the pFc' region, designated an F(ab')2 fragment, retains both of the antigen binding sites of an intact antibody. Similarly, an antibody from which the Fc region has been enzymatically cleaved, or which has been produced without the Fc region, designated as Fab fragment, retains one of the antigen binding sites of an intact antibody molecule. Proceeding further, Fab fragments consist of a covalently bound antibody light chain and a portion of the antibody heavy chain denoted Fd. The Fd fragments are the major determinant of antibody specificity (a single Fd fragment may be associated with up to ten different light chains without altering antibody specificity) and Fd fragments retain epitope-binding ability in isolation. In some embodiments, the antibody is a humanized antibody. As used herein, "humanized" describes antibodies wherein some, most or all of the amino acids outside the CDR regions are replaced with corresponding amino acids derived from human immunoglobulin molecules. Methods of humanization include, but are not limited to, those described in U.S. Pat. Nos. 4,816,567, 5,225,539, 5,585,089, 5,693,761, 5,693,762 and 5,859,205, which are hereby incorporated by reference. In some embodiments, the antibody is a fully human antibody. Fully human monoclonal antibodies also can be prepared by immunizing mice transgenic for large portions of human immunoglobulin heavy and light chain loci. See, e.g., U.S. Pat. Nos. 5,591,669, 5,598,369, 5,545,806, 5,545,807, 6,150,584, and references cited therein, the contents of which are incorporated herein by reference. These animals have been genetically modified such that there is a functional deletion in the production of endogenous (e.g., murine) antibodies. The animals are further modified to contain all or a portion of the human germ-line immunoglobulin gene locus such that immunization of these animals will result in the production of fully human
antibodies to the antigen of interest. Following immunization of these mice (e.g., XenoMouse (Abgenix), HuMAb mice (Medarex/GenPharm)), monoclonal antibodies can be prepared according to standard hybridoma technology. These monoclonal antibodies will have human immunoglobulin amino acid sequences and therefore will not provoke human anti-mouse antibody (KAMA) responses when administered to humans. In vitro methods also exist for producing human antibodies. These include phage display technology (U.S. Pat. Nos.5,565,332 and 5,573,905) and in vitro stimulation of human B cells (U.S. Pat. Nos. 5,229,275 and 5,567,610). The contents of these patents are incorporated herein by reference. The antibody of the present invention may be of any isotype. The choice of isotype typically will be guided by the desired effector functions, such as ADCC induction. Exemplary isotypes are IgGl, IgG2, IgG3, and IgG4. Either of the human light chain constant regions, kappa or lambda, may be used. If desired, the class of a human monoclonal antibody of the present invention may be switched by known methods. Typical, class switching techniques may be used to convert one IgG subclass to another, for instance from IgG1 to IgG2. Thus, the effector function of the human monoclonal antibodies of the present invention may be changed by isotype switching to, e.g., an IgGl, IgG2, IgG3, IgG4, IgD, IgA, IgE, or IgM antibody for various therapeutic uses. In some embodiments, the antibody of the present invention is a full- length antibody. In some embodiments, the full-length antibody is an IgG1 antibody. In some embodiments, the full-length antibody is an IgG4 antibody. In some embodiments, the specific IgG4 antibody is a stabilized IgG4 antibody. Examples of suitable stabilized IgG4 antibodies are antibodies wherein arginine at position 409 in a heavy chain constant region of human IgG4, which is indicated in the EU index as in Kabat et al. supra, is substituted with lysine, threonine, methionine, or leucine, preferably lysine (described in WO2006/033386) and/or wherein the hinge region comprises a Cys-Pro-Pro-Cys sequence. Other suitable stabilized IgG4 antbodies are disclosed in WO2008145142, which is hereby incorporated by reference in its entirety. In some embodiments, the human monoclonal antibody of the present invention is an antibody of a non-IgG4 type, e.g. IgGl, IgG2 or IgG3 which has been mutated such that the ability to mediate effector functions, such as ADCC, has been reduced or even eliminated. Such mutations have e.g. been described in Dall'Acqua WF et al., J Immunol. 177(2): 1129-1138 (2006) and Hezareh M, J Virol.75(24): 12161-12168 (2001). Monoclonal antibodies that are CD39 inhibitors are well known in the art and includes as example those described in the international patent applications WO2009/095478,
WO2012/085132, WO2016/073845, WO2019/027935, WO2021/055329, WO2021/056610, WO2022/111576. As example, antibodies having specificity for CD39 includes, but are not limited to, TTX-030 (Trishula Therapeutics), TTX-030-001 (Trishula Therapeutics), TTX-030- 002 (Trishula Therapeutics), IPH52 (Innate Pharma), IPH5201 (Innate Pharma), OREG- 103/BY40 (Orega Biotech), BA54g (Orega Biotech), BY12 (Orega Biotech), SRF370 (Surface Oncology), SRF365 (Surface Oncology), SRF367 (Surface Oncology), SRF617 (Surface Oncology), 9-8B (Igenica Therapeutics), ES014 (Elpiscience Biopharma), ES002 (Elpiscience Biopharma), ES002023 (Elpiscience Biopharma), EMB04 (EpimAb Biotherapeutics) or AB598 (Arcus Biosciences). In some embodiments, the antibody having specificity for CD39 is TTX-030, IPH5201, BY40, BA54g, BY12, SRF617, 9-8B, ES002023 or ES014. In some embodiments, the VH region of the TTX-030 antibody consists in the sequence of SEQ ID NO:2. According to this embodiment, the VH-CDR1 of the TTX-030 antibody is defined by SEQ ID NO:3 (SYEMH), the VH-CDR2 of the TTX-030 antibody is defined by SEQ ID NO:4 (RINPSVGSTWYAQKFQG) and the VH-CDR3 of the TTX-030 antibody is defined by SEQ ID NO:5 (GKREGGTEYLRK). SEQ ID NO: 2 > VH domain of TTX-030 (FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4) QVQLVQSGAEVKKPGASVKVSCKASGYTFKSYEMHWVRQAPGQGLEWMGRINPSVGSTWYAQKFQGRVT MTRDTSTSTVYMELSSLRSEDTAVYYCARGKREGGTEYLRKWGQGTLVTVSS In some embodiments, the VL region of the TTX-030 antibody consists of the sequence of SEQ ID NO:6. According to this embodiment, the VL-CDR1 of TTX-030 antibody is defined by SEQ ID NO:7 (RASQSVASSYLA), the VL-CDR2 of the TTX-030 antibody is defined by SEQ ID NO:8 (GASNRHT) and the VL-CDR3 of the TTX-030 antibody is defined by SEQ ID NO:9 (QQYHNAIT). SEQ ID NO: 6 > VL domain of TTX-030 (FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4) EIVLTQSPGTLSLSPGERATLSCRASQSVASSYLAWYQQKPGQAPRLLIYGASNRHTGIPDRFSGSGSG TDFTLTISRLEPEDFAVYYCQQYHNAITFGGGTKVEIK In some embodiments, the VH region of the IPH52 antibody consists in the sequence of SEQ ID NO:10. According to this embodiment, the VH-CDR1 of IPH52 antibody is defined by SEQ ID NO:11 (DYNMH), the VH-CDR2 of the IPH52 antibody is defined by SEQ ID NO:12 (YIVPLNGGSTFNQKFKG) and the VH-CDR3 of the IPH52 antibody is defined by SEQ ID NO:13 (GGTRFAY).
SEQ ID NO: 10 > VH domain of IPH52 (FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4) EVQLQQSGPELVKPGASVKMSCKASGYTFTDYNMHWVKQSHGRTLEWIGYIVPLNGGSTFNQKFKGRA TLTVNTSSRTAYMELRSLTSEDSAAYYCARGGTRFAYWGQGTLVTVSA In some embodiments, the VL region of the IPH52 antibody consists of the sequence of SEQ ID NO:14. According to this embodiment, the VL-CDR1 of the IPH52 antibody is defined by SEQ ID NO:15 (RASESVDNFGVSFMY), the VL-CDR2 of the IPH52 antibody is defined by SEQ ID NO:16 (GASNQGS) and the VL-CDR3 of the IPH52 antibody is defined by SEQ ID NO:17 (QQTKEVPYT). SEQ ID NO: 14 > VL domain of IPH52 (FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4) DIVLTQSPASLAVSLGQRATISCRASESVDNFGVSFMYWFQQKPGQPPNLLIYGASNQGSGVPARFRGS GSGTDFSLNIHPMEADDTAMYFCQQTKEVPYTFGGGTKLEIK In some embodiments, the VH region of the SRF617 antibody consists in the sequence of SEQ ID NO:18. According to this embodiment, the VH-CDR1 of the SRF617 antibody is defined by SEQ ID NO:19 (GTFSSEGIS), the VH-CDR2 of the SRF617 antibody is defined by SEQ ID NO:20 (SILPIFGTANYAQKFQG) and the VH-CDR3 of the SRF617 antibody is defined by SEQ ID NO:21 (AREAGYYRYRYFDL). SEQ ID NO: 18 > VH domain of SRF617 (FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4) QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSEGISWVRQAPGQGLEWMGSILPIFGTANYAQKFQGRVT ITADESTSTAYMELSSLRSEDTAVYYCAREAGYYRYRYFDLWGKGTLVTVSS In some embodiments, the VL region of the SRF617 antibody consists of the sequence of SEQ ID NO:22. According to this embodiment, the VL-CDR1 of the SRF617 antibody is defined by SEQ ID NO:23 (RASQSVSSNLA), the VL-CDR2 of the SRF617 antibody is defined by SEQ ID NO:24 (GASTRAT) and the VL-CDR3 of the SRF617 antibody is defined by SEQ ID NO:25 (QQHALWPLT). SEQ ID NO: 22 > VL domain of SRF617 (FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4) EIVMTQSPATLSVSPGERATLSCRASQSVSSNLAWYQQKPGQAPRLLIYGASTRATGIPARFSGSGSGT EFTLTISSLQSEDFAVYYCQQHALWPLTFGGGTKVEIK In some embodiments, the VH region of the BY40 antibody consists in the sequence of SEQ ID NO:26. According to this embodiment, the VH-CDR1 of the BY40 antibody is defined
by SEQ ID NO:27 (GYTFTHYG), the VH-CDR2 of the BY40 antibody is defined by SEQ ID NO:28 (INTYTGEP) and the VH-CDR3 of the BY40 antibody is defined by SEQ ID NO:29 (ARRRYEGNYVFYYFDYWGQGTTLTVSS). SEQ ID NO: 26 > VH domain of BY40 (FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4) TRVKKPRETVKISCKASGYTFTHYGMNWVKQAPGKGLKWMGWINTYTGEPTYADDFKGRFAFSLEASVS TAYLQINNLKNEDTATYFCARRRYEGNYVFYYFDYWGQGTTLTVSSAKTTPPSVYPLAPGSAAQTNSMV TLGCLVKGYFPEQVTVTWNSGSLSSGVHTFPAVLQSDLYTLSSSVTVPS In some embodiments, the VL region of the BY40 antibody consists of the sequence of SEQ ID NO:30. According to this embodiment, the VL-CDR1 of the BY40 antibody is defined by SEQ ID NO:31 (RASENIYSYFS), the VL-CDR2 of the BY40 antibody is defined by SEQ ID NO:32 (TAKTLAE) and the VL-CDR3 of the BY40 antibody is defined by SEQ ID NO:33 (QHHYVTPYTFGGGTKLEIKR). SEQ ID NO:30 > VL domain of BY40 (FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4) DIQMTGSPASLSASVGETVTITCRASENIYSYFSWYQQKQGKSPQLLVYTAKTLAEGVPSRFSGSGSGT QFSLKINSLQPEDFGSYYCQHHYVTPYTFGGGTKLEIKRADAAPTVSIFPPSSEQLTSGGASVVCFLNN FYPKDINVKWKIDGSERQNGVLNSWTD In some embodiments, the VH region of the BA54g antibody consists in the sequence of SEQ ID NO:34. According to this embodiment, the VH-CDR1 of the BA54g antibody is defined by SEQ ID NO:35 (GGSRKLSCAASGFTFSSFGMH), the VH-CDR2 of the BA54g antibody is defined by SEQ ID NO:36 (YISSGSSIIYYADTVKG) and the VH-CDR3 of the BA54g antibody is defined by SEQ ID NO:37 (WSTTVVATDYWGQGTTLTVS). SEQ ID NO: 34 > VH domain of BA54g (FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4) DVQLVESGGGLVQPGGSRKLSCAASGFTFSSFGMHWVRQAPEKGLEWVAYISSGSSIIYYADTVKGRFT ISRDNPKNTLFLQMTSLGSEDTAMYYCARWSTTVVATDYWGQGTTLTVS In some embodiments, the VL region of the BA54g antibody consists of the sequence of SEQ ID NO:38. According to this embodiment, the VL-CDR1 of the BA54g antibody is defined by SEQ ID NO:39 (KASENVVTYVS), the VL-CDR2 of the BA54g antibody is defined by SEQ ID NO:40 (GASNRYT) and the VL-CDR3 of the BA54g antibody is defined by SEQ ID NO:41 (CGQGYSYPYTFGGGTKLEIKR).
SEQ ID NO:38 > VL domain of BA54g (FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4) NIVMTQSPKSMSMSVGERVTLTCKASENVVTYVSWYQQKPEQSPKLLIYGASNRYTGVPDRFTGSGSAT DFTLTISSVQAEDLADYHCGQGYSYPYTFGGGTKLEIKR In some embodiments, the VH region of the 9-8B antibody consists in the sequence of SEQ ID NO:42. According to this embodiment, the VH-CDR1 of the 9-8B antibody is defined by SEQ ID NO:43 (HYGMN), the VH-CDR2 of the 9-8B antibody is defined by SEQ ID NO:44 (WINTYTGELTYADDFKG) and the VH-CDR3 of the 9-8B antibody is defined by SEQ ID NO:45 (RAYYRYDYVMDY). SEQ ID NO: 42 > VH domain of 9-8B (FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4) QIQLVQSGPELKKPGETVKISCKASGYTFTHYGMNWVKQAPGKGLKWMGWINTYTGELTYADDFKGRFA FSLETSASTAYLQINNLKNEDTATYFCARRAYYRYDYVMDYWGQGTSVTVSS In some embodiments, the VL region of the 9-8B antibody consists of the sequence of SEQ ID NO:46. According to this embodiment, the VL-CDR1 of the 9-8B antibody is defined by SEQ ID NO:47 (KASHNVGTNVA), the VL-CDR2 of the 9-8B antibody is defined by SEQ ID NO:48 (SASYRYS) and the VL-CDR3 of the 9-8B antibody is defined by SEQ ID NO:49 (HQYNNYPYT). SEQ ID NO: 46 > VL domain of 9-8B (FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4) DIVMTQSQKFMSTSVGDRVSVTCKASHNVGTNVAWYQQKPGQSPKALIYSASYRYSGVPGRFTGSGSGT DFTLTISNVQSEDLAEYFCHQYNNYPYTFGGGTKLEIK In some embodiments, the antibody of the present invention is a single chain antibody. As used herein the term “single domain antibody” has its general meaning in the art and refers to the single heavy chain variable domain of antibodies of the type that can be found in Camelid mammals which are naturally devoid of light chains. Such single domain antibody are also “nanobody®”. For a general description of (single) domain antibodies, reference is also made to the prior art cited above, as well as to EP 0368684, Ward et al. (Nature 1989 Oct 12; 341 (6242): 544-6), Holt et al., Trends Biotechnol., 2003, 21(11):484-490; and WO 06/030220, WO 06/003388. The amino acid sequence and structure of a single domain antibody can be considered to be comprised of four framework regions or "FRs" which are referred to in the art and herein as "Framework region 1" or "FRl "; as "Framework region 2" or "FR2"; as "Framework region 3 " or "FR3"; and as "Framework region 4" or “FR4” respectively; which framework regions are interrupted by three complementary determining regions or "CDRs", which are referred to in the art as "Complementarity Determining Region for "CDRl”; as
Complementarity Determining Region 2 or CDR2 and as Complementarity Determining Region 3" or "CDR3", respectively. Accordingly, the single domain antibody can be defined as an amino acid sequence with the general structure: FRl - CDRl - FR2 - CDR2 - FR3 - CDR3 - FR4 in which FRl to FR4 refer to framework regions 1 to 4 respectively, and in which CDRl to CDR3 refer to the complementarity determining regions 1 to 3. In some embodiments, the antibody leads to the depletion of CD39 expressing cancer cells. As used herein, the term “depletion” with respect to cancer cells, refers to a measurable decrease in the number of CD39 expressing cancer cells in the patient. The reduction can be at least about 10%, e.g., at least about 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or more. In some embodiments, the term refers to a decrease in the number of CD39 cancer cells in the patient below detectable limits. In some embodiments, the antibody suitable for depletion of CD39 cancer cells mediates antibody-dependant cell-mediated cytotoxicity. As used herein the term “antibody-dependent cell-mediated cytotoxicity” or “ADCC” refer to a cell-mediated reaction in which non-specific cytotoxic cells (e.g., T gamma delta lymphocytes, Natural Killer (NK) cells, neutrophils, and macrophages) recognize bound antibody on a target cell and subsequently cause lysis of the target cell. While not wishing to be limited to any particular mechanism of action, these cytotoxic cells that mediate ADCC generally express Fc receptors (FcRs). In some embodiments, the CD39 inhibitor is an inhibitor of CD39 expression. An “inhibitor of expression” refers to a natural or synthetic compound that has a biological effect to inhibit the expression of a gene. In a preferred embodiment of the invention, said inhibitor of gene expression is a siRNA, an antisense oligonucleotide or a ribozyme. For example, anti- sense oligonucleotides, including anti-sense RNA molecules and anti-sense DNA molecules, would act to directly block the translation of CD39 mRNA by binding thereto and thus preventing protein translation or increasing mRNA degradation, thus decreasing the level of CD39, and thus activity, in a cell. For example, antisense oligonucleotides of at least about 15 bases and complementary to unique regions of the mRNA transcript sequence encoding CD39 can be synthesized, e.g., by conventional phosphodiester techniques. Methods for using antisense techniques for specifically inhibiting gene expression of genes whose sequence is known are well known in the art (e.g. see U.S. Pat. Nos. 6,566,135; 6,566,131; 6,365,354; 6,410,323; 6,107,091; 6,046,321; and 5,981,732). Small inhibitory RNAs (siRNAs) can also
function as inhibitors of expression in the method of the present invention. CD39 gene expression can be reduced by contacting a subject or cell with a small double stranded RNA (dsRNA), or a vector or construct causing the production of a small double stranded RNA, such that CD39 gene expression is specifically inhibited (i.e. RNA interference or RNAi). Antisense oligonucleotides, siRNAs, shRNAs and ribozymes of the invention may be delivered in vivo alone or in association with a vector. In its broadest sense, a "vector" is any vehicle capable of facilitating the transfer of the antisense oligonucleotide, siRNA, shRNA or ribozyme nucleic acid to the cells and typically cells expressing CD39. Typically, the vector transports the nucleic acid to cells with reduced degradation relative to the extent of degradation that would result in the absence of the vector. In general, the vectors useful in the invention include, but are not limited to, plasmids, phagemids, viruses, other vehicles derived from viral or bacterial sources that have been manipulated by the insertion or incorporation of the antisense oligonucleotide, siRNA, shRNA or ribozyme nucleic acid sequences. Viral vectors are a preferred type of vector and include, but are not limited to nucleic acid sequences from the following viruses: retrovirus, such as moloney murine leukemia virus, harvey murine sarcoma virus, murine mammary tumor virus, and rous sarcoma virus; adenovirus, adeno-associated virus; SV40-type viruses; polyoma viruses; Epstein-Barr viruses; papilloma viruses; herpes virus; vaccinia virus; polio virus; and RNA virus such as a retrovirus. One can readily employ other vectors not named but known to the art. By a "therapeutically effective amount" of the inhibitor as above described is meant a sufficient amount to provide a therapeutic effect. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed, the age, body weight, general health, sex and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidential with the specific polypeptide employed; and like factors well known in the medical arts. For example, it is well within the skill of the art to start doses of the compound at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. However, the daily dosage of the products may be varied over a wide range from 0.01 to 1,000 mg per adult per day. Typically,
the compositions contain 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 250 and 500 mg of the active ingredient for the symptomatic adjustment of the dosage to the subject to be treated. A medicament typically contains from about 0.01 mg to about 500 mg of the active ingredient, preferably from 1 mg to about 100 mg of the active ingredient. An effective amount of the drug is ordinarily supplied at a dosage level from 0.0002 mg/kg to about 20 mg/kg of body weight per day, especially from about 0.001 mg/kg to 7 mg/kg of body weight per day. Typically, the inhibitor of the present invention is combined with pharmaceutically acceptable excipients, and optionally sustained-release matrices, such as biodegradable polymers, to form pharmaceutical compositions. "Pharmaceutically" or "pharmaceutically acceptable" refer to molecular entities and compositions that do not produce an adverse, allergic or other untoward reaction when administered to a mammal, especially a human, as appropriate. A pharmaceutically acceptable carrier or excipient refers to a non-toxic solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. Typically, the pharmaceutical compositions contain vehicles, which are pharmaceutically acceptable for a formulation capable of being injected. These may be in particular isotonic, sterile, saline solutions (monosodium or disodium phosphate, sodium, potassium, calcium or magnesium chloride and the like or mixtures of such salts), or dry, especially freeze-dried compositions which upon addition, depending on the case, of sterilized water or physiological saline, permit the constitution of injectable solutions. The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions; formulations including sesame oil, peanut oil or aqueous propylene glycol; and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi. Sterile injectable solutions are prepared by incorporating the inhibitor at the required amount in the appropriate solvent with several of the other ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
As used herein, the term treatment or treat refer to both prophylactic or preventive treatment as well as curative or disease modifying treatment, including treatment of subject at risk of contracting the disease or suspected to have contracted the disease as well as subjects who are ill or have been diagnosed as suffering from a disease or medical condition, and includes suppression of clinical relapse. The treatment may be administered to a subject having a medical disorder or who ultimately may acquire the disorder, in order to prevent, cure, delay the onset of, reduce the severity of, or ameliorate one or more symptoms of a disorder or recurring disorder, or in order to prolong the survival of a subject beyond that expected in the absence of such treatment. By "therapeutic regimen" is meant the pattern of treatment of an illness, e.g., the pattern of dosing used during therapy. A therapeutic regimen may include an induction regimen and a maintenance regimen. The phrase "induction regimen" or "induction period" refers to a therapeutic regimen (or the portion of a therapeutic regimen) that is used for the initial treatment of a disease. The general goal of an induction regimen is to provide a high level of drug to a subject during the initial period of a treatment regimen. An induction regimen may employ (in part or in whole) a "loading regimen", which may include administering a greater dose of the drug than a physician would employ during a maintenance regimen, administering a drug more frequently than a physician would administer the drug during a maintenance regimen, or both. The phrase "maintenance regimen" or "maintenance period" refers to a therapeutic regimen (or the portion of a therapeutic regimen) that is used for the maintenance of a subject during treatment of an illness, e.g., to keep the subject in remission for long periods of time (months or years). A maintenance regimen may employ continuous therapy (e.g., administering a drug at a regular intervals, e.g., weekly, monthly, yearly, etc.) or intermittent therapy (e.g., interrupted treatment, intermittent treatment, treatment at relapse, or treatment upon achievement of a particular predetermined criteria [e.g., pain, disease manifestation, etc.]). The Inventors also herein demonstrate that CD39 inhibition potentiate anti-CD20 monoclonal antibody therapy. Accordingly, in a second aspect, the present invention relates to a method of treating a B-cell lymphoma in a subject in need thereof comprising administering said subject with a CD39 inhibitor and an anti-CD20 monoclonal antibody. In some embodiments, the present invention relates to i) a CD39 inhibitor, and ii) an anti-CD20 monoclonal antibody, as a combined preparation for simultaneous, separate or sequential use in the treatment of a B-cell lymphoma. In particular, the use of the CD39 inhibitor of the present invention is particularly useful to improve anti-CD20 monoclonal antibody efficacy.
Accordingly, in some embodiments, the CD39 inhibitor according to the present invention is particularly suitable for improving anti-CD20 monoclonal antibody efficacy in a subject suffering from a B-cell lymphoma. As example, anti-CD20 monoclonal antibodies include, but are not limited to, Rituximab (Roche), Ocrelizumab (Roche), Obinutuzumab (Roche), Ibritumomab (Bayer Schering), Ofatumumab (HuMax-CD20, Gemnab), Ublituximab (TG Therapeutics), IMMU- 106 (Immunomedics), AME-133v (Applied Molecular Evolution), TRU-015 (Trubion) or Tositumomab (GlaxoSmithKline). In some embodiments, the anti-CD20 antibody is Obinutuzumab. In some embodiments, the B-cell lymphoma is resistant to obinutuzumab. In some embodiments, the anti-CD20 monoclonal antibody is rituximab. Thus, in some embodiments, the B-cell lymphoma is resistant to rituximab. The Inventors also herein demonstrate that CD39 inhibition potentiates anti-PD1 monoclonal antibody therapy. Accordingly, in a third aspect, the present invention relates to a method of treating a B-cell lymphoma in a subject in need thereof comprising administering said subject with a CD39 inhibitor and an anti-PD1 monoclonal antibody. In some embodiments, the present invention relates to a method of treating a B-cell lymphoma in a subject in need thereof comprising administering said subject with a CD39 inhibitor, an anti- PD1 monoclonal antibody and Ibrutinib. In some embodiments, the present invention relates to i) a CD39 inhibitor, and ii) an anti-PD1 monoclonal antibody, as a combined preparation for simultaneous, separate or sequential use in the treatment of a B-cell lymphoma. In particular, the use of the CD39 inhibitor of the present invention is particularly useful to improve anti-PD1 monoclonal antibody efficacy. Accordingly, in some embodiments, the CD39 inhibitor according to the present invention is particularly suitable for improving anti-PD1 monoclonal antibody efficacy in a subject suffering from a B-cell lymphoma. As example, anti-PD1 monoclonal antibodies include, but are not limited to, Pembrolizumab (Merck), Nivolumab (Ono Pharmaceutical), BMS-936559 (Bristol-Myers Squibb), Cemiplimab (Regeneron), Cemiplimab-rwlc (Sanofi), Avelumab (Merck), Durvalumab (AstraZeneca), Atezolizumab (Roche) or Spartalizumab (Novartis). In some embodiments, the anti-PD1 monoclonal antibody is nivolumab. Thus, in some embodiments, the B-cell lymphoma is resistant to nivolumab.
In a more particular aspect, the present invention relates to a method of treating a B-cell lymphoma in a subject in need thereof comprising administering said subject with a CD39 inhibitor, an anti-CD20 monoclonal antibody and an anti-PD1 monoclonal antibody. In some embodiments, the present invention relates to i) a CD39 inhibitor, ii) an anti-CD20 monoclonal antibody and iii) an anti-PD1 monoclonal antibody as a combined preparation for simultaneous, separate or sequential use in the treatment of a B-cell lymphoma. In particular, the use of the CD39 inhibitor of the present invention is particularly useful to improve anti-CD20 monoclonal antibody efficacy and anti-PD1 monoclonal antibody efficacy. Accordingly, in some embodiments, the CD39 inhibitor according to the present invention is particularly suitable for improving anti-CD20 monoclonal antibody efficacy and anti-PD1 monoclonal antibody efficacy in a subject suffering from a B-cell lymphoma. In a more particular aspect, the present invention relates to a method of treating a B-cell lymphoma in a subject in need thereof comprising administering said subject with a CD39 inhibitor and a PDE-4 inhibitor. In some embodiments, the PDE-4 inhibitor is Roflumilast. In some embodiments, the present invention relates to a method of treating a B-cell lymphoma in a subject in need thereof comprising administering said subject with a CD39 inhibitor and a BTK inhibitor. In some embodiments, the BTK inhibitor is Ibrutinib. In some embodiments, the present invention relates to a method of treating a B-cell lymphoma in a subject in need thereof comprising administering said subject with a CD39 inhibitor and a chemotherapy. In some embodiments, the present invention relates to a method of treating a B-cell lymphoma in a subject in need thereof comprising administering said subject with a CD39 inhibitor and at least a chemotherapy. In some embodiments, the B-cell lymphoma is Follicular Lymphoma (FL), Diffuse Large B-cell Lymphoma (DLBCL), Mantle cell lymphoma (MCL), Waldenstrom Macroglobulinemia (WM), lymphoblastic lymphoma, Primary Mediastinal Large B-Cell Lymphoma (PMBCL), Marginal Zone B-cell Lymphoma (MZL) or Burkitt lymphoma. In some embodiments, the B-cell lymphoma is a non-Hodgkin lymphoma. In some embodiments, the B-cell lymphoma is a Follicular Lymphoma (FL). In some embodiment, the B-cell lymphoma is a Diffuse Large B Cell Lymphoma (DLBCL). In some embodiment, the B-cell lymphoma is a Mantle Cell Lymphoma.
As used herein, the term “simultaneous use” denotes the use of the CD39 inhibitor, the anti-CD20 monoclonal antibody and/or the anti-PD1 monoclonal antibody occurring at the same time. As used herein, the term “separate use” denotes the use of the CD39 inhibitor, the anti-CD20 monoclonal antibody and/or the anti-PD1 monoclonal antibody not occurring at the same time. As used herein, the term “sequential use” denotes the use of the CD39 inhibitor, the anti-CD20 monoclonal antibody and/or the anti-PD1 monoclonal antibody occurring by following an order. In some embodiments, the CD39 inhibitor according to the present invention is particularly suitable for preventing B-cell lymphoma relapse. In a more particular aspect, the CD39 inhibitor of the present invention is particularly useful to prevent relapse after putatively successful treatment with anti-CD20 monoclonal antibody (e.g. Rituximab) and/or a chemotherapy (e.g. CHOP). In a more particular aspect, the CD39 inhibitor of the present invention is particularly useful to prevent relapse after putatively successful treatment with anti- PD1 monoclonal antibody (e.g. nivolumab) and/or a chemotherapy. In a more particular aspect, the CD39 inhibitor of the present invention is particularly useful to prevent relapse after putatively successful treatment with a PDE-4 inhibitor. In a more particular aspect, the CD39 inhibitor of the present invention is particularly useful to prevent relapse after putatively successful treatment with a BTK inhibitor. In some embodiments, the CD39 inhibitor according to the present invention is particularly suitable for treating a B-cell lymphoma relapse. Thus, the present invention also relates to a method for preventing relapse of a subject suffering from a B-cell lymphoma comprising administering said subject with a therapeutically effective amount of a CD39 inhibitor. In a more particular embodiment, the present invention also relates to a method for preventing relapse of a subject suffering from a B-cell lymphoma who was treated with anti-CD20 monoclonal antibody and/or a chemotherapy comprising administering said subject with a therapeutically effective amount of a CD39 inhibitor. In a more particular embodiment, the present invention also relates to a method for preventing relapse of a subject suffering from a B-cell lymphoma who was treated with anti-PD1 monoclonal antibody and/or a chemotherapy comprising administering said subject with a therapeutically effective amount of a CD39 inhibitor. In some embodiments, the present invention also relates to a method for preventing relapse of a subject suffering from a B-cell
lymphoma who was treated with anti-CD20 monoclonal antibody comprising administering said subject with a therapeutically effective amount of a CD39 inhibitor. In some embodiments, the present invention also relates to a method for preventing relapse of a subject suffering from a B-cell lymphoma who was treated with anti-PD1 monoclonal antibody comprising administering said subject with a therapeutically effective amount of a CD39 inhibitor. In some embodiments, the anti-CD20 monoclonal antibody is obinutuzumab. In some embodiments, the anti-CD20 monoclonal antibody is a rituximab. In some embodiments the anti-PD1 monoclonal antibody is nivolumab. In some embodiments, the chemotherapy is CHOP therapy. As used herein, the term "relapse" refers to the return of cancer after a period of improvement in which no cancer could be detected. Finally, the Inventors herein demonstrate that ENTPD1 gene expression is correlated with the survival time of a subject suffering from a B-cell lymphoma, in particular follicular lymphoma. Accordingly, in a fourth aspect, the present invention relates to a method for predicting the survival time of a subject suffering from a B-cell lymphoma comprising determining the level of expression of ENTPD1 gene in a sample from said subject. As used herein, the term “sample” refers to any biological sample of a subject and can include, by way of example and not limitation, bodily fluids and/or tissue extracts such as homogenates or solubilized tissue obtained from a subject. Tissue extracts are obtained routinely from tissue biopsy. As example, a biological sample may be a tumor sample, bodily fluids such as blood sample, plasma sample, serum sample, cerebrospinal fluid, pleural effusion, ascetic effusion, urinary sample, saliva sample, or in case of fetus, amniotic fluid or chorionic villy or any other bodily secretion or derivative thereof. In some embodiment, the biological sample is a tumor sample or a bodily fluid sample which may contain cell free DNA/RNA associated tumour (circulating tumour DNA/RNA). In some embodiment, the sample is a lymphatic tissue, bone, cerebrospinal fluid, digestive tract, sinus, testicles, thyroid gland or skin. In some embodiments, the present invention relates to a method for predicting the survival time of subject suffering from a B-cell lymphoma comprising i) determining the expression level of ENTPD1 gene in a sample obtained from a subject ii) comparing the expression level determined at step i) with a predetermined reference value and iii) providing a
good prognosis when the expression level determined at step i) is lower than the predetermined reference value, or providing a bad prognosis when the expression level determined at step i) is higher than the predetermined reference value. In some embodiments, the B-cell lymphoma is Follicular Lymphoma (FL), Diffuse Large B-cell Lymphoma (DLBCL), Mantle cell lymphoma (MCL), Waldenstrom Macroglobulinemia (WM), lymphoblastic lymphoma, Primary Mediastinal Large B-Cell Lymphoma (PMBCL), Marginal Zone B-cell Lymphoma (MZL) or Burkitt lymphoma. In some embodiments, the B-cell lymphoma is a non-Hodgkin lymphoma. In some embodiments, the B-cell lymphoma is a Follicular Lymphoma (FL). In some embodiment, the B-cell lymphoma is a Diffuse Large B Cell Lymphoma (DLBCL). In some embodiments, the B-cell lymphoma is a Mantle Cell Lymphoma (MCL). As used herein, the term “survival time” denotes the percentage of people in a study or treatment group who are still alive for a certain period of time after they were diagnosed with or started treatment for a disease, such as B-cell lymphoma (according to the invention). The survival time rate is often stated as a five-year survival rate, which is the percentage of people in a study or treatment group who are alive five years after their diagnosis or the start of treatment. As used herein and according to the invention, the term “survival time” can regroup the term “Overall survival (OS)”. As used herein, the term “OS” denotes the time from diagnosis of a disease such as B- cell lymphoma (according to the invention) until death from any cause. The overall survival rate is often stated as a two-year survival rate, which is the percentage of people in a study or treatment group who are alive two years after their diagnosis or the start of treatment. Measuring the expression level of CD39 can be done by measuring the gene expression level of CD39 or by measuring the level of the protein CD39 and can be performed by a variety of techniques well known in the art. Typically, the expression level of a gene may be determined by determining the quantity of mRNA. Methods for determining the quantity of mRNA are well known in the art. For example the nucleic acid contained in the samples (e.g., cell or tissue prepared from the patient) is first extracted according to standard methods, for example using lytic enzymes or chemical solutions or extracted by nucleic-acid-binding resins following the manufacturer's instructions. The extracted mRNA is then detected by hybridization (e. g.,
Northern blot analysis, in situ hybridization) and/or amplification (e.g., RT-PCR). Other methods of Amplification include ligase chain reaction (LCR), transcription-mediated amplification (TMA), strand displacement amplification (SDA) and nucleic acid sequence based amplification (NASBA). Nucleic acids having at least 10 nucleotides and exhibiting sequence complementarity or homology to the mRNA of interest herein find utility as hybridization probes or amplification primers. It is understood that such nucleic acids need not be identical, but are typically at least about 80% identical to the homologous region of comparable size, more preferably 85% identical and even more preferably 90-95% identical. In certain embodiments, it will be advantageous to use nucleic acids in combination with appropriate means, such as a detectable label, for detecting hybridization. Typically, the nucleic acid probes include one or more labels, for example to permit detection of a target nucleic acid molecule using the disclosed probes. In various applications, such as in situ hybridization procedures, a nucleic acid probe includes a label (e.g., a detectable label). A “detectable label” is a molecule or material that can be used to produce a detectable signal that indicates the presence or concentration of the probe (particularly the bound or hybridized probe) in a sample. Thus, a labeled nucleic acid molecule provides an indicator of the presence or concentration of a target nucleic acid sequence (e.g., genomic target nucleic acid sequence or mRNA) (to which the labeled uniquely specific nucleic acid molecule is bound or hybridized) in a sample. A label associated with one or more nucleic acid molecules (such as a probe generated by the disclosed methods) can be detected either directly or indirectly. A label can be detected by any known or yet to be discovered mechanism including absorption, emission and/ or scattering of a photon (including radio frequency, microwave frequency, infrared frequency, visible frequency and ultra-violet frequency photons). Detectable labels include colored, fluorescent, phosphorescent and luminescent molecules and materials, catalysts (such as enzymes) that convert one substance into another substance to provide a detectable difference (such as by converting a colorless substance into a colored substance or vice versa, or by producing a precipitate or increasing sample turbidity), haptens that can be detected by antibody binding interactions, and paramagnetic and magnetic molecules or materials. Particular examples of detectable labels include fluorescent molecules (or fluorochromes). Numerous fluorochromes are known to those skilled in the art, and can be selected, for example from Life Technologies (formerly Invitrogen), e.g., see, The Handbook— A Guide to Fluorescent Probes and Labeling Technologies). Examples of particular fluorophores that can be attached (for example, chemically conjugated) to a nucleic acid
molecule (such as a uniquely specific binding region) are provided in U.S. Pat. No.5,866, 366 to Nazarenko et al., such as 4-acetamido-4'-isothiocyanatostilbene-2,2' disulfonic acid, acridine and derivatives such as acridine and acridine isothiocyanate, 5-(2'-aminoethyl) aminonaphthalene-1-sulfonic acid (EDANS), 4-amino -N- [3 vinylsulfonyl)phenyl]naphthalimide-3,5 disulfonate (Lucifer Yellow VS), N-(4-anilino-1- naphthyl)maleimide, antl1ranilamide, Brilliant Yellow, coumarin and derivatives such as coumarin, 7-amino-4-methylcoumarin (AMC, Coumarin 120), 7-amino-4- trifluoromethylcouluarin (Coumarin 151); cyanosine; 4',6-diarninidino-2-phenylindole (DAPI); 5',5"dibromopyrogallol-sulfonephthalein (Bromopyrogallol Red); 7 -diethylamino -3 - (4'-isothiocyanatophenyl)-4-methylcoumarin; diethylenetriamine pentaacetate; 4,4'- diisothiocyanatodihydro-stilbene-2,2'-disulfonic acid; 4,4'-diisothiocyanatostilbene-2,2'- disulfor1ic acid; 5-[dimethylamino] naphthalene-1-sulfonyl chloride (DNS, dansyl chloride); 4-(4'-dimethylaminophenylazo)benzoic acid (DABCYL); 4-dimethylaminophenylazophenyl- 4'-isothiocyanate (DABITC); eosin and derivatives such as eosin and eosin isothiocyanate; erythrosin and derivatives such as erythrosin B and erythrosin isothiocyanate; ethidium; fluorescein and derivatives such as 5-carboxyfluorescein (FAM), 5-(4,6dicl1lorotriazin-2- yDarninofluorescein (DTAF), 2'7'dimethoxy-4'5'-dichloro-6-carboxyfluorescein (JOE), fluorescein, fluorescein isothiocyanate (FITC), and QFITC Q(RITC); 2',7'-difluorofluorescein (OREGON GREEN®); fluorescamine; IR144; IR1446; Malachite Green isothiocyanate; 4- methylumbelliferone; ortho cresolphthalein; nitrotyrosine; pararosaniline; Phenol Red; B- phycoerythrin; o-phthaldialdehyde; pyrene and derivatives such as pyrene, pyrene butyrate and succinimidyl 1-pyrene butyrate; Reactive Red 4 (Cibacron Brilliant Red 3B-A); rhodamine and derivatives such as 6-carboxy-X-rhodamine (ROX), 6-carboxyrhodamine (R6G), lissamine rhodamine B sulfonyl chloride, rhodamine (Rhod), rhodamine B, rhodamine 123, rhodamine X isothiocyanate, rhodamine green, sulforhodamine B, sulforhodamine 101 and sulfonyl chloride derivative of sulforhodamine 101 (Texas Red); N,N,N',N'-tetramethyl-6-carboxyrhodamine (TAMRA); tetramethyl rhodamine; tetramethyl rhodamine isothiocyanate (TRITC); riboflavin; rosolic acid and terbium chelate derivatives. Other suitable fluorophores include thiol-reactive europium chelates which emit at approximately 617 nm (Heyduk and Heyduk, Analyt. Biochem.248:216-27, 1997; J. Biol. Chem.274:3315-22, 1999), as well as GFP, LissamineTM, diethylaminocoumarin, fluorescein chlorotriazinyl, naphthofluorescein, 4,7-dichlororhodamine and xanthene (as described in U.S. Pat. No. 5,800,996 to Lee et al.) and derivatives thereof. Other fluorophores known to those skilled in the art can also be used, for example those available from Life Technologies (Invitrogen; Molecular Probes (Eugene, Oreg.)) and
including the ALEXA FLUOR® series of dyes (for example, as described in U.S. Pat. Nos. 5,696,157, 6, 130, 101 and 6,716,979), the BODIPY series of dyes (dipyrromethene boron difluoride dyes, for example as described in U.S. Pat. Nos. 4,774,339, 5,187,288, 5,248,782, 5,274,113, 5,338,854, 5,451,663 and 5,433,896), Cascade Blue (an amine reactive derivative of the sulfonated pyrene described in U.S. Pat. No.5,132,432) and Marina Blue (U.S. Pat. No. 5,830,912). In addition to the fluorochromes described above, a fluorescent label can be a fluorescent nanoparticle, such as a semiconductor nanocrystal, e.g., a QUANTUM DOT® (obtained, for example, from Life Technologies (Quantum Dot Corp, Invitrogen Nanocrystal Technologies, Eugene, Oreg.); see also, U.S. Pat. Nos.6,815,064; 6,682,596; and 6,649, 138). Semiconductor nanocrystals are microscopic particles having size-dependent optical and/or electrical properties. When semiconductor nanocrystals are illuminated with a primary energy source, a secondary emission of energy occurs of a frequency that corresponds to the band gap of the semiconductor material used in the semiconductor nanocrystal. This emission can he detected as colored light of a specific wavelength or fluorescence. Semiconductor nanocrystals with different spectral characteristics are described in e.g., U.S. Pat. No. 6,602,671. Semiconductor nanocrystals that can he coupled to a variety of biological molecules (including dNTPs and/or nucleic acids) or substrates by techniques described in, for example, Bruchez et al., Science 281 :20132016, 1998; Chan et al., Science 281:2016-2018, 1998; and U.S. Pat. No. 6,274,323. Formation of semiconductor nanocrystals of various compositions are disclosed in, e.g., U.S. Pat. Nos. 6,927, 069; 6,914,256; 6,855,202; 6,709,929; 6,689,338; 6,500,622; 6,306,736; 6,225,198; 6,207,392; 6,114,038; 6,048,616; 5,990,479; 5,690,807; 5,571,018; 5,505,928; 5,262,357 and in U.S. Patent Publication No. 2003/0165951 as well as PCT Publication No. 99/26299 (published May 27, 1999). Separate populations of semiconductor nanocrystals can be produced that are identifiable based on their different spectral characteristics. For example, semiconductor nanocrystals can be produced that emit light of different colors based on their composition, size or size and composition. For example, quantum dots that emit light at different wavelengths based on size (565 nm, 655 nm, 705 nm, or 800 nm emission wavelengths), which are suitable as fluorescent labels in the probes disclosed herein are available from Life Technologies (Carlsbad, Calif.). Additional labels include, for example, radioisotopes (such as 3H), metal chelates such as DOTA and DPTA chelates of radioactive or paramagnetic metal ions like Gd3+. Detectable labels that can be used with nucleic acid molecules also include enzymes, for example horseradish peroxidase, alkaline phosphatase, acid phosphatase, glucose oxidase,
beta-galactosidase, beta-glucuronidase, or beta-lactamase. Alternatively, an enzyme can be used in a metallographic detection scheme. For example, silver in situ hybridization (SISH) procedures involve metallographic detection schemes for identification and localization of a hybridized genomic target nucleic acid sequence. Metallographic detection methods include using an enzyme, such as alkaline phosphatase, in combination with a water-soluble metal ion and a redox-inactive substrate of the enzyme. The substrate is converted to a redox-active agent by the enzyme, and the redoxactive agent reduces the metal ion, causing it to form a detectable precipitate. (See, for example, U.S. Patent Application Publication No. 2005/0100976, PCT Publication No. 2005/ 003777 and U.S. Patent Application Publication No. 2004/ 0265922). Metallographic detection methods also include using an oxido-reductase enzyme (such as horseradish peroxidase) along with a water soluble metal ion, an oxidizing agent and a reducing agent, again to form a detectable precipitate. (See, for example, U.S. Pat. No.6,670,113). Probes made using the disclosed methods can be used for nucleic acid detection, such as ISH procedures (for example, fluorescence in situ hybridization (FISH), chromogenic in situ hybridization (CISH) and silver in situ hybridization (SISH)) or comparative genomic hybridization (CGH). Numerous procedures for FISH, CISH, and SISH are known in the art. For example, procedures for performing FISH are described in U.S. Pat. Nos. 5,447,841; 5,472,842; and 5,427,932; and for example, in Pinkel et al., Proc. Natl. Acad. Sci. 83:2934- 2938, 1986; Pinkel et al., Proc. Natl. Acad. Sci.85:9138-9142, 1988; and Lichter et al., Proc. Natl. Acad. Sci. 85:9664-9668, 1988. CISH is described in, e.g., Tanner et al., Am.1. Pathol. 157:1467-1472, 2000 and U.S. Pat. No.6,942,970. Additional detection methods are provided in U.S. Pat. No. 6,280,929. Numerous reagents and detection schemes can be employed in conjunction with FISH, CISH, and SISH procedures to improve sensitivity, resolution, or other desirable properties. As discussed above probes labeled with fluorophores (including fluorescent dyes and QUANTUM DOTS®) can be directly optically detected when performing FISH. Alternatively, the probe can be labeled with a nonfluorescent molecule, such as a hapten (such as the following non-limiting examples: biotin, digoxigenin, DNP (dinitrophenol), and various oxazoles, pyrrazoles, thiazoles, nitroaryls, benzofurazans, triterpenes, ureas, thioureas, rotenones, coumarin, courmarin-based compounds, Podophyllotoxin, Podophyllotoxin-based compounds, and combinations thereof), ligand or other indirectly detectable moiety. Probes labeled with such non-fluorescent molecules (and the target nucleic acid sequences to which they bind) can then be detected by contacting the sample (e.g., the cell or tissue sample to which the probe is bound) with a labeled detection reagent, such as an antibody (or receptor, or other
specific binding partner) specific for the chosen hapten or ligand. The detection reagent can be labeled with a fluorophore (e.g., QUANTUM DOT®) or with another indirectly detectable moiety, or can be contacted with one or more additional specific binding agents (e.g., secondary or specific antibodies), which can be labeled with a fluorophore. In other examples, the probe, or specific binding agent (such as an antibody, e.g., a primary antibody, receptor or other binding agent) is labeled with an enzyme that is capable of converting a fluorogenic or chromogenic composition into a detectable fluorescent, colored or otherwise detectable signal (e.g., as in deposition of detectable metal particles in SISH). As indicated above, the enzyme can be attached directly or indirectly via a linker to the relevant probe or detection reagent. Examples of suitable reagents (e.g., binding reagents) and chemistries (e.g., linker and attachment chemistries) are described in U.S. Patent Application Publication Nos.2006/0246524; 2006/0246523, and 2007/ 0117153. It will be appreciated by those skilled in the art that by appropriately selecting labelled probe-specific binding agent pairs, multiplex detection schemes can be produced to facilitate detection of multiple target nucleic acid sequences (e.g., genomic target nucleic acid sequences) in a single assay (e.g., on a single cell or tissue sample or on more than one cell or tissue sample). For example, a first probe that corresponds to a first target sequence can be labelled with a first hapten, such as biotin, while a second probe that corresponds to a second target sequence can be labelled with a second hapten, such as DNP. Following exposure of the sample to the probes, the bound probes can he detected by contacting the sample with a first specific binding agent (in this case avidin labelled with a first fluorophore, for example, a first spectrally distinct QUANTUM DOT®, e.g., that emits at 585 nm) and a second specific binding agent (in this case an anti- DNP antibody, or antibody fragment, labelled with a second fluorophore (for example, a second spectrally distinct QUANTUM DOT®, e.g., that emits at 705 nm). Additional probes/binding agent pairs can he added to the multiplex detection scheme using other spectrally distinct fluorophores. Numerous variations of direct, and indirect (one step, two step or more) can be envisioned, all of which are suitable in the context of the disclosed probes and assays. Probes typically comprise single-stranded nucleic acids of between 10 to 1000 nucleotides in length, for instance of between 10 and 800, more preferably of between 15 and 700, typically of between 20 and 500. Primers typically are shorter single-stranded nucleic acids, of between 10 to 25 nucleotides in length, designed to perfectly or almost perfectly match a nucleic acid of interest, to be amplified. The probes and primers are “specific” to the nucleic acids they hybridize to, i.e. they preferably hybridize under high stringency hybridization conditions
(corresponding to the highest melting temperature Tm, e.g., 50 % formamide, 5x or 6x SCC. SCC is a 0.15 M NaCl, 0.015 M Na-citrate). The nucleic acid primers or probes used in the above amplification and detection method may be assembled as a kit. Such a kit includes consensus primers and molecular probes. A preferred kit also includes the components necessary to determine if amplification has occurred. The kit may also include, for example, PCR buffers and enzymes; positive control sequences, reaction control primers; and instructions for amplifying and detecting the specific sequences. In another embodiment, the expression level is determined by DNA chip analysis. Such DNA chip or nucleic acid microarray consists of different nucleic acid probes that are chemically attached to a substrate, which can be a microchip, a glass slide or a microsphere- sized bead. A microchip may be constituted of polymers, plastics, resins, polysaccharides, silica or silica-based materials, carbon, metals, inorganic glasses, or nitrocellulose. Probes comprise nucleic acids such as cDNAs or oligonucleotides that may be about 10 to about 60 base pairs. To determine the expression level, a sample from a test subject, optionally first subjected to a reverse transcription, is labelled and contacted with the microarray in hybridization conditions, leading to the formation of complexes between target nucleic acids that are complementary to probe sequences attached to the microarray surface. The labelled hybridized complexes are then detected and can be quantified or semi-quantified. Labelling may be achieved by various methods, e.g. by using radioactive or fluorescent labelling. Many variants of the microarray hybridization technology are available to the man skilled in the art (see e.g. the review by Hoheisel, Nature Reviews, Genetics, 2006, 7:200-210). Expression level of a gene may be expressed as absolute expression level or normalized expression level. Typically, expression levels are normalized by correcting the absolute expression level of a gene by comparing its expression to the expression of a gene that is not a relevant for determining the cancer stage of the patient, e.g., a housekeeping gene that is constitutively expressed. Suitable genes for normalization include housekeeping genes such as the actin gene ACTB, ribosomal 18S gene, GUSB, PGK1, TFRC, GAPDH, GUSB, TBP and ABL1. This normalization allows the comparison of the expression level in one sample, e.g., a patient sample, to another sample, or between samples from different sources. According to the invention, the level of CD39 proteins may also be measured and can be performed by a variety of techniques well known in the art. In a particular embodiment, the
detection of the expression level of CD39 can be performed by flow cytometry. When this method is used, the method consists of determining the amount of CD39 expressed on tumor cells. According to the invention and the flow cytometry method, when the florescence intensity is high or bright, the level of CD39 express on tumor cells is high and thus the expression level of CD39 is high and when the florescence intensity is low or dull, the level of CD39 express on tumor cells is low and thus the expression level of CD39 is low. For measuring the expression level of CD39, techniques like ELISA (see below) or ELLA allowing to measure the level of the soluble proteins are also suitable. In the present application, the “level of protein” or the “protein level expression” or the “protein concentration” means the quantity or concentration of said protein. In another embodiment, the “level of protein” means the level of CD39 protein fragments. In still another embodiment, the “level of protein” means the quantitative measurement of CD39 protein expression relative to an internal control. Typically protein concentration may be measured for example by capillary electrophoresis-mass spectroscopy technique (CE-MS) or ELISA performed on the sample. Such methods comprise contacting a sample with a binding partner capable of selectively interacting with proteins present in the sample. The binding partner is generally an antibody that may be polyclonal or monoclonal, preferably monoclonal. The presence of the protein can be detected using standard electrophoretic and immunodiagnostic techniques, including immunoassays such as competition, direct reaction, or sandwich type assays. Such assays include, but are not limited to, Western blots; agglutination tests; enzyme-labeled and mediated immunoassays, such as ELISAs; biotin/avidin type assays; radioimmunoassays; immunoelectrophoresis; immunoprecipitation, capillary electrophoresis- mass spectroscopy technique (CE-MS), etc. The reactions generally include revealing labels such as fluorescent, chemioluminescent, radioactive, enzymatic labels or dye molecules, or other methods for detecting the formation of a complex between the antigen and the antibody or antibodies reacted therewith. The aforementioned assays generally involve separation of unbound protein in a liquid phase from a solid phase support to which antigen-antibody complexes are bound. Solid supports which can be used in the practice of the invention include substrates such as nitrocellulose (e. g., in membrane or microtiter well form); polyvinylchloride (e. g., sheets or microtiter wells); polystyrene latex (e.g., beads or microtiter plates); polyvinylidine fluoride;
diazotized paper; nylon membranes; activated beads, magnetically responsive beads, and the like. More particularly, an ELISA method can be used, wherein the wells of a microtiter plate are coated with a set of antibodies against the proteins to be tested. A sample containing or suspected of containing the marker protein is then added to the coated wells. After a period of incubation sufficient to allow the formation of antibody-antigen complexes, the plate(s) can be washed to remove unbound moieties and a detectably labeled secondary binding molecule is added. The secondary binding molecule is allowed to react with any captured sample marker protein, the plate is washed and the presence of the secondary binding molecule is detected using methods well known in the art. Predetermined reference values used for comparison of the expression levels may comprise “cut-off” or “threshold” values that may be determined as described herein. Each reference (“cut-off”) value for CD39 level may be predetermined by carrying out a method comprising the steps of: a) providing a collection of samples from patients suffering of a cancer and/or samples of the corresponding uninvolved tissues as described in the invention; b) determining the level of CD39 for each sample contained in the collection provided at step a); c) ranking the tumor tissue samples according to said level d) classifying said samples in pairs of subsets of increasing, respectively decreasing, number of members ranked according to their expression level, e) providing, for each sample provided at step a), information relating to the actual clinical outcome for the corresponding cancer patient; f) for each pair of subsets of samples, obtaining a Kaplan Meier percentage of survival curve; g) for each pair of subsets of samples calculating the statistical significance (p value) between both subsets h) selecting as reference value for the level, the value of level for which the p value is the smallest. For example the expression level of CD39 may be assessed for 100 cancer samples of 100 patients. The 100 samples are ranked according to their expression level. Sample 1 has the highest expression level and sample 100 has the lowest expression level. A first grouping provides two subsets: on one side sample Nr 1 and on the other side the 99 other samples. The
next grouping provides on one side samples 1 and 2 and on the other side the 98 remaining samples etc., until the last grouping: on one side samples 1 to 99 and on the other side sample Nr 100. According to the information relating to the actual clinical outcome for the corresponding cancer patient, Kaplan Meier curves are prepared for each of the 99 groups of two subsets. Also for each of the 99 groups, the p value between both subsets was calculated. The reference value is selected such as the discrimination based on the criterion of the minimum p value is the strongest. In other terms, the expression level corresponding to the boundary between both subsets for which the p value is minimum is considered as the reference value. It should be noted that the reference value is not necessarily the median value of expression levels. In routine work, the reference value (cut-off value) may be used in the present method to discriminate cancer samples and therefore the corresponding patients. Kaplan–Meier curves of percentage of survival as a function of time are commonly used to measure the fraction of patients living for a certain amount of time after treatment and are well known by the man skilled in the art. The man skilled in the art also understands that the same technique of assessment of the expression level of a protein should of course be used for obtaining the reference value and thereafter for assessment of the expression level of a protein of a patient subjected to the method of the invention. The invention will be further illustrated by the following figures and examples. However, these examples and figures should not be interpreted in any way as limiting the scope of the present invention. FIGURES: Figure 1. (A) CD39 and A2aR expression provided by flow cytometry on cell surface of RL cells cultured in 2D and 3D suspension (after three days of culture) (n = 3). (B) CD39 expression followed by flow cytometry upon γδ T cell primary cell culture. Upper panel represents ratio of mean fluorescence and lower panel CD39+ percent of expressing γδ T cells. Figure 2. MALC were co-cultured or not with LTγδ cells (ratio E/T: 0.5/1) and treated or not by GA101 (10µg/ml), POM1 (10 or 100µM) or combination. (A) Viability was determined by Trypan blue assay on 5 MALC dissociated and pooled. (B) Depletion was determined by comparison to cell number of UT condition. Each symbol and color represents a donor and an experiment, SD represents 3 independent experiments.
Figure 3. Characterization of PD1, CD39, CD73 expression on CD4+, CD8+ and B cells. For each patient tested, 10 PDLS were pooled, dissociated and stained with CD4, CD8, CD3, CD19, CD10 markers for the different cell populations and CD73, CD39and PD-1 for the ICP and analyzed by flow cytometry. Figure 4. PDLS morphology after CD39 targeting. PDLS were established from 8 different FL patients and after 3 days of culture were treated by GA101 at 10µg/mL and/or Nivolumab at 10µg/mL and/or POM1 at 10µM or 100µM. Quantification of center and periphery areas (µm²) was performed with the Columbus software. Figure 5. CD19+ cell depletion 72h post-treatment. PDLS were established from 8 different FL patients and after 3 days of culture were treated by GA101 at 10µg/mL and/or Nivolumab at 10µg/mL and/or POM1 at 10µM or 100µM.10 PDLS were pooled, dissociated, stained and analyzed by flow cytometry. Figure 6. FL Patient survival depending on their level of CD39 expression (high or low). Figure 7. Characterization of CD39, CD73 and A2aR expression on MCL cell lines. Figure 8. Viability of MCL cell lines treated or not with POM1 at 2,5 µM, 5µM or 10µM. Figure 9. B cells count on PDLS established from MCL patients treated with POM-1. EXAMPLE: Material and Methods ULA-MALC: a scaffold-free model adapted for drug screening MALC were produced by adaptation of the HD method where RL cell’s suspension was prepared in complete medium containing 1% methylcellulose (a gelling agent that forces cell- cell interaction)13. 20µL of this suspension were dropped into coverslips of a 24-well culture plate and after 24 hours’ incubation, all drops were transferred by returning the coverslip to a dish previously coated with 4% agarose. All of the MALC culture medium was then renewed every 5 days. Although the HD method allowed a better understanding of FL biology and drug responses in a more relevant model than 2D cultures, it was not suitable for drug screening due
to the manual transfer of neoaggregates into agarose-precoated wells. To fit a scaffold-free strategy, the “ultra-low attachment method” was the most adapted12. In this method, 100µL of cell suspension were placed into 96-wells plate ultra-low attachment plate and a centrifugation (1000rpm, 10 min) was than performed to promote cell aggregation. The plate was placed into an incubator at 37°C and 5% CO2. 100µL of medium were renewed every 3 days in order to provide sufficient nutriments to the cell culture and spheroid growth.3D culture of several B- NHL cell lines were tested (RL, WSU, DOHH-2 for follicular lymphoma and Ocily-7, Ocily- 1, Ocily-10, Ocily-3 for DLBCL). RL MALC were the most compact and spherical models obtained. Primary FL cell culture and PDLS (Patient Derived Lymphoma Spheroid) generation. Fresh tissues from lymph nodes were dissociated using the gentleMACS™ Octo Dissociator (Miltenyi, Paris, France). Cell suspensions were frozen in 4% human albumin (VIALEBEX 40 mg/ml, LFB Biomedicaments)/10% DMSO until FL diagnosis. After diagnosis, cells were thawed in complete medium and their phenotypes were analysed by Fortessa X20 (BD Biosciences Le Pont de Claix, France) after staining by fluorochrome- labelled antibodies (see flow cytometry section). PDLS were established according to the following protocol: 25000 cells in 100 Μl of enriched medium supplemented with cytokines (IMDM medium + 10% HiClone serum, 5.10-5M 2-ME, 50 μg/ml gentamicin, 40 μg/ml apotransferrin, 1 mM sodium pyruvate, 1X nonessential amino acids and 20 mM HEPES, 0.2 μM ODN, 15ng/mL IL-15, 10ng/mL IL-2, 50ng/mL IL-4, 50ng/mL CD40L) were seeded in 96-well round bottom ULA plates (Corning, Samois sur Seine, France), centrifuged 10 minutes at 1000 rpm and cultured at 37 °C in a humidified 5% CO2 atmosphere. At day 3 of culture, 100 μL of fresh enriched medium containing or not treatments were added and PDLS were cultured at 37 °C in a humidified 5% CO2 atmosphere until the different time points. Results Preliminary results obtained showed that LTγδ from healthy donors express CD39 and A2aR (Figure 1) and that CD39 inhibition with POM1 increases GA101-induced ADCC (Figure 2). Moreover, it seems that LTγδ that better respond are those that express the most CD39 and CD16, the Fc fragment receptor responsible for the ADCC phenomenon (data not shown). Interestingly, it has also been shown in biopsies from FL patients that the TIL (CD4 or CD8) express CD39 and CD73 in a variable way depending on the donors tested (Figure 3). The effect of CD39 targeting was evaluated from the cells of these patients, grown for 3 days
and treated for 24 hours with POM1. As observed in Figure 4 and Figure 5, POM1 potentiates the effect of GA101 (anti-CD20) and/or Nivolumab (anti-PD1). CD39 is also overexpressed in MCL cell lines (Figure 7). The effect of CD39 targeting was evaluated from MCL cell lines treated with POM1 (Figure 8). As depicted in Figure 9, POM1 potentiates the effect of Roflutinib and Ibrutinib in PDLS. These results demonstrate that the adenosine pathway could be a pathway whose targeting could improve existing treatments. Finally, bioinformatic analysis showed that the level of expression of ENTPD1 gene, the gene coding for CD39, is correlated with poor prognosis in FL patients (Figure 6). Conclusion The Inventors herein demonstrate that CD39 is a relevant therapeutic target in B-cell lymphoma, in particular Follicular Lymphoma, Diffuse Large B-Cell Lymphoma and Mantle Cell Lymphoma. They also demonstrate that CD39 inhibition potentiates anti-CD20 monoclonal antibody therapy and/or anti-PD1 monoclonal antibody therapy, and that ENTPD1 overexpression is correlated with poor prognosis in FL patients. REFERENCES: Throughout this application, various references describe the state of the art to which this invention pertains. The disclosures of these references are hereby incorporated by reference into the present disclosure. 1. Carbone, et al. Follicular lymphoma. Nat Rev Dis Primers 2019;5:83. 2. Dada, et al. Diagnosis and management of follicular lymphoma: A comprehensive review. Eur J Haematol 2019;103:152. 3. Seyfizadeh N, et al. A molecular perspective on rituximab: A monoclonal antibody for B cell non Hodgkin lymphoma and other affections. Crit Rev Oncol Hematol. janv 2016;97:275-90. 4. Laurent C, et al. Several immune escape patterns in non-Hodgkin's lymphomas. Oncoimmunology 2015;4:e1026530. 5. Gravelle P, et al. Impaired functional responses in follicular lymphoma CD8+TIM-3+ T lymphocytes following TCR engagement. OncoImmunology 2016;5:e1224044. 6. Tosolini M, et al. Large-scale microarray profiling reveals four stages of immune escape in non-Hodgkin lymphomas. OncoImmunology 2016;5:e1188246. 7. Rossi C, et al. Boosting γδ T cell-mediated antibody-dependent cellular cytotoxicity by PD- 1 blockade in follicular lymphoma. OncoImmunology 8, 1554175 (2019).
8. Gravelle P, et al. Innate predisposition to immune escape in follicular lymphoma cells. OncoImmunology 1, 555–556 (2012). 9. Decaup E, et al. Anti-tumor activity of obinutuzumab and rituximab in a follicular lymphoma 3D model. Blood Cancer J.10 (2013). 10. Gravelle P, et al. Cell Growth in Aggregates Determines Gene Expression, Proliferation, Survival, Chemoresistance, and Sensitivity to Immune Effectors in Follicular Lymphoma. Am. J. Pathol.184, 282–295 (2014). 11. Decaup E, et al. A tridimensional model for NK cell-mediated ADCC of Follicular Lymphoma. Frontiers in Immunology. Accepted august 1st 2019. 12. Gava, F, Faria C, al.3D Model Characterization by 2D and 3D Imaging in t(14;18)-Positive B-NHL: Perspectives for In Vitro Drug Screens in Follicular Lymphoma.22 (2021). 13. Gravelle, P. et al. Cell growth in aggregates determines gene expression, proliferation, survival, chemoresistance, and sensitivity to immune effectors in follicular lymphoma. The American journal of pathology 184, 282–295 (2014).
Claims
CLAIMS: 1. A method of treating a B-cell lymphoma in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a CD39 inhibitor.
2. The method according to claim 1, wherein the B-cell lymphoma is a non-Hodgkin lymphoma.
3. The method according to claim 1, wherein the B-cell lymphoma is a follicular lymphoma, a diffuse large B-cell lymphoma or a mantle cell lymphoma.
4. The method according to claim 1 to 3, wherein the B-cell lymphoma is resistant to an anti-CD20 monoclonal antibody.
5. The method according to claim 1 comprising administering a CD39 inhibitor with an anti-CD20 monoclonal antibody.
6. The method according to claim 5 for preventing B-cell lymphoma relapse in a subject who was treated with an anti-CD20 monoclonal antibody.
7. The method according to claim 4 to 6, wherein the anti-CD20 monoclonal antibody is rituximab.
8. The method according to claim 1 comprising administering a CD39 inhibitor with an anti-PD1 therapy.
9. The method according to claim 8 for preventing B-cell lymphoma relapse in a subject who was treated with an anti-PD1 therapy.
10. The method according to claim 8 to 9, wherein the anti-PD1 monoclonal antibody is nivolumab.
11. The method according to claim 1 to 10 comprising administering a CD39 inhibitor with an anti-CD20 monoclonal antibody and an anti-PD1 monoclonal antibody.
12. The method according to claim 1 to 11, wherein the CD39 inhibitor is an antibody having specificity for CD39.
13. The method according to claim 12, wherein the antibody having specificity for CD39 is IPH52, TTX-030, BY40, BA54g, BY12, SRF617, 9-8B, ES002023 or ES014.
14. A method for predicting the survival time of a subject suffering from a follicular lymphoma comprising determining the level of expression of ENTPD1 gene in a sample from said subject.
15. The method for predicting the survival time of subject suffering from a follicular lymphoma according to claim 14 comprising i) determining the expression level of ENTPD1 gene in a sample obtained from a subject ii) comparing the expression level determined at step i) with a predetermined reference value and iii) providing a good prognosis when the expression level determined at step i) is lower than the predetermined reference value, or providing a bad prognosis when the expression level determined at step i) is higher than the predetermined reference value.
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