US20240033353A1 - Cd70 combination therapy - Google Patents
Cd70 combination therapy Download PDFInfo
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- US20240033353A1 US20240033353A1 US18/334,582 US202318334582A US2024033353A1 US 20240033353 A1 US20240033353 A1 US 20240033353A1 US 202318334582 A US202318334582 A US 202318334582A US 2024033353 A1 US2024033353 A1 US 2024033353A1
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- combination
- antibody
- antigen binding
- bcl
- venetoclax
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Definitions
- the present invention relates to combination therapies, particularly combination therapies for the treatment of myeloid malignancy.
- the combination therapies are particularly useful for the treatment of acute myeloid leukemia (AML).
- the combination therapies include an antibody or antigen binding fragment thereof that binds to CD70 and a BCL-2 inhibitor, for example venetoclax or a pharmaceutically acceptable salt thereof.
- the combination therapies may further include an additional anti-cancer agent, for example an agent used for the treatment of AML such as azacitidine or decitabine.
- CD70 has been identified as a molecular target of particular interest owing to its constitutive expression on many types of hematological malignancies and solid carcinomas (Junker et al. (2005) J Urol. 173:2150-3; Sloan et al. (2004) Am J Pathol. 164:315-23; Held-Feindt and Mentlein (2002) Int J Cancer 98:352-6; Hishima et al. (2000) Am J Surg Pathol. 24:742-6; Lens et al. (1999) Br J Haematol. 106:491-503; Boursalian et al. (2009) Adv Exp Med Biol. 647:108-119; Wajant H.
- CD70 is a type II transmembrane glycoprotein belonging to the tumour necrosis factor (TNF) superfamily, which mediates its effects through binding to its cognate cell surface receptor, CD27. Both CD70 and CD27 are expressed by multiple cell types of the immune system and the CD70-CD27 signalling pathway has been implicated in the regulation of several different aspects of the immune response. This is reflected in the fact that CD70 overexpression occurs in various auto-immune diseases including rheumatoid and psoriatic arthritis and lupus (Boursalian et al. (2009) Adv Exp Med Biol. 647:108-119; Han et al. (2005) Lupus 14(8):598-606; Lee et al. (2007) J Immunol. 179(4):2609-2615; Oelke et al. (2004) Arthritis Rheum. 50(6):1850-1860).
- TNF tumour necrosis factor
- CD70 expression has been linked to poor prognosis for several cancers including B cell lymphoma, renal cell carcinoma and breast cancer (Bertrand et al. (2013) Genes Chromosomes Cancer 52(8):764-774; Jilaveanu et al. (2012) Hum Pathol. 43(9):1394-1399; Petrau et al. (2014) J Cancer 5(9):761-764). CD70 expression has also been found on metastatic tissue in a high percentage of cases indicating a key role for this molecule in cancer progression (Jacobs et al. (2015) Oncotarget 6(15):13462-13475).
- CD70 binding to CD27 on regulatory T cells has been shown to augment the frequency of Tregs, reduce tumour-specific T cells responses and promote tumour growth in mice (Claus et al. (2012) Cancer Res. 72(14):3664-3676).
- CD70-CD27 signalling can also dampen the immune response by tumour-induced apoptosis of T-lymphocytes, as demonstrated in renal cell carcinoma, glioma and glioblastoma cells (Chahlavi et al. (2005) Cancer Res.
- CD70 expression has also been linked to T cell exhaustion whereby the lymphocytes adopt a more differentiated phenotype and fail to kill the tumour cells (Wang et al. (2012) Cancer Res 72(23):6119-6129; Yang et al. (2014) Leukemia 28(9):1872-1884).
- CD70 is an attractive target for anti-cancer therapy and antibodies targeting this cell surface protein are in clinical development (Jacob et al. (2015) Pharmacol Ther. 155:1-10; Silence et al. (2014) mAbs 6(2):523-532).
- the present invention is directed to combination therapies comprising antibodies or antigen binding fragments thereof that bind to CD70.
- a BCL-2 inhibitor for example venetoclax or a pharmaceutically acceptable salt thereof.
- BCL-2 inhibitor for example venetoclax or a pharmaceutically acceptable salt thereof.
- venetoclax is an example of a potent, selective small-molecule inhibitor of the BCL-2 protein.
- the combination of an antibody or antigen binding fragment thereof that binds to CD70 and a BCL-2 inhibitor, for example venetoclax or a pharmaceutically acceptable salt thereof provides an effective therapy for the treatment of cancer, particularly myeloid malignancies such as acute myeloid leukemia (AML).
- AML acute myeloid leukemia
- the present invention provides a combination comprising (i) an antibody or antigen binding fragment thereof that binds to CD70; and (ii) a BCL-2 inhibitor.
- the BCL-2 inhibitor is Compound (I) as shown below or a pharmaceutically acceptable salt thereof.
- Compound (I) is also referred to herein as venetoclax.
- the antibody or antigen binding fragment that binds to CD70 is selected from: (i) an antibody or antigen binding fragment comprising a variable heavy chain domain (VH) and a variable light chain domain (VL) comprising the heavy chain CDRs (HCDR3, HCDR2 and HCDR1) and light chain CDRs (LCDR3, LCDR2 and LCDR1): HCDR3 comprising or consisting of SEQ ID NO: 3; HCDR2 comprising or consisting of SEQ ID NO: 2; HCDR1 comprising or consisting of SEQ ID NO: 1; LCDR3 comprising or consisting of SEQ ID NO: 7; LCDR2 comprising or consisting of SEQ ID NO: 6; and LCDR1 comprising or consisting of SEQ ID NO: 5; (ii) an antibody or antigen binding fragment comprising a VH domain comprising an amino acid sequence at least 70%, at least 80%, at least 90%, at least 95% identical to SEQ ID NO:4 and a VL domain comprising an amino acid
- the CD70 antibody or antigen binding fragment of the combinations may possess one or more effector functions.
- the antibody or antigen binding fragment has ADCC activity; and/or comprises a defucosylated antibody domain; and/or has CDC activity; and/or has ADCP activity.
- the CD70 antibody is ARGX-110.
- the CD70 antigen binding fragment of the combinations is independently selected from the group consisting of: an antibody light chain variable domain (VL); an antibody heavy chain variable domain (VH); a single chain antibody (scFv); a F(ab′)2 fragment; a Fab fragment; an Fd fragment; an Fv fragment; a one-armed (monovalent) antibody; diabodies, triabodies, tetrabodies or any antigen-binding molecule formed by combination, assembly or conjugation of such antigen binding fragments.
- VL antibody light chain variable domain
- VH antibody heavy chain variable domain
- scFv single chain antibody
- F(ab′)2 fragment a Fab fragment
- Fd fragment an Fv fragment
- a one-armed (monovalent) antibody diabodies, triabodies, tetrabodies or any antigen-binding molecule formed by combination, assembly or conjugation of such antigen binding fragments.
- the CD70 antibody or antigen binding fragment thereof and the BCL-2 inhibitor are formulated as separate compositions.
- the CD70 antibody or antigen binding fragment thereof and venetoclax or a pharmaceutically acceptable salt thereof are formulated as separate compositions.
- the combinations of the invention may comprise one or more additional therapeutic agents, for example at least one additional anti-cancer agent, preferably an agent for the treatment of a myeloid malignancy.
- the additional anti-cancer agent is an agent for the treatment of acute myeloid leukemia (AML).
- the combinations comprise a hypomethylating agent, preferably azacitidine or decitabine.
- the present invention provides combinations according to the first aspect of the invention for use in therapy.
- the present invention provides combinations according to the first aspect of the invention for use in the treatment of a malignancy, preferably a myeloid malignancy, in a human subject.
- the present invention also provides a method for treating a malignancy, preferably a myeloid malignancy, in a human subject, said method comprising administering to the subject an effective amount of any of the combinations according to the first aspect of the invention.
- the present invention also provides an antibody or antigen binding fragment thereof that binds to CD70 for use in the treatment of a malignancy, preferably a myeloid malignancy, in a human subject, wherein the antibody molecule is administered in combination with a BCL-2 inhibitor, preferably compound (I) or a pharmaceutically acceptable salt thereof.
- a BCL-2 inhibitor preferably compound (I) or a pharmaceutically acceptable salt thereof, for use in the treatment of a myeloid malignancy in a human subject, wherein the BCL-2 inhibitor, preferably compound (I) or the pharmaceutically acceptable salt thereof, is administered in combination with an antibody or antigen binding fragment thereof that binds to CD70.
- the combinations of the invention are particularly advantageous because they exhibit synergistic efficacy.
- the dose at which the CD70 antibody or antigen binding fragment thereof is administered and/or provided in the combination, and the dose at which the BCL-2 inhibitor is administered and/or provided in the combination are each selected such that the combination provides synergistic treatment.
- the CD70 antibody or antigen binding fragment thereof and the BCL-2 inhibitor are each present in the combination in an amount sufficient to provide synergistic cell killing when cultured with an AML cell line selected from: NOMO-1, MOLM-13, NB4 and MV4-11.
- said malignancies may be newly-diagnosed myeloid malignancies; relapsed or refractory myeloid malignancies; or myeloid malignancies selected from: acute myeloid leukemia (AML); myelodysplastic syndromes (MDS); myeloproliferative neoplasms (MPN); chronic myeloid leukemia (CML); and chronic myelomonocytic leukemia (CMML).
- AML acute myeloid leukemia
- MDS myelodysplastic syndromes
- MPN myeloproliferative neoplasms
- CML chronic myeloid leukemia
- CMML chronic myelomonocytic leukemia
- the combinations of the invention are for the treatment of acute myeloid leukemia (AML).
- the subject or patient treated in accordance with the methods of the invention is a newly-diagnosed AML patient who is ineligible for standard intensive chemotherapy.
- the subject may be a newly-diagnosed AML patient aged 75 years or older or a newly-diagnosed AML patient having a comorbidity that precludes use of standard intensive chemotherapy.
- the CD70 antibody or antigen binding fragment thereof is administered at a dose in the range of 0.1-25 mg/kg, preferably 10 mg/kg.
- the BCL-2 inhibitor preferably venetoclax or pharmaceutically acceptable salt thereof, may be administered in a dose in the range 100 mg-600 mg.
- the methods described herein comprise administering a combination additionally comprising azacitidine wherein the azacitidine is administered at a dose of 75 mg/m 2 .
- the methods described herein comprise administering a combination additionally comprising decitabine wherein the decitabine is administered at a dose of 20 mg/m 2 .
- the methods further comprise monitoring of the patient's blast count.
- the patient's peripheral blood and/or bone marrow blast count may be reduced, for example reduced to less than 25%, for example reduced to 5%, for example reduced to less than 5%, for example reduced to minimal residual disease levels, for example reduced to undetectable levels.
- the bone marrow blast count is reduced to between 5% and 25% and the bone marrow blast percentage is reduced by more than 50% as compared to pretreatment.
- the methods induce a partial response. In certain embodiments, the methods induce a complete response, optionally with platelet recovery and/or neutrophil recovery. The methods may induce transfusion independence of red blood cells or platelets, or both, for 8 weeks or longer, 10 weeks or longer, 12 weeks or longer. In certain embodiments, the methods reduce the mortality rate after a 30-day period or after a 60-day period.
- the methods increase survival.
- the methods may increase survival relative to the standard of care agent or agents used to treat the particular myeloid malignancy being treated with the combination.
- the methods may induce a minimal residual disease status that is negative.
- the methods further comprise a step of subjecting the subject to a bone marrow transplantation.
- the methods may further comprise a step of administering one or more additional anti-cancer agents.
- the one or more additional cancer agents may be selected from any agents suitable for the treatment of myeloid malignancies, preferably AML.
- Preferred agents may be selected from selectin inhibitors (e.g. GMI-1271); FMS-like tyrosine kinase receptor 3 (FLT3) inhibitors (e.g. midostaurin); cyclin-dependent kinase inhibitors; aminopeptidase inhibitors; JAK/STAT inhibitors; cytarabine; anthracycline compounds (e.g.
- FIG. 1 Cusatuzumab and decitabine co-treatment synergistically eliminates NOMO-1 AML cells.
- NOMO-1 AML cells were treated with vehicle, cusatuzumab, venetoclax or decitabine alone or in combination in a constant ratio in the presence of carboxyfluorescein succinimidyl ester (CFSE)-labeled NK cells (ratio 1:1).
- CFSE carboxyfluorescein succinimidyl ester
- NOMO-1 AML cell numbers per well were counted after 72 hours, the degree of viable cells was determined by Annexin V staining, and the effect of drug treatment was calculated as the ratio of surviving cells to vehicle-treated cells.
- Combination index (CI) values were calculated, and values between 0 and 10 were plotted against fraction affected (Fa) values.
- Fa-CI plot [Chou-Talalay plot] assessing synergism and/or antagonism is illustrated. Fa values of 0, 0.5, and 1 correspond to 0, 50, and 100% killed cells. A CI of ⁇ 1, 1, >1 represents synergism, additivity, and antagonism, respectively. IC 50 s indicates the Fa values reached at the IC 50 concentrations for the Ve/Cusa (lower Fa) and Ve/De/Cusa (higher Fa) combinations.
- Ve/De venetoclax and decitabine
- De/Cusa decitabine and cusatuzumab
- Ve/Cusa venetoclax and cusatuzumab
- Ve/De/Cusa venetoclax and decitabine and cusatuzumab.
- FIGS. 2 A- 2 D Cusatuzumab and decitabine co-treatment synergistically eliminates NOMO-1 AML cells. Individual CI-Fa plots of the data for each combination presented in FIG. 1 .
- FIG. 2 A venetoclax and decitabine
- FIG. 2 B decitabine and cusatuzumab
- FIG. 2 C venetoclax and cusatuzumab
- FIG. 2 D venetoclax, decitabine and cusatuzumab.
- FIGS. 3 A- 3 D Cusatuzumab and decitabine co-treatment synergistically eliminates NB4 AML cells.
- NB4 AML cells were treated with vehicle, cusatuzumab, venetoclax or decitabine alone or in combination in a constant ratio in the presence of CFSE-labeled NK cells (ratio 1:1).
- NB4 AML cell numbers per well were counted after 72 hours, the degree of viable cells was determined by Annexin V staining, and the effect of drug treatment was calculated as the ratio of surviving cells to vehicle-treated cells.
- Combination index (CI) values were calculated, and values between 0 and 10 were plotted against fraction affected (Fa) values.
- Fa-CI plot [Chou-Talalay plot] assessing synergism and/or antagonism is illustrated. Fa values of 0, 0.5, and 1 correspond to 0, 50, and 100% killed cells.
- FIG. 3 A venetoclax and decitabine
- FIG. 3 B venetoclax and cusatuzumab
- FIG. 3 C decitabine and cusatuzumab
- FIG. 3 D venetoclax, decitabine and cusatuzumab.
- FIGS. 4 A- 4 D Cusatuzumab and decitabine co-treatment synergistically eliminates MOLM-13 AML cells.
- MOLM-13 AML cells were treated with vehicle, cusatuzumab, venetoclax or decitabine alone or in combination in a constant ratio in the presence of CFSE-labeled NK cells (ratio 1:1).
- MOLM-13 AML cell numbers per well were counted after 72 hours, the degree of viable cells was determined by Annexin V staining, and the effect of drug treatment was calculated as the ratio of surviving cells to vehicle-treated cells.
- Combination index (CI) values were calculated, and values plotted against fraction affected (Fa) values.
- Fa-CI plot [Chou-Talalay plot] assessing synergism and/or antagonism is illustrated. Fa values of 0, 0.5, and 1 correspond to 0, 50, and 100% killed cells.
- FIG. 4 A venetoclax and decitabine
- FIG. 4 B venetoclax and cusatuzumab
- FIG. 4 C decitabine and cusatuzumab
- FIG. 4 D venetoclax, decitabine and cusatuzumab.
- FIG. 5 Cusatuzumab and decitabine co-treatment synergistically eliminates MV4-11 AML cells.
- MV4-11 AML cells were treated with vehicle, cusatuzumab, venetoclax or decitabine alone or in combination in a constant ratio in the presence of CFSE-labeled NK cells (ratio 1:1).
- MV4-11 AML cell numbers per well were counted after 72 hours, the degree of viable cells was determined by Annexin V staining, and the effect of drug treatment was calculated as the ratio of surviving cells to vehicle-treated cells.
- Combination index (CI) values were calculated, and values plotted against fraction affected (Fa) values.
- Fa-CI plot [Chou-Talalay plot] assessing synergism and/or antagonism is illustrated. Fa values of 0, 0.5, and 1 correspond to 0, 50, and 100% killed cells.
- FIGS. 6 A- 6 B Combined venetoclax and cusatuzumab treatment synergistically eliminates leukemic stem cells (LSCs) in vitro.
- LSCs leukemic stem cells
- CD34 + CD38 ⁇ AML LSCs from patients P1-3 were cultured with cusatuzumab (Cusa: 0.3 ⁇ g/ml) or venetoclax (Ve: 6 nM) alone or in combination in the presence of NK cells (ratio 1:1) overnight in duplicates followed by plating in methylcellulose. Colony formation was assessed 14 days later.
- FIG. 6 A Absolute number of colonies per well for first plating following treatment
- FIGS. 7 A- 7 B Combined venetoclax and cusatuzumab treatment synergistically eliminates LSCs in vitro. Data presented correspond to the data of FIG. 6 , normalized to the mean number of colonies per well following vehicle treatment for each patient. ( FIG. 7 A ) first plating; ( FIG. 7 B ) second plating.
- FIGS. 8 A- 8 B Combined venetoclax and cusatuzumab treatment synergistically eliminates LSCs in vitro.
- CD34 + CD38 ⁇ AML LSCs from patients P4 and P5 were cultured with cusatuzumab (Cusa: 0.3 ⁇ g/ml), venetoclax (Ve: 6 nM) or decitabine (0.01 ⁇ M) alone or in combination in the presence of NK cells (ratio 1:1) overnight in duplicates followed by plating in methylcellulose. Colony formation was assessed 14 days later. Data are represented as mean ⁇ S.D ( FIG. 8 A ) Results from a single patient; ( FIG. 8 B ) Results from P4 and P5.
- FIG. 9 CD70 mRNA expression (as percentage of housekeeping gene) following treatment with vehicle (Veh) or venetoclax (Ven) for 24 or 48 hrs.
- Combination therapy refers to a treatment in which a subject, for example a human subject, is given two or more therapeutic agents.
- the “combinations” described herein are for use in combination therapy.
- the two or more therapeutic agents are typically administered so as to treat a single disease, herein a cancer or malignancy.
- the combinations or combination therapies of the present invention comprise antibodies or antigen binding fragments that bind to CD70 and a BCL-2 inhibitor, preferably the small-molecule inhibitor venetoclax or a pharmaceutically acceptable salt thereof.
- the agents included in the combination therapies may be co-formulated for administration or may be provided separately, for example as separate compositions, for administration to a subject or patient in need thereof.
- antibody As used herein, the term “antibody” is intended to encompass full-length antibodies and variants thereof, including but not limited to modified antibodies, humanised antibodies, germlined antibodies.
- the term “antibody” is typically used herein to refer to immunoglobulin polypeptides having a combination of two heavy and two light chains wherein the polypeptide has significant specific immunoreactive activity to an antigen of interest (herein CD70).
- CD70 an antigen of interest
- the antibodies comprise two identical light polypeptide chains of molecular weight approximately 23,000 Daltons, and two identical heavy chains of molecular weight 53,000-70,000.
- the four chains are joined by disulfide bonds in a “Y” configuration wherein the light chains bracket the heavy chains starting at the mouth of the “Y” and continuing through the variable region.
- the light chains of an antibody are classified as either kappa or lambda ( ⁇ , ⁇ ).
- Each heavy chain class may be bound with either a kappa or lambda light chain.
- the light and heavy chains are covalently bonded to each other, and the “tail” portions of the two heavy chains are bonded to each other by covalent disulfide linkages or non-covalent linkages when the immunoglobulins are generated either by hybridomas, B cells or genetically engineered host cells.
- the amino acid sequences run from an N-terminus at the forked ends of the Y configuration to the C-terminus at the bottom of each chain.
- heavy chains are classified as gamma, mu, alpha, delta, or epsilon, ( ⁇ , ⁇ , ⁇ , ⁇ , ⁇ ) with some subclasses among them (e.g., ⁇ 1- ⁇ 4). It is the nature of this chain that determines the “class” of the antibody as IgG, IgM, IgA, IgD or IgE, respectively.
- the immunoglobulin subclasses e.g., IgG1, IgG2, IgG3, IgG4, IgA1, etc. are well characterized and are known to confer functional specialization.
- the term “antibody” as used herein encompasses antibodies from any class or subclass of antibody.
- Antigen binding fragment refers to fragments that are parts or portions of a full-length antibody or antibody chain comprising fewer amino acid residues than an intact or complete antibody whilst retaining antigen binding activity.
- An antigen-binding fragment of an antibody includes peptide fragments that exhibit specific immuno-reactive activity to the same antigen as the antibody (e.g. CD70).
- antigen binding fragment as used herein is intended to encompass antibody fragments selected from: an antibody light chain variable domain (VL); an antibody heavy chain variable domain (VH); a single chain antibody (scFv); a F(ab′)2 fragment; a Fab fragment; an Fd fragment; an Fv fragment; a one-armed (monovalent) antibody; diabodies, triabodies, tetrabodies or any antigen-binding molecule formed by combination, assembly or conjugation of such antigen binding fragments.
- the term “antigen binding fragment” as used herein may also encompass antibody fragments selected from the group consisting of: unibodies; domain antibodies; and nanobodies. Fragments can be obtained, for example, via chemical or enzymatic treatment of an intact or complete antibody or antibody chain or by recombinant means.
- the antibodies and antigen binding fragments of the present combinations and methods may be monospecific and contain one or more binding sites which specifically bind a particular target.
- multispecific antibody formats for example bispecific antibodies, wherein the multispecific antibody binds to two or more target antigens.
- multispecific antibodies are typically engineered to include different combinations or pairings of heavy and light chain polypeptides with different VH-VL pairs.
- Multispecific, notably bispecific antibodies may be engineered so as to adopt the overall conformation of a native antibody, for example a Y-shaped antibody having Fab arms of different specificities conjugated to an Fc region.
- multispecific antibodies, for example bispecific antibodies may be engineered so as to adopt a non-native conformation, for example wherein the variable domains or variable domain pairs having different specificities are positioned at opposite ends of the Fc region.
- Modified antibody includes synthetic forms of antibodies which are altered such that they are not naturally occurring, e.g., antibodies that comprise at least two heavy chain portions but not two complete heavy chains (such as, domain deleted antibodies or minibodies); multispecific forms of antibodies (e.g., bispecific, trispecific, etc.) altered to bind to two or more different antigens or to different epitopes on a single antigen); heavy chain molecules joined to scFv molecules and the like. scFv molecules are known in the art and are described, e.g., in U.S. Pat. No. 5,892,019.
- modified antibody includes multivalent forms of antibodies (e.g., trivalent, tetravalent, etc., antibodies that bind to three or more copies of the same antigen).
- a modified antibody of the invention is a fusion protein comprising at least one heavy chain portion lacking a CH2 domain and comprising a binding domain of a polypeptide comprising the binding portion of one member of a receptor ligand pair.
- “Humanising substitutions” refers to amino acid substitutions in which the amino acid residue present at a particular position in the VH or VL domain of an antibody is replaced with an amino acid residue which occurs at an equivalent position in a reference human VH or VL domain.
- the reference human VH or VL domain may be a VH or VL domain encoded by the human germline. Humanising substitutions may be made in the framework regions and/or the CDRs of the antibodies, defined herein.
- Humanised variants refers to a variant antibody which contains one or more “humanising substitutions” compared to a reference antibody, wherein a portion of the reference antibody (e.g. the VH domain and/or the VL domain or parts thereof containing at least one CDR) has an amino acid derived from a non-human species, and the “humanising substitutions” occur within the amino acid sequence derived from a non-human species.
- a portion of the reference antibody e.g. the VH domain and/or the VL domain or parts thereof containing at least one CDR
- the “humanising substitutions” occur within the amino acid sequence derived from a non-human species.
- “Germlined variants” The term “germlined variant” or “germlined antibody” is used herein to refer specifically to “humanised variants” in which the “humanising substitutions” result in replacement of one or more amino acid residues present at (a) particular position(s) in the VH or VL domain of an antibody with an amino acid residue which occurs at an equivalent position in a reference human VH or VL domain encoded by the human germline. It is typical that for any given “germlined variant”, the replacement amino acid residues substituted into the germlined variant are taken exclusively, or predominantly, from a single human germline-encoded VH or VL domain.
- the terms “humanised variant” and “germlined variant” are often used interchangeably.
- a camelid-derived (e.g. llama derived) VH or VL domain results in production of a “humanised variant” of the camelid (llama)-derived VH or VL domain. If the amino acid residues substituted in are derived predominantly or exclusively from a single human germline-encoded VH or VL domain sequence, then the result may be a “human germlined variant” of the camelid (llama)-derived VH or VL domain.
- CD70 refers to a member of the TNF ligand family which is a ligand for TNFRSF7/CD27. CD70 is also known as CD27L or TNFSF7.
- human CD70 protein or “human CD70 antigen” or “human CD70” are used interchangeably to refer specifically to the human homolog, including the native human CD70 protein naturally expressed in the human body and/or on the surface of cultured human cell lines, as well as recombinant forms and fragments thereof.
- Specific examples of human CD70 include the polypeptide having the amino acid sequence shown under NCBI Reference Sequence Accession No. NP_001243, or the extracellular domain thereof.
- BCL-2 family refers to the collection of pro- and anti-apoptotic proteins related to BCL-2, see Delbridge et al. (2016) Nat Rev Cancer. 16(2): 99-109. There are at least 16 members of this family categorized into three functional groups: (i) the BCL-2 like proteins (e.g. BCL-2, BCL-X L/ BCL2L1, BCLW BCL2L2, MCL2, BFL1/BCL2A1); (ii) BAX and BAK; and (iii) the BH3-only proteins (e.g. BIM, PUMA, BAD, BMF, BID, NOXA, HRK, BIK).
- BIM the BCL-2 like proteins
- BCL-2 BCL-X L/ BCL2L1, BCLW BCL2L2, MCL2, BFL1/BCL2A1
- BAX and BAK BH3-only proteins
- BH3-only proteins e.g. BIM, PUMA, BAD, BMF, BID, NO
- the BCL-2 family of proteins play an integral role in regulating the intrinsic apoptotic pathway with the anti-apoptotic members of the family (e.g. BCL-2, BCL-X L ) typically antagonizing the pro-apoptotic members (e.g. BAX and BIM).
- BCL-2, BCL-X L the anti-apoptotic members of the family
- BAX and BIM the pro-apoptotic members
- Deregulation of BCL-2 family members has been observed in many cancers, for example by gene translocations, amplifications, overexpression and mutations. The downstream effect of this deregulation is frequently apoptosis-resistance, which fuels cancer growth.
- BCL-2 refers to the first member of the BCL-2 protein family to be identified in humans i.e. B-cell lymphoma 2.
- the cDNA encoding human BCL-2 was cloned in 1986 and the key role of this protein in inhibiting apoptosis was elucidated in 1988.
- BCL-2 has been found to be upregulated in several different types of cancer. For example, BCL-2 is activated by the t(14;18) chromosomal translocation in follicular lymphoma.
- BCL-2 Amplification of the BCL-2 gene has also been reported in different cancers including leukemias (such as CLL), lymphomas (such as B-cell lymphoma) and some solid tumours (e.g. small-cell lung carcinoma).
- Human BCL-2 is encoded by the BCL2 gene (UniProtKB—P10415) and has the amino acid sequences shown under NCBI Reference Sequences NP_000624.2 and NP_000648.2.
- BCL-2 inhibitor refers to any agent, compound or molecule capable of specifically inhibiting the activity of BCL-2, in particular an agent, compound or molecule capable of inhibiting the anti-apoptotic activity of BCL-2.
- BCL-2 inhibitors suitable for use in the combinations described herein include B cell lymphoma homology 3 (BH3) mimetic compounds (Merino et al. (2016) Cancer Cell. 34(6): 879-891).
- BCL-2 inhibitors include but are not limited to venetoclax, ABT-737 (Oltersdorf, T. et al. (2005) Nature 435: 677-681), navitoclax/ABT-263 (Tse, C. et al.
- Venetoclax As used herein, the term “venetoclax” refers to the compound having the chemical structure shown below:
- Venetoclax is a potent, selective, orally-bioavailable inhibitor of the BCL-2 protein. It has the empirical formula C 45 H 50 ClN 7 O 7 S and a molecular weight of 868.44. It has very low aqueous solubility.
- Venetoclax can be described chemically as 4-(4- ⁇ [2-(4-chlorophenyl)-4,4dimethylcyclohex-1-en-1-yl]methyl ⁇ piperazin-1-yl)-N-( ⁇ 3-nitro-4-[(tetrahydro-2H-pyran-4ylmethyl)amino]phenyl ⁇ sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide).
- Alternative names for venetoclax include ABT-199; chemical name 1257044-40-8; GDC-0199.
- Venetoclax received approval in 2015 from the US Food and Drug Adminstration (FDA) for the treatment of adult patients with chronic lymphocytic leukemia (CLL) or small lymphocytic leukemia (SLL) who have received at least one prior therapy. Venetoclax is also approved in the US for use in combination with azacitidine or decitabine or low-dose cytarabine for the treatment of newly-diagnosed acute myeloid leukemia (AML) in adults aged 75 years or older or who have comorbidities that preclude use of intensive induction chemotherapy.
- FDA US Food and Drug Adminstration
- Myeloid malignancy refers to any clonal disease of hematopoietic stem or progenitor cells. Myeloid malignancies or myeloid malignant diseases include chronic and acute conditions. Chronic conditions include myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN) and chronic myelomonocytic leukemia (CMML), and acute conditions include acute myeloid leukemia (AML).
- MDS myelodysplastic syndromes
- MPN myeloproliferative neoplasms
- CMML chronic myelomonocytic leukemia
- AML acute myeloid leukemia
- AML acute myeloid leukemia
- AML refers to haematopoietic neoplasms involving myeloid cells. AML is characterised by clonal proliferation of myeloid precursors with reduced differentiation capacity. AML patients exhibit an accumulation of blast cells in the bone marrow. “Blast cells”, or simply “blasts”, as used herein refers to clonal myeloid progenitor cells exhibiting disrupted differentiation potential. Blast cells typically also accumulate in the peripheral blood of AML patients. Typically AML is diagnosed if the patient exhibits 20% or more blast cells in the bone marrow or peripheral blood.
- Standard intensive chemotherapy refers to the so-called “7+3” induction chemotherapy characterised by 7 days of high dose cytarabine followed by 3 days of anthracycline administration (e.g. daunorubicin or idarubicin).
- Standard intensive chemotherapy can be given to eligible newly-diagnosed AML patients with the aim of inducing complete remission of AML, typically with the intention of the patient undergoing a stem cell transplant following successful chemotherapy. As explained herein, not all newly-diagnosed AML patients are eligible for this standard intensive chemotherapy.
- LSCs are a subset of the blast cells associated with AML. LSCs are blast cells having stem cell properties such that, if transplanted into an immuno-deficient recipient, they are capable of initiating leukemic disease. LSCs can self-renew by giving rise to leukemia and also partially differentiate into non-LSC conventional blast cells that resemble the original disease but are unable to self-renew. LSCs occur with a frequency in the range of 1 in 10,000 to 1 in 1 million as a proportion of primary AML blast cells (Pollyea and Jordan (2017) Blood 129: 1627-1635, incorporated herein by reference). LSCs may be characterised as cells that are CD34+, CD38 ⁇ , optionally also CD45 ⁇ and/or CD123+. LSCs may also be characterised as CD45dim, SSClo, CD90+CD34+ cells.
- Anti-cancer agent refers to any agent that is capable of preventing, inhibiting or treating cancer growth directly or indirectly. Such agents include chemotherapeutic agents, immunotherapeutic agents, anti-angiogenic agents, radionuclides, etc, many examples of which are known to those skilled in the art.
- the present invention provides a combination therapy comprising (i) an antibody or antigen binding fragment thereof that binds to CD70; and (ii) a BCL-2 inhibitor.
- CD70 has already been characterised as an attractive target for anti-cancer therapy.
- CD70 is constitutively expressed on many types of hematological malignancies and solid carcinomas and its expression has been linked to poor prognosis for several cancers.
- Antibodies targeting CD70 have been developed and some have been taken forward into clinical development.
- Antibodies targeting CD70 have been found to be particularly effective for the treatment of myeloid malignancies, particularly the treatment of subjects with acute myeloid leukemia (AML).
- AML acute myeloid leukemia
- LSCs leukemic stem cells
- the present invention combines CD70 antibodies or antigen binding fragments thereof with a BCL-2 inhibitor.
- the BCL-2 protein is a member of the BCL-2 family. This family comprises more than 20 proteins. Members of the BCL-2 family are involved in the regulation of the intrinsic apoptosis pathway and play a fundamental role in regulating the balance between cell survival and death.
- the BCL-2 protein is an anti-apoptotic member of the BCL-2 family and is up-regulated in many different types of cancer.
- the overexpression of BCL-2 allows tumour cells to evade apoptosis by sequestering pro-apoptotic proteins.
- BCL-2 is highly expressed in many hematologic malignancies and is the predominant pro-survival protein in diseases such as chronic lymphocytic leukemia (CLL), follicular lymphoma and mantle cell lymphoma.
- CLL chronic lymphocytic leukemia
- follicular lymphoma follicular lymphoma
- mantle cell lymphoma mantle cell lymphoma.
- Inhibition of BCL-2 inhibits the anti-apoptotic or pro-survival activity of this protein.
- Anti-apoptotic members of the BCL-2 family, including BCL-2 have been reported as overexpressed in primary AML samples (Bogenberger et al.
- LSCs leukemic stem cells
- the combination of the present invention is considered to be particularly effective for the treatment of AML due to the combined therapeutic effect of the CD70 antibodies or antigen binding fragments and the BCL-2 inhibitor, particularly the combined effect at the level of the LSCs.
- the self-renewal capacity of LSCs means that the persistence of these cells is a major factor contributing to disease relapse.
- combinations of the invention exhibit synergistic treatment efficacy against AML cells—that is, the level of inhibition induced by the combination is greater than the additive effect of the monotherapies alone.
- Methods for determining synergistic interaction are familiar to the skilled person and are described in the Examples.
- a preferred method for determining whether synergistic effects arise from a combination is the Chou-Talalay method (Chou, TC. Cancer Res . (2010) 70(2); 440-6, incorporated herein by reference).
- the synergistic efficacy of the combinations of the invention translated into potent inhibition of primary LSC cells from AML patients.
- the combination therapy of the present invention thus targets both the blast cells and the LSC compartment thereby improving the likelihood of disease remission whilst reducing the risk of relapse.
- the BCL-2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof.
- Venetoclax is a small-molecule inhibitor of BCL-2, described in US2010/0305122 (incorporated herein by reference).
- venetoclax By inhibiting BCL-2, venetoclax inhibits the anti-apoptotic or pro-survival activity of this protein. Venetoclax induces apoptosis rapidly in the majority of CLL cells and BCL-2-overexpressing lymphoma cell lines.
- venetoclax may be useful as a therapy for AML (Konopleva et al. (2016) Cancer Discov. 6(10); 1106-17). However, it was found to have limited activity as a monotherapy. Subsequent studies investigated the efficacy of venetoclax in combination with hypomethylating agents, namely azacitidine and decitadine, and these combinations were found to be particularly efficacious (Bogenberger et al. (2015) Leuk Lymphoma 56(1): 226-229). Clinical trials have been carried out to test the combination of venetoclax with either azacitidine, decitabine, or low-dose cytarabine (Dinardo et al. (2016) Lancet Oncol.
- the BCL-2 inhibitor is a B cell lymphoma homology 3 (BH3) mimetic compound.
- the BCL-2 inhibitor is selected from ABT-737, navitoclax, BM-1197, S44563, BCL2-32, AZD4320 or S55746.
- Antibodies or antigen binding fragments that bind to CD70 and that may be incorporated into any of the combinations described herein include but are not limited to: CD70 antibodies or antigen binding fragments that inhibit interaction of CD70 with CD27; CD70 antibodies or antigen binding fragments that compete with CD27 for CD70 binding; CD70 antibodies or antigen binding fragments that inhibit CD70-induced CD27 signalling; CD70 antibodies or antigen binding fragments that inhibit Treg activation and/or proliferation; CD70 antibodies or antigen binding fragments that deplete CD70-expressing cells; CD70 antibodies or antigen binding fragments that induce lysis of CD70-expressing cells; CD70 antibodies or antigen binding fragments that possess ADCC, CDC functionality, and/or induce ADCP.
- CD70 antibodies are ARGX-110 described in WO2012/123586 (incorporated herein by reference), SGN-70 (WO2006/113909, and McEarChern et al. (2008) Clin Cancer Res. 14(23):7763, both incorporated herein by reference) and those CD70 antibodies described in WO2006/044643 and WO2007/038637 (each incorporated herein by reference).
- WO2006/044643 describes CD70 antibodies containing an antibody effector domain which can mediate one or more of ADCC, ADCP or CDC and either exert a cytostatic or cytotoxic effect on a CD70-expressing cancer or exert an immunosuppressive effect on a CD70-expressing immunological disorder in the absence of conjugation to a cytostatic or cytotoxic agent.
- the antibodies exemplified therein are based on the antigen-binding regions of two monoclonal antibodies, denoted 1F6 and 2F2.
- WO2007/038637 describes fully human monoclonal antibodies that bind to CD70. These antibodies are characterised by binding to human CD70 with a K D of 1 ⁇ 10 7 M or less. The antibodies also bind to, and are internalised by, renal cell carcinoma tumor cell lines which express CD70, such as 786-0.
- ARGX-110 is an IgG1 anti-CD70 antibody, also known as cusatuzumab.
- ARGX-110 has been shown to inhibit the interaction of CD70 with its receptor CD27 (Silence et al. (2014) MAbs . March-April; 6(2):523-32, incorporated herein by reference).
- ARGX-110 has been shown to inhibit CD70-induced CD27 signalling.
- Levels of CD27 signalling may be determined by, for example, measurement of serum soluble CD27 as described in Riether et al. ( J. Exp. Med . (2017) 214(2); 359-380) or of IL-8 expression as described in Silence et al. ( MAbs (2014) 6(2): 523-32).
- ARGX-110 has also been demonstrated to deplete CD70-expressing tumour cells.
- ARGX-110 has been shown to lyse CD70-expressing tumour cells via antibody dependent cell-mediated cytotoxicity (ADCC) and complement dependent cytotoxicity (CDC), and also to increase antibody dependent cellular phagocytosis (ADCP) of CD70-expressing cells (Silence et al., ibid).
- ADCC antibody dependent cell-mediated cytotoxicity
- CDC complement dependent cytotoxicity
- ADCP antibody dependent cellular phagocytosis
- the CDR, VH and VL amino acid sequences of ARGX-110 or cusatuzumab are shown in the table below.
- the antibody or antigen binding fragment thereof that binds to CD70 comprises a variable heavy chain domain (VH) and a variable light chain domain (VL) wherein the VH and VL domains comprise the CDR sequences:
- the antibody or antigen binding fragment thereof that binds to CD70 is an IgG, preferably an IgG1.
- the antibody or antigen binding fragment thereof that binds to CD70 comprises a variable heavy chain domain (VH domain) comprising or consisting of a sequence at least 70%, at least 80%, at least 90% or at least 95% identical to SEQ ID NO: 4 and a variable light chain domain (VL domain) comprising or consisting of a sequence at least 70%, at least 80%, at least 90% or at least 95% identical to SEQ ID NO: 8.
- VH domain variable heavy chain domain
- VL domain variable light chain domain
- the antibody molecule that binds to CD70 comprises a variable heavy chain domain (VH domain) comprising or consisting of SEQ ID NO: 4 and a variable light chain domain (VL domain) comprising or consisting of SEQ ID NO: 8.
- VH domain variable heavy chain domain
- VL domain variable light chain domain
- the VH and/or VL domains may retain the CDR sequences of the reference sequence.
- the CD70 antibodies or antigen binding fragments defined herein with reference to SEQ ID NOs: 4 and 8 may retain the CDR sequences as represented by SEQ ID NOs: 1-3 and 5-7.
- CD70 antibody or antigen binding fragments thereof that may be incorporated into the combinations described herein include antibody drug conjugates (ADCs).
- ADCs are antibodies attached to active agents, for example auristatins and maytansines or other cytotoxic agents. Certain ADCs maintain antibody blocking and/or effector function (e.g. ADCC, CDC, ADCP) while also delivering the conjugated active agent to cells expressing the target (e.g. CD70).
- anti-CD70 ADCs examples include vorsetuzumab mafodotin (also known as SGN-75, Seattle Genetics), SGN-70A (Seattle Genetics), and MDX-1203/BMS936561 (Bristol-Myers Squibb), each of which may be used in accordance with the invention.
- Suitable anti-CD70 ADCs are also described in WO2008074004 and WO2004073656, each of which is incorporated herein by reference.
- the CD70 antibodies or antigen binding fragments described herein are combined with venetoclax or a pharmaceutically acceptable salt thereof.
- Venetoclax is a small molecule inhibitor of BCL-2 as described elsewhere herein.
- Venetoclax for use in the combination therapies described herein may be provided in any suitable form such that it effectively inhibits the BCL-2 protein.
- Such forms include but are not limited to any suitable polymorphic, amorphous or crystalline forms or any isomeric or tautomeric forms.
- the combination therapies described herein comprise venetoclax synthesised according to the process described in US2010/0305122 (incorporated herein by reference).
- the combination therapies described herein comprise venetoclax according to the forms or synthesised according to the processes described in any one of EP3333167, WO2017/156398, WO2018/029711, CN107089981 (A), WO2018/069941, WO2017/212431, WO2018/009444, CN107648185 (A), WO2018/167652, WO2018/157803, CZ201769 (each incorporated herein by reference).
- the combination therapies described herein comprise venetoclax in any of the crystalline or salt forms described in WO2012/071336 (incorporated herein by reference).
- Pharmaceutically acceptable salts for use in accordance with the present invention include salts of acidic or basic groups.
- Pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzensulfonate, p-toluenesulfonate and pamoate (i.e., 1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts.
- Pharmaceutically acceptable salts may be formed with various amino acids.
- Venetoclax for use in the combination therapies described herein may also be provided in the form of a hydrate, anhydrate or solvate.
- Venetoclax is marketed and sold by AbbVie Inc and Genentech under the trade name Venclexta®.
- the combinations described herein comprise an antibody or antigen binding fragment thereof that binds CD70 and Venclexta®.
- the combinations of the present invention may include one or more additional agents, for example one or more additional anti-cancer agents.
- the combination comprises one or more “nucleoside metabolic inhibitors” (NMIs).
- NMIs are molecules that interfere with epigenetic modification (e.g. methylation, demethylation, acetylation, or deacetylation) of nucleotides (DNA and/or RNA).
- nucleoside metabolic inhibitors include hypomethylating agents (HMAs), isocitrate dehydrogenase (IDH) inhibitors, histone deacetylase (HDAC) inhibitors, and bromodomain and extraterminal (BET) inhibitors.
- HMAs hypomethylating agents
- IDH isocitrate dehydrogenase
- HDAC histone deacetylase
- BET bromodomain and extraterminal
- Preferred nucleoside metabolic inhibitors are hypomethylating agents. Hypomethylating agents inhibit normal methylation of DNA and/or RNA. Examples of hypomethylating agents are azacitidine, decitabine and guadecitabine.
- the combinations of the invention additionally comprise azacitidine (also referred to herein as azacytidine, AZA or aza).
- azacitidine also referred to herein as azacytidine, AZA or aza.
- the present invention provides a combination comprising (i) an antibody or antigen binding fragment thereof that binds to CD70; (ii) venetoclax or a pharmaceutically acceptable salt thereof; and (iii) azacitidine.
- the combinations of the invention additionally comprise decitabine.
- the present invention provides a combination comprising (i) an antibody or antigen binding fragment thereof that binds to CD70; (ii) venetoclax or a pharmaceutically acceptable salt thereof; and (iii) decitabine.
- Azacitidine is an analogue of cytidine and decitabine is its deoxy derivative.
- Azacitdine and decitabine are inhibitors of DNA methyltransferases (DNMT) known to upregulate gene expression by promoter hypomethylation. Such hypomethylation disrupts cell function, thereby resulting in cytotoxic effects.
- DNMT DNA methyltransferases
- the combinations of the present invention additionally comprise cytarabine.
- Cytarabine also known as “cytosine arabinose” or “ara-C” is a chemotherapeutic drug commonly used to treat AML.
- High-dose cytarabine forms part of the “7+3” standard induction chemotherapy typically used for newly-diagnosed AML patients.
- Low-dose cytarabine may be used for AML patients who are not eligible for the standard induction chemotherapy.
- low-dose cytarabine is prescribed in combination with venetoclax for newly-diagnosed AML patients ineligible for standard induction chemotherapy.
- the combinations of the present invention may additionally comprise low-dose cytarabine.
- the combinations of the present invention comprise an additional anti-cancer agent.
- the one or more additional cancer agents may be selected from any agents suitable for the treatment of myeloid malignancies, preferably AML.
- Preferred agents may be selected from: selectin inhibitors (e.g. GMI-1271); FMS-like tyrosine kinase receptor 3 (FLT3) inhibitors (e.g. midostaurin or gilteritinib); cyclin-dependent kinase inhibitors; aminopeptidase inhibitors; JAK/STAT inhibitors; cytarabine; fludarabine; anthracycline compounds (e.g.
- the agents of the combinations described herein may be combined or formulated in any manner allowing the combination therapy to be administered to a subject or patient in need thereof, preferably a human subject or patient in need thereof.
- the combination may be formulated for single dose administration or for multiple dose administration.
- the agents of the combinations may be co-formulated i.e. formulated as a single pharmaceutical composition.
- the combination or composition is suitable for simultaneous administration of the agents.
- the agents of the combinations described herein are formulated as separate compositions or pharmaceutical compositions.
- the agents are formulated separately, the possibility exists for simultaneous or separate administration of the different agents or compositions. If the different compositions are administered separately, there may be sequential administration of the agents in any preferred order. The interval between administration of the agents may be any suitable time interval. The administration of the different compositions may be carried out once (for a single dose administration) or repeatedly (for a multiple dose administration).
- CD70 antibodies or antigen binding fragments of the combinations described herein may be formulated using any suitable pharmaceutical carriers, adjuvants and/or excipients. Techniques for formulating antibodies for human therapeutic use are well known in the art and are reviewed, for example, in Wang et al. (2007) Journal of Pharmaceutical Sciences, 96:1-26, the contents of which are incorporated herein in their entirety.
- compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances (for example sodium carboxymethylcellulose), polyethylene glycol, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.
- ion exchangers alumina, aluminum stearate, lecithin
- serum proteins such as human serum albumin
- buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial
- the BCL-2 inhibitor (preferably venetoclax or a pharmaceutically acceptable salt thereof) may be formulated using any suitable pharmaceutical carriers, adjuvants and/or excipients.
- suitable agents include, for example, encapsulating materials or additives such as absorption accelerators, antioxidants, binders, buffers, coating agents, coloring agents, diluents, disintegrating agents, emulsifiers, extenders, fillers, flavoring agents, humectants, lubricants, perfumes, preservatives, propellants, releasing agents, sterilizing agents, sweeteners, solubilizers, wetting agents and mixtures thereof.
- compositions are formulated for administration to a subject via any suitable route of administration including but not limited to intramuscular, intravenous, intradermal, intraperitoneal injection, subcutaneous, epidural, nasal, oral, rectal, topical, inhalational, buccal (e.g., sublingual), and transdermal administration.
- the compositions are formulated as aqueous solutions, tablets, capsules, powders or any other suitable dosage form.
- Excipients for preparation of compositions comprising a BCL-2 inhibitor (preferably venetoclax) to be administered orally in solid dosage form include, for example, agar, alginic acid, aluminum hydroxide, benzyl alcohol, benzyl benzoate, 1,3-butylene glycol, carbomers, castor oil, cellulose, cellulose acetate, cocoa butter, corn starch, corn oil, cottonseed oil, cross-povidone, diglycerides, ethanol, ethyl cellulose, ethyl laureate, ethyl oleate, fatty acid esters, gelatin, germ oil, glucose, glycerol, groundnut oil, hydroxypropylmethyl cellulose, isopropanol, isotonic saline, lactose, magnesium hydroxide, magnesium stearate, malt, mannitol, monoglycerides, olive oil, peanut oil, potassium phosphate salts, potato starch, povidone, propy
- Excipients for preparation of compositions comprising a BCL-2 inhibitor (preferably venetoclax) to be administered orally in liquid dosage forms include, for example, 1,3-butylene glycol, castor oil, corn oil, cottonseed oil, ethanol, fatty acid esters of sorbitan, germ oil, groundnut oil, glycerol, isopropanol, olive oil, polyethylene glycols, propylene glycol, sesame oil, water and mixtures thereof.
- Excipients for preparation of compositions comprising a BCL-2 inhibitor (preferably venetoclax) to be administered osmotically include, for example, chlorofluorohydrocarbons, ethanol, water and mixtures thereof.
- Excipients for preparation of compositions comprising a BCL-2 inhibitor (preferably venetoclax) to be administered parenterally include, for example, 1,3-butanediol, castor oil, corn oil, cottonseed oil, dextrose, germ oil, groundnut oil, liposomes, oleic acid, olive oil, peanut oil, Ringer's solution, safflower oil, sesame oil, soybean oil, U.S. P. or isotonic sodium chloride solution, water and mixtures thereof.
- the separate compositions may be formulated for the same route of administration.
- the separate compositions may be formulated for different routes of administration.
- the CD70 antibody or antigen binding fragment may be formulated for intravenous administration and the BCL-2 inhibitor (preferably venetoclax) may be formulated for oral administration.
- Venclexta® is a venetoclax product marketed and sold by AbbVie Inc and Genentech.
- Venclexta® tablets for oral administration are supplied as pale yellow or beige tablets that contain 10, 50, or 100 mg venetoclax as the active ingredient.
- Each tablet also contains the following inactive ingredients: copovidone, colloidal silicon dioxide, polysorbate 80, sodium stearyl fumarate, and calcium phosphate dibasic.
- the 10 mg and 100 mg coated tablets include the following: iron oxide yellow, polyvinyl alcohol, polyethylene glycol, talc, and titanium dioxide.
- the 50 mg coated tablets also include the following: iron oxide yellow, iron oxide red, iron oxide black, polyvinyl alcohol, talc, polyethylene glycol and titanium dioxide.
- the CD70 antibody or antigen binding fragment may be formulated for intravenous administration whilst the Venclexta® is provided as one or more of the tablet forms described above.
- the one or more additional agents may be formulated for administration via the same route or via a different route as compared with the other agents.
- the combination includes (i) an antibody or antigen binding fragment thereof that binds to CD70; (ii) venetoclax or a pharmaceutically acceptable thereof; and (iii) azacitidine
- the antibody or antigen binding fragment may be administered intravenously, the venetoclax or pharmaceutically acceptable salt thereof may be administered orally whilst the azacitidine may be administered subcutaneously via injection.
- the combination includes (i) an antibody or antigen binding fragment thereof that binds to CD70; (ii) venetoclax or a pharmaceutically acceptable thereof; and (iii) decitabine
- the antibody or antigen binding fragment may be administered intravenously, the venetoclax or pharmaceutically acceptable salt thereof may be administered orally whilst the decitabine may be administered subcutaneously via injection.
- the combination therapies described in accordance with the first aspect of the invention can be used in methods of treating a malignancy, particularly a myeloid malignancy, in a human subject.
- the present invention provides an antibody or antigen binding fragment thereof that binds to CD70 for use in the treatment of a malignancy, particularly a myeloid malignancy, in a human subject, wherein the antibody or antigen binding fragment thereof is administered in combination with a BCL-2 inhibitor.
- the present invention also provides a BCL-2 inhibitor for use in the treatment of a malignancy, particularly a myeloid malignancy, in a human subject, wherein the BCL-2 inhibitor is administered in combination with an antibody or antigen binding fragment that binds to CD70.
- the BCL-2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof.
- the present invention further provides a combination in accordance with the first aspect of the invention for use in the treatment of a malignancy, particularly a myeloid malignancy, in a human subject.
- the present invention provides a method for treating a malignancy, particularly a myeloid malignancy, in a human subject, said method comprising administering to the subject a combination in accordance with the first aspect of the invention.
- the invention also provides a method for treating a malignancy, particularly a myeloid malignancy, in a human subject, said method comprising the steps of (i) administering to the subject an antibody or antigen binding fragment thereof that binds to CD70; and (ii) administering to the subject a BCL-2 inhibitor, preferably venetoclax or a pharmaceutically acceptable salt thereof. Steps (i) and (ii) of the method may be performed in either order.
- malignancy encompasses diseases in which abnormal cells proliferate in an uncontrolled manner and invade the surrounding tissues. Malignant cells that have entered the body's blood and lymph systems are capable of travelling to distal sites in the body and seeding at secondary locations.
- the methods described herein are for treating malignancies comprising the production of cancer progenitor or stem cells expressing CD70, CD27, or both.
- upregulated CD70 expression has been detected in different types of cancers including renal cell carcinomas, metastatic breast cancers, brain tumours, leukemias, lymphomas and nasopharyngeal carcinomas.
- Co-expression of CD70 and CD27 has also been detected in malignancies of the hematopoietic lineage including acute lymphoblastic lymphoma and T cell lymphoma.
- the methods described herein are for the treatment of any of the aforementioned malignancies associated with CD70 expression, CD27 expression or both.
- the methods described herein are for treating myeloid malignancies, wherein a myeloid malignancy refers to any clonal disease of hematopoietic stem or progenitor cells.
- the myeloid malignancy treated in accordance with the methods of the invention may be a newly-diagnosed myeloid malignancy or a relapsed/refractory myeloid malignancy.
- the myeloid malignancy is selected from: acute myeloid leukemia (AML); myelodysplastic syndromes (MDS); myeloproliferative neoplasms (MPN); chronic myeloid leukemia (CML); and chronic myelomonocytic leukemias (CMML).
- AML acute myeloid leukemia
- MDS myelodysplastic syndromes
- MN myeloproliferative neoplasms
- CML chronic myeloid leukemia
- CMML chronic myelomonocytic leukemias
- the myeloid malignancy is acute myeloid leukemia (AML).
- Myeloid malignancies can be categorised and diagnosed according to the WHO 2008 classification, taken in combination with the 2016 update to this classification, see in particular Arber et al. (2016) Blood 127(20):2391-2405, incorporated herein by reference.
- AML Acute myeloid leukemia
- AML refers to haematopoietic neoplasms involving myeloid cells.
- AML is characterised by clonal proliferation of myeloid precursors with reduced differentiation capacity.
- AML patients exhibit an accumulation of blast cells in the bone marrow.
- Blast cells also accumulate in the peripheral blood of AML patients.
- AML is diagnosed if the patient exhibits 20% or more blast cells in the bone marrow or peripheral blood.
- AML in general encompasses the following subtypes: AML with recurrent genetic abnormalities; AML with myelodysplasia-related changes; therapy-related myeloid neoplasms; myeloid sarcoma; myeloid proliferations related to Down syndrome; blastic plasmacytoid dendritic cell neoplasm; and AML not otherwise categorized (e.g. acute megakaryoblastic leukemia, acute basophilic leukemia).
- AML can also be categorised according to the French-American-British (FAB) classification, encompassing the subtypes: M0 (acute myeloblastic leukemia, minimally differentiated); M1 (acute myeloblastic leukemia, without maturation); M2 (acute myeloblastic leukemia, with granulocytic maturation); M3 (promyelocytic, or acute promyelocytic leukemia (APL)); M4 (acute myelomonocytic leukemia); M4eo (myelomonocytic together with bone marrow eosinophilia); M5 (acute monoblastic leukemia (M5a) or acute monocytic leukemia (M5b)); M6 (acute erythroid leukemias, including erythroleukemia (M6a) and very rare pure erythroid leukaemia (M6b)); or M7 (acute megakaryoblastic le
- AML refers to any of the conditions encompassed by the WHO and/or FAB classifications, unless specified otherwise. Certain AML subtypes are considered to be of more favourable prognosis, some of intermediate prognosis and some of poor prognosis. The skilled person is aware of which subtypes would fall into which risk category.
- MDS Myelodysplastic syndrome
- MDS is characterised by dysplasia, cytopenia and/or abnormal changes in bone marrow cellularity and/or myeloid differentiation, for example increased blast cell infiltration.
- MDS in general encompasses the following subtypes: MDS with single lineage dysplasia (previously called “refractory cytopenia with unilineage dysplasia”, which includes refractory anemia, refractory neutropenia, and refractory thrombocytopenia); MDS with ring sideroblasts, which includes subgroups with single lineage dysplasia and multilineage dysplasia (previously called “refractory anemia with ring sideroblasts”); MDS with multilineage dysplasia (previously called “refractory cytopenia with multilineage dysplasia”); MDS with excess blasts (MDS-EB, previously called “refractory anemia with excess blasts”), which can be further subclassified into MDS
- MDS can also be categorised according to the French-American-British (FAB) classification, encompassing the subtypes: M9980/3 (refractory anaemia (RA)); M9982/3 (refractory anaemia with ring sideroblasts (RARS)); M9983/3 (refractory anaemia with excess blasts (RAEB)); M9984/3 (refractory anaemia with excess blasts in transformation (RAEB-T)); and M9945/3 (chronic myelomonocytic leukemia (CMML)).
- FAB French-American-British
- MDS refers to any of the conditions encompassed by the WHO and/or FAB classifications, unless specified otherwise.
- the WHO categorisation is preferred herein.
- MDS Myeloproliferative neoplasms
- CML chronic myeloid leukemia
- CCL chronic neutrophilic leukemia
- PV polycythemia vera
- PMF primary myelofibrosis
- ET Essential thrombocythemia
- CMML Chronic myelomonocytic leukemia
- aCML atypical chronic myeloid leukemia
- the patients or subjects treated in accordance with the methods described herein, particularly those having AML, may have newly-diagnosed disease, relapsed disease or primary refractory disease.
- a standard approach to treatment for newly-diagnosed AML patients is the “standard 7+3 intensive chemotherapy” approach characterised by 7 days of high dose cytarabine followed by 3 days of anthracycline administration (e.g. daunorubicin or idarubicin).
- Intensive chemotherapy is given with the aim of inducing complete remission of AML, typically with the intention of the patient undergoing a stem cell transplant following successful chemotherapy.
- Standard intensive chemotherapy is associated with significant toxicity and side-effects, meaning it is not suitable for patients unable to tolerate these effects. These patients are termed “ineligible for standard intensive chemotherapy”.
- a patient may be ineligible for standard intensive chemotherapy because, for example, they exhibit one or more comorbidities indicating they would not tolerate the toxicity, or the prognostic factors characterising their disease indicate an unfavourable outcome of standard intensive chemotherapy. Determination of an individual patient's eligibility for standard intensive chemotherapy would be performed by a clinician taking into account the individual patient's medical history and clinical guidelines (e.g. the National Comprehensive Cancer Network (NCCN) guidelines, incorporated herein by reference). AML patients over the age of 60 are often assessed as ineligible for standard intensive chemotherapy, with other factors to be considered including the cytogenetics and/or molecular abnormalities of the AML being treated.
- NCCN National Comprehensive Cancer Network
- a patient ineligible for standard intensive chemotherapy may instead receive chemotherapy of reduced intensity, such as low dose cytarabine (LDAC).
- LDAC low dose cytarabine
- Patients ineligible for standard intensive chemotherapy and for whom LDAC is not appropriate can receive best supportive care (BSC), including hydroxyurea (HU) and transfusion support.
- BSC best supportive care
- Patients or subjects treated in accordance with the methods described herein may be those classified as “ineligible for standard intensive chemotherapy”.
- the combinations of the invention comprise targeted therapies that may be predicted to have fewer side-effects.
- patients deemed ineligible for standard intensive chemotherapy for any of the reasons identified above, may be treated with the combinations according to the present invention.
- venetoclax is authorised in the US for use in combination with azacitidine, decitabine or low-dose cytarabine for the treatment of newly-diagnosed AML in adults who are aged 75 years or older or who have comorbidities that preclude use of intensive induction chemotherapy.
- the BCL-inhibitor is venetoclax or a pharmaceutically acceptable salt thereof
- patients or subjects treated in accordance with the methods described herein are newly-diagnosed AML patients aged 75 years or older.
- patients or subjects treated in accordance with the methods described herein are newly-diagnosed AML patients having comorbidities that preclude use of intensive induction therapy.
- Patients having a comorbidity precluding use of intensive induction chemotherapy may be classified as such based on at least one of the following criteria: baseline Eastern Cooperative Oncology Group (ECOG) performance status of 2-3, severe cardiac or pulmonary comorbidity, moderate hepatic impairment, or CLcr ⁇ 45 ml/min.
- ECOG Eastern Cooperative Oncology Group
- Such embodiments are particularly preferred when the BCL-2 inhibitor in the combination according to the invention is venetoclax or a pharmaceutically acceptable salt thereof.
- Patients or subjects treated in accordance with the methods described herein may be eligible for other treatments, for example standard intensive chemotherapy, but may receive the combination therapies described herein as an alternative treatment option.
- patients or subjects treated in accordance with the methods described herein may be newly-diagnosed AML patients otherwise eligible for standard intensive chemotherapy.
- the methods described herein may include administration of one or more additional therapeutic agents, for example, additional anti-cancer agents.
- the methods comprise the administration of one or more agents for use in treating myeloid malignancies, for example agents suitable for use in treating AML.
- agents include but are not limited to: selectin inhibitors (e.g. GMI-1271); FMS-like tyrosine kinase receptor 3 (FLT3) inhibitors (e.g. midostaurin or gilteritinib); cyclin-dependent kinase inhibitors; aminopeptidase inhibitors; JAK/STAT inhibitors; cytarabine; fludarabine; anthracycline compounds (e.g.
- selectin inhibitors e.g. GMI-1271
- FMS-like tyrosine kinase receptor 3 (FLT3) inhibitors e.g. midostaurin or gilteritinib
- cyclin-dependent kinase inhibitors aminopeptidase inhibitors
- the methods described herein comprise administration of a further agent that is a nucleoside metabolic inhibitor, preferably a hypomethylating agent.
- a nucleoside metabolic inhibitor preferably a hypomethylating agent.
- Particularly preferred hypomethylating agents are azacitidine and decitabine.
- the combinations of the invention comprising (i) a CD70 antibody or antigen binding fragment thereof; and (ii) a BCL-2 inhibitor, preferably venetoclax or a pharmaceutically acceptable salt, may be formulated so as to include additional agents, for example azacitidine or decitabine.
- the methods wherein the combination is administered to a subject may comprise a further step of administering the additional agent, for example azacitidine or decitabine.
- the present invention provides a method for treating a myeloid malignancy, preferably AML, in a human subject, said method comprising administering to the subject: (i) an antibody or antigen binding fragment thereof that binds to CD70; (ii) a BCL-2 inhibitor, preferably venetoclax or a pharmaceutically acceptable salt thereof; and (iii) azacitidine or decitabine.
- a combination for use in treating a myeloid malignancy, preferably AML, in a human subject comprising: (i) an antibody or antigen binding fragment thereof that binds to CD70; (ii) a BCL-2 inhibitor, preferably venetoclax or a pharmaceutically acceptable salt thereof; and (iii) azacitidine or decitabine.
- combinations of the invention exhibit synergistic treatment efficacy against AML cells—that is, the level of inhibition induced by the combination is greater than the additive effect of the monotherapies alone.
- a CI of ⁇ 1 shows synergy
- a CI>1 shows antagonism
- the dose at which the CD70 antibody or antigen binding fragment thereof is administered and/or provided in the combination, and the dose at which the BCL-2 inhibitor is administered and/or provided in the combination are each selected such that the combination provides synergistic treatment—that is, where the combination exhibits a CI of less than 1 as determined by the Chou-Talalay method.
- the doses are such that the combination exhibits a CI of less than 0.5.
- the dose at which the CD70 antibody or antigen binding fragment thereof is administered and/or provided in the combination, and the dose at which the BCL-2 inhibitor is administered and/or provided in the combination are each selected such that the combination exhibits a CI of less than 1 and Fa of >0.5, as determined by the Chou-Talalay method.
- the combination includes an HMA
- the dose at which the CD70 antibody or antigen binding fragment thereof is administered and/or provided in the combination, the dose at which the BCL-2 inhibitor is administered and/or provided in the combination, and the dose at which the HMA is administered and/or provided in the combination are each selected such that the combination provides synergistic efficacy in treatment.
- CD70 antibodies are effective for the treatment of myeloid malignancy, particularly AML, at relatively low dose. Therefore, in certain embodiments of all methods of the invention the CD70 antibody or antigen binding fragment thereof is administered at a dose in the range from 0.1 mg/kg to 25 mg/kg per dose, for example in the range of from 0.1 mg/kg to 20 mg/kg. In certain embodiments, the CD70 antibody or antigen binding fragment thereof is administered at a dose in the range from 1 mg/kg to 20 mg/kg per dose.
- Ranges described herein include the end points of the range unless indicated otherwise—for example, administration at a dose in the range of 0.1-25 mg/kg includes administration at a dose of 0.1 mg/kg and administration at a dose of 25 mg/kg, as well as all doses between the two end points.
- the CD70 antibody or antigen binding fragment thereof is administered at a dose in the range from 0.1 mg/kg to 15 mg/kg. In certain embodiments the CD70 antibody or antigen binding fragment thereof is administered at a dose in the range from 0.5 mg/kg to 2 mg/kg. In certain embodiments the CD70 antibody or antigen binding fragment thereof is administered at a dose of 1 mg/kg, 3 mg/kg, 10 mg/kg, or 20 mg/kg. In certain preferred embodiments the CD70 antibody or antigen binding fragment thereof is administered at a dose of 1 mg/kg. In certain preferred embodiments the CD70 antibody or antigen binding fragment thereof is administered at a dose of 10 mg/kg.
- each dose of the CD70 antibody or antigen binding fragment is administered.
- each dose of the CD70 antibody or antigen-binding fragment thereof is separated by 10-20 days, optionally 12-18 days.
- each dose of anti-CD70 antibody is separated by 14-17 days.
- the BCL-2 inhibitor, preferably venetoclax or pharmaceutically acceptable salt thereof, of the combination may be dosed according to any regimen determined to be effective for the compound.
- the FDA prescribing information for use of Venclexta® in treating AML proposes a dosing schedule having a ramp-up phase followed by a maintenance phase.
- a dosing schedule is recommended consisting of: 100 mg Venclexta® on day 1; 200 mg Venclexta® on day 2; 400 mg Venclexta® on day 3; and 400 mg Venclexta® in combination with 75 mg/m 2 azacitidine or 20 mg/m 2 decitabine daily thereafter until disease progression or unacceptable toxicity is observed.
- a dosing schedule is recommended consisting of: 100 mg Venclexta® on day 1; 200 mg Venclexta® on day 2; 400 mg Venclexta® on day 3; and 600 mg Venclexta® in combination with 20 mg/m 2 daily thereafter until disease progression or unacceptable toxicity is observed.
- each dose, for example oral dose, of the venetoclax or pharmaceutically acceptable salt thereof is in the range from 100 mg-600 mg. In certain embodiments, the venetoclax or pharmaceutically acceptable salt thereof is dosed daily at 400 mg. In certain embodiments, the venetoclax or pharmaceutically acceptable salt thereof is dosed daily at 600 mg. As described above, the daily fixed-dosing of venetoclax may be preceded by a ramp-up period, for example 3 days, wherein increasing doses of venetoclax are administered to the patient until the maintenance daily dose is reached.
- the nucleoside metabolic inhibitor may be administered at a dose in the range of 20-100 mg/m 2 per day.
- ranges described herein include the end points of the range unless indicated otherwise—for example, administration at a dose in the range of 20-100 mg/m 2 per day includes administration at a dose of 20 mg/m 2 per day and administration at a dose of 100 mg/m 2 per day, as well as all doses between the two end points.
- the nucleoside metabolic inhibitor is azacitidine and is administered at a dose in the range of 70-80 mg/m 2 per day. In certain preferred embodiments the nucleoside metabolic inhibitor is azacitidine and is administered at a dose of 75 mg/m 2 per day.
- the nucleoside metabolic inhibitor is decitabine and is administered at a dose in the range of 15-25 mg/m 2 per day. In certain preferred embodiments the nucleoside metabolic inhibitor is decitabine and is administered at a dose of 20 mg/m 2 per day.
- the nucleoside metabolic inhibitor may be administered over a dosing period of a daily dose for 5-10 days. That is, a dose of the nucleoside inhibitor is administered every day for a period or 5, 6, 7, 8, 9, or 10 days in length. In certain preferred embodiments the nucleoside metabolic inhibitor is administered over a dosing period of a daily dose for 7 days.
- the preferred nucleoside metabolic inhibitor is azacitidine.
- the nucleoside metabolic inhibitor is administered according to a dosage regimen of repeated dosing periods, wherein the end of one dosing period and the start of the next dosing period are separated by 18-25 days. That is, the dosage regimen includes at least 2 dosing periods in which a dose of the nucleoside inhibitor is administered every day (for example for a period 5, 6, 7, 8, 9 or 10 days in length), wherein the end of the one dosing period and the start of the next dosing period are separated by 18, 19, 20, 21, 22, 23, 24, or 25 days. In certain embodiments the end of one dosing period and the start of the next dosing period are separated by 21 days.
- each dosing period is of the same length (e.g. 7 days). In certain embodiments, the end of each dosing period and the start of the next dosing period are separated by the same number of days (e.g. 21 days).
- the first dose of nucleoside metabolic inhibitor is administered 7-21 days after the first dose of CD70 antibody or antigen binding fragment thereof. In certain embodiments the first dose of nucleoside metabolic inhibitor is administered 10-17 days after the first dose of CD70 antibody or antigen binding fragment thereof. In certain embodiments the first dose of nucleoside metabolic inhibitor is administered 14 days after the first dose of CD70 antibody or antigen binding fragment thereof.
- one of the daily doses of the nucleoside metabolic inhibitor is administered on the same day as a dose of the CD70 antibody or antigen binding fragment thereof. That is, in embodiments of the methods of the invention in which the subject is administered both a CD70 antibody (or antigen binding fragment thereof) and a nucleoside metabolic inhibitor, the dosage regimes of both the CD70 antibody and the nucleoside metabolic inhibitor are such that at least one of the scheduled doses of the CD70 antibody is on the same day as one of the scheduled daily doses of the nucleoside metabolic inhibitor. That day could be the first, second, third, fourth, fifth, sixth or seventh day of the dosing period of the nucleoside metabolic inhibitor.
- a dose of the CD70 antibody or antigen binding fragment thereof is administered every 14-17 days and the nucleoside metabolic inhibitor is administered according to a dosage regimen of repeated dosing periods of a daily dose for 7 days, wherein the end of one dosing period and the start of the next dosing period are separated by 21 days, and wherein the first daily dose of the first dosing period is administered 14 days after the first dose of the anti-CD70 antibody or antigen-binding fragment thereof.
- one patient treatment cycle consists of 28 days and the nucleoside metabolic inhibitor, preferably azacitidine or decitabine, is administered every day for a period of 5, 6, 7, 8, 9 or 10 days beginning on day 1 of the cycle.
- the methods of treatment described herein may comprise multiple treatment cycles. Each treatment cycle may replicate the preceding treatment cycle.
- a patient treated with a CD70 antibody, a BCL-inhibitor (preferably venetoclax or a pharmaceutically acceptable salt thereof) and azacitidine is treated according to a cycle consisting of 28 days wherein azacitidine is administered daily on the first 7 days of the 28-day cycle.
- a patient treated with a CD70 antibody, a BCL-inhibitor (preferably venetoclax or a pharmaceutically acceptable salt thereof) and decitabine is treated according to a cycle consisting of 28 days wherein decitabine is administered daily on the first 5 days of the 28-day cycle.
- the CD70 antibody may be administered on day 3 and/or day 17 of the 28-day cycle.
- the CD70 antibody is ARGX-110.
- the CD70 antibody (for example ARGX-110) is administered at a dose of 10 mg/kg.
- NMI e.g. azacitidine
- treatment according to the invention comprises administering to the patient a CD70 antibody, a BCL-2 inhibitor (for example venetoclax) and a NMI as a combination therapy according to any of the embodiments described above in a first stage (induction therapy), and in a subsequent second stage administering to the patient a CD70 antibody, a BCL-2 inhibitor (for example venetoclax) and a NMI as a combination therapy but wherein the dose of the NMI in the second stage (maintenance therapy) is lower than the dose of NMI administered in the first stage.
- the dose of the NMI in the second stage may be zero.
- the dose of CD70 antibody administered in the second stage is any dose according to the embodiments already described. That is, in certain embodiments the dose is in the range from 0.1 mg/kg to 25 mg/kg, for example 0.1 mg/kg to 20 mg/kg, for example from 1 mg/kg to 20 mg/kg. In certain embodiments the dose is in the range of from 0.1 mg/kg to 15 mg/kg per dose. In certain embodiments the dose is in the range from 0.5 mg/kg to 2 mg/kg. In certain embodiments the dose is 1 mg/kg, 3 mg/kg, 10 mg/kg, or 20 mg/kg. In certain embodiments the dose is 1 mg/kg. In certain embodiments the dose is 10 mg/kg.
- the duration of the first stage i.e. induction therapy
- the timing of the transition to the second stage i.e. maintenance therapy
- the extent to which the dose of NMI is tapered or stopped entirely are factors that will be tailored to the individual patient and determined by their clinician according to the individual patient's response to therapy and their medical history. Therefore the following embodiments are provided by way of non-limiting example.
- the induction therapy is administered to the patient until their bone marrow and/or peripheral blood blast percentage is less than 10%, optionally less than 5%.
- the induction therapy is administered for at least 5 NMI dosing periods, optionally at least 6, 7, 8, 9, or at least 10 NMI dosing periods.
- the dose of the NMI in the maintenance period is no more than 50 mg/m 2 per day, optionally no more than 40 mg/m 2 per day, optionally no more than 30 mg/m2 per day, optionally no more than 20 mg/m 2 per day. In certain embodiments, the dose of the NMI in the maintenance period is zero.
- the agents of the combinations may be formulated for administration by any suitable routes of administration.
- the administration of the agents in accordance with the methods of the invention can be via any suitable routes and need not be via the same route for individual agents.
- the CD70 antibody or antigen binding fragment thereof may be administered intravenously whilst the BCL-2 inhibitor (e.g. venetoclax) is administered orally.
- the patient or subject receives a hypomethylating agent such as azacitidine or decitabine, such agent may be administered intravenously or subcutaneously via injection.
- blast cells or “blasts” refer to myeloblasts or myeloid blasts which are the myeloid progenitor cells within the bone marrow.
- blasts are not found in the peripheral blood circulation and there should be less than 5% blast cells in the bone marrow.
- myeloid malignancies particularly AML and MDS
- there is increased production of abnormal blasts with disrupted differentiation potential and the overproduction of these abnormal blasts can be detected by monitoring the patient's blast count in the peripheral blood circulation or the bone marrow or both.
- the proportion of blast cells in the bone marrow or peripheral blood can be assessed by methods known in the art, for example flow cytometric or cell morphologic assessment of cells obtained from a bone marrow biopsy of the subject, or a peripheral blood smear.
- the proportion of blasts is determined versus total cells in the sample.
- flow cytometry can be used to determine the proportion of blast cells using the number of CD45 dim , SSC low cells relative to total cell number.
- cell morphological assessment can be used to determine the number of morphologically identified blasts relative to the total number of cells in the field of view being examined.
- methods for reducing the proportion of blasts cells in the peripheral blood to less than 25%, less than 20%, for example less than 10%. In certain embodiments are provided methods for reducing the proportion of blasts cells in the peripheral blood to less than 5%. In certain embodiments are provided methods for reducing the proportion of blast cells in the peripheral blood to between about 5% and about 25%, wherein the peripheral blood blast cell percentage is also reduced by more than 50% as compared with the peripheral blast cell percentage prior to performing the method (or pretreatment).
- cell morphological assessment For clinical determination of blast cell percentage, typically cell morphological (also known as cytomorphology) assessment is preferred.
- a complete response or “complete remission” is defined as: bone marrow blasts ⁇ 5%; absence of circulating blasts and blasts with Auer rods; absence of extramedullary disease; ANC ⁇ 1.0 ⁇ 10 9 /L (1000 ⁇ L); platelet count ⁇ 100 ⁇ 10 9 /L (100,000 ⁇ L), see Döhner et al. (2017) Blood 129(4): 424-447.
- the methods may achieve a complete response with platelet recovery i.e. a response wherein the platelet count is >100 ⁇ 10 9 /L (100,000/ ⁇ L).
- the methods may achieve a complete response with neutrophil recovery i.e. a response wherein the neutrophil count is >1.0 ⁇ 10 9 /L (1000/ ⁇ L).
- the methods may induce a transfusion independence of red blood cells or platelets, or both, for 8 weeks or longer, 10 weeks or longer, 12 weeks or longer.
- the methods described herein induce a minimal or measurable residual disease (or MRD) status that is negative, see Schuurhuis et al. (2016) Blood. 131(12): 1275-1291.
- the methods described herein induce a complete response without minimal residual disease (CR MRD ⁇ ), see Döhner et al. ibid.
- a partial response or partial remission includes a decrease of the bone marrow blast percentage of 5% to 25% and a decrease of pretreatment bone marrow blast percentage by at least 50%, see Döhner et al. ibid.
- the methods described herein may increase survival.
- the term “survival” as used herein may refer to overall survival, 1-year survival, 2-year survival, 5-year survival, event-free survival, progression-free survival.
- the methods described herein may increase survival as compared with the gold-standard treatment for the particular disease or condition to be treated.
- the gold-standard treatment may also be identified as the best practice, the standard of care, the standard medical care or standard therapy. For any given disease, there may be one or more gold-standard treatments depending on differing clinical practice, for example in different countries.
- the treatments already available for myeloid malignancies are varied and include chemotherapy, radiation therapy, stem cell transplant and certain targeted therapies.
- the methods of the present invention may increase or improve survival relative to patients undergoing any of the standard treatments for myeloid malignancy.
- the methods described herein may include a further step of subjecting the patient or subject to a bone marrow transplant.
- the methods described herein may also be used to prepare a patient or subject having a myeloid malignancy for a bone marrow transplantation.
- the methods of the present invention may be carried out so as to reduce the absolute or relative numbers of blast cells in the bone marrow or peripheral blood.
- the methods are carried out so as to reduce the blast cell count in the bone marrow and/or peripheral blood prior to transplant.
- the methods may be used to reduce the blast cell count to less than 5% to prepare the patient or subject for a bone marrow transplant.
- kits packaged so as to include instructions for use.
- the BCL-2 antagonist, venetoclax targets and eliminates leukemic stem cells (LSCs) by suppression of oxidative phosphorylation and demonstrated very promising activity in older AML patients in clinical phase I and II studies in combination with standard of care (Pollyea et al., Nature Medicine (2016) 24; 1859-1866).
- LSCs leukemic stem cells
- novel agents such as venetoclax, there are still patients that become refractory or relapse. It was hypothesized that combining venetoclax and cusatuzumab with distinct but complementary mechanisms of action could successfully eliminate LSCs.
- MOLM-13 AML cells express FLT3-ITD and NOMO-1 cells express t(9;11)(p22;q23). Each of these genetic aberrations conveys a poor prognosis to patient outcome.
- NB-4 is an acute promyelocytic leukemia (APL) cell line, where APL is a subset of AML patients.
- APL acute promyelocytic leukemia
- NOMO-1 and MOLM-13 cells express high levels of CD70 as measured at the mRNA and protein levels.
- the MOLM-13 AML cells also express BCL-2 and are sensitive to BCL-2 inhibition (Lin et al. Scientific Reports (2016) 6; 27696).
- MOLM-13 (Matsuo et al., Leukemia (1997) 11(9): 1469-77), NOMO-1 (Kato et al., Acta Haematol Jpn, 1986), MV4-11 and NB4 (Lanotte et al., Blood (1991) 77(5); 1080-86) cells were purchased from ATCC. The cell lines were tested mycoplasma-free and were grown in FCS-containing medium recommended by ATCC with GlutaMAX supplement, 100 U/mL penicillin, and 100 ⁇ g/mL of streptomycin in a humidified atmosphere of 95% air and 5% CO 2 at 37° C.
- AML cells from each AML cell line were treated with decitabine, cusatuzumab or venetoclax alone to determine the IC 50 for each treatment.
- 10 5 AML cells were treated with a concentration range of cusatuzumab (0.1, 1.0 and 10 ⁇ g/ml), venetoclax (0.5 and 200 nM), decitabine (0.01-1 ⁇ M) or vehicle in the presence of CFSE-labelled NK cells derived from healthy individuals (ratio 1:1).
- the assay was performed in triplicate.
- the IC 50 determination identified the following working concentrations for the subsequent synergy experiments:
- NOMO-1, MOLM-13, NB-4 or MV4-11 AML cell lines were treated with vehicle, decitabine, cusatuzumab or venetoclax alone, a double combination of venetoclax and decitabine, decitabine and cusatuzumab, or venetoclax and cusatuzumab, or a triple combination of decitabine, cusatuzumab and venetoclax. All combinations were tested at three high and three low concentrations (above and below the identified IC 50 s) and in a constant ratio. Cells were cultured in the presence of CFSE-labeled NK cells (ratio 1:1). Viable AML cell numbers were assessed 72 hours later by Annexin V staining, and the effect of drug treatment was calculated as the ratio of surviving cells to vehicle-treated cells.
- the Combination Index (CI) was calculated and plotted against Fraction affected (Fa) using CompuSyn software.
- the resultant plot of the combination index (CI) against fraction affected (Fa) for all combinations is shown in FIG. 1 , with the individual combinations shown in FIGS. 2 A- 2 D .
- Fa values of 0, 0.5, and 1 correspond to 0, 50, and 100% killed cells.
- a CI of ⁇ 1, 1, >1 represents synergism, additivity, and antagonism, respectively.
- IC 50 s indicates Fa values reached for the combination of respective IC 50 concentrations.
- LSCs primary CD34 + CD38 ⁇ leukemic stem cells
- CD34 + CD38 ⁇ AML LSCs from three AML patients were cultured overnight in the presence of NK cells (ratio 1:1) with cusatuzumab (Cusa: 0.3 ⁇ g/ml) or venetoclax (Ve: 6 nM) as monotherapy or in combination overnight in duplicates followed by plating in methylcellulose.
- CD34 + CD38 ⁇ AML LSCs from two further AML patients were cultured overnight in the presence of NK cells (ratio 1:1) with cusatuzumab (Cusa: 0.3 ⁇ g/ml), decitabine (0.01 ⁇ M), or venetoclax (Ve: 6 nM) as monotherapy or in combination. Colony formation was assessed 14 days later.
- Venetoclax and/or decitabine in combination with cusatuzumab synergistically eliminated CD70-expressing NOMO-1 AML cells in a broad dose range see FIG. 1 and FIG. 2 B- 2 D ).
- CD34 + CD38 ⁇ LSCs from five AML patients were treated (P1-P5).
- the patient characteristics are shown below.
- FIGS. 6 A- 6 B and FIGS. 7 A- 7 B The results for patients P1, P2 and P3 are shown in FIGS. 6 A- 6 B and FIGS. 7 A- 7 B .
- FIG. 6 shows the absolute numbers of colonies formed per well following treatment, indicative of the number of LSCs.
- FIG. 7 shows the same data expressed as a ratio of the mean colonies per well for the vehicle treated group for each patient.
- FIGS. 6 and 7 show that the synergistic effect between cusatuzumab and venetoclax observed in the AML cell lines translated into a potent and significant reduction in the number of LSCs compared to either treatment alone ( FIG. 6 A and FIG. 7 A ).
- FIGS. 6 B and 7 B show that the effect of reducing LSC numbers was maintained when the first colonies were re-plated in the absence of the treatment molecules.
- FIGS. 8 A- 8 B The results for patients P4 and P5 are shown in FIGS. 8 A- 8 B .
- the triple combination of cusatuzumab, decitabine and venetoclax showed equivalent efficacy to the dual combination of cusatuzumab and venetoclax. This is in line with the fact that no increase in synergy was observed for the triple combination compared to the Ven/Cusa combination ( FIG. 1 ).
- the Combination Index (CI) provided by the Chou-Talalay method is an established means for determining whether drug combinations interact in a synergistic, additive or antagonistic manner. It was hypothesised that venetoclax and cusatuzumab may act in a synergistic manner since mechanistically it could be shown that treatment with venetoclax results in up-regulation of CD70 on AML cells ( FIGS. 9 and 10 ). This could mean that venetoclax renders LSCs more susceptible to cytolytic killing with cusatuzumab. However, as noted in Chou 2010 (Chou Cancer Res . (2010) Jan. 15;70(2):440-6, incorporated herein by reference), synergistic effects between drugs are hard to predict, even in cases where there is some knowledge of the mechanism by which each individual drug acts.
- FIGS. 1 - 5 demonstrate that the Ven/Cusa combination exhibited a strong synergistic effect against AML cells, especially at high effect levels.
- the potent synergy was maintained for the triple combination further including decitabine as a hypomethylating agent.
- the triplet combination cusatuzumab/venetoclax/decitabine reduced colony and re-plating capacity of primary human LSCs to the same extent as the cusatuzumab/venetoclax combination treatment. It may be, therefore, that effective treatment of AML can be achieved using the combination of cusatuzumab and venetoclax without the need to include a HMA such as decitabine, thereby reducing the exposure of the patient to toxic therapies.
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Abstract
Description
- This application is a Division of U.S. patent application Ser. No. 16/719,220, filed on Dec. 18, 2019, which claims the benefit of priority of Great Britain Patent Application Nos. 1820582.3, filed Dec. 18, 2018; 1911007.1, filed Aug. 1, 2019; and 1917701.3, filed Dec. 4, 2019, the disclosures of which are herby incorporated herein by reference in their entireties.
- The instant application contains a Sequence Listing which has been submitted electronically in ST.26 XML format and is hereby incorporated by reference in its entirety. Said ST.26 XML copy, created on Jun. 13, 2023, is named 198969.XML and is 7,957 bytes in size.
- The present invention relates to combination therapies, particularly combination therapies for the treatment of myeloid malignancy. The combination therapies are particularly useful for the treatment of acute myeloid leukemia (AML). The combination therapies include an antibody or antigen binding fragment thereof that binds to CD70 and a BCL-2 inhibitor, for example venetoclax or a pharmaceutically acceptable salt thereof. The combination therapies may further include an additional anti-cancer agent, for example an agent used for the treatment of AML such as azacitidine or decitabine.
- In recent years, the development of new cancer treatments has focussed on molecular targets, particularly proteins, implicated in cancer progression. The list of molecular targets involved in tumour growth, invasion and metastasis continues to expand, and includes proteins overexpressed by tumour cells as well as targets associated with systems supporting tumour growth such as the vasculature and immune system. The number of therapeutic or anti-cancer agents designed to interact with these molecular targets also continues to increase. A large number of targeted cancer medicines are now approved for clinical use with many more in the developmental pipeline.
- CD70 has been identified as a molecular target of particular interest owing to its constitutive expression on many types of hematological malignancies and solid carcinomas (Junker et al. (2005) J Urol. 173:2150-3; Sloan et al. (2004) Am J Pathol. 164:315-23; Held-Feindt and Mentlein (2002) Int J Cancer 98:352-6; Hishima et al. (2000) Am J Surg Pathol. 24:742-6; Lens et al. (1999) Br J Haematol. 106:491-503; Boursalian et al. (2009) Adv Exp Med Biol. 647:108-119; Wajant H. (2016) Expert Opin Ther Targets 20(8):959-973). CD70 is a type II transmembrane glycoprotein belonging to the tumour necrosis factor (TNF) superfamily, which mediates its effects through binding to its cognate cell surface receptor, CD27. Both CD70 and CD27 are expressed by multiple cell types of the immune system and the CD70-CD27 signalling pathway has been implicated in the regulation of several different aspects of the immune response. This is reflected in the fact that CD70 overexpression occurs in various auto-immune diseases including rheumatoid and psoriatic arthritis and lupus (Boursalian et al. (2009) Adv Exp Med Biol. 647:108-119; Han et al. (2005) Lupus 14(8):598-606; Lee et al. (2007) J Immunol. 179(4):2609-2615; Oelke et al. (2004) Arthritis Rheum. 50(6):1850-1860).
- CD70 expression has been linked to poor prognosis for several cancers including B cell lymphoma, renal cell carcinoma and breast cancer (Bertrand et al. (2013) Genes Chromosomes Cancer 52(8):764-774; Jilaveanu et al. (2012) Hum Pathol. 43(9):1394-1399; Petrau et al. (2014) J Cancer 5(9):761-764). CD70 expression has also been found on metastatic tissue in a high percentage of cases indicating a key role for this molecule in cancer progression (Jacobs et al. (2015) Oncotarget 6(15):13462-13475). Constitutive expression of CD70 and its receptor CD27 on tumour cells of hematopoietic lineage has been linked to a role of the CD70-CD27 signalling axis in directly regulating tumour cell proliferation and survival (Goto et al. (2012) Leuk Lymphoma 53(8):1494-1500; Lens et al. (1999) Br J Haematol. 106(2); 491-503; Nilsson et al. (2005) Exp Hematol. 33(12):1500-1507; van Doom et al (2004) Cancer Res. 64(16):5578-5586).
- Upregulated CD70 expression on tumours, particularly solid tumours that do not co-express CD27, also contributes to immunosuppression in the tumour microenvironment in a variety of ways. For example, CD70 binding to CD27 on regulatory T cells has been shown to augment the frequency of Tregs, reduce tumour-specific T cells responses and promote tumour growth in mice (Claus et al. (2012) Cancer Res. 72(14):3664-3676). CD70-CD27 signalling can also dampen the immune response by tumour-induced apoptosis of T-lymphocytes, as demonstrated in renal cell carcinoma, glioma and glioblastoma cells (Chahlavi et al. (2005) Cancer Res. 65(12):5428-5438; Diegmann et al. (2006) Neoplasia 8(11):933-938); Wischusen et al. (2002) Cancer Res 62(9):2592-2599). Finally, CD70 expression has also been linked to T cell exhaustion whereby the lymphocytes adopt a more differentiated phenotype and fail to kill the tumour cells (Wang et al. (2012) Cancer Res 72(23):6119-6129; Yang et al. (2014) Leukemia 28(9):1872-1884).
- Given the importance of CD70 in cancer development, CD70 is an attractive target for anti-cancer therapy and antibodies targeting this cell surface protein are in clinical development (Jacob et al. (2015) Pharmacol Ther. 155:1-10; Silence et al. (2014) mAbs 6(2):523-532).
- The present invention is directed to combination therapies comprising antibodies or antigen binding fragments thereof that bind to CD70. As noted above, the list of proteins implicated in tumour growth continues to expand, and combination therapies that target two or more of these proteins are becoming increasingly attractive as anti-cancer treatments. In the combination therapies of the invention, an antibody or antigen binding fragment thereof that binds to CD70 is combined with a BCL-2 inhibitor, for example venetoclax or a pharmaceutically acceptable salt thereof. Overexpression of BCL-2 in cancer cells confers resistance to apoptosis and therefore inhibition of this protein can promote tumour cell death. As explained elsewhere herein, venetoclax is an example of a potent, selective small-molecule inhibitor of the BCL-2 protein. As reported herein, the combination of an antibody or antigen binding fragment thereof that binds to CD70 and a BCL-2 inhibitor, for example venetoclax or a pharmaceutically acceptable salt thereof, provides an effective therapy for the treatment of cancer, particularly myeloid malignancies such as acute myeloid leukemia (AML).
- In a first aspect, the present invention provides a combination comprising (i) an antibody or antigen binding fragment thereof that binds to CD70; and (ii) a BCL-2 inhibitor. In certain preferred embodiments, the BCL-2 inhibitor is Compound (I) as shown below or a pharmaceutically acceptable salt thereof.
- Compound (I) is also referred to herein as venetoclax.
- In certain embodiments, the antibody or antigen binding fragment that binds to CD70 is selected from: (i) an antibody or antigen binding fragment comprising a variable heavy chain domain (VH) and a variable light chain domain (VL) comprising the heavy chain CDRs (HCDR3, HCDR2 and HCDR1) and light chain CDRs (LCDR3, LCDR2 and LCDR1): HCDR3 comprising or consisting of SEQ ID NO: 3; HCDR2 comprising or consisting of SEQ ID NO: 2; HCDR1 comprising or consisting of SEQ ID NO: 1; LCDR3 comprising or consisting of SEQ ID NO: 7; LCDR2 comprising or consisting of SEQ ID NO: 6; and LCDR1 comprising or consisting of SEQ ID NO: 5; (ii) an antibody or antigen binding fragment comprising a VH domain comprising an amino acid sequence at least 70%, at least 80%, at least 90%, at least 95% identical to SEQ ID NO:4 and a VL domain comprising an amino acid sequence at least 70%, at least 80%, at least 90%, at least 95% identical to SEQ ID NO:8; or (iii) ARGX-110. In certain embodiments, the antibody is an IgG, preferably an IgG1.
- The CD70 antibody or antigen binding fragment of the combinations may possess one or more effector functions. In certain embodiments, the antibody or antigen binding fragment has ADCC activity; and/or comprises a defucosylated antibody domain; and/or has CDC activity; and/or has ADCP activity. In preferred embodiments, the CD70 antibody is ARGX-110.
- In certain embodiments, the CD70 antigen binding fragment of the combinations is independently selected from the group consisting of: an antibody light chain variable domain (VL); an antibody heavy chain variable domain (VH); a single chain antibody (scFv); a F(ab′)2 fragment; a Fab fragment; an Fd fragment; an Fv fragment; a one-armed (monovalent) antibody; diabodies, triabodies, tetrabodies or any antigen-binding molecule formed by combination, assembly or conjugation of such antigen binding fragments.
- In certain embodiments, the CD70 antibody or antigen binding fragment thereof and the BCL-2 inhibitor are formulated as separate compositions. In certain embodiments, the CD70 antibody or antigen binding fragment thereof and venetoclax or a pharmaceutically acceptable salt thereof are formulated as separate compositions.
- The combinations of the invention may comprise one or more additional therapeutic agents, for example at least one additional anti-cancer agent, preferably an agent for the treatment of a myeloid malignancy. In certain embodiments, the additional anti-cancer agent is an agent for the treatment of acute myeloid leukemia (AML). In preferred embodiments, the combinations comprise a hypomethylating agent, preferably azacitidine or decitabine.
- In a further aspect, the present invention provides combinations according to the first aspect of the invention for use in therapy. In particular, the present invention provides combinations according to the first aspect of the invention for use in the treatment of a malignancy, preferably a myeloid malignancy, in a human subject. The present invention also provides a method for treating a malignancy, preferably a myeloid malignancy, in a human subject, said method comprising administering to the subject an effective amount of any of the combinations according to the first aspect of the invention.
- The present invention also provides an antibody or antigen binding fragment thereof that binds to CD70 for use in the treatment of a malignancy, preferably a myeloid malignancy, in a human subject, wherein the antibody molecule is administered in combination with a BCL-2 inhibitor, preferably compound (I) or a pharmaceutically acceptable salt thereof. The present invention also provides a BCL-2 inhibitor, preferably compound (I) or a pharmaceutically acceptable salt thereof, for use in the treatment of a myeloid malignancy in a human subject, wherein the BCL-2 inhibitor, preferably compound (I) or the pharmaceutically acceptable salt thereof, is administered in combination with an antibody or antigen binding fragment thereof that binds to CD70.
- The combinations of the invention are particularly advantageous because they exhibit synergistic efficacy. Preferably, therefore, in embodiments of all aspects of the invention, the dose at which the CD70 antibody or antigen binding fragment thereof is administered and/or provided in the combination, and the dose at which the BCL-2 inhibitor is administered and/or provided in the combination, are each selected such that the combination provides synergistic treatment.
- In certain preferred embodiments of the combination of the invention, the CD70 antibody or antigen binding fragment thereof and the BCL-2 inhibitor are each present in the combination in an amount sufficient to provide synergistic cell killing when cultured with an AML cell line selected from: NOMO-1, MOLM-13, NB4 and MV4-11.
- Regarding the malignancies to be treated using combinations of the invention, said malignancies may be newly-diagnosed myeloid malignancies; relapsed or refractory myeloid malignancies; or myeloid malignancies selected from: acute myeloid leukemia (AML); myelodysplastic syndromes (MDS); myeloproliferative neoplasms (MPN); chronic myeloid leukemia (CML); and chronic myelomonocytic leukemia (CMML). In particularly preferred embodiment, the combinations of the invention are for the treatment of acute myeloid leukemia (AML).
- In certain embodiments, the subject or patient treated in accordance with the methods of the invention is a newly-diagnosed AML patient who is ineligible for standard intensive chemotherapy. The subject may be a newly-diagnosed AML patient aged 75 years or older or a newly-diagnosed AML patient having a comorbidity that precludes use of standard intensive chemotherapy.
- In certain embodiments, the CD70 antibody or antigen binding fragment thereof is administered at a dose in the range of 0.1-25 mg/kg, preferably 10 mg/kg. Alternatively or in addition, the BCL-2 inhibitor, preferably venetoclax or pharmaceutically acceptable salt thereof, may be administered in a dose in the
range 100 mg-600 mg. In preferred embodiments, the methods described herein comprise administering a combination additionally comprising azacitidine wherein the azacitidine is administered at a dose of 75 mg/m2. In further preferred embodiments, the methods described herein comprise administering a combination additionally comprising decitabine wherein the decitabine is administered at a dose of 20 mg/m2. - In certain embodiments, the methods further comprise monitoring of the patient's blast count. The patient's peripheral blood and/or bone marrow blast count may be reduced, for example reduced to less than 25%, for example reduced to 5%, for example reduced to less than 5%, for example reduced to minimal residual disease levels, for example reduced to undetectable levels. In certain embodiments, the bone marrow blast count is reduced to between 5% and 25% and the bone marrow blast percentage is reduced by more than 50% as compared to pretreatment.
- In certain embodiments, the methods induce a partial response. In certain embodiments, the methods induce a complete response, optionally with platelet recovery and/or neutrophil recovery. The methods may induce transfusion independence of red blood cells or platelets, or both, for 8 weeks or longer, 10 weeks or longer, 12 weeks or longer. In certain embodiments, the methods reduce the mortality rate after a 30-day period or after a 60-day period.
- In certain embodiments, the methods increase survival. For example, the methods may increase survival relative to the standard of care agent or agents used to treat the particular myeloid malignancy being treated with the combination. The methods may induce a minimal residual disease status that is negative.
- In certain embodiments, the methods further comprise a step of subjecting the subject to a bone marrow transplantation. Alternatively or in addition, the methods may further comprise a step of administering one or more additional anti-cancer agents. The one or more additional cancer agents may be selected from any agents suitable for the treatment of myeloid malignancies, preferably AML. Preferred agents may be selected from selectin inhibitors (e.g. GMI-1271); FMS-like tyrosine kinase receptor 3 (FLT3) inhibitors (e.g. midostaurin); cyclin-dependent kinase inhibitors; aminopeptidase inhibitors; JAK/STAT inhibitors; cytarabine; anthracycline compounds (e.g. daunorubicin, idarubicin); doxorubicin; hydroxyurea; Vyxeos; IDH1 or IDH2 inhibitors such as Idhifa (or Enasidenib) or Tibsovo (or ivosidenib); Smoothened inhibitors such as Glasdegib, BET bromodomain inhibitors, CD123 or CD33 targeting agents, HDAC inhibitors, LSC targeting agents, AML bone marrow niche targeting agents, and NEDD8-activating enzyme inhibitors such as Pevonedistat.
-
FIG. 1 : Cusatuzumab and decitabine co-treatment synergistically eliminates NOMO-1 AML cells. NOMO-1 AML cells were treated with vehicle, cusatuzumab, venetoclax or decitabine alone or in combination in a constant ratio in the presence of carboxyfluorescein succinimidyl ester (CFSE)-labeled NK cells (ratio 1:1). NOMO-1 AML cell numbers per well were counted after 72 hours, the degree of viable cells was determined by Annexin V staining, and the effect of drug treatment was calculated as the ratio of surviving cells to vehicle-treated cells. Combination index (CI) values were calculated, and values between 0 and 10 were plotted against fraction affected (Fa) values. Fa-CI plot [Chou-Talalay plot] assessing synergism and/or antagonism is illustrated. Fa values of 0, 0.5, and 1 correspond to 0, 50, and 100% killed cells. A CI of <1, 1, >1 represents synergism, additivity, and antagonism, respectively. IC50s indicates the Fa values reached at the IC50 concentrations for the Ve/Cusa (lower Fa) and Ve/De/Cusa (higher Fa) combinations. Ve/De, venetoclax and decitabine; De/Cusa, decitabine and cusatuzumab; Ve/Cusa, venetoclax and cusatuzumab; Ve/De/Cusa, venetoclax and decitabine and cusatuzumab. -
FIGS. 2A-2D : Cusatuzumab and decitabine co-treatment synergistically eliminates NOMO-1 AML cells. Individual CI-Fa plots of the data for each combination presented inFIG. 1 . (FIG. 2A ) venetoclax and decitabine; (FIG. 2B ) decitabine and cusatuzumab; (FIG. 2C ) venetoclax and cusatuzumab; (FIG. 2D ) venetoclax, decitabine and cusatuzumab. -
FIGS. 3A-3D : Cusatuzumab and decitabine co-treatment synergistically eliminates NB4 AML cells. NB4 AML cells were treated with vehicle, cusatuzumab, venetoclax or decitabine alone or in combination in a constant ratio in the presence of CFSE-labeled NK cells (ratio 1:1). NB4 AML cell numbers per well were counted after 72 hours, the degree of viable cells was determined by Annexin V staining, and the effect of drug treatment was calculated as the ratio of surviving cells to vehicle-treated cells. Combination index (CI) values were calculated, and values between 0 and 10 were plotted against fraction affected (Fa) values. Fa-CI plot [Chou-Talalay plot] assessing synergism and/or antagonism is illustrated. Fa values of 0, 0.5, and 1 correspond to 0, 50, and 100% killed cells. (FIG. 3A ) venetoclax and decitabine; (FIG. 3B ) venetoclax and cusatuzumab; (FIG. 3C ) decitabine and cusatuzumab; (FIG. 3D ) venetoclax, decitabine and cusatuzumab. -
FIGS. 4A-4D : Cusatuzumab and decitabine co-treatment synergistically eliminates MOLM-13 AML cells. MOLM-13 AML cells were treated with vehicle, cusatuzumab, venetoclax or decitabine alone or in combination in a constant ratio in the presence of CFSE-labeled NK cells (ratio 1:1). MOLM-13 AML cell numbers per well were counted after 72 hours, the degree of viable cells was determined by Annexin V staining, and the effect of drug treatment was calculated as the ratio of surviving cells to vehicle-treated cells. Combination index (CI) values were calculated, and values plotted against fraction affected (Fa) values. Fa-CI plot [Chou-Talalay plot] assessing synergism and/or antagonism is illustrated. Fa values of 0, 0.5, and 1 correspond to 0, 50, and 100% killed cells. (FIG. 4A ) venetoclax and decitabine; (FIG. 4B ) venetoclax and cusatuzumab; (FIG. 4C ) decitabine and cusatuzumab; (FIG. 4D ) venetoclax, decitabine and cusatuzumab. -
FIG. 5 : Cusatuzumab and decitabine co-treatment synergistically eliminates MV4-11 AML cells. MV4-11 AML cells were treated with vehicle, cusatuzumab, venetoclax or decitabine alone or in combination in a constant ratio in the presence of CFSE-labeled NK cells (ratio 1:1). MV4-11 AML cell numbers per well were counted after 72 hours, the degree of viable cells was determined by Annexin V staining, and the effect of drug treatment was calculated as the ratio of surviving cells to vehicle-treated cells. Combination index (CI) values were calculated, and values plotted against fraction affected (Fa) values. Fa-CI plot [Chou-Talalay plot] assessing synergism and/or antagonism is illustrated. Fa values of 0, 0.5, and 1 correspond to 0, 50, and 100% killed cells. -
FIGS. 6A-6B : Combined venetoclax and cusatuzumab treatment synergistically eliminates leukemic stem cells (LSCs) in vitro. CD34+CD38− AML LSCs from patients P1-3 were cultured with cusatuzumab (Cusa: 0.3 μg/ml) or venetoclax (Ve: 6 nM) alone or in combination in the presence of NK cells (ratio 1:1) overnight in duplicates followed by plating in methylcellulose. Colony formation was assessed 14 days later. (FIG. 6A ) Absolute number of colonies per well for first plating following treatment; (FIG. 6B ) Cells harvested from the first plating were re-plated (2nd plating) and colonies per well assessed 14 days later. Data are represented as mean±S.D. Statistics: One-way-ANOVA; Tukey's post-test; *, P<0.05; **, P<0.01; ***, P<0.001. -
FIGS. 7A-7B : Combined venetoclax and cusatuzumab treatment synergistically eliminates LSCs in vitro. Data presented correspond to the data ofFIG. 6 , normalized to the mean number of colonies per well following vehicle treatment for each patient. (FIG. 7A ) first plating; (FIG. 7B ) second plating. -
FIGS. 8A-8B : Combined venetoclax and cusatuzumab treatment synergistically eliminates LSCs in vitro. CD34+CD38− AML LSCs from patients P4 and P5 were cultured with cusatuzumab (Cusa: 0.3 μg/ml), venetoclax (Ve: 6 nM) or decitabine (0.01 μM) alone or in combination in the presence of NK cells (ratio 1:1) overnight in duplicates followed by plating in methylcellulose. Colony formation was assessed 14 days later. Data are represented as mean±S.D (FIG. 8A ) Results from a single patient; (FIG. 8B ) Results from P4 and P5. -
FIG. 9 : CD70 mRNA expression (as percentage of housekeeping gene) following treatment with vehicle (Veh) or venetoclax (Ven) for 24 or 48 hrs. -
FIG. 10 : CD70 protein and mRNA expression by MOLM-13 and NOMO-1 cells in the presence (gray bars) and absence (black bars) of venetoclax. Significance was determined using a Student's t-test. MFI=mean fluorescence intensity. *** P<0.001. - Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one skilled in the art in the technical field of the invention.
- “Combination therapy”—As used herein, the term “combination therapy” refers to a treatment in which a subject, for example a human subject, is given two or more therapeutic agents. The “combinations” described herein are for use in combination therapy. The two or more therapeutic agents are typically administered so as to treat a single disease, herein a cancer or malignancy. The combinations or combination therapies of the present invention comprise antibodies or antigen binding fragments that bind to CD70 and a BCL-2 inhibitor, preferably the small-molecule inhibitor venetoclax or a pharmaceutically acceptable salt thereof. As described elsewhere herein, the agents included in the combination therapies may be co-formulated for administration or may be provided separately, for example as separate compositions, for administration to a subject or patient in need thereof.
- “Antibody”—As used herein, the term “antibody” is intended to encompass full-length antibodies and variants thereof, including but not limited to modified antibodies, humanised antibodies, germlined antibodies. The term “antibody” is typically used herein to refer to immunoglobulin polypeptides having a combination of two heavy and two light chains wherein the polypeptide has significant specific immunoreactive activity to an antigen of interest (herein CD70). For antibodies of the IgG class, the antibodies comprise two identical light polypeptide chains of molecular weight approximately 23,000 Daltons, and two identical heavy chains of molecular weight 53,000-70,000. The four chains are joined by disulfide bonds in a “Y” configuration wherein the light chains bracket the heavy chains starting at the mouth of the “Y” and continuing through the variable region. The light chains of an antibody are classified as either kappa or lambda (κ,λ). Each heavy chain class may be bound with either a kappa or lambda light chain. In general, the light and heavy chains are covalently bonded to each other, and the “tail” portions of the two heavy chains are bonded to each other by covalent disulfide linkages or non-covalent linkages when the immunoglobulins are generated either by hybridomas, B cells or genetically engineered host cells. In the heavy chain, the amino acid sequences run from an N-terminus at the forked ends of the Y configuration to the C-terminus at the bottom of each chain.
- Those skilled in the art will appreciate that heavy chains are classified as gamma, mu, alpha, delta, or epsilon, (γ, μ, α, δ, ε) with some subclasses among them (e.g., γ1-γ4). It is the nature of this chain that determines the “class” of the antibody as IgG, IgM, IgA, IgD or IgE, respectively. The immunoglobulin subclasses (isotypes) e.g., IgG1, IgG2, IgG3, IgG4, IgA1, etc. are well characterized and are known to confer functional specialization. The term “antibody” as used herein encompasses antibodies from any class or subclass of antibody.
- “Antigen binding fragment”—The term “antigen binding fragment” as used herein refers to fragments that are parts or portions of a full-length antibody or antibody chain comprising fewer amino acid residues than an intact or complete antibody whilst retaining antigen binding activity. An antigen-binding fragment of an antibody includes peptide fragments that exhibit specific immuno-reactive activity to the same antigen as the antibody (e.g. CD70). The term “antigen binding fragment” as used herein is intended to encompass antibody fragments selected from: an antibody light chain variable domain (VL); an antibody heavy chain variable domain (VH); a single chain antibody (scFv); a F(ab′)2 fragment; a Fab fragment; an Fd fragment; an Fv fragment; a one-armed (monovalent) antibody; diabodies, triabodies, tetrabodies or any antigen-binding molecule formed by combination, assembly or conjugation of such antigen binding fragments. The term “antigen binding fragment” as used herein may also encompass antibody fragments selected from the group consisting of: unibodies; domain antibodies; and nanobodies. Fragments can be obtained, for example, via chemical or enzymatic treatment of an intact or complete antibody or antibody chain or by recombinant means.
- “Specificity” and “Multispecific antibodies”—The antibodies and antigen binding fragments for use in the combination therapies described herein bind to particular target antigens, e.g. CD70. It is preferred that the antibodies and antigen binding fragments “specifically bind” to their target antigen, wherein the term “specifically bind” refers to the ability of any antibody or antigen binding fragment to preferentially immunoreact with a given target e.g. CD70. The antibodies and antigen binding fragments of the present combinations and methods may be monospecific and contain one or more binding sites which specifically bind a particular target. The antibodies and antigen binding fragments of the present combinations and methods may be incorporated into “multispecific antibody” formats, for example bispecific antibodies, wherein the multispecific antibody binds to two or more target antigens. In order to achieve multiple specificities, “multispecific antibodies” are typically engineered to include different combinations or pairings of heavy and light chain polypeptides with different VH-VL pairs. Multispecific, notably bispecific antibodies, may be engineered so as to adopt the overall conformation of a native antibody, for example a Y-shaped antibody having Fab arms of different specificities conjugated to an Fc region. Alternatively multispecific antibodies, for example bispecific antibodies, may be engineered so as to adopt a non-native conformation, for example wherein the variable domains or variable domain pairs having different specificities are positioned at opposite ends of the Fc region.
- “Modified antibody”—As used herein, the term “modified antibody” includes synthetic forms of antibodies which are altered such that they are not naturally occurring, e.g., antibodies that comprise at least two heavy chain portions but not two complete heavy chains (such as, domain deleted antibodies or minibodies); multispecific forms of antibodies (e.g., bispecific, trispecific, etc.) altered to bind to two or more different antigens or to different epitopes on a single antigen); heavy chain molecules joined to scFv molecules and the like. scFv molecules are known in the art and are described, e.g., in U.S. Pat. No. 5,892,019. In addition, the term “modified antibody” includes multivalent forms of antibodies (e.g., trivalent, tetravalent, etc., antibodies that bind to three or more copies of the same antigen). In another embodiment, a modified antibody of the invention is a fusion protein comprising at least one heavy chain portion lacking a CH2 domain and comprising a binding domain of a polypeptide comprising the binding portion of one member of a receptor ligand pair.
- “Humanising substitutions”—As used herein, the term “humanising substitutions” refers to amino acid substitutions in which the amino acid residue present at a particular position in the VH or VL domain of an antibody is replaced with an amino acid residue which occurs at an equivalent position in a reference human VH or VL domain. The reference human VH or VL domain may be a VH or VL domain encoded by the human germline. Humanising substitutions may be made in the framework regions and/or the CDRs of the antibodies, defined herein.
- “Humanised variants”—As used herein the term “humanised variant” or “humanised antibody” refers to a variant antibody which contains one or more “humanising substitutions” compared to a reference antibody, wherein a portion of the reference antibody (e.g. the VH domain and/or the VL domain or parts thereof containing at least one CDR) has an amino acid derived from a non-human species, and the “humanising substitutions” occur within the amino acid sequence derived from a non-human species.
- “Germlined variants”—The term “germlined variant” or “germlined antibody” is used herein to refer specifically to “humanised variants” in which the “humanising substitutions” result in replacement of one or more amino acid residues present at (a) particular position(s) in the VH or VL domain of an antibody with an amino acid residue which occurs at an equivalent position in a reference human VH or VL domain encoded by the human germline. It is typical that for any given “germlined variant”, the replacement amino acid residues substituted into the germlined variant are taken exclusively, or predominantly, from a single human germline-encoded VH or VL domain. The terms “humanised variant” and “germlined variant” are often used interchangeably. Introduction of one or more “humanising substitutions” into a camelid-derived (e.g. llama derived) VH or VL domain results in production of a “humanised variant” of the camelid (llama)-derived VH or VL domain. If the amino acid residues substituted in are derived predominantly or exclusively from a single human germline-encoded VH or VL domain sequence, then the result may be a “human germlined variant” of the camelid (llama)-derived VH or VL domain.
- “CD70”—As used herein, the terms “CD70” or “CD70 protein” or “CD70 antigen” are used interchangeably and refer to a member of the TNF ligand family which is a ligand for TNFRSF7/CD27. CD70 is also known as CD27L or TNFSF7. The terms “human CD70 protein” or “human CD70 antigen” or “human CD70” are used interchangeably to refer specifically to the human homolog, including the native human CD70 protein naturally expressed in the human body and/or on the surface of cultured human cell lines, as well as recombinant forms and fragments thereof. Specific examples of human CD70 include the polypeptide having the amino acid sequence shown under NCBI Reference Sequence Accession No. NP_001243, or the extracellular domain thereof.
- “BCL-2 family”—As used herein, the term “BCL-2 family” or “BCL-2 protein family” refers to the collection of pro- and anti-apoptotic proteins related to BCL-2, see Delbridge et al. (2016) Nat Rev Cancer. 16(2): 99-109. There are at least 16 members of this family categorized into three functional groups: (i) the BCL-2 like proteins (e.g. BCL-2, BCL-XL/BCL2L1, BCLW BCL2L2, MCL2, BFL1/BCL2A1); (ii) BAX and BAK; and (iii) the BH3-only proteins (e.g. BIM, PUMA, BAD, BMF, BID, NOXA, HRK, BIK). The BCL-2 family of proteins play an integral role in regulating the intrinsic apoptotic pathway with the anti-apoptotic members of the family (e.g. BCL-2, BCL-XL) typically antagonizing the pro-apoptotic members (e.g. BAX and BIM). Deregulation of BCL-2 family members has been observed in many cancers, for example by gene translocations, amplifications, overexpression and mutations. The downstream effect of this deregulation is frequently apoptosis-resistance, which fuels cancer growth.
- “BCL-2”—As used herein, “BCL-2” or the “BCL-2 protein” refers to the first member of the BCL-2 protein family to be identified in humans i.e. B-
cell lymphoma 2. The cDNA encoding human BCL-2 was cloned in 1986 and the key role of this protein in inhibiting apoptosis was elucidated in 1988. BCL-2 has been found to be upregulated in several different types of cancer. For example, BCL-2 is activated by the t(14;18) chromosomal translocation in follicular lymphoma. Amplification of the BCL-2 gene has also been reported in different cancers including leukemias (such as CLL), lymphomas (such as B-cell lymphoma) and some solid tumours (e.g. small-cell lung carcinoma). Human BCL-2 is encoded by the BCL2 gene (UniProtKB—P10415) and has the amino acid sequences shown under NCBI Reference Sequences NP_000624.2 and NP_000648.2. - “BCL-2 inhibitor”—As used herein, a BCL-2 inhibitor refers to any agent, compound or molecule capable of specifically inhibiting the activity of BCL-2, in particular an agent, compound or molecule capable of inhibiting the anti-apoptotic activity of BCL-2. Examples of BCL-2 inhibitors suitable for use in the combinations described herein include B cell lymphoma homology 3 (BH3) mimetic compounds (Merino et al. (2018) Cancer Cell. 34(6): 879-891). Particular BCL-2 inhibitors include but are not limited to venetoclax, ABT-737 (Oltersdorf, T. et al. (2005) Nature 435: 677-681), navitoclax/ABT-263 (Tse, C. et al. (2008) Cancer Res. 68: 3421-3428), BM-1197 (Bai, L. et al. (2014) PLoS ONE 9: e99404), S44563 (Nemati, F. et al. (2014) PLoS ONE 9: e80836), BCL2-32 (Adam, A. et al. (2014) Blood 124: 5304), AZD4320 (Hennessy, E. J. et al. (2015) ACS Medicinal Chemistry annual meeting https://www.acsmedchem.org/ama/orig/abstracts/mediabstractf2015.pdf_abstr.24), and S55746 (International Standard Randomised Controlled Trial Number Registry. ISRCTN http://www.isrctn.com/ISRCTN04804337 (2016). Further examples of BCL-2 inhibitors are described in Ashkenazi, A et al. (2017) Nature Reviews Drug Discovery 16: 273-284, incorporated herein by reference.
- “Venetoclax”—As used herein, the term “venetoclax” refers to the compound having the chemical structure shown below:
- This compound is referred to herein as “compound (I)”. Venetoclax is a potent, selective, orally-bioavailable inhibitor of the BCL-2 protein. It has the empirical formula C45H50ClN7O7S and a molecular weight of 868.44. It has very low aqueous solubility. Venetoclax can be described chemically as 4-(4-{[2-(4-chlorophenyl)-4,4dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide). Alternative names for venetoclax include ABT-199; chemical name 1257044-40-8; GDC-0199.
- Venetoclax received approval in 2015 from the US Food and Drug Adminstration (FDA) for the treatment of adult patients with chronic lymphocytic leukemia (CLL) or small lymphocytic leukemia (SLL) who have received at least one prior therapy. Venetoclax is also approved in the US for use in combination with azacitidine or decitabine or low-dose cytarabine for the treatment of newly-diagnosed acute myeloid leukemia (AML) in adults aged 75 years or older or who have comorbidities that preclude use of intensive induction chemotherapy.
- “Myeloid malignancy”—As used herein, the term “myeloid malignancy” refers to any clonal disease of hematopoietic stem or progenitor cells. Myeloid malignancies or myeloid malignant diseases include chronic and acute conditions. Chronic conditions include myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN) and chronic myelomonocytic leukemia (CMML), and acute conditions include acute myeloid leukemia (AML).
- “Acute myeloid malignancy”—As used herein, “acute myeloid leukemia” or “AML” refers to haematopoietic neoplasms involving myeloid cells. AML is characterised by clonal proliferation of myeloid precursors with reduced differentiation capacity. AML patients exhibit an accumulation of blast cells in the bone marrow. “Blast cells”, or simply “blasts”, as used herein refers to clonal myeloid progenitor cells exhibiting disrupted differentiation potential. Blast cells typically also accumulate in the peripheral blood of AML patients. Typically AML is diagnosed if the patient exhibits 20% or more blast cells in the bone marrow or peripheral blood.
- “Standard intensive chemotherapy”—As used herein, “standard intensive chemotherapy” (also referred to herein as “intensive induction therapy” or “induction therapy”) refers to the so-called “7+3” induction chemotherapy characterised by 7 days of high dose cytarabine followed by 3 days of anthracycline administration (e.g. daunorubicin or idarubicin). Standard intensive chemotherapy can be given to eligible newly-diagnosed AML patients with the aim of inducing complete remission of AML, typically with the intention of the patient undergoing a stem cell transplant following successful chemotherapy. As explained herein, not all newly-diagnosed AML patients are eligible for this standard intensive chemotherapy.
- “Leukemic stem cells”—As used herein, “leukemic stem cells” or “LSCs” are a subset of the blast cells associated with AML. LSCs are blast cells having stem cell properties such that, if transplanted into an immuno-deficient recipient, they are capable of initiating leukemic disease. LSCs can self-renew by giving rise to leukemia and also partially differentiate into non-LSC conventional blast cells that resemble the original disease but are unable to self-renew. LSCs occur with a frequency in the range of 1 in 10,000 to 1 in 1 million as a proportion of primary AML blast cells (Pollyea and Jordan (2017) Blood 129: 1627-1635, incorporated herein by reference). LSCs may be characterised as cells that are CD34+, CD38−, optionally also CD45− and/or CD123+. LSCs may also be characterised as CD45dim, SSClo, CD90+CD34+ cells.
- “Anti-cancer agent”—As used herein, an anti-cancer agent refers to any agent that is capable of preventing, inhibiting or treating cancer growth directly or indirectly. Such agents include chemotherapeutic agents, immunotherapeutic agents, anti-angiogenic agents, radionuclides, etc, many examples of which are known to those skilled in the art.
- The present invention provides a combination therapy comprising (i) an antibody or antigen binding fragment thereof that binds to CD70; and (ii) a BCL-2 inhibitor.
- As described elsewhere herein, CD70 has already been characterised as an attractive target for anti-cancer therapy. CD70 is constitutively expressed on many types of hematological malignancies and solid carcinomas and its expression has been linked to poor prognosis for several cancers. Antibodies targeting CD70 have been developed and some have been taken forward into clinical development.
- Antibodies targeting CD70 have been found to be particularly effective for the treatment of myeloid malignancies, particularly the treatment of subjects with acute myeloid leukemia (AML). The results from a Phase I/II clinical trial testing the CD70 antibody, ARGX-110, in patients having AML revealed surprising efficacy in this indication, particularly in newly-diagnosed patients classified as unfit for standard intensive chemotherapy (see WO2018/229303). It is particularly notable that in the clinical studies, the CD70 antibody, when used in combination with azacitidine, efficiently reduced leukemic stem cells (LSCs) in the AML patients. Testing of the LSCs isolated from the patients in the trial revealed evidence of increased asymmetric division of LSCs, indicative of differentiation into myeloid cells. Taken together, these results indicate that CD70 antibodies deplete the LSC pool in AML patients thereby increasing the prospect of remission and reducing the risk of relapse.
- The present invention combines CD70 antibodies or antigen binding fragments thereof with a BCL-2 inhibitor.
- The BCL-2 protein is a member of the BCL-2 family. This family comprises more than 20 proteins. Members of the BCL-2 family are involved in the regulation of the intrinsic apoptosis pathway and play a fundamental role in regulating the balance between cell survival and death.
- The BCL-2 protein is an anti-apoptotic member of the BCL-2 family and is up-regulated in many different types of cancer. The overexpression of BCL-2 allows tumour cells to evade apoptosis by sequestering pro-apoptotic proteins. BCL-2 is highly expressed in many hematologic malignancies and is the predominant pro-survival protein in diseases such as chronic lymphocytic leukemia (CLL), follicular lymphoma and mantle cell lymphoma. Inhibition of BCL-2 inhibits the anti-apoptotic or pro-survival activity of this protein. Anti-apoptotic members of the BCL-2 family, including BCL-2, have been reported as overexpressed in primary AML samples (Bogenberger et al. (2014) Leukemia 28(2); 1657-65). BCL-2 overexpression has also been reported in leukemic stem cells (LSCs) obtained from AML patients (Lagadinou et al. (2013) Cell Stem Cell 12(3); 329-341). Inhibition of BCL-2 in ex vivo LSC populations led to selective eradication of quiescent LSCs (Lagadinou et al. (2013) Cell Stem Cell 12(3); 329-341).
- Without wishing to be bound by theory, the combination of the present invention is considered to be particularly effective for the treatment of AML due to the combined therapeutic effect of the CD70 antibodies or antigen binding fragments and the BCL-2 inhibitor, particularly the combined effect at the level of the LSCs. The self-renewal capacity of LSCs means that the persistence of these cells is a major factor contributing to disease relapse.
- As demonstrated in the Examples, combinations of the invention exhibit synergistic treatment efficacy against AML cells—that is, the level of inhibition induced by the combination is greater than the additive effect of the monotherapies alone. Methods for determining synergistic interaction are familiar to the skilled person and are described in the Examples. A preferred method for determining whether synergistic effects arise from a combination is the Chou-Talalay method (Chou, TC. Cancer Res. (2010) 70(2); 440-6, incorporated herein by reference).
- The synergistic efficacy of the combinations of the invention translated into potent inhibition of primary LSC cells from AML patients. The combination therapy of the present invention thus targets both the blast cells and the LSC compartment thereby improving the likelihood of disease remission whilst reducing the risk of relapse.
- In certain preferred embodiments of the combinations of the invention, the BCL-2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof. Venetoclax is a small-molecule inhibitor of BCL-2, described in US2010/0305122 (incorporated herein by reference).
- By inhibiting BCL-2, venetoclax inhibits the anti-apoptotic or pro-survival activity of this protein. Venetoclax induces apoptosis rapidly in the majority of CLL cells and BCL-2-overexpressing lymphoma cell lines.
- Early studies indicated that venetoclax may be useful as a therapy for AML (Konopleva et al. (2016) Cancer Discov. 6(10); 1106-17). However, it was found to have limited activity as a monotherapy. Subsequent studies investigated the efficacy of venetoclax in combination with hypomethylating agents, namely azacitidine and decitadine, and these combinations were found to be particularly efficacious (Bogenberger et al. (2015) Leuk Lymphoma 56(1): 226-229). Clinical trials have been carried out to test the combination of venetoclax with either azacitidine, decitabine, or low-dose cytarabine (Dinardo et al. (2018) Lancet Oncol. 19(2): 216-228; Dinardo et al. (2019) Blood 133(1); 7-17). The results of these trials have led to FDA approval for use of venetoclax in combination with azacitidine, decitabine or low-dose cytarabine for the treatment of newly-diagnosed acute myeloid leukemia (AML) in adults who are age 75 years or older, or who have comorbidities that preclude the use of intensive induction chemotherapy.
- In certain alternative embodiments of the invention, the BCL-2 inhibitor is a B cell lymphoma homology 3 (BH3) mimetic compound. In certain embodiments, the BCL-2 inhibitor is selected from ABT-737, navitoclax, BM-1197, S44563, BCL2-32, AZD4320 or S55746.
- CD70 Antibodies
- Antibodies or antigen binding fragments that bind to CD70 and that may be incorporated into any of the combinations described herein include but are not limited to: CD70 antibodies or antigen binding fragments that inhibit interaction of CD70 with CD27; CD70 antibodies or antigen binding fragments that compete with CD27 for CD70 binding; CD70 antibodies or antigen binding fragments that inhibit CD70-induced CD27 signalling; CD70 antibodies or antigen binding fragments that inhibit Treg activation and/or proliferation; CD70 antibodies or antigen binding fragments that deplete CD70-expressing cells; CD70 antibodies or antigen binding fragments that induce lysis of CD70-expressing cells; CD70 antibodies or antigen binding fragments that possess ADCC, CDC functionality, and/or induce ADCP.
- Exemplary CD70 antibodies are ARGX-110 described in WO2012/123586 (incorporated herein by reference), SGN-70 (WO2006/113909, and McEarChern et al. (2008) Clin Cancer Res. 14(23):7763, both incorporated herein by reference) and those CD70 antibodies described in WO2006/044643 and WO2007/038637 (each incorporated herein by reference).
- WO2006/044643 describes CD70 antibodies containing an antibody effector domain which can mediate one or more of ADCC, ADCP or CDC and either exert a cytostatic or cytotoxic effect on a CD70-expressing cancer or exert an immunosuppressive effect on a CD70-expressing immunological disorder in the absence of conjugation to a cytostatic or cytotoxic agent. The antibodies exemplified therein are based on the antigen-binding regions of two monoclonal antibodies, denoted 1F6 and 2F2.
- WO2007/038637 describes fully human monoclonal antibodies that bind to CD70. These antibodies are characterised by binding to human CD70 with a KD of 1×107 M or less. The antibodies also bind to, and are internalised by, renal cell carcinoma tumor cell lines which express CD70, such as 786-0.
- ARGX-110 is an IgG1 anti-CD70 antibody, also known as cusatuzumab. ARGX-110 has been shown to inhibit the interaction of CD70 with its receptor CD27 (Silence et al. (2014) MAbs. March-April; 6(2):523-32, incorporated herein by reference). In particular, ARGX-110 has been shown to inhibit CD70-induced CD27 signalling. Levels of CD27 signalling may be determined by, for example, measurement of serum soluble CD27 as described in Riether et al. (J. Exp. Med. (2017) 214(2); 359-380) or of IL-8 expression as described in Silence et al. (MAbs (2014) 6(2): 523-32). Without being bound by theory, inhibiting CD27 signalling is thought to reduce activation and/or proliferation of Treg cells, thereby reducing inhibition of anti-tumour effector T cells. ARGX-110 has also been demonstrated to deplete CD70-expressing tumour cells. In particular, ARGX-110 has been shown to lyse CD70-expressing tumour cells via antibody dependent cell-mediated cytotoxicity (ADCC) and complement dependent cytotoxicity (CDC), and also to increase antibody dependent cellular phagocytosis (ADCP) of CD70-expressing cells (Silence et al., ibid).
- The CDR, VH and VL amino acid sequences of ARGX-110 or cusatuzumab are shown in the table below.
-
TABLE 1 ARGX-110 Sequence SEQ ID NO. HCDR1 VYYMN 1 HCDR2 DINNEGGTTYYADSVKG 2 HCDR3 DAGYSNHVPIFDS 3 VH EVQLVESGGGLVQPGGSLRLSCAAS 4 GFTFSVYYMNWVRQAPGKGLEWVSD INNEGGTTYYADSVKGRFTISRDNS KNSLYLQMNSLRAEDTAVYYCARDA GYSNHVPIFDSWGQGT LVTVSS LCDR1 GLKSGSVTSDNFPT 5 LCDR2 NTNTRHS 6 LCDR3 ALFISNPSVE 7 VL QAVVTQEPSLTVSPGGTVTLTCGLK 8 SGSVTSDNFPTWYQQTPGQAPRLLI YNTNTRHSGVPDRFSGSILGNKAAL TITGAQADDEAEYFCALFISNPSVE FGGGTQLTVLG - In certain embodiments, the antibody or antigen binding fragment thereof that binds to CD70 comprises a variable heavy chain domain (VH) and a variable light chain domain (VL) wherein the VH and VL domains comprise the CDR sequences:
-
- HCDR3 comprising or consisting of SEQ ID NO: 3;
- HCDR2 comprising or consisting of SEQ ID NO: 2;
- HCDR1 comprising or consisting of SEQ ID NO: 1;
- LCDR3 comprising or consisting of SEQ ID NO: 7;
- LCDR2 comprising or consisting of SEQ ID NO: 6; and
- LCDR1 comprising or consisting of SEQ ID NO: 5.
- In certain embodiments, the antibody or antigen binding fragment thereof that binds to CD70, optionally the antibody or antigen binding fragment having the CDR sequences shown above, is an IgG, preferably an IgG1. In certain embodiments, the antibody or antigen binding fragment thereof that binds to CD70 comprises a variable heavy chain domain (VH domain) comprising or consisting of a sequence at least 70%, at least 80%, at least 90% or at least 95% identical to SEQ ID NO: 4 and a variable light chain domain (VL domain) comprising or consisting of a sequence at least 70%, at least 80%, at least 90% or at least 95% identical to SEQ ID NO: 8. In certain embodiments, the antibody molecule that binds to CD70 comprises a variable heavy chain domain (VH domain) comprising or consisting of SEQ ID NO: 4 and a variable light chain domain (VL domain) comprising or consisting of SEQ ID NO: 8. For embodiments wherein the VH and/or VL domains are defined as having a particularly percentage identity to a reference sequence, the VH and/or VL domains may retain the CDR sequences of the reference sequence. In particular, the CD70 antibodies or antigen binding fragments defined herein with reference to SEQ ID NOs: 4 and 8 may retain the CDR sequences as represented by SEQ ID NOs: 1-3 and 5-7.
- CD70 antibody or antigen binding fragments thereof that may be incorporated into the combinations described herein include antibody drug conjugates (ADCs). ADCs are antibodies attached to active agents, for example auristatins and maytansines or other cytotoxic agents. Certain ADCs maintain antibody blocking and/or effector function (e.g. ADCC, CDC, ADCP) while also delivering the conjugated active agent to cells expressing the target (e.g. CD70). Examples of anti-CD70 ADCs include vorsetuzumab mafodotin (also known as SGN-75, Seattle Genetics), SGN-70A (Seattle Genetics), and MDX-1203/BMS936561 (Bristol-Myers Squibb), each of which may be used in accordance with the invention. Suitable anti-CD70 ADCs are also described in WO2008074004 and WO2004073656, each of which is incorporated herein by reference.
- Venetoclax
- In certain preferred embodiments of the invention, the CD70 antibodies or antigen binding fragments described herein are combined with venetoclax or a pharmaceutically acceptable salt thereof. Venetoclax is a small molecule inhibitor of BCL-2 as described elsewhere herein.
- Venetoclax for use in the combination therapies described herein may be provided in any suitable form such that it effectively inhibits the BCL-2 protein. Such forms include but are not limited to any suitable polymorphic, amorphous or crystalline forms or any isomeric or tautomeric forms. In certain embodiments, the combination therapies described herein comprise venetoclax synthesised according to the process described in US2010/0305122 (incorporated herein by reference). In alternative embodiments, the combination therapies described herein comprise venetoclax according to the forms or synthesised according to the processes described in any one of EP3333167, WO2017/156398, WO2018/029711, CN107089981 (A), WO2018/069941, WO2017/212431, WO2018/009444, CN107648185 (A), WO2018/167652, WO2018/157803, CZ201769 (each incorporated herein by reference). In certain embodiments, the combination therapies described herein comprise venetoclax in any of the crystalline or salt forms described in WO2012/071336 (incorporated herein by reference).
- Pharmaceutically acceptable salts for use in accordance with the present invention include salts of acidic or basic groups. Pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzensulfonate, p-toluenesulfonate and pamoate (i.e., 1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Pharmaceutically acceptable salts may be formed with various amino acids. Suitable base salts include, but are not limited to, aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, and diethanolamine salts.
- Venetoclax for use in the combination therapies described herein may also be provided in the form of a hydrate, anhydrate or solvate.
- Venetoclax is marketed and sold by AbbVie Inc and Genentech under the trade name Venclexta®. In certain embodiments, the combinations described herein comprise an antibody or antigen binding fragment thereof that binds CD70 and Venclexta®.
- Additional Agents
- The combinations of the present invention may include one or more additional agents, for example one or more additional anti-cancer agents.
- In certain embodiments, the combination comprises one or more “nucleoside metabolic inhibitors” (NMIs). NMIs are molecules that interfere with epigenetic modification (e.g. methylation, demethylation, acetylation, or deacetylation) of nucleotides (DNA and/or RNA). Examples of nucleoside metabolic inhibitors include hypomethylating agents (HMAs), isocitrate dehydrogenase (IDH) inhibitors, histone deacetylase (HDAC) inhibitors, and bromodomain and extraterminal (BET) inhibitors. Preferred nucleoside metabolic inhibitors are hypomethylating agents. Hypomethylating agents inhibit normal methylation of DNA and/or RNA. Examples of hypomethylating agents are azacitidine, decitabine and guadecitabine.
- In preferred embodiments, the combinations of the invention additionally comprise azacitidine (also referred to herein as azacytidine, AZA or aza). Thus, in preferred embodiments, the present invention provides a combination comprising (i) an antibody or antigen binding fragment thereof that binds to CD70; (ii) venetoclax or a pharmaceutically acceptable salt thereof; and (iii) azacitidine.
- In further preferred embodiments, the combinations of the invention additionally comprise decitabine. Thus, in preferred embodiments, the present invention provides a combination comprising (i) an antibody or antigen binding fragment thereof that binds to CD70; (ii) venetoclax or a pharmaceutically acceptable salt thereof; and (iii) decitabine.
- Azacitidine is an analogue of cytidine and decitabine is its deoxy derivative. Azacitdine and decitabine are inhibitors of DNA methyltransferases (DNMT) known to upregulate gene expression by promoter hypomethylation. Such hypomethylation disrupts cell function, thereby resulting in cytotoxic effects.
- In certain embodiments, the combinations of the present invention additionally comprise cytarabine. Cytarabine (also known as “cytosine arabinose” or “ara-C”) is a chemotherapeutic drug commonly used to treat AML. High-dose cytarabine forms part of the “7+3” standard induction chemotherapy typically used for newly-diagnosed AML patients. Low-dose cytarabine may be used for AML patients who are not eligible for the standard induction chemotherapy. For example, low-dose cytarabine is prescribed in combination with venetoclax for newly-diagnosed AML patients ineligible for standard induction chemotherapy. The combinations of the present invention may additionally comprise low-dose cytarabine.
- In certain embodiments, the combinations of the present invention comprise an additional anti-cancer agent. The one or more additional cancer agents may be selected from any agents suitable for the treatment of myeloid malignancies, preferably AML. Preferred agents may be selected from: selectin inhibitors (e.g. GMI-1271); FMS-like tyrosine kinase receptor 3 (FLT3) inhibitors (e.g. midostaurin or gilteritinib); cyclin-dependent kinase inhibitors; aminopeptidase inhibitors; JAK/STAT inhibitors; cytarabine; fludarabine; anthracycline compounds (e.g. daunorubicin, idarubicin); doxorubicin; hydroxyurea; Vyxeos; IDH1 or IDH2 inhibitors such as Idhifa (or Enasidenib) or Tibsovo (or ivosidenib); Smoothened inhibitors such as Glasdegib; BET bromodomain inhibitors; CD123 or CD33 targeting agents; HDAC inhibitors; LSC targeting agents; AML bone marrow niche targeting agents; NEDD8-activating enzyme inhibitors such as Pevonedistat; G-CSF, and topoisomerase inhibitors such as mitoxantrone, selinexor and etoposide.
- Formulation of the Combination
- The agents of the combinations described herein may be combined or formulated in any manner allowing the combination therapy to be administered to a subject or patient in need thereof, preferably a human subject or patient in need thereof. The combination may be formulated for single dose administration or for multiple dose administration.
- In certain embodiments, the agents of the combinations may be co-formulated i.e. formulated as a single pharmaceutical composition. For embodiments wherein the agents are co-formulated, the combination or composition is suitable for simultaneous administration of the agents.
- In preferred embodiments, the agents of the combinations described herein are formulated as separate compositions or pharmaceutical compositions. For embodiments wherein the agents are formulated separately, the possibility exists for simultaneous or separate administration of the different agents or compositions. If the different compositions are administered separately, there may be sequential administration of the agents in any preferred order. The interval between administration of the agents may be any suitable time interval. The administration of the different compositions may be carried out once (for a single dose administration) or repeatedly (for a multiple dose administration).
- The CD70 antibodies or antigen binding fragments of the combinations described herein may be formulated using any suitable pharmaceutical carriers, adjuvants and/or excipients. Techniques for formulating antibodies for human therapeutic use are well known in the art and are reviewed, for example, in Wang et al. (2007) Journal of Pharmaceutical Sciences, 96:1-26, the contents of which are incorporated herein in their entirety. Pharmaceutically acceptable excipients that may be used to formulate the antibody compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances (for example sodium carboxymethylcellulose), polyethylene glycol, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.
- The BCL-2 inhibitor (preferably venetoclax or a pharmaceutically acceptable salt thereof) may be formulated using any suitable pharmaceutical carriers, adjuvants and/or excipients. Suitable agents include, for example, encapsulating materials or additives such as absorption accelerators, antioxidants, binders, buffers, coating agents, coloring agents, diluents, disintegrating agents, emulsifiers, extenders, fillers, flavoring agents, humectants, lubricants, perfumes, preservatives, propellants, releasing agents, sterilizing agents, sweeteners, solubilizers, wetting agents and mixtures thereof.
- In certain embodiments, the compositions are formulated for administration to a subject via any suitable route of administration including but not limited to intramuscular, intravenous, intradermal, intraperitoneal injection, subcutaneous, epidural, nasal, oral, rectal, topical, inhalational, buccal (e.g., sublingual), and transdermal administration. In certain embodiments, the compositions are formulated as aqueous solutions, tablets, capsules, powders or any other suitable dosage form.
- Excipients for preparation of compositions comprising a BCL-2 inhibitor (preferably venetoclax) to be administered orally in solid dosage form include, for example, agar, alginic acid, aluminum hydroxide, benzyl alcohol, benzyl benzoate, 1,3-butylene glycol, carbomers, castor oil, cellulose, cellulose acetate, cocoa butter, corn starch, corn oil, cottonseed oil, cross-povidone, diglycerides, ethanol, ethyl cellulose, ethyl laureate, ethyl oleate, fatty acid esters, gelatin, germ oil, glucose, glycerol, groundnut oil, hydroxypropylmethyl cellulose, isopropanol, isotonic saline, lactose, magnesium hydroxide, magnesium stearate, malt, mannitol, monoglycerides, olive oil, peanut oil, potassium phosphate salts, potato starch, povidone, propylene glycol, Ringer's solution, safflower oil, sesame oil, sodium carboxymethyl cellulose, sodium phosphate salts, sodium lauryl sulfate, sodium sorbitol, soybean oil, stearic acids, stearyl fumarate, sucrose, surfactants, talc, tragacanth, tetrahydrofurfuryl alcohol, triglycerides, water, and mixtures thereof. Excipients for preparation of compositions comprising a BCL-2 inhibitor (preferably venetoclax) to be administered orally in liquid dosage forms include, for example, 1,3-butylene glycol, castor oil, corn oil, cottonseed oil, ethanol, fatty acid esters of sorbitan, germ oil, groundnut oil, glycerol, isopropanol, olive oil, polyethylene glycols, propylene glycol, sesame oil, water and mixtures thereof. Excipients for preparation of compositions comprising a BCL-2 inhibitor (preferably venetoclax) to be administered osmotically include, for example, chlorofluorohydrocarbons, ethanol, water and mixtures thereof. Excipients for preparation of compositions comprising a BCL-2 inhibitor (preferably venetoclax) to be administered parenterally include, for example, 1,3-butanediol, castor oil, corn oil, cottonseed oil, dextrose, germ oil, groundnut oil, liposomes, oleic acid, olive oil, peanut oil, Ringer's solution, safflower oil, sesame oil, soybean oil, U.S. P. or isotonic sodium chloride solution, water and mixtures thereof.
- For embodiments wherein the agents of the combination are formulated separately i.e. as separate compositions, the separate compositions may be formulated for the same route of administration. For embodiments wherein the agents of the combination are formulated separately i.e. as separate compositions, the separate compositions may be formulated for different routes of administration. For example, the CD70 antibody or antigen binding fragment may be formulated for intravenous administration and the BCL-2 inhibitor (preferably venetoclax) may be formulated for oral administration.
- As noted above, the combination therapies of the present invention may comprise Venclexta®. Venclexta® is a venetoclax product marketed and sold by AbbVie Inc and Genentech. Venclexta® tablets for oral administration are supplied as pale yellow or beige tablets that contain 10, 50, or 100 mg venetoclax as the active ingredient. Each tablet also contains the following inactive ingredients: copovidone, colloidal silicon dioxide,
polysorbate 80, sodium stearyl fumarate, and calcium phosphate dibasic. In addition, the 10 mg and 100 mg coated tablets include the following: iron oxide yellow, polyvinyl alcohol, polyethylene glycol, talc, and titanium dioxide. The 50 mg coated tablets also include the following: iron oxide yellow, iron oxide red, iron oxide black, polyvinyl alcohol, talc, polyethylene glycol and titanium dioxide. For embodiments wherein a CD70 antibody or antigen binding fragment thereof is combined with Venclexta®, the CD70 antibody or antigen binding fragment may be formulated for intravenous administration whilst the Venclexta® is provided as one or more of the tablet forms described above. - For combinations of the invention comprising or consisting of agents in addition to the CD70 antibodies or antigen binding fragments and a BCL-2 inhibitor (preferably venetoclax), the one or more additional agents may be formulated for administration via the same route or via a different route as compared with the other agents. For example, in preferred embodiments wherein the combination includes (i) an antibody or antigen binding fragment thereof that binds to CD70; (ii) venetoclax or a pharmaceutically acceptable thereof; and (iii) azacitidine, the antibody or antigen binding fragment may be administered intravenously, the venetoclax or pharmaceutically acceptable salt thereof may be administered orally whilst the azacitidine may be administered subcutaneously via injection. In preferred embodiments wherein the combination includes (i) an antibody or antigen binding fragment thereof that binds to CD70; (ii) venetoclax or a pharmaceutically acceptable thereof; and (iii) decitabine, the antibody or antigen binding fragment may be administered intravenously, the venetoclax or pharmaceutically acceptable salt thereof may be administered orally whilst the decitabine may be administered subcutaneously via injection.
- The combination therapies described in accordance with the first aspect of the invention can be used in methods of treating a malignancy, particularly a myeloid malignancy, in a human subject.
- The present invention provides an antibody or antigen binding fragment thereof that binds to CD70 for use in the treatment of a malignancy, particularly a myeloid malignancy, in a human subject, wherein the antibody or antigen binding fragment thereof is administered in combination with a BCL-2 inhibitor. The present invention also provides a BCL-2 inhibitor for use in the treatment of a malignancy, particularly a myeloid malignancy, in a human subject, wherein the BCL-2 inhibitor is administered in combination with an antibody or antigen binding fragment that binds to CD70.
- In preferred embodiments, the BCL-2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof.
- The present invention further provides a combination in accordance with the first aspect of the invention for use in the treatment of a malignancy, particularly a myeloid malignancy, in a human subject.
- In a yet further aspect, the present invention provides a method for treating a malignancy, particularly a myeloid malignancy, in a human subject, said method comprising administering to the subject a combination in accordance with the first aspect of the invention. The invention also provides a method for treating a malignancy, particularly a myeloid malignancy, in a human subject, said method comprising the steps of (i) administering to the subject an antibody or antigen binding fragment thereof that binds to CD70; and (ii) administering to the subject a BCL-2 inhibitor, preferably venetoclax or a pharmaceutically acceptable salt thereof. Steps (i) and (ii) of the method may be performed in either order.
- All embodiments described above in relation to the combination of the first aspect of the invention are equally applicable to the methods described herein.
- The term “malignancy” encompasses diseases in which abnormal cells proliferate in an uncontrolled manner and invade the surrounding tissues. Malignant cells that have entered the body's blood and lymph systems are capable of travelling to distal sites in the body and seeding at secondary locations. In certain embodiment, the methods described herein are for treating malignancies comprising the production of cancer progenitor or stem cells expressing CD70, CD27, or both. As noted elsewhere herein, upregulated CD70 expression has been detected in different types of cancers including renal cell carcinomas, metastatic breast cancers, brain tumours, leukemias, lymphomas and nasopharyngeal carcinomas. Co-expression of CD70 and CD27 has also been detected in malignancies of the hematopoietic lineage including acute lymphoblastic lymphoma and T cell lymphoma. In certain embodiments, the methods described herein are for the treatment of any of the aforementioned malignancies associated with CD70 expression, CD27 expression or both.
- In particular embodiments, the methods described herein are for treating myeloid malignancies, wherein a myeloid malignancy refers to any clonal disease of hematopoietic stem or progenitor cells. The myeloid malignancy treated in accordance with the methods of the invention may be a newly-diagnosed myeloid malignancy or a relapsed/refractory myeloid malignancy.
- In certain embodiments, the myeloid malignancy is selected from: acute myeloid leukemia (AML); myelodysplastic syndromes (MDS); myeloproliferative neoplasms (MPN); chronic myeloid leukemia (CML); and chronic myelomonocytic leukemias (CMML). In preferred embodiments, the myeloid malignancy is acute myeloid leukemia (AML).
- Myeloid malignancies can be categorised and diagnosed according to the WHO 2008 classification, taken in combination with the 2016 update to this classification, see in particular Arber et al. (2016) Blood 127(20):2391-2405, incorporated herein by reference.
- Acute myeloid leukemia (AML) refers to haematopoietic neoplasms involving myeloid cells. AML is characterised by clonal proliferation of myeloid precursors with reduced differentiation capacity. AML patients exhibit an accumulation of blast cells in the bone marrow. Blast cells also accumulate in the peripheral blood of AML patients. Typically AML is diagnosed if the patient exhibits 20% or more blast cells in the bone marrow or peripheral blood.
- According to the WHO classification, AML in general encompasses the following subtypes: AML with recurrent genetic abnormalities; AML with myelodysplasia-related changes; therapy-related myeloid neoplasms; myeloid sarcoma; myeloid proliferations related to Down syndrome; blastic plasmacytoid dendritic cell neoplasm; and AML not otherwise categorized (e.g. acute megakaryoblastic leukemia, acute basophilic leukemia).
- AML can also be categorised according to the French-American-British (FAB) classification, encompassing the subtypes: M0 (acute myeloblastic leukemia, minimally differentiated); M1 (acute myeloblastic leukemia, without maturation); M2 (acute myeloblastic leukemia, with granulocytic maturation); M3 (promyelocytic, or acute promyelocytic leukemia (APL)); M4 (acute myelomonocytic leukemia); M4eo (myelomonocytic together with bone marrow eosinophilia); M5 (acute monoblastic leukemia (M5a) or acute monocytic leukemia (M5b)); M6 (acute erythroid leukemias, including erythroleukemia (M6a) and very rare pure erythroid leukaemia (M6b)); or M7 (acute megakaryoblastic leukemia).
- As used herein, “AML” refers to any of the conditions encompassed by the WHO and/or FAB classifications, unless specified otherwise. Certain AML subtypes are considered to be of more favourable prognosis, some of intermediate prognosis and some of poor prognosis. The skilled person is aware of which subtypes would fall into which risk category.
- Myelodysplastic syndrome (MDS) is characterised by dysplasia, cytopenia and/or abnormal changes in bone marrow cellularity and/or myeloid differentiation, for example increased blast cell infiltration. According to the WHO classification, MDS in general encompasses the following subtypes: MDS with single lineage dysplasia (previously called “refractory cytopenia with unilineage dysplasia”, which includes refractory anemia, refractory neutropenia, and refractory thrombocytopenia); MDS with ring sideroblasts, which includes subgroups with single lineage dysplasia and multilineage dysplasia (previously called “refractory anemia with ring sideroblasts”); MDS with multilineage dysplasia (previously called “refractory cytopenia with multilineage dysplasia”); MDS with excess blasts (MDS-EB, previously called “refractory anemia with excess blasts”), which can be further subclassified into MDS-EB-1 and MDS-EB-2 based on blast percentages; MDS with isolated del(5q); and MDS, unclassified.
- MDS can also be categorised according to the French-American-British (FAB) classification, encompassing the subtypes: M9980/3 (refractory anaemia (RA)); M9982/3 (refractory anaemia with ring sideroblasts (RARS)); M9983/3 (refractory anaemia with excess blasts (RAEB)); M9984/3 (refractory anaemia with excess blasts in transformation (RAEB-T)); and M9945/3 (chronic myelomonocytic leukemia (CMML)).
- As used herein, “MDS” refers to any of the conditions encompassed by the WHO and/or FAB classifications, unless specified otherwise. For both AML and MDS, the WHO categorisation is preferred herein.
- Myeloproliferative neoplasms (MPN) are similar to MDS but according to the WHO classification, MPN in general encompasses the following subtypes: chronic myeloid leukemia (CML); chronic neutrophilic leukemia (CNL); polycythemia vera (PV); primary myelofibrosis (PMF); Essential thrombocythemia (ET); chronic eosinophilic leukemia, not otherwise specified; and MPN unclassifiable.
- Chronic myelomonocytic leukemia (CMML) and atypical chronic myeloid leukemia (aCML) fall within the category of MDS/MPN disorders according to the WHO classification, for the reason that they represent myeloid neoplasms with clinical, laboratory and morphologic features that overlap between MDS and MPN.
- Patient Characteristics
- The patients or subjects treated in accordance with the methods described herein, particularly those having AML, may have newly-diagnosed disease, relapsed disease or primary refractory disease.
- A standard approach to treatment for newly-diagnosed AML patients is the “standard 7+3 intensive chemotherapy” approach characterised by 7 days of high dose cytarabine followed by 3 days of anthracycline administration (e.g. daunorubicin or idarubicin). Intensive chemotherapy is given with the aim of inducing complete remission of AML, typically with the intention of the patient undergoing a stem cell transplant following successful chemotherapy.
- Standard intensive chemotherapy is associated with significant toxicity and side-effects, meaning it is not suitable for patients unable to tolerate these effects. These patients are termed “ineligible for standard intensive chemotherapy”. A patient may be ineligible for standard intensive chemotherapy because, for example, they exhibit one or more comorbidities indicating they would not tolerate the toxicity, or the prognostic factors characterising their disease indicate an unfavourable outcome of standard intensive chemotherapy. Determination of an individual patient's eligibility for standard intensive chemotherapy would be performed by a clinician taking into account the individual patient's medical history and clinical guidelines (e.g. the National Comprehensive Cancer Network (NCCN) guidelines, incorporated herein by reference). AML patients over the age of 60 are often assessed as ineligible for standard intensive chemotherapy, with other factors to be considered including the cytogenetics and/or molecular abnormalities of the AML being treated.
- A patient ineligible for standard intensive chemotherapy may instead receive chemotherapy of reduced intensity, such as low dose cytarabine (LDAC). Patients ineligible for standard intensive chemotherapy and for whom LDAC is not appropriate can receive best supportive care (BSC), including hydroxyurea (HU) and transfusion support.
- Patients or subjects treated in accordance with the methods described herein may be those classified as “ineligible for standard intensive chemotherapy”. The combinations of the invention comprise targeted therapies that may be predicted to have fewer side-effects. As such, patients deemed ineligible for standard intensive chemotherapy, for any of the reasons identified above, may be treated with the combinations according to the present invention.
- As discussed above, venetoclax is authorised in the US for use in combination with azacitidine, decitabine or low-dose cytarabine for the treatment of newly-diagnosed AML in adults who are aged 75 years or older or who have comorbidities that preclude use of intensive induction chemotherapy. Thus, in certain embodiments, particularly embodiments wherein the BCL-inhibitor is venetoclax or a pharmaceutically acceptable salt thereof, patients or subjects treated in accordance with the methods described herein are newly-diagnosed AML patients aged 75 years or older. In further embodiments, patients or subjects treated in accordance with the methods described herein are newly-diagnosed AML patients having comorbidities that preclude use of intensive induction therapy. Patients having a comorbidity precluding use of intensive induction chemotherapy may be classified as such based on at least one of the following criteria: baseline Eastern Cooperative Oncology Group (ECOG) performance status of 2-3, severe cardiac or pulmonary comorbidity, moderate hepatic impairment, or CLcr<45 ml/min. Such embodiments are particularly preferred when the BCL-2 inhibitor in the combination according to the invention is venetoclax or a pharmaceutically acceptable salt thereof.
- Patients or subjects treated in accordance with the methods described herein may be eligible for other treatments, for example standard intensive chemotherapy, but may receive the combination therapies described herein as an alternative treatment option. For example, patients or subjects treated in accordance with the methods described herein may be newly-diagnosed AML patients otherwise eligible for standard intensive chemotherapy.
- Additional Agents for Treatment
- The methods described herein may include administration of one or more additional therapeutic agents, for example, additional anti-cancer agents. In certain embodiments, the methods comprise the administration of one or more agents for use in treating myeloid malignancies, for example agents suitable for use in treating AML. Such agents include but are not limited to: selectin inhibitors (e.g. GMI-1271); FMS-like tyrosine kinase receptor 3 (FLT3) inhibitors (e.g. midostaurin or gilteritinib); cyclin-dependent kinase inhibitors; aminopeptidase inhibitors; JAK/STAT inhibitors; cytarabine; fludarabine; anthracycline compounds (e.g. daunorubicin, idarubicin); doxorubicin; hydroxyurea; Vyxeos; IDH1 or IDH2 inhibitors such as Idhifa (or Enasidenib) or Tibsovo (or ivosidenib); Smoothened inhibitors such as Glasdegib; BET bromodomain inhibitors; CD123 or CD33 targeting agents; HDAC inhibitors; LSC targeting agents; AML bone marrow niche targeting agents; NEDD8-activating enzyme inhibitors such as Pevonedistat; G-CSF, and topoisomerase inhibitors such as mitoxantrone, selinexor and etoposide.
- In preferred embodiments, the methods described herein comprise administration of a further agent that is a nucleoside metabolic inhibitor, preferably a hypomethylating agent. Particularly preferred hypomethylating agents are azacitidine and decitabine. As described herein above, in certain embodiments the combinations of the invention comprising (i) a CD70 antibody or antigen binding fragment thereof; and (ii) a BCL-2 inhibitor, preferably venetoclax or a pharmaceutically acceptable salt, may be formulated so as to include additional agents, for example azacitidine or decitabine.
- Alternatively, for embodiments wherein the combination consists of (i) an antibody or antigen binding fragment that binds to CD70; and (ii) a BCL-2 inhibitor, preferably venetoclax or a pharmaceutically acceptable salt thereof, the methods wherein the combination is administered to a subject, may comprise a further step of administering the additional agent, for example azacitidine or decitabine. Thus, in a preferred embodiment, the present invention provides a method for treating a myeloid malignancy, preferably AML, in a human subject, said method comprising administering to the subject: (i) an antibody or antigen binding fragment thereof that binds to CD70; (ii) a BCL-2 inhibitor, preferably venetoclax or a pharmaceutically acceptable salt thereof; and (iii) azacitidine or decitabine. Also provided herein is a combination for use in treating a myeloid malignancy, preferably AML, in a human subject, said combination comprising: (i) an antibody or antigen binding fragment thereof that binds to CD70; (ii) a BCL-2 inhibitor, preferably venetoclax or a pharmaceutically acceptable salt thereof; and (iii) azacitidine or decitabine.
- Dosing
- As demonstrated in the Examples, combinations of the invention exhibit synergistic treatment efficacy against AML cells—that is, the level of inhibition induced by the combination is greater than the additive effect of the monotherapies alone.
- Methods for determining synergistic interaction are familiar to the skilled person and are described in the Examples. A preferred method for determining whether synergistic effects arise from a combination is the Chou-Talalay method (Chou, TC. Cancer Res. 2010 Jan. 15; 70(2):440-6, incorporated herein by reference).
- According to the Chou-Talalay method, a CI of <1 shows synergy, CI=1 shows an additive effect, and a CI>1 shows antagonism. As presented in
FIG. 1 , the presence and extent of the synergy arising from combinations of the invention varies according to the strength of the inhibitory effect of the combination. The strength of the combination's inhibitory effect itself is dependent on the total concentration of the combination. - Preferably, therefore, in embodiments of all aspects of the invention, the dose at which the CD70 antibody or antigen binding fragment thereof is administered and/or provided in the combination, and the dose at which the BCL-2 inhibitor is administered and/or provided in the combination, are each selected such that the combination provides synergistic treatment—that is, where the combination exhibits a CI of less than 1 as determined by the Chou-Talalay method. Preferably the doses are such that the combination exhibits a CI of less than 0.5.
- Preferably, in certain embodiments, the dose at which the CD70 antibody or antigen binding fragment thereof is administered and/or provided in the combination, and the dose at which the BCL-2 inhibitor is administered and/or provided in the combination, are each selected such that the combination exhibits a CI of less than 1 and Fa of >0.5, as determined by the Chou-Talalay method.
- As shown in the Examples, synergy was also observed for a combination of an anti-CD70 antibody (ARGX-110), a BCL-2 inhibitor (venetoclax) and an HMA (decitabine). Therefore, in certain preferred embodiments of aspects of the invention where the combination includes an HMA, the dose at which the CD70 antibody or antigen binding fragment thereof is administered and/or provided in the combination, the dose at which the BCL-2 inhibitor is administered and/or provided in the combination, and the dose at which the HMA is administered and/or provided in the combination are each selected such that the combination provides synergistic efficacy in treatment.
- It has been found that CD70 antibodies, particularly ARGX-110, are effective for the treatment of myeloid malignancy, particularly AML, at relatively low dose. Therefore, in certain embodiments of all methods of the invention the CD70 antibody or antigen binding fragment thereof is administered at a dose in the range from 0.1 mg/kg to 25 mg/kg per dose, for example in the range of from 0.1 mg/kg to 20 mg/kg. In certain embodiments, the CD70 antibody or antigen binding fragment thereof is administered at a dose in the range from 1 mg/kg to 20 mg/kg per dose. Ranges described herein include the end points of the range unless indicated otherwise—for example, administration at a dose in the range of 0.1-25 mg/kg includes administration at a dose of 0.1 mg/kg and administration at a dose of 25 mg/kg, as well as all doses between the two end points.
- In certain embodiments of methods of the invention, the CD70 antibody or antigen binding fragment thereof is administered at a dose in the range from 0.1 mg/kg to 15 mg/kg. In certain embodiments the CD70 antibody or antigen binding fragment thereof is administered at a dose in the range from 0.5 mg/kg to 2 mg/kg. In certain embodiments the CD70 antibody or antigen binding fragment thereof is administered at a dose of 1 mg/kg, 3 mg/kg, 10 mg/kg, or 20 mg/kg. In certain preferred embodiments the CD70 antibody or antigen binding fragment thereof is administered at a dose of 1 mg/kg. In certain preferred embodiments the CD70 antibody or antigen binding fragment thereof is administered at a dose of 10 mg/kg.
- In certain embodiments, multiple doses of the CD70 antibody or antigen binding fragment are administered. In certain such embodiments, each dose of the CD70 antibody or antigen-binding fragment thereof is separated by 10-20 days, optionally 12-18 days. In certain embodiments each dose of anti-CD70 antibody is separated by 14-17 days.
- The BCL-2 inhibitor, preferably venetoclax or pharmaceutically acceptable salt thereof, of the combination may be dosed according to any regimen determined to be effective for the compound. The FDA prescribing information for use of Venclexta® in treating AML proposes a dosing schedule having a ramp-up phase followed by a maintenance phase. In situations where Venclexta® is prescribed in combination with azacitidine or decitabine, a dosing schedule is recommended consisting of: 100 mg Venclexta® on
day 1; 200 mg Venclexta® onday 2; 400 mg Venclexta® onday 3; and 400 mg Venclexta® in combination with 75 mg/m2 azacitidine or 20 mg/m2 decitabine daily thereafter until disease progression or unacceptable toxicity is observed. In situations where Venclexta® is prescribed in combination with low-dose cytarabine, a dosing schedule is recommended consisting of: 100 mg Venclexta® onday 1; 200 mg Venclexta® onday 2; 400 mg Venclexta® onday 3; and 600 mg Venclexta® in combination with 20 mg/m2 daily thereafter until disease progression or unacceptable toxicity is observed. - In certain embodiments, each dose, for example oral dose, of the venetoclax or pharmaceutically acceptable salt thereof is in the range from 100 mg-600 mg. In certain embodiments, the venetoclax or pharmaceutically acceptable salt thereof is dosed daily at 400 mg. In certain embodiments, the venetoclax or pharmaceutically acceptable salt thereof is dosed daily at 600 mg. As described above, the daily fixed-dosing of venetoclax may be preceded by a ramp-up period, for example 3 days, wherein increasing doses of venetoclax are administered to the patient until the maintenance daily dose is reached.
- For embodiments of the invention wherein the combination comprises a nucleoside metabolic inhibitor or the method comprises administering a nucleoside metabolic inhibitor, the nucleoside metabolic inhibitor may be administered at a dose in the range of 20-100 mg/m2 per day. As already noted, ranges described herein include the end points of the range unless indicated otherwise—for example, administration at a dose in the range of 20-100 mg/m2 per day includes administration at a dose of 20 mg/m2 per day and administration at a dose of 100 mg/m2 per day, as well as all doses between the two end points.
- In certain embodiments, the nucleoside metabolic inhibitor is azacitidine and is administered at a dose in the range of 70-80 mg/m2 per day. In certain preferred embodiments the nucleoside metabolic inhibitor is azacitidine and is administered at a dose of 75 mg/m2 per day.
- In certain embodiments, the nucleoside metabolic inhibitor is decitabine and is administered at a dose in the range of 15-25 mg/m2 per day. In certain preferred embodiments the nucleoside metabolic inhibitor is decitabine and is administered at a dose of 20 mg/m2 per day.
- For embodiments wherein the combination of the invention includes a nucleoside metabolic inhibitor or the method involves administration of a nucleoside metabolic inhibitor, the nucleoside metabolic inhibitor may be administered over a dosing period of a daily dose for 5-10 days. That is, a dose of the nucleoside inhibitor is administered every day for a period or 5, 6, 7, 8, 9, or 10 days in length. In certain preferred embodiments the nucleoside metabolic inhibitor is administered over a dosing period of a daily dose for 7 days. The preferred nucleoside metabolic inhibitor is azacitidine.
- In certain embodiments, the nucleoside metabolic inhibitor is administered according to a dosage regimen of repeated dosing periods, wherein the end of one dosing period and the start of the next dosing period are separated by 18-25 days. That is, the dosage regimen includes at least 2 dosing periods in which a dose of the nucleoside inhibitor is administered every day (for example for a
period - In certain embodiments, each dosing period is of the same length (e.g. 7 days). In certain embodiments, the end of each dosing period and the start of the next dosing period are separated by the same number of days (e.g. 21 days).
- In certain embodiments, the first dose of nucleoside metabolic inhibitor is administered 7-21 days after the first dose of CD70 antibody or antigen binding fragment thereof. In certain embodiments the first dose of nucleoside metabolic inhibitor is administered 10-17 days after the first dose of CD70 antibody or antigen binding fragment thereof. In certain embodiments the first dose of nucleoside metabolic inhibitor is administered 14 days after the first dose of CD70 antibody or antigen binding fragment thereof.
- In certain embodiments, one of the daily doses of the nucleoside metabolic inhibitor is administered on the same day as a dose of the CD70 antibody or antigen binding fragment thereof. That is, in embodiments of the methods of the invention in which the subject is administered both a CD70 antibody (or antigen binding fragment thereof) and a nucleoside metabolic inhibitor, the dosage regimes of both the CD70 antibody and the nucleoside metabolic inhibitor are such that at least one of the scheduled doses of the CD70 antibody is on the same day as one of the scheduled daily doses of the nucleoside metabolic inhibitor. That day could be the first, second, third, fourth, fifth, sixth or seventh day of the dosing period of the nucleoside metabolic inhibitor.
- In certain embodiments, a dose of the CD70 antibody or antigen binding fragment thereof is administered every 14-17 days and the nucleoside metabolic inhibitor is administered according to a dosage regimen of repeated dosing periods of a daily dose for 7 days, wherein the end of one dosing period and the start of the next dosing period are separated by 21 days, and wherein the first daily dose of the first dosing period is administered 14 days after the first dose of the anti-CD70 antibody or antigen-binding fragment thereof.
- In certain embodiments, one patient treatment cycle consists of 28 days and the nucleoside metabolic inhibitor, preferably azacitidine or decitabine, is administered every day for a period of 5, 6, 7, 8, 9 or 10 days beginning on
day 1 of the cycle. The methods of treatment described herein may comprise multiple treatment cycles. Each treatment cycle may replicate the preceding treatment cycle. In certain embodiments, a patient treated with a CD70 antibody, a BCL-inhibitor (preferably venetoclax or a pharmaceutically acceptable salt thereof) and azacitidine is treated according to a cycle consisting of 28 days wherein azacitidine is administered daily on the first 7 days of the 28-day cycle. In certain embodiments, a patient treated with a CD70 antibody, a BCL-inhibitor (preferably venetoclax or a pharmaceutically acceptable salt thereof) and decitabine is treated according to a cycle consisting of 28 days wherein decitabine is administered daily on the first 5 days of the 28-day cycle. For embodiments wherein the patient is treated according to a 28-day cycle with a CD70 antibody, a BCL-inhibitor ((preferably venetoclax or a pharmaceutically acceptable salt thereof) and a nucleoside metabolic inhibitor (preferably azacitidine or decitabine), the CD70 antibody may be administered onday 3 and/or day 17 of the 28-day cycle. In preferred embodiments, the CD70 antibody is ARGX-110. In further preferred embodiments, the CD70 antibody (for example ARGX-110) is administered at a dose of 10 mg/kg. - It is a further advantage of the invention that following an initial period of combination therapy, the administration of an NMI (e.g. azacitidine) can be tapered or stopped. There is the potential for accumulated toxicity arising from prolonged periods of NMI treatment, for example cytopenias arising from the effect of NMIs on non-blast cell types. Therefore, by tapering or stopping the dose of NMI after an initial period, the risk of such toxicity will be reduced and non-blast cell types can recover. In certain embodiments, treatment according to the invention comprises administering to the patient a CD70 antibody, a BCL-2 inhibitor (for example venetoclax) and a NMI as a combination therapy according to any of the embodiments described above in a first stage (induction therapy), and in a subsequent second stage administering to the patient a CD70 antibody, a BCL-2 inhibitor (for example venetoclax) and a NMI as a combination therapy but wherein the dose of the NMI in the second stage (maintenance therapy) is lower than the dose of NMI administered in the first stage. The dose of the NMI in the second stage may be zero.
- In such embodiments, the dose of CD70 antibody administered in the second stage (i.e. maintenance therapy) is any dose according to the embodiments already described. That is, in certain embodiments the dose is in the range from 0.1 mg/kg to 25 mg/kg, for example 0.1 mg/kg to 20 mg/kg, for example from 1 mg/kg to 20 mg/kg. In certain embodiments the dose is in the range of from 0.1 mg/kg to 15 mg/kg per dose. In certain embodiments the dose is in the range from 0.5 mg/kg to 2 mg/kg. In certain embodiments the dose is 1 mg/kg, 3 mg/kg, 10 mg/kg, or 20 mg/kg. In certain embodiments the dose is 1 mg/kg. In certain embodiments the dose is 10 mg/kg.
- The duration of the first stage (i.e. induction therapy), the timing of the transition to the second stage (i.e. maintenance therapy) and the extent to which the dose of NMI is tapered or stopped entirely are factors that will be tailored to the individual patient and determined by their clinician according to the individual patient's response to therapy and their medical history. Therefore the following embodiments are provided by way of non-limiting example. In certain embodiments the induction therapy is administered to the patient until their bone marrow and/or peripheral blood blast percentage is less than 10%, optionally less than 5%. In certain embodiments, the induction therapy is administered for at least 5 NMI dosing periods, optionally at least 6, 7, 8, 9, or at least 10 NMI dosing periods.
- In certain embodiments, the dose of the NMI in the maintenance period is no more than 50 mg/m2 per day, optionally no more than 40 mg/m2 per day, optionally no more than 30 mg/m2 per day, optionally no more than 20 mg/m2 per day. In certain embodiments, the dose of the NMI in the maintenance period is zero.
- As explained elsewhere herein, the agents of the combinations may be formulated for administration by any suitable routes of administration. Thus, the administration of the agents in accordance with the methods of the invention can be via any suitable routes and need not be via the same route for individual agents. For example, the CD70 antibody or antigen binding fragment thereof may be administered intravenously whilst the BCL-2 inhibitor (e.g. venetoclax) is administered orally. For embodiments wherein the patient or subject receives a hypomethylating agent such as azacitidine or decitabine, such agent may be administered intravenously or subcutaneously via injection.
- Treatment Outcomes
- In certain embodiments, the methods described herein involve monitoring the patient's blast count i.e. the number of blast cells. As used herein, “blast cells” or “blasts” refer to myeloblasts or myeloid blasts which are the myeloid progenitor cells within the bone marrow. In healthy individuals, blasts are not found in the peripheral blood circulation and there should be less than 5% blast cells in the bone marrow. In subjects with myeloid malignancies, particularly AML and MDS, there is increased production of abnormal blasts with disrupted differentiation potential, and the overproduction of these abnormal blasts can be detected by monitoring the patient's blast count in the peripheral blood circulation or the bone marrow or both.
- The proportion of blast cells in the bone marrow or peripheral blood can be assessed by methods known in the art, for example flow cytometric or cell morphologic assessment of cells obtained from a bone marrow biopsy of the subject, or a peripheral blood smear. The proportion of blasts is determined versus total cells in the sample. For example, flow cytometry can be used to determine the proportion of blast cells using the number of CD45dim, SSClow cells relative to total cell number. By way of further example, cell morphological assessment can be used to determine the number of morphologically identified blasts relative to the total number of cells in the field of view being examined.
- In certain embodiments are provided methods for reducing the proportion of blasts cells in the bone marrow to less than 25%, less than 20%, for example less than 10%. In certain embodiments are provided methods for reducing the proportion of blasts cells in the bone marrow to less than 5%. In certain embodiments are provided methods for reducing the proportion of blast cells in the bone marrow to between about 5% and about 25%, wherein the bone marrow blast cell percentage is also reduced by more than 50% as compared with the bone marrow blast cell percentage prior to performing the method (or pretreatment).
- In certain embodiments are provided methods for reducing the proportion of blasts cells in the peripheral blood to less than 25%, less than 20%, for example less than 10%. In certain embodiments are provided methods for reducing the proportion of blasts cells in the peripheral blood to less than 5%. In certain embodiments are provided methods for reducing the proportion of blast cells in the peripheral blood to between about 5% and about 25%, wherein the peripheral blood blast cell percentage is also reduced by more than 50% as compared with the peripheral blast cell percentage prior to performing the method (or pretreatment).
- For clinical determination of blast cell percentage, typically cell morphological (also known as cytomorphology) assessment is preferred.
- In particular embodiments, the methods described herein induce a complete response. In the context of AML treatment, a complete response or “complete remission” is defined as: bone marrow blasts <5%; absence of circulating blasts and blasts with Auer rods; absence of extramedullary disease; ANC≥1.0×109/L (1000 μL); platelet count ≥100×109/L (100,000 μL), see Döhner et al. (2017) Blood 129(4): 424-447.
- The methods may achieve a complete response with platelet recovery i.e. a response wherein the platelet count is >100×109/L (100,000/μL). The methods may achieve a complete response with neutrophil recovery i.e. a response wherein the neutrophil count is >1.0×109/L (1000/μL). Alternatively or in addition, the methods may induce a transfusion independence of red blood cells or platelets, or both, for 8 weeks or longer, 10 weeks or longer, 12 weeks or longer.
- In particular embodiments, the methods described herein induce a minimal or measurable residual disease (or MRD) status that is negative, see Schuurhuis et al. (2018) Blood. 131(12): 1275-1291.
- In certain embodiments, the methods described herein induce a complete response without minimal residual disease (CRMRD−), see Döhner et al. ibid.
- The method may achieve a partial response or induce partial remission. In the context of AML treatment, a partial response or partial remission includes a decrease of the bone marrow blast percentage of 5% to 25% and a decrease of pretreatment bone marrow blast percentage by at least 50%, see Döhner et al. ibid.
- The methods described herein may increase survival. The term “survival” as used herein may refer to overall survival, 1-year survival, 2-year survival, 5-year survival, event-free survival, progression-free survival. The methods described herein may increase survival as compared with the gold-standard treatment for the particular disease or condition to be treated. The gold-standard treatment may also be identified as the best practice, the standard of care, the standard medical care or standard therapy. For any given disease, there may be one or more gold-standard treatments depending on differing clinical practice, for example in different countries. The treatments already available for myeloid malignancies are varied and include chemotherapy, radiation therapy, stem cell transplant and certain targeted therapies. Furthermore, clinical guidelines in both the US and Europe govern the standard treatment of myeloid malignancies, for example AML, see O'Donnell et al. (2017) Journal of the National Comprehensive Cancer Network 15(7):926-957 and Döhner et al. (2017) Blood 129(4):424-447, both incorporated by reference.
- The methods of the present invention may increase or improve survival relative to patients undergoing any of the standard treatments for myeloid malignancy.
- The methods described herein may include a further step of subjecting the patient or subject to a bone marrow transplant. The methods described herein may also be used to prepare a patient or subject having a myeloid malignancy for a bone marrow transplantation. As described above, the methods of the present invention may be carried out so as to reduce the absolute or relative numbers of blast cells in the bone marrow or peripheral blood. In certain embodiments, the methods are carried out so as to reduce the blast cell count in the bone marrow and/or peripheral blood prior to transplant. The methods may be used to reduce the blast cell count to less than 5% to prepare the patient or subject for a bone marrow transplant.
- The combinations of the invention described herein may be provided in the form of a kit packaged so as to include instructions for use.
- Various publications are cited in the foregoing description and throughout the following examples, each of which is incorporated by reference herein in its entirety.
- In a
recent Phase 1 clinical trial, treatment of older and unfit AML patients with the ADCC-enhanced humanized monoclonal anti-CD70 antibody (mAb) cusatuzumab (also referred to herein as ARGX-110) in combination with HMA demonstrated promising clinical activity and a favorable tolerability profile. - The BCL-2 antagonist, venetoclax, targets and eliminates leukemic stem cells (LSCs) by suppression of oxidative phosphorylation and demonstrated very promising activity in older AML patients in clinical phase I and II studies in combination with standard of care (Pollyea et al., Nature Medicine (2018) 24; 1859-1866). However, even with novel agents such as venetoclax, there are still patients that become refractory or relapse. It was hypothesized that combining venetoclax and cusatuzumab with distinct but complementary mechanisms of action could successfully eliminate LSCs.
- Methods
- To test this hypothesis, a drug-combination study was carried out according to the Chou-Talalay method (Chou T C, Cancer Research (2010) 70(2); 440-6) in CD70-expressing AML cell lines such as MOLM-13, NB-4, and NOMO-1 cells in vitro. MOLM-13 AML cells express FLT3-ITD and NOMO-1 cells express t(9;11)(p22;q23). Each of these genetic aberrations conveys a poor prognosis to patient outcome. NB-4 is an acute promyelocytic leukemia (APL) cell line, where APL is a subset of AML patients. Of note, NOMO-1 and MOLM-13 cells express high levels of CD70 as measured at the mRNA and protein levels. The MOLM-13 AML cells also express BCL-2 and are sensitive to BCL-2 inhibition (Lin et al. Scientific Reports (2016) 6; 27696).
- MOLM-13 (Matsuo et al., Leukemia (1997) 11(9): 1469-77), NOMO-1 (Kato et al., Acta Haematol Jpn, 1986), MV4-11 and NB4 (Lanotte et al., Blood (1991) 77(5); 1080-86) cells were purchased from ATCC. The cell lines were tested mycoplasma-free and were grown in FCS-containing medium recommended by ATCC with GlutaMAX supplement, 100 U/mL penicillin, and 100 μg/mL of streptomycin in a humidified atmosphere of 95% air and 5% CO2 at 37° C.
- Initially, cells from each AML cell line were treated with decitabine, cusatuzumab or venetoclax alone to determine the IC50 for each treatment. 105 AML cells were treated with a concentration range of cusatuzumab (0.1, 1.0 and 10 μg/ml), venetoclax (0.5 and 200 nM), decitabine (0.01-1 μM) or vehicle in the presence of CFSE-labelled NK cells derived from healthy individuals (ratio 1:1). The assay was performed in triplicate.
- The IC50 determination identified the following working concentrations for the subsequent synergy experiments:
-
- 1) IC50s, MOLM-13: (decitabine: 0.01 nM, venetoclax: 0.42 nM, cusatuzumab: 0.68 μg/ml)
- 2) IC50s, NOMO-1: (decitabine: 0.001 nM, venetoclax: 3.4 nM, cusatuzumab: 0.14 μg/ml)
- 3) IC50s, NB4: (decitabine: 4.8 nM, venetoclax: 17.3 nM, cusatuzumab: 0.3 μg/ml)
- 4) IC50s, MV4-11: (decitabine: 2.36 nM, venetoclax: 5 nM, cusatuzumab: 1.2 μg/ml)
- To determine synergy, a constant combination ratio experiment was carried out at equipotency ratio (IC501/IC502, or IC501/IC502/IC503) so that each drug contributed equally to cell killing. Combination drug dose responses were assessed in two technical replicates for every dose/dose combination as previously described (Riether et al., Sci Transl Med (2015) 7(298); 298ra119.
- NOMO-1, MOLM-13, NB-4 or MV4-11 AML cell lines were treated with vehicle, decitabine, cusatuzumab or venetoclax alone, a double combination of venetoclax and decitabine, decitabine and cusatuzumab, or venetoclax and cusatuzumab, or a triple combination of decitabine, cusatuzumab and venetoclax. All combinations were tested at three high and three low concentrations (above and below the identified IC50s) and in a constant ratio. Cells were cultured in the presence of CFSE-labeled NK cells (ratio 1:1). Viable AML cell numbers were assessed 72 hours later by Annexin V staining, and the effect of drug treatment was calculated as the ratio of surviving cells to vehicle-treated cells.
- The Combination Index (CI) was calculated and plotted against Fraction affected (Fa) using CompuSyn software. The resultant plot of the combination index (CI) against fraction affected (Fa) for all combinations is shown in
FIG. 1 , with the individual combinations shown inFIGS. 2A-2D . - Fa values of 0, 0.5, and 1 correspond to 0, 50, and 100% killed cells. A CI of <1, 1, >1 represents synergism, additivity, and antagonism, respectively. IC50s indicates Fa values reached for the combination of respective IC50 concentrations. The principles and advantages of the Fa-CI plot method of assessing synergism are provided in, for example, Chou T C, Cancer Research (2010) 70(2); 440-6 and Zhao et al. Front Biosci (Elite Ed). (2010) 2; 241-249 (each of which is incorporated herein by reference in its entirety).
- In addition, the effect of the cusatuzumab/venetoclax and the cusatuzumab/venetoclax/HMA combination was tested on primary LSCs from AML patients. Primary CD34+CD38− leukemic stem cells (LSCs) were isolated from newly-diagnosed AML patients and treated with cusatuzumab, decitabine, or venetoclax monotherapy or in combination. The effect on colony formation and re-plating capacity of the LSCs was then assessed.
- Specifically, CD34+CD38− AML LSCs from three AML patients (P1, P2 and P3) were cultured overnight in the presence of NK cells (ratio 1:1) with cusatuzumab (Cusa: 0.3 μg/ml) or venetoclax (Ve: 6 nM) as monotherapy or in combination overnight in duplicates followed by plating in methylcellulose. CD34+CD38− AML LSCs from two further AML patients (P4 and P5) were cultured overnight in the presence of NK cells (ratio 1:1) with cusatuzumab (Cusa: 0.3 μg/ml), decitabine (0.01 μM), or venetoclax (Ve: 6 nM) as monotherapy or in combination. Colony formation was assessed 14 days later.
- Results
- 1. Cusatuzumab Used in Combination with Venetoclax and/or Decitabine Demonstrated Synergy in the Elimination of AML Cell Lines In Vitro
- Venetoclax and/or decitabine in combination with cusatuzumab synergistically eliminated CD70-expressing NOMO-1 AML cells in a broad dose range (see
FIG. 1 andFIG. 2B-2D ). - At the higher effect levels (Fa>0.7), which are more relevant in tumor killing (Chou, 2010), the combinations demonstrated strong synergy. Importantly, the CI of the venetoclax and cusatuzumab (Ven/Cusa) and venetoclax, cusatuzumab and decitabine (Ven/Cusa/Dec) were approaching 0.1, indicating very strong synergy. Venetoclax and decitabine (Ven/Dec) and cusatuzumab and decitabine (Cusa/Dec) also achieved synergy at higher effect levels, with a maximal CI ˜0.5. The synergistic effect of the Ven/Cusa combination was similar to the synergistic effect observed for Ven/Cusa/Dec combination.
- Similar results were observed in the NB4 and MV4-11 AML cell lines, with all cusatuzumab combinations exhibiting potent synergy at high effect levels (Fa>0.5) (see
FIGS. 3A-3D andFIG. 5 ). - In the MOLM-13 cell line, all double combinations showed a synergistic effect at lower effect levels. Venetoclax/decitabine and cusatutzumab/decitabine showed a synergy only at drug concentrations below a Fa of 0.4 and 0.6, respectively. At higher effect levels (Fa ˜0.7 to 0.8), which are more relevant in tumor killing, the combination of cusatutzumab/venetoclax demonstrated strong synergy (see
FIGS. 4A-4D ), though some antagonism was observed at the highest effect levels. The triple combination of venetoclax, decitabine and cusatuzumab showed low levels of antagonism at all effect levels. - 2. Cusatuzumab Used in Combination with Venetoclax and/or Decitabine Demonstrated Synergy in the Elimination of Primary Human AML Leukemic Stem Cells (LSCs) In Vitro
- To assess the effect of the cusatuzumab/venetoclax combination on primary human AML LSCs, CD34+CD38− LSCs from five AML patients were treated (P1-P5). The patient characteristics are shown below.
-
TABLE 2 Patient characteristics P1-P5 ID Age (y) Sex FAB Risk Cytogenetics Mutations 1 72 M M4 Int. NK ASXL1, DNMT3A, IDH2, SRSF2 2 62 M M4 Adv. Monosomy 7 — 3 50 M M2 Adv. del(16), IDH2, t(11; 16), DNMT3A trisomy 14 4 75 M Sec. AML. Int NK DNMT3a, U2AF1 5 80 F M2 Adv. NK FLT3-ITD - The results for patients P1, P2 and P3 are shown in
FIGS. 6A-6B andFIGS. 7A-7B .FIG. 6 shows the absolute numbers of colonies formed per well following treatment, indicative of the number of LSCs.FIG. 7 shows the same data expressed as a ratio of the mean colonies per well for the vehicle treated group for each patient. -
FIGS. 6 and 7 show that the synergistic effect between cusatuzumab and venetoclax observed in the AML cell lines translated into a potent and significant reduction in the number of LSCs compared to either treatment alone (FIG. 6A andFIG. 7A ). -
FIGS. 6B and 7B show that the effect of reducing LSC numbers was maintained when the first colonies were re-plated in the absence of the treatment molecules. - The results for patients P4 and P5 are shown in
FIGS. 8A-8B . In these patients, the triple combination of cusatuzumab, decitabine and venetoclax showed equivalent efficacy to the dual combination of cusatuzumab and venetoclax. This is in line with the fact that no increase in synergy was observed for the triple combination compared to the Ven/Cusa combination (FIG. 1 ). - 3. Venetoclax Increased CD70 Expression
- The effect of venetoclax on expression of CD70 at both the mRNA and protein level was assessed. The results are shown in
FIG. 9 andFIG. 10 , and clearly demonstrate that CD70 expression was up-regulated in AML cells in the presence of venetoclax. - The present experiments were performed to determine whether combination therapy with cusatuzumab and venetoclax and/or a hypomethylating agent (e.g. azacitidine or decitabine) could provide effective treatment for AML greater than each monotherapy alone. It was further explored whether the combination treatments could exhibit synergistic therapeutic effects.
- The Combination Index (CI) provided by the Chou-Talalay method is an established means for determining whether drug combinations interact in a synergistic, additive or antagonistic manner. It was hypothesised that venetoclax and cusatuzumab may act in a synergistic manner since mechanistically it could be shown that treatment with venetoclax results in up-regulation of CD70 on AML cells (
FIGS. 9 and 10 ). This could mean that venetoclax renders LSCs more susceptible to cytolytic killing with cusatuzumab. However, as noted in Chou 2010 (Chou Cancer Res. (2010) Jan. 15;70(2):440-6, incorporated herein by reference), synergistic effects between drugs are hard to predict, even in cases where there is some knowledge of the mechanism by which each individual drug acts. - The data presented in
FIGS. 1-5 demonstrate that the Ven/Cusa combination exhibited a strong synergistic effect against AML cells, especially at high effect levels. The potent synergy was maintained for the triple combination further including decitabine as a hypomethylating agent. - This synergy is particularly advantageous since this indicates that, when the drugs are in combination, significantly lower concentrations of each drug can be used compared to the concentrations required to achieve the same effect as monotherapies.
- Because the cell line experiments exhibited a strong synergistic effect of the venetoclax/cusatuzumab combination, the combination was tested on primary AML LSCs. Primary LSCs provide a rigorous and more clinically relevant assessment of potential therapeutic benefit, as these cells drive the aberrant proliferation characteristic of AML. The synergistic effect of the Ven/Cusa combination therapy observed in the cell lines translated to a potent reduction of primary AML leukemic stem cells (LSCs) from human patients (
FIGS. 6-8 ). These data demonstrate that for all patient samples the combination therapy inhibited LSC colony formation to an extent significantly greater than either therapy alone. The data appear to show a synergy between the components of the Ven/Cusa combination. (Due to the low numbers of primary cells available, it was not feasible to test the synergistic effect using the Chou-Talalay method). - When the effect of the cusatuzumab/venetoclax treatment on LSC function was analyzed in a more stringent way by serial re-plating experiments in vitro, the impaired colony formation after combination treatment observed after the first plating was maintained during subsequent the re-plating. This was the case even though cusatuzumab and venetoclax were not present in the re-plating, indicating an effective reduction of LSCs and their proliferative potential.
- The triplet combination cusatuzumab/venetoclax/decitabine reduced colony and re-plating capacity of primary human LSCs to the same extent as the cusatuzumab/venetoclax combination treatment. It may be, therefore, that effective treatment of AML can be achieved using the combination of cusatuzumab and venetoclax without the need to include a HMA such as decitabine, thereby reducing the exposure of the patient to toxic therapies.
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BR112021025375A2 (en) * | 2019-06-20 | 2022-02-01 | Celgene Corp | Azacitidine in combination with venetoclax, gilteritinib, midostaurin or other compounds for the treatment of leukemia or myelodysplastic syndrome |
TW202138388A (en) | 2019-12-30 | 2021-10-16 | 美商西根公司 | Methods of treating cancer with nonfucosylated anti-cd70 antibodies |
CN116249519A (en) * | 2020-08-29 | 2023-06-09 | 阿根思有限公司 | Methods of treating patients with reduced sensitivity to BCL-2 inhibitors |
WO2023003990A1 (en) * | 2021-07-21 | 2023-01-26 | Emory University | Bak activators, pharmaceutical compositions, and uses in treating cancer |
CN117916266A (en) * | 2021-09-02 | 2024-04-19 | 弗哈夫曼拉罗切有限公司 | Antibodies for the treatment of AML |
WO2023081721A1 (en) * | 2021-11-03 | 2023-05-11 | Board Of Regents, The University Of Texas System | Methods relating to treatment of acute myeloid leukemia |
IL313670A (en) | 2021-12-30 | 2024-08-01 | Biomea Fusion Inc | Pyrazine compounds as inhibitors of flt3 |
CN114949230A (en) * | 2022-06-13 | 2022-08-30 | 厦门大学附属第一医院 | Combined pharmaceutical composition for preventing and/or treating acute myeloid leukemia and application thereof |
CN117771177A (en) * | 2023-08-02 | 2024-03-29 | 首都医科大学附属北京儿童医院 | Venezuela self-microemulsifying drug release system and preparation method and application thereof |
Family Cites Families (73)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5892019A (en) | 1987-07-15 | 1999-04-06 | The United States Of America, As Represented By The Department Of Health And Human Services | Production of a single-gene-encoded immunoglobulin |
US5859205A (en) | 1989-12-21 | 1999-01-12 | Celltech Limited | Humanised antibodies |
US5573924A (en) | 1992-09-08 | 1996-11-12 | Immunex Corporation | CD27 ligand |
DE19747418C1 (en) | 1997-10-27 | 1999-07-15 | Deutsches Krebsforsch | Inhibitor protein of the wnt signaling pathway |
US6500633B1 (en) | 2000-04-26 | 2002-12-31 | Atairgin Technologies, Inc. | Method of detecting carcinomas |
US20030148321A1 (en) | 2001-08-24 | 2003-08-07 | Iris Pecker | Methods and kits for diagnosing and monitoring hematopoietic cancers |
AU2002351828A1 (en) | 2001-11-05 | 2003-05-19 | Deutsches Krebsforschungszentrum | Novel genetic markers for leukemias |
US20050118656A1 (en) | 2001-11-27 | 2005-06-02 | Terrett Jonathan A. | Methods for diagnosis and treatment of epithelial-derived cancers |
US7261892B2 (en) | 2001-11-27 | 2007-08-28 | Celltech R&D Limited | Methods for diagnosis and treatment of epithelial-derived cancers |
US8404716B2 (en) | 2002-10-15 | 2013-03-26 | Celgene Corporation | Methods of treating myelodysplastic syndromes with a combination therapy using lenalidomide and azacitidine |
US8039218B2 (en) | 2002-11-14 | 2011-10-18 | John Wayne Cancer Institute | Detection of cancer cells in body fluids |
US20080025989A1 (en) | 2003-02-20 | 2008-01-31 | Seattle Genetics, Inc. | Anti-cd70 antibody-drug conjugates and their use for the treatment of cancer and immune disorders |
US7662387B2 (en) | 2003-02-20 | 2010-02-16 | Seattle Genetics | Anti-cd70 antibody-drug conjugates and their use for the treatment of cancer and immune disorders |
MXPA06014075A (en) | 2004-06-03 | 2007-03-15 | Novimmune Sa | Anti-cd3 antibodies and methods of use thereof. |
US7641903B2 (en) | 2004-10-15 | 2010-01-05 | Seattle Genetics, Inc. | Anti-CD70 antibody and its use for the treatment and prevention of cancer and immune disorders |
EP1799262A4 (en) | 2004-10-15 | 2009-10-21 | Seattle Genetics Inc | Anti-cd70 antibody and its use for the treatment and prevention of cancer and immune disorders |
US8337838B2 (en) | 2004-10-15 | 2012-12-25 | Seattle Genetics, Inc. | Anti-CD70 antibody and its use for the treatment and prevention of cancer and immune disorders |
JP5122441B2 (en) | 2005-04-19 | 2013-01-16 | シアトル ジェネティックス, インコーポレイテッド | Humanized anti-CD70 binding agents and uses thereof |
WO2006113747A2 (en) | 2005-04-19 | 2006-10-26 | Prediction Sciences Llc | Diagnostic markers of breast cancer treatment and progression and methods of use thereof |
WO2007011856A2 (en) | 2005-07-15 | 2007-01-25 | The Trustees Of Columbia University In The City Of New York | Compositions and methods for differential diagnosis of chronic lymphocytic leukemia |
EA016186B1 (en) | 2005-09-26 | 2012-03-30 | Медарекс, Инк. | Human monoclonal antibodies to cd70 and use thereof |
US7723477B2 (en) | 2005-10-31 | 2010-05-25 | Oncomed Pharmaceuticals, Inc. | Compositions and methods for inhibiting Wnt-dependent solid tumor cell growth |
AU2007257692B2 (en) | 2006-06-12 | 2013-11-14 | Aptevo Research And Development Llc | Single-chain multivalent binding proteins with effector function |
EP2055400A1 (en) | 2006-07-24 | 2009-05-06 | Senda Kensetsu Kabushiki Kaisha | Method of descaling metal wire rod and apparatus therefor |
WO2008070593A2 (en) | 2006-12-01 | 2008-06-12 | Seattle Genetics, Inc. | Variant target binding agents and uses thereof |
CA2672468A1 (en) | 2006-12-14 | 2008-06-19 | Medarex, Inc. | Human antibodies that bind cd70 and uses thereof |
KR100807069B1 (en) | 2007-09-21 | 2008-02-25 | 고려대학교 산학협력단 | Pharmaceutical composition for treating cancer |
KR20100089869A (en) | 2007-11-05 | 2010-08-12 | 노파르티스 아게 | Methods and compositions for measuring wnt activation and for treating wnt-related cancers |
GB2461546B (en) | 2008-07-02 | 2010-07-07 | Argen X Bv | Antigen binding polypeptides |
WO2010014948A1 (en) | 2008-08-01 | 2010-02-04 | The University Of Utah Research Foundation | Methods of treatment using wnt inhibitors |
WO2010019921A2 (en) | 2008-08-15 | 2010-02-18 | The Regents Of The University Of California | Biomarkers for diagnosis and treatment of chronic lymphocytic leukemia |
MX2011003183A (en) | 2008-09-26 | 2011-04-21 | Oncomed Pharm Inc | Frizzled-binding agents and uses thereof. |
JP5748653B2 (en) | 2009-04-10 | 2015-07-15 | 協和発酵キリン株式会社 | Hematological tumor therapy using anti-TIM-3 antibody |
US8546399B2 (en) | 2009-05-26 | 2013-10-01 | Abbvie Inc. | Apoptosis inducing agents for the treatment of cancer and immune and autoimmune diseases |
DK2464232T3 (en) | 2009-08-10 | 2016-01-04 | Samumed Llc | INDAZOLE INHIBITORS OF THE WNT SIGNAL ROAD AND THERAPEUTIC APPLICATIONS THEREOF |
US20120178111A1 (en) | 2009-09-23 | 2012-07-12 | Diamandis Eleftherios P | Methods and compositions for the detection of lung cancers |
JP5828765B2 (en) | 2009-12-29 | 2015-12-09 | 協和発酵キリン株式会社 | Anti-CD27 antibody |
AU2011262758B8 (en) | 2010-06-11 | 2014-09-04 | Kyowa Kirin Co., Ltd. | Anti-tim-3 antibody |
NZ610151A (en) | 2010-11-23 | 2015-06-26 | Abbvie Inc | Salts and crystalline forms of an apoptosis-inducing agent |
ES2566538T3 (en) | 2011-01-19 | 2016-04-13 | Cantargia Ab | Anti-IL1RAP antibodies and their use for the treatment of solid tumors |
EP2686347B1 (en) | 2011-03-16 | 2018-05-02 | argenx BVBA | Antibodies to cd70 |
US8841418B2 (en) | 2011-07-01 | 2014-09-23 | Cellerant Therapeutics, Inc. | Antibodies that specifically bind to TIM3 |
US8987422B2 (en) | 2011-09-22 | 2015-03-24 | Amgen Inc. | CD27L antigen binding proteins |
WO2013093508A2 (en) | 2011-12-22 | 2013-06-27 | Oslo University Hospital Hf | Wnt pathway inhibitors |
AU2013232087B2 (en) | 2012-03-15 | 2018-02-08 | Janssen Biotech, Inc. | Human anti-CD27 antibodies, methods and uses |
EP2827878A1 (en) | 2012-03-21 | 2015-01-28 | Erytech Pharma | Medicament for the treatment of acute myeloid leukemia (aml) |
WO2013177420A2 (en) | 2012-05-23 | 2013-11-28 | St. Jude Children's Research Hospital | Methods and compositions for the treatment of bcr-abl positive lymphoblastic leukemias |
CN106188045B (en) | 2012-06-15 | 2018-01-16 | 广州源生医药科技有限公司 | As the compound of WNT signal transduction inhibitors, composition and its application |
WO2014045101A1 (en) | 2012-09-21 | 2014-03-27 | Cellzome Gmbh | Tetrazolo quinoxaline derivatives as tankyrase inhibitors |
EP2935334A4 (en) | 2012-12-21 | 2016-10-26 | Cellerant Therapeutics Inc | Antibodies that bind membrane-bound il1rap |
RS56169B1 (en) | 2013-02-14 | 2017-11-30 | Bristol Myers Squibb Co | Tubulysin compounds, methods of making and use |
JOP20200096A1 (en) | 2014-01-31 | 2017-06-16 | Children’S Medical Center Corp | Antibody molecules to tim-3 and uses thereof |
JP6606505B2 (en) | 2014-03-11 | 2019-11-13 | ザ ボード オブ トラスティーズ オブ ザ レランド スタンフォード ジュニア ユニバーシティー | Anti-SIRPα antibody and bispecific macrophage enhancing antibody |
WO2016111947A2 (en) | 2015-01-05 | 2016-07-14 | Jounce Therapeutics, Inc. | Antibodies that inhibit tim-3:lilrb2 interactions and uses thereof |
TWI717375B (en) | 2015-07-31 | 2021-02-01 | 德商安美基研究(慕尼黑)公司 | Antibody constructs for cd70 and cd3 |
WO2017044752A1 (en) | 2015-09-10 | 2017-03-16 | University Of Pittsburgh-Of The Commonwealth System Of Higher Education | Anti-fibrotic effect of cd70 |
AU2016348388B2 (en) | 2015-11-03 | 2023-11-30 | Janssen Biotech, Inc. | Antibodies specifically binding PD-1 and their uses |
EA039859B1 (en) | 2016-02-03 | 2022-03-21 | Эмджен Рисерч (Мюник) Гмбх | Bispecific antibody constructs binding egfrviii and cd3 |
EP3426655A1 (en) | 2016-03-10 | 2019-01-16 | Assia Chemical Industries Ltd. | Solid state forms of venetoclax and processes for preparation of venetoclax |
WO2017160954A1 (en) * | 2016-03-15 | 2017-09-21 | Seattle Genetics, Inc. | Combinations of pbd-based antibody drug conjugates with bcl-2 inhibitors |
RU2018146513A (en) | 2016-06-09 | 2020-07-09 | Др. Редди'С Лабораторис Лимитед | SOLID FORMS OF VENETO-KLAX AND METHODS FOR PRODUCING A VENETO-KLAX |
EP3481397A1 (en) | 2016-07-06 | 2019-05-15 | Concert Pharmaceuticals Inc. | Deuterated venetoclax |
CN107648185A (en) | 2016-07-25 | 2018-02-02 | 常州爱诺新睿医药技术有限公司 | A kind of unformed Venetoclax and pharmaceutic adjuvant solid dispersions and preparation method thereof |
US20190177317A1 (en) | 2016-08-12 | 2019-06-13 | Mylan Laboratories Limited | Process for the preparation of venetoclax |
US10800777B2 (en) | 2016-10-14 | 2020-10-13 | Mylan Laboratories Limited | Polymorphic forms of VENCLEXTA |
EP3333167A1 (en) | 2016-12-09 | 2018-06-13 | LEK Pharmaceuticals d.d. | Solid forms of venetoclax |
CZ201769A3 (en) | 2017-02-06 | 2018-08-15 | Zentiva, K.S. | Solid forms of Venetoclax |
WO2018157803A1 (en) | 2017-02-28 | 2018-09-07 | 苏州科睿思制药有限公司 | Venetoclax crystal forms and preparation method therefor |
WO2018167652A1 (en) | 2017-03-13 | 2018-09-20 | Laurus Labs Limited | Process for preparation of amorphous form of venetoclax |
CN107089981A (en) | 2017-04-24 | 2017-08-25 | 杭州科耀医药科技有限公司 | A kind of inhibitor Venetoclax of BCL 2 synthetic method |
GB2567613A (en) * | 2017-06-16 | 2019-04-24 | Argenx Bvba | Treatment for acute myeloid leukaemia |
GB201800649D0 (en) * | 2018-01-16 | 2018-02-28 | Argenx Bvba | CD70 Combination Therapy |
UY38511A (en) | 2018-12-18 | 2020-07-31 | Argenx Bvba | COMBINATION THERAPY CD70 |
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CN113226317A (en) | 2021-08-06 |
AU2019409936A1 (en) | 2021-05-27 |
DK3890740T3 (en) | 2023-05-08 |
CN113226317B (en) | 2022-08-16 |
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